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Sample records for autosomal dominant cataract

  1. Further evidence for P59L mutation in GJA3 associated with autosomal dominant congenital cataract

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    Li Wang

    2016-01-01

    Full Text Available Context: Congenital cataracts are one of the common eye disorders leading to visual impairment or blindness in children worldwide. We found a Chinese family with autosomal dominant pulverulent cataract. Aims: To identify the pathogenic gene mutation in a Chinese family with autosomal dominant inherited pulverulent cataract. Subjects and Methods: After obtained informed consent, detailed ophthalmic examinations were carried out; genomic DNAs were obtained from seven family members in a three-generation Chinese family with three affected. All exons of candidate genes were amplified by polymerase chain reaction and were sequenced performed by bidirectional sequencing. Results: By sequencing the encoding regions of the candidate genes, a missense mutation (c. 176C>T was detected in gap junction protein alpha 3 genes (GJA3, which resulted in the substitution of highly conserved proline by leucine at codon 59 (p.P59L. The mutation co-segregated with all patients and was absent in 100 normal Chinese controls. Conclusions: The study identified a missense mutation (c. 176C>T in GJA3 gene associated with autosomal dominant congenital pulverulent cataract in a Chinese family. It gave further evidence of phenotype heterogeneity for P59L mutation in GJA3 associated with congenital cataract.

  2. A novel mutation in CRYAB associated with autosomal dominant congenital nuclear cataract in a Chinese family.

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    Chen, Qiang; Ma, Junjie; Yan, Ming; Mothobi, Maneo Emily; Liu, Yuanyuan; Zheng, Fang

    2009-07-10

    To identify the genetic defects associated with autosomal dominant congenital nuclear cataract in a Chinese family. Clinical data were collected, and the phenotypes of the affected members in this family were recorded by slit-lamp photography. Genomic DNA was isolated from peripheral blood. Mutations were screened in cataract-associated candidate genes through polymerase chain reaction (PCR) analyses and sequencing. Structural models of the wild-type and mutant alphaB-crystallin were generated and analyzed by SWISS-MODEL. Mutation screening identified only one heterozygous G-->A transition at nucleotide 32 in the first exon of alphaB-crystallin (CRYAB), resulting in an amino acid change from arginine to histidine at codon 11 (R11H). This mutation segregated in all available affected family members but was not observed in any of the unaffected persons of the family. The putative mutation disrupted a restriction site for the enzyme, Fnu4HI, in the affected family members. The disruption, however, was not found in any of the randomly selected ophthalmologically normal individuals or in 40 unrelated senile cataract patients. Computer-assisted prediction suggested that this mutation affected the biochemical properties as well as the structure of alphaB-crystallin. These results supported the idea that the novel R11H mutation was responsible for the autosomal dominant nuclear congenital cataract in this pedigree.

  3. A nonsense mutation in CRYGC associated with autosomal dominant congenital nuclear cataract in a Chinese family.

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    Yao, Ke; Jin, Chongfei; Zhu, Ning; Wang, Wei; Wu, Renyi; Jiang, Jin; Shentu, Xingchao

    2008-07-09

    To identify the genetic defect associated with autosomal dominant congenital nuclear cataract in a Chinese family. Family history and phenotypic data were recorded, and the phenotypes were documented by slit lamp photography. The genomic DNA was extracted from peripheral blood leukocytes. All the exons and flanking intronic sequences of CRYGC and CRYGD were amplified by polymerase chain reaction (PCR) and screened for mutation by direct DNA sequencing. Structural models of the wild type and mutant gammaC-crystallin were generated and analyzed by SWISS-MODEL. Sequencing of the coding regions of CRYGC and CRYGD showed the presence of a heterozygous C>A transversion at c.327 of the coding sequence in exon 3 of CRYGC (c.327C>A), which results in the substitution of a wild type cysteine to a nonsense codon (C109X). One and a half Greek key motifs at the COOH-terminus were found to be absent in the structural model of the mutant truncated gammaC-crystallin. A novel nonsense mutation in CRYGC was detected in a Chinese family with consistent autosomal dominant congenital nuclear cataract, providing clear evidence of a relationship between the genotype and the corresponding cataract phenotype.

  4. A novel GJA8 mutation (p.V44A causing autosomal dominant congenital cataract.

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    Yanan Zhu

    Full Text Available To examine the mechanism by which a novel connexin 50 (Cx50 mutation, Cx50 V44A, in a Chinese family causes suture-sparing autosomal dominant congenital nuclear cataracts.Family history and clinical data were recorded and direct gene sequencing was used to identify the disease-causing mutation. The Cx50 gene was cloned from a human lens cDNA library. Connexin protein distributions were assessed by fluorescence microscopy. Hemichannel functions were analyzed by dye uptake assay. Formation of functional channels was assessed by dye transfer experiments.Direct sequencing of the candidate GJA8 gene revealed a novel c.131T>C transition in exon 2, which cosegregated with the disease in the family and resulted in the substitution of a valine residue with alanine at codon 44 (p. V44A in the extracellular loop 1 of the Cx50 protein. Both Cx50 and Cx50V44A formed functional gap junctions, as shown by the neurobiotin transfer assay. However, unlike wild-type Cx50, Cx50V44A was unable to form open hemichannels in dye uptake experiments.This work identified a unique congenital cataract in the Chinese population, caused by the novel mutation Cx50V44A, and it showed that the V44A mutation specifically impairs the gating of the hemichannels but not the gap junction channels. The dysfunctional hemichannels resulted in the development of human congenital cataracts.

  5. A R54L mutation of CRYAA associated with autosomal dominant nuclear cataracts in a Chinese family.

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    Yang, Zhenfei; Su, Dongmei; Li, Qian; Ma, Zicheng; Yang, Fan; Zhu, Siquan; Ma, Xu

    2013-12-01

    To identify the genetic defect in a three-generation Chinese family with congenital cataracts. The phenotype of a three-generation Chinese family with congenital cataract was recruited. Detailed family history and clinical data of the family were recorded. Candidate genes sequencing was performed to screen out the disease-causing mutation. Bioinformatics analysis was performed to predict the function of mutant gene. The phenotype of the family was identified as nuclear cataract. Direct sequencing revealed a c.161 G > T transversion in exon 1 of crystallin alpha-A (CRYAA). This mutation co-segregated with all affected individuals in the family and was not found in unaffected family members nor in the 100 unrelated controls. Bioinformatics analysis indicated that the 54th amino acid position was highly conserved and the mutation R54L caused an increase of local hydrophobicity around the substitution site. This study identified a novel disease-causing mutation c.161 G > T (p.R54L) in CRYAA in a Chinese family with autosomal dominant nuclear cataracts, this is the first report relating a G > T mutation in CRYAA leading to congenital nuclear cataract.

  6. The myosin chaperone UNC45B is involved in lens development and autosomal dominant juvenile cataract

    DEFF Research Database (Denmark)

    Hansen, Lars; Comyn, Sophie; Mang, Yuan

    2014-01-01

    Genome-wide linkage analysis, followed by targeted deep sequencing, in a Danish multigeneration family with juvenile cataract revealed a region of chromosome 17 co-segregating with the disease trait. Affected individuals were heterozygous for two potentially protein-disrupting alleles in this reg...... advance online publication, 19 February 2014; doi:10.1038/ejhg.2014.21....

  7. A novel T→G splice site mutation of CRYBA1/A3 associated with autosomal dominant nuclear cataracts in a Chinese family.

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    Yang, Zhenfei; Su, Dongmei; Li, Qian; Yang, Fan; Ma, Zicheng; Zhu, Siquan; Ma, Xu

    2012-01-01

    The purpose of this study was to identify the disease-causing mutation and the molecular phenotype that are responsible for the presence of an autosomal dominant congenital nuclear cataract disease in a Chinese family. The family history and clinical data were recorded. The patients were given a physical examination and their blood samples were collected for DNA extraction. Direct sequencing was used to detect the mutation. Transcription analysis of the mutant crystallin, beta A1 (CRYBA1/A3) gene was performed to verify whether the defective mutation had influenced the splice of the mature mRNA. The phenotype of the congenital cataract in the family was identified as a nuclear cataract type, by using slit-lamp photography. Direct sequencing revealed a novel mutation IVS3+2 T→G in CRYBA1/A3. This mutation co-segregated with all affected individuals in the family, but was not found in unaffected family members nor in the 100 unrelated controls. Transcription analysis of the mutant CRYBA1/A3 gene indicated that this mutation had influenced the splice of the mature mRNA. Our study identified a novel splice site mutation in CRYBA1/A3. This mutation was responsible for aberrant splicing of the mature mRNA and had caused the congenital nuclear cataracts in the family. This is the first report relating an IVS3+2 T→G mutation of CRYBA1/A3 to congenital cataracts.

  8. [Autosomal dominant polycystic kidney].

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    Jorge Adad, S; Estevão Barbosa, M; Fácio Luíz, J M; Furlan Rodrigues, M C; Iwamoto, S

    1996-01-01

    A 48-year-old male had autosomic dominant polycystic kidneys with dimensions, to the best of our knowledge, never previously reported; the right kidney weighed 15,100 g and measured 53 x 33 x 9cm and the left one 10.200 g and 46 x 21 x 7cm, with cysts measuring up to 14cm in diameter. Nephrectomy was done to control persistent hematuria and to relief disconfort caused by the large kidneys. The renal function is stable four years after transplantation.

  9. Autosomal dominant adult neuronal ceroid lipofuscinosis

    NARCIS (Netherlands)

    Nijssen, Peter C.G.

    2011-01-01

    this thesis investigates a family with autosomal dominant neuronal ceroid lipofuscinosis, with chapters on clinical neurology, neuropathology, neurogenetics, neurophysiology, auditory and visual aspects.

  10. Autosomal dominant hereditary ataxia in Sri Lanka

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    Sumathipala, Dulika S; Abeysekera, Gayan S; Jayasekara, Rohan W; Tallaksen, Chantal ME; Dissanayake, Vajira HW

    2013-01-01

    Background Spinocerebellar ataxias (SCA) are a group of hereditary neurodegenerative disorders. Prevalence of SCA subtypes differ worldwide. Autosomal dominant ataxias are the commonest types of inherited ataxias seen in Sri Lanka. The aim of the study is to determine the genetic etiology of patients with autosomal dominant ataxia in Sri Lanka and to describe the clinical features of each genetic subtype. Methods ...

  11. Autosomal Dominant Polycystic Kidney Disease

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    ... NIH Director Organization Budget History NIH Almanac Public Involvement Outreach & Education Visitor Information RePORT NIH Fact Sheets Home > Autosomal ... other than the observation that 50 percent of children born to an affected parent would develop the disease. Diagnosis of well-established ...

  12. Autosomal-dominant osteopetrosis: An incidental finding

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    Rajathi Maria

    2010-01-01

    Full Text Available Osteopetrosis is a descriptive term that refers to a group of rare, heritable disorders of the skeleton. Osteopetrotic conditions vary greatly in their presentation and severity, from just as an incidental finding on radiographs to causing life-threatening complications such as bone marrow suppression. It is caused by failure of osteoclast development and function. Osteopetrosis can be inherited as autosomal-recessive, autosomal-dominant or as X-linked traits, with the most severe forms being the autosomal-recessive ones. The severity of the disease is mild to moderate in the autosomal-dominant forms, with normal life expectancy. Diagnosis is largely based on clinical and radiographic evaluation. The present paper reports a case of autosomal-dominant osteopetrosis complicated by osteomyelitis with a short review of the condition.

  13. Autosomal dominant inheritance of Weaver syndrome.

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    Fryer, A; Smith, C; Rosenbloom, L; Cole, T

    1997-01-01

    Most report of Weaver syndrome have been sporadic cases and the genetic basis of the syndrome is uncertain. This report of an affected father and daughter provides evidence for autosomal dominant inheritance.

  14. Genetics Home Reference: autosomal dominant hypocalcemia

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    ... individuals have features of a kidney disorder called Bartter syndrome in addition to hypocalcemia. These features can include ... sometimes referred to as autosomal dominant hypocalcemia with Bartter syndrome or Bartter syndrome type V. There are two ...

  15. Ant-egg cataract. A study of a family with dominantly inherited congenital (ant-egg) cataract, including a histological examination of the formed elements

    DEFF Research Database (Denmark)

    Nissen, Steffen; Schrøder, H D

    1979-01-01

    A family with "ant-egg" cataract in three generations is described. The cataract is congenital, probably of autosomal dominant inheritance. Light microscopy of the ant-eggs showed that they are made up of a peripheral zone of lens material and a large almost homogenous centre. Element analysis by......-ray spectrophotometry showed a high content of calcium and phosphorus in the centre. The cataract has been easy to operate on and the postoperative visual results have been good....

  16. Clinical neurogenetics: autosomal dominant spinocerebellar ataxia.

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    Shakkottai, Vikram G; Fogel, Brent L

    2013-11-01

    The autosomal dominant spinocerebellar ataxias are a diverse and clinically heterogeneous group of disorders characterized by degeneration and dysfunction of the cerebellum and its associated pathways. Clinical and diagnostic evaluation can be challenging because of phenotypic overlap among causes, and a stratified and systematic approach is essential. Recent advances include the identification of additional genes causing dominant genetic ataxia, a better understanding of cellular pathogenesis in several disorders, the generation of new disease models that may stimulate development of new therapies, and the use of new DNA sequencing technologies, including whole-exome sequencing, to improve diagnosis. Copyright © 2013 Elsevier Inc. All rights reserved.

  17. Autosomal dominant craniometaphyseal dysplasia with atypical features.

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    McKay, D R; Fialkov, J A

    2002-03-01

    Craniometaphyseal dysplasia (CMD) is a rare genetic disorder of bone modelling characterised by hyperostosis and sclerosis of the craniofacial bones, and abnormal modelling of the metaphyses. Clinically, autosomal dominant (AD) CMD is characterised by facial distortion and cranial-nerve compression. The goals of surgical treatment for AD CMD are cosmetic recontouring of the sclerotic craniofacial bones, correction of nasal obstruction and correction or prevention of neurological manifestations. We describe the successful correction of AD CMD craniofacial manifestations in an individual with atypical findings, and outline an approach for correcting the craniofacial deformities associated with this rare disorder. Copyright 2002 The British Association of Plastic Surgeons.

  18. Autosomal dominant cortical tremor, myoclonus and epilepsy.

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    Striano, Pasquale; Zara, Federico

    2016-09-01

    The term 'cortical tremor' was first introduced by Ikeda and colleagues to indicate a postural and action-induced shivering movement of the hands which mimics essential tremor, but presents with the electrophysiological findings of cortical reflex myoclonus. The association between autosomal dominant cortical tremor, myoclonus and epilepsy (ADCME) was first recognized in Japanese families and is now increasingly reported worldwide, although it is described using different acronyms (BAFME, FAME, FEME, FCTE and others). The disease usually takes a benign course, although drug-resistant focal seizures or slight intellectual disability occur in some cases. Moreover, a worsening of cortical tremor and myoclonus is common in advanced age. Although not yet recognized by the International League Against Epilepsy (ILAE), this is a well-delineated epilepsy syndrome with remarkable features that clearly distinguishes it from other myoclonus epilepsies. Moreover, genetic studies of these families show heterogeneity and different susceptible chromosomal loci have been identified.

  19. MRI of autosomal dominant pure spastic paraplegia

    DEFF Research Database (Denmark)

    Krabbe, K.; Nielsen, J.E.; Fallentin, E.

    1997-01-01

    We examined 16 patients with autosomal dominant pure spastic paraplegia (HSP) and 15 normal controls matched for age and sex using MRI of the brain and spinal cord. Images were assessed qualitatively by two independent radiologists, blinded to the clinical diagnosis. Areas of the brain and corpus...... callosum on one midsagittal slice and the area of the brain on one axial slice were measured and a "corpus-callosum index" expressing the size of the corpus callosum relative to that of the brain was calculated. Cross-sectional areas and anteroposterior and transverse diameters of the spinal cord...... at the levels of C 2, C 5, T 3, T 6, T 9 and T 11 were measured. No significant differences between patients and controls were found on qualitative evaluation of the images. The patients had a significantly smaller corpus callosum and "corpus-callosum index" than controls. This finding, not reported previously...

  20. Autosomal Dominant Growth Hormone Deficiency (Type II).

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    Alatzoglou, Kyriaki S; Kular, Dalvir; Dattani, Mehul T

    2015-06-01

    Isolated growth hormone deficiency (IGHD) is the commonest pituitary hormone deficiency resulting from congenital or acquired causes, although for most patients its etiology remains unknown. Among the known factors, heterozygous mutations in the growth hormone gene (GH1) lead to the autosomal dominant form of GHD, also known as type II GHD. In many cohorts this is the commonest form of congenital isolated GHD and is mainly caused by mutations that affect the correct splicing of GH-1. These mutations cause skipping of the third exon and lead to the production of a 17.5-kDa GH isoform that exerts a dominant negative effect on the secretion of the wild type GH. The identification of these mutations has clinical implications for the management of patients, as there is a well-documented correlation between the severity of the phenotype and the increased expression of the 17.5-kDa isoform. Patients with type II GHD have a variable height deficit and severity of GHD and may develop additional pituitary hormone defiencies over time, including ACTH, TSH and gonadotropin deficiencies. Therefore, their lifelong follow-up is recommended. Detailed studies on the effect of heterozygous GH1 mutations on the trafficking, secretion and action of growth hormone can elucidate their mechanism on a cellular level and may influence future treatment options for GHD type II.

  1. Monozygotic twins with CAPN5 autosomal dominant neovascular inflammatory vitreoretinopathy

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    Rowell HA

    2012-12-01

    Full Text Available Hannah A Rowell,1,2 Alexander G Bassuk,3,4 Vinit B Mahajan1,21Omics Laboratory, 2Department of Ophthalmology and Visual Sciences, 3Department of Pediatrics, 4Department of Neurology, University of Iowa, Iowa City, IA, USABackground: The purpose of this study was to describe the clinical findings in a set of monozygotic twins with autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV over a 23-year period.Methods: A pair of female twins were examined between 26 and 49 years of age. The concordance and discordance of their clinical features were determined. The CAPN5 gene was sequenced using genomic DNA.Results: Both twins of an affected father demonstrated Stage I ADNIV with mild vitreous cells and a negative b-wave on electroretinography. Genetic analysis confirmed a guanine to thymine nucleotide (c.728G>T, pArg243Leu mutation in the CAPN5 gene. Over the course of 23 years, each twin progressed to stage III disease, showing posterior uveitis, cystoid macular edema, intraocular fibrosis, early retinal neovascularization, retinal degeneration, and cataract. Disease progression varied moderately between each twin and was asymmetrical between eyes. Twin A had 20/70 and 20/125 in the right and left eye, respectively, and underwent vitrectomy surgery and intravitreal injections with bevacizumab for recurrent cystoid macular edema. Twin B maintained 20/20 and 20/40 in the right and left eye, respectively without intervention.Conclusion: There was asymmetry between the eyes and some discordance in the rate of disease progression in these monozygotic twins with ADNIV. The overall high disease concordance suggests genetic factors play a major role in clinical manifestations in CAPN5 vitreoretinopathy.Keywords: autosomal dominant neovascular inflammatory vitreoretinopathy, ADNIV, CAPN5, calpain-5, monozygotic twins

  2. MRI of autosomal dominant pure spastic paraplegia

    International Nuclear Information System (INIS)

    Krabbe, K.; Fallentin, E.; Herning, M.; Nielsen, J.E.; Fenger, K.

    1997-01-01

    We examined 16 patients with autosomal dominant pure spastic paraplegia (HSP) and 15 normal controls matched for age and sex using MRI of the brain and spinal cord. Images were assessed qualitatively by two independent radiologists, blinded to the clinical diagnosis. Areas of the brain and corpus callosum on one midsagittal slice and the area of the brain on one axial slice were measured and a ''corpus-callosum index'' expressing the size of the corpus callosum relative to that of the brain was calculated. Cross-sectional areas and anteroposterior and transverse diameters of the spinal cord at the levels of C 2, C 5, T 3, T 6, T 9 and T 11 were measured. No significant differences between patients and controls were found on qualitative evaluation of the images. The patients had a significantly smaller corpus callosum and ''corpus-callosum index'' than controls. This finding, not reported previously, might indicate that the disease process in pure HSP is not confined to the spinal cord. The anteroposterior diameters of the spinal cord at T 3 and T 9 were significantly smaller in patients than in controls. This might correspond to the degeneration of the pyramidal tracts and the dorsal columns described at neuropathological examination. (orig.). With 1 fig., 3 tabs

  3. MRI of autosomal dominant pure spastic paraplegia

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    Krabbe, K.; Fallentin, E.; Herning, M. [Danish Research Center of Magnetic Resonance, Hvidovre Hospital, Kettegaard alle 30, DK-2650 Hvidovre (Denmark); Nielsen, J.E.; Fenger, K. [Institute of Medical Biochemistry and Genetics, Laboratory of Medical Genetics, Section of Neurogenetics, University of Copenhagen (Denmark)

    1997-10-01

    We examined 16 patients with autosomal dominant pure spastic paraplegia (HSP) and 15 normal controls matched for age and sex using MRI of the brain and spinal cord. Images were assessed qualitatively by two independent radiologists, blinded to the clinical diagnosis. Areas of the brain and corpus callosum on one midsagittal slice and the area of the brain on one axial slice were measured and a ``corpus-callosum index`` expressing the size of the corpus callosum relative to that of the brain was calculated. Cross-sectional areas and anteroposterior and transverse diameters of the spinal cord at the levels of C 2, C 5, T 3, T 6, T 9 and T 11 were measured. No significant differences between patients and controls were found on qualitative evaluation of the images. The patients had a significantly smaller corpus callosum and ``corpus-callosum index`` than controls. This finding, not reported previously, might indicate that the disease process in pure HSP is not confined to the spinal cord. The anteroposterior diameters of the spinal cord at T 3 and T 9 were significantly smaller in patients than in controls. This might correspond to the degeneration of the pyramidal tracts and the dorsal columns described at neuropathological examination. (orig.). With 1 fig., 3 tabs.

  4. Monozygotic twins with CAPN5 autosomal dominant neovascular inflammatory vitreoretinopathy.

    Science.gov (United States)

    Rowell, Hannah A; Bassuk, Alexander G; Mahajan, Vinit B

    2012-01-01

    The purpose of this study was to describe the clinical findings in a set of monozygotic twins with autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) over a 23-year period. A pair of female twins were examined between 26 and 49 years of age. The concordance and discordance of their clinical features were determined. The CAPN5 gene was sequenced using genomic DNA. Both twins of an affected father demonstrated Stage I ADNIV with mild vitreous cells and a negative b-wave on electroretinography. Genetic analysis confirmed a guanine to thymine nucleotide (c.728G>T, pArg243Leu) mutation in the CAPN5 gene. Over the course of 23 years, each twin progressed to stage III disease, showing posterior uveitis, cystoid macular edema, intraocular fibrosis, early retinal neovascularization, retinal degeneration, and cataract. Disease progression varied moderately between each twin and was asymmetrical between eyes. Twin A had 20/70 and 20/125 in the right and left eye, respectively, and underwent vitrectomy surgery and intravitreal injections with bevacizumab for recurrent cystoid macular edema. Twin B maintained 20/20 and 20/40 in the right and left eye, respectively without intervention. There was asymmetry between the eyes and some discordance in the rate of disease progression in these monozygotic twins with ADNIV. The overall high disease concordance suggests genetic factors play a major role in clinical manifestations in CAPN5 vitreoretinopathy.

  5. A novel HSF4 gene mutation (p.R405X causing autosomal recessive congenital cataracts in a large consanguineous family from Pakistan

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    Cheema Abdul

    2008-11-01

    Full Text Available Abstract Background Hereditary cataracts are most frequently inherited as autosomal dominant traits, but can also be inherited in an autosomal recessive or X-linked fashion. To date, 12 loci for autosomal recessive cataracts have been mapped including a locus on chromosome 16q22 containing the disease-causing gene HSF4 (Genbank accession number NM_001040667. Here, we describe a family from Pakistan with the first nonsense mutation in HSF4 thus expanding the mutational spectrum of this heat shock transcription factor gene. Methods A large consanguineous Pakistani family with autosomal recessive cataracts was collected from Quetta. Genetic linkage analysis was performed for the common known autosomal recessive cataracts loci and linkage to a locus containing HSF4 (OMIM 602438 was found. All exons and adjacent splice sites of the heat shock transcription factor 4 gene (HSF4 were sequenced. A mutation-specific restriction enzyme digest (HphI was performed for all family members and unrelated controls. Results The disease phenotype perfectly co-segregated with markers flanking the known cataract gene HSF4, whereas other autosomal recessive loci were excluded. A maximum two-point LOD score with a Zmax = 5.6 at θ = 0 was obtained for D16S421. Direct sequencing of HSF4 revealed the nucleotide exchange c.1213C > T in this family predicting an arginine to stop codon exchange (p.R405X. Conclusion We identified the first nonsense mutation (p.R405X in exon 11 of HSF4 in a large consanguineous Pakistani family with autosomal recessive cataract.

  6. Genetics Home Reference: autosomal dominant leukodystrophy with autonomic disease

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    ... have muscle stiffness (spasticity) or weakness and involuntary rhythmic shaking, called intention tremor because it worsens during ... Hobson G, Brusco A, Brussino A, Padiath QS. Analysis of LMNB1 duplications in autosomal dominant leukodystrophy provides ...

  7. Genetics Home Reference: autosomal dominant congenital stationary night blindness

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    ... collapse boxes. Description Autosomal dominant congenital stationary night blindness is a disorder of the retina , which is the specialized tissue at the back of the eye that detects light and color. People with this condition typically have difficulty seeing ...

  8. Genetics Home Reference: autosomal dominant nocturnal frontal lobe epilepsy

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    ... with ADNFLE have experienced psychiatric disorders (such as schizophrenia), behavioral problems, or intellectual disability. It is unclear ... Epilepsy Society Citizens United for Research in Epilepsy (CURE) GeneReviews (1 link) Autosomal Dominant Nocturnal Frontal Lobe ...

  9. A novel frameshift mutation in CX46 associated with hereditary dominant cataracts in a Chinese family

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    Xiu-Kun Cui

    2017-05-01

    Full Text Available AIM: To investigate the genetic mutations that are associated the hereditary autosomal dominant cataract in a Chinese family. METHODS: A Chinese family consisting of 20 cataract patients (including 9 male and 11 female and 2 unaffected individuals from 5 generations were diagnosed to be a typical autosomal dominant cataract pedigree. Genomic DNA samples were extracted from the peripheral blood cells of the participants in this pedigree. Exon sequence was used for genetic mutation screening. In silico analysis was used to study the structure characteristics of connexin 46 (CX46 mutant. Immunoblotting was conduceted for testing the expression of CX46. RESULTS: To determine the involved genetic mutations, 11 well-known cataract-associated genes (cryaa, cryab, crybb1, crybb2, crygc, crygd, Gja3, Gja8, Hsf4, Mip and Pitx3 were chosen for genetic mutation test by using exon sequencing. A novel cytosine insertion at position 1195 of CX46 cDNA (c.1194_1195ins C was found in the samples of 5 tested cataract patients but not in the unaffected 2 individuals nor in normal controls, which resulted in 30 amino acids more extension in CX46C-terminus (cx46fs400 compared with the wild-type CX46. In silico protein structure analysis indicated that the mutant showed distinctive hydrophobicity and protein secondary structure compared with the wild-type CX46. The immunoblot results revealed that CX46 protein, which expressed in the aging cataract lens tissues, was absence in the proband lens. In contrast, CX50, alpha A-crystallin and alphaB-crystallin expressed equally in both proband and aging cataract tissues. Those results revealed that the cx46fs400 mutation could impair CX46 protein expression. CONCLUSION: The insertion of cytosine at position 1195 of CX46 cDNA is a novel mutation site that is associated with the autosomal dominant cataracts in this Chinese family. The C-terminal frameshift mutation is involved in regulating CX46 protein expression.

  10. Autosomal dominant frontometaphyseal dysplasia : Delineation of the clinical phenotype

    NARCIS (Netherlands)

    Wade, Emma M.; Jenkins, Zandra A.; Daniel, Philip B.; Morgan, Tim; Addor, Marie C.; Ades, Lesley C.; Bertola, Debora; Bohring, Axel; Carter, Erin; Cho, Tae-Joon; de Geus, Christa M.; Duba, Hans-Christoph; Fletcher, Elaine; Hadzsiev, Kinga; Hennekam, Raoul C. M.; Kim, Chong A.; Krakow, Deborah; Morava, Eva; Neuhann, Teresa; Sillence, David; Superti-Furga, Andrea; Veenstra-Knol, Hermine E.; Wieczorek, Dagmar; Wilson, Louise C.; Markie, David M.; Robertson, Stephen P.

    Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who

  11. Autosomal dominant frontometaphyseal dysplasia: Delineation of the clinical phenotype

    NARCIS (Netherlands)

    Wade, Emma M.; Jenkins, Zandra A.; Daniel, Philip B.; Morgan, Tim; Addor, Marie C.; Adés, Lesley C.; Bertola, Debora; Bohring, Axel; Carter, Erin; Cho, Tae-Joon; de Geus, Christa M.; Duba, Hans-Christoph; Fletcher, Elaine; Hadzsiev, Kinga; Hennekam, Raoul C. M.; Kim, Chong A.; Krakow, Deborah; Morava, Eva; Neuhann, Teresa; Sillence, David; Superti-Furga, Andrea; Veenstra-Knol, Hermine E.; Wieczorek, Dagmar; Wilson, Louise C.; Markie, David M.; Robertson, Stephen P.

    2017-01-01

    Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who

  12. Genetics Home Reference: autosomal dominant partial epilepsy with auditory features

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    ... for This Condition ADLTE ADPEAF Autosomal dominant lateral temporal lobe epilepsy Epilepsy, partial, with auditory features ETL1 Related Information ... W, Nakken KO, Fischer C, Steinlein OK. Familial temporal lobe epilepsy with aphasic seizures and linkage to chromosome 10q22- ...

  13. A further patient with Pai syndrome with autosomal dominant inheritance?

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    Rudnik-Schöneborn, S; Zerres, K

    1994-01-01

    We report a patient with median cleft of the upper lip, cutaneous facial polyps, and lipoma of the corpus callosum who represents a further case of Pai syndrome. The father of the patient showed coloboma of the right iris and shared some facial dysmorphism with his son, thus raising the question of autosomal dominant inheritance.

  14. Case report: Autosomal dominant non-epidermolytic palmoplantar ...

    African Journals Online (AJOL)

    Palmoplantar keratoderma (PPK) is a hereditary cutaneous disorder characterized by a marked hyperkeratosis of the palms and soles. A variant that was inherited in an autosomal dominant form was highlighted in a 20-month-old girl-child. The proband was brought to the Paediatric Outpatient Department by her mother ...

  15. Gene therapy in animal models of autosomal dominant retinitis pigmentosa

    Science.gov (United States)

    Rossmiller, Brian; Mao, Haoyu

    2012-01-01

    Gene therapy for dominantly inherited genetic disease is more difficult than gene-based therapy for recessive disorders, which can be treated with gene supplementation. Treatment of dominant disease may require gene supplementation partnered with suppression of the expression of the mutant gene either at the DNA level, by gene repair, or at the RNA level by RNA interference or transcriptional repression. In this review, we examine some of the gene delivery approaches used to treat animal models of autosomal dominant retinitis pigmentosa, focusing on those models associated with mutations in the gene for rhodopsin. We conclude that combinatorial approaches have the greatest promise for success. PMID:23077406

  16. Autosomal dominant arteriopathy with sub cortical infarcts and leucoencephalopathy (CADASIL)

    International Nuclear Information System (INIS)

    Ojeda, Adriana; Tiezzi, Gerardo; Uriarte, Ana M.; Eguren, Leonor

    2002-01-01

    Cerebral autosomal dominant arteriopathy with sub cortical infarcts and leucoencephalopathy (CASADIL) is a systemic hereditary, vascular disease that involves small arteries. Recurrent ischemia, pseudo bulbar paralysis and dementia are characteristic. Other manifestations include migraine and depression. We report an Argentine family with VI generations with evidence of disease in IV. MR examinations were performed on 21 family members (both symptomatic and asymptomatic). The main findings on MR on symptomatic and asymptomatic patients were small lesions with high signal on T2 localised in periventricular white matter, brain stem, basal ganglia and thalamus, and confluent patches on white matter although with high signal on T2 images, usually symmetric. In conclusion we can assess that diffuse myelin loss and small infarcts occurring in cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy well demonstrated with MR. In addition, some of the abnormalities in pre symptomatic patients can be identified on MR images. (author)

  17. Mutations in AAGAB underlie autosomal dominant punctate palmoplantar keratoderma.

    Science.gov (United States)

    Dinani, N; Ali, M; Liu, L; McGrath, J; Mellerio, J

    2017-04-01

    Punctate palmoplantar keratoderma type 1 (PPPK1) is a rare autosomal dominant inherited skin disease, characterized by multiple hyperkeratotic lesions on the palms and soles. The causative gene for PPPK1 has been identified as AAGAB, which encodes α- and γ-adaptin-binding protein p34. We describe the clinical features in three unrelated families with PPPK1, and report three recurrent causative mutations in AAGAB. © 2017 British Association of Dermatologists.

  18. Autosomal dominant syndrome resembling Coffin-Siris syndrome.

    Science.gov (United States)

    Flynn, Maureen A; Milunsky, Jeff M

    2006-06-15

    Coffin-Siris syndrome is a multiple congenital anomaly/mental retardation syndrome with phenotypic variability [OMIM 135900]. The diagnosis is based solely on clinical findings, as there is currently no molecular, biochemical, or cytogenetic analysis available to confirm a diagnosis. Although typically described as an autosomal recessive disorder, autosomal dominant inheritance has also been infrequently reported. We describe a mother and her two daughters who all have features that resemble Coffin-Siris syndrome. However, this is not a completely convincing diagnosis given that hypertelorism is not a feature of Coffin-Siris syndrome and the family is relatively mildly affected. Yet, this family provides further evidence of an autosomal dominant mode of inheritance for a likely variant of Coffin-Siris syndrome (at least in some families). In addition, Sibling 1 had premature thelarche. She is the second reported individual within the spectrum of Coffin-Siris syndrome to have premature thelarche, indicating that it may be a rare clinical feature. Copyright 2006 Wiley-Liss, Inc.

  19. Evidence for autosomal dominant inheritance of ablepharon-macrostomia syndrome.

    Science.gov (United States)

    Rohena, Luis; Kuehn, Devon; Marchegiani, Shannon; Higginson, Jason D

    2011-04-01

    Ablepharon-macrostomia syndrome (AMS) is characterized by absent or short eyelids, macrostomia, ear anomalies, absent lanugo and hair, redundant skin, abnormal genitalia, and developmental delay in two-thirds of the reported patients. Additional anomalies include dry skin, growth retardation, hearing loss, camptodactyly, hypertelorism, absent zygomatic arches, and umbilical abnormalities. We present the second familial case of ablepharon-macrostomia syndrome in a newborn female and her 22-year-old father making autosomal dominant inheritance more likely than the previously proposed autosomal recessive transmission for this disorder. These cases likely represent the 16th and 17th reported cases of AMS and the first case suspected on prenatal ultrasound. Additionally, the child shows more prominent features of the disorder when compared to her father documenting variable expression and possible anticipation. This article is a US Government work and, as such, is in the public domain in the United States of America. Published 2011 Wiley-Liss, Inc.

  20. Novel autosomal dominant TNNT1 mutation causing nemaline myopathy.

    Science.gov (United States)

    Konersman, Chamindra G; Freyermuth, Fernande; Winder, Thomas L; Lawlor, Michael W; Lagier-Tourenne, Clotilde; Patel, Shailendra B

    2017-11-01

    Nemaline myopathy (NEM) is one of the three major forms of congenital myopathy and is characterized by diffuse muscle weakness, hypotonia, respiratory insufficiency, and the presence of nemaline rod structures on muscle biopsy. Mutations in troponin T1 (TNNT1) is 1 of 10 genes known to cause NEM. To date, only homozygous nonsense mutations or compound heterozygous truncating or internal deletion mutations in TNNT1 gene have been identified in NEM. This extended family is of historical importance as some members were reported in the 1960s as initial evidence that NEM is a hereditary disorder. Proband and extended family underwent Sanger sequencing for TNNT1. We performed RT-PCR and immunoblot on muscle to assess TNNT1 RNA expression and protein levels in proband and father. We report a novel heterozygous missense mutation of TNNT1 c.311A>T (p.E104V) that segregated in an autosomal dominant fashion in a large family residing in the United States. Extensive sequencing of the other known genes for NEM failed to identify any other mutant alleles. Muscle biopsies revealed a characteristic pattern of nemaline rods and severe myofiber hypotrophy that was almost entirely restricted to the type 1 fiber population. This novel mutation alters a residue that is highly conserved among vertebrates. This report highlights not only a family with autosomal dominant inheritance of NEM, but that this novel mutation likely acts via a dominant negative mechanism. © 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

  1. Pathogenesis and potential therapy of autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    O.O. Melnyk

    2017-10-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is a hereditary disease characterized by progressive growth of the cyst and an increase in the total volume of the kidneys which leads to kidney failure. The main causes of ADPKD are mutations in the genes PKD1 and PKD2 which encode the formation of polycystin-1 and polycystin-2 proteins. There is a connection between structural and functional defects in the primary cilia with the ADPKD. The most promising drugs for the treatment of ADPKD today are vasopressin-2 receptor antagonists, m-TOR and c-AMP inhibitors.

  2. Mutation in LIM2 Is Responsible for Autosomal Recessive Congenital Cataracts.

    Directory of Open Access Journals (Sweden)

    Bushra Irum

    Full Text Available To identify the molecular basis of non-syndromic autosomal recessive congenital cataracts (arCC in a consanguineous family.All family members participating in the study received a comprehensive ophthalmic examination to determine their ocular phenotype and contributed a blood sample, from which genomic DNA was extracted. Available medical records and interviews with the family were used to compile the medical history of the family. The symptomatic history of the individuals exhibiting cataracts was confirmed by slit-lamp biomicroscopy. A genome-wide linkage analysis was performed to localize the disease interval. The candidate gene, LIM2 (lens intrinsic membrane protein 2, was sequenced bi-directionally to identify the disease-causing mutation. The physical changes caused by the mutation were analyzed in silico through homology modeling, mutation and bioinformatic algorithms, and evolutionary conservation databases. The physiological importance of LIM2 to ocular development was assessed in vivo by real-time expression analysis of Lim2 in a mouse model.Ophthalmic examination confirmed the diagnosis of nuclear cataracts in the affected members of the family; the inheritance pattern and cataract development in early infancy indicated arCC. Genome-wide linkage analysis localized the critical interval to chromosome 19q with a two-point logarithm of odds (LOD score of 3.25. Bidirectional sequencing identified a novel missense mutation, c.233G>A (p.G78D in LIM2. This mutation segregated with the disease phenotype and was absent in 192 ethnically matched control chromosomes. In silico analysis predicted lower hydropathicity and hydrophobicity but higher polarity of the mutant LIM2-encoded protein (MP19 compared to the wild-type. Moreover, these analyses predicted that the mutation would disrupt the secondary structure of a transmembrane domain of MP19. The expression of Lim2, which was detected in the mouse lens as early as embryonic day 15 (E15

  3. Cataracts

    Science.gov (United States)

    ... Oncology Oculoplastics/Orbit Refractive Management/Intervention Retina/Vitreous Uveitis Focus On Pediatric Ophthalmology ... Are Cataracts? Pediatric Cataracts Cataract Diagnosis and Treatment Cataract Surgery IOL Implants: Lens Replacement After Cataracts ...

  4. Autosomal dominant distal myopathy: Linkage to chromosome 14

    Energy Technology Data Exchange (ETDEWEB)

    Laing, N.G.; Laing, B.A.; Wilton, S.D.; Dorosz, S.; Mastaglia, F.L.; Kakulas, B.A. [Australian Neuromuscular Research Institute, Perth (Australia); Robbins, P.; Meredith, C.; Honeyman, K.; Kozman, H.

    1995-02-01

    We have studied a family segregating a form of autosomal dominant distal myopathy (MIM 160500) and containing nine living affected individuals. The myopathy in this family is closest in clinical phenotype to that first described by Gowers in 1902. A search for linkage was conducted using microsatellite, VNTR, and RFLP markers. In total, 92 markers on all 22 autosomes were run. Positive linkage was obtained with 14 of 15 markers tested on chromosome 14, with little indication of linkage elsewhere in the genome. Maximum two-point LOD scores of 2.60 at recombination fraction .00 were obtained for the markers MYH7 and D14S64 - the family structure precludes a two-point LOD score {ge} 3. Recombinations with D14S72 and D14S49 indicate that this distal myopathy locus, MPD1, should lie between these markers. A multipoint analysis assuming 100% penetrance and using the markers D14S72, D14S50, MYH7, D14S64, D14S54, and D14S49 gave a LOD score of exactly 3 at MYH7. Analysis at a penetrance of 80% gave a LOD score of 2.8 at this marker. This probable localization of a gene for distal myopathy, MPD1, on chromosome 14 should allow other investigators studying distal myopathy families to test this region for linkage in other types of the disease, to confirm linkage or to demonstrate the likely genetic heterogeneity. 24 refs., 3 figs., 1 tab.

  5. Autism in siblings with autosomal dominant nocturnal frontal lobe epilepsy.

    Science.gov (United States)

    Miyajima, Tomoko; Kumada, Tomohiro; Saito, Keiko; Fujii, Tatsuya

    2013-02-01

    In 1999, Hirose et al. reported a Japanese family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) associated with a neuronal nicotinic acetylcholine receptor α4 subunit mutation (S252L). We followed the siblings of this family, and found that the elder brother had Asperger's disorder without mental retardation (MR) and the younger brother had autistic disorder with profound MR. The clinical epileptic features of the siblings were very similar, and both had deficits in socialization, but their cognitive development differed markedly. It thus seems that epilepsy is the direct phenotype of the S252L mutation, whereas other various factors modulate the cognitive and social development. No patients with ADNFLE have previously been reported to have autism spectrum disorder or profound MR. Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  6. Autosomal dominant inheritance Caffey-Silverman disease hyperostosis corticalis infantum

    International Nuclear Information System (INIS)

    Rogoyski, A.; Jakubowska, K.; Tronowska, T.D.

    1984-01-01

    A case of Caffey-Silverman disease is described in an infant aged 4.5 months. The case was erroneously diagnosed in the initial stage of the disease as osteitis. The correct diagnosis was established after radiological examination of the skeleton. The pathological lesions involved the mandible, both clavicles, all ribs, left shoulder blade, both radial bones and left ulna. Follow-up radiological examination after 12 months demonstrated nearly complete disappearance of the previously observed skeletal changes. At the age of 18 months the condition of the child was good and its development was normal. Radiological changes indicating past Caffey-Silverman disease were disclosed in the mother and maternal grandmother of the child. This indicates an autosomal dominant type of inheritance of the disease. (Author)

  7. A Japanese Family With Autosomal Dominant Oculocutaneous Albinism Type 4.

    Science.gov (United States)

    Oki, Ryoko; Yamada, Kisaburo; Nakano, Satoko; Kimoto, Kenichi; Yamamoto, Ken; Kondo, Hiroyuki; Kubota, Toshiaki

    2017-02-01

    We report the clinical characteristics of a Japanese family with autosomal dominant oculocutaneous albinism and a SLC45A2 gene mutation. A total of 16 members of a Japanese family with general hypopigmentation and foveal hypoplasia underwent detailed clinical examinations. We evaluated the severity of foveal hypoplasia using spectral-domain optical coherence tomography (SD-OCT) and graded it according to the criteria of Thomas et al. DNA was extracted from 17 family members and used for genome-wide single nucleotide polymorphism genotyping and linkage analysis. Mutational search was performed for the SLC45A2 gene responsible for oculocutaneous albinism type 4 (OCA4). All 16 patients exhibited hypopigmentation of their hair and/or iris. They showed foveal hypoplasia, including 3 patients with grade 1 foveal hypoplasia, 7 with grade 2, and 6 with grade 3. No patient had grade 4 foveal hypoplasia. Optical coherence tomography showed macular ganglion cell complex thinning in the temporal area, and a slight reduction of visual field sensitivity in the centrotemporal area. A maximum multipoint parametric logarithm of the odds (LOD) score of approximately 2.00 to 3.56 was obtained on chromosome 5, spanning approximately 7.2 Mb between rs13187570 and rs395967 that included the SLC45A2 gene. All affected members showed a novel heterozygous variant, c.208T>C (p.Y70H), in the SLC45A2 gene, which supported a diagnosis of OCA4. The present study reports a very rare family with autosomal dominant OCA4 whose diagnosis was confirmed by a mutational analysis. Most family members exhibited mild general hypopigmentation and low-grade foveal hypoplasia.

  8. Deletion at the GCNT2 Locus Causes Autosomal Recessive Congenital Cataracts.

    Science.gov (United States)

    Irum, Bushra; Khan, Shahid Y; Ali, Muhammad; Daud, Muhammad; Kabir, Firoz; Rauf, Bushra; Fatima, Fareeha; Iqbal, Hira; Khan, Arif O; Al Obaisi, Saif; Naeem, Muhammad Asif; Nasir, Idrees A; Khan, Shaheen N; Husnain, Tayyab; Riazuddin, Sheikh; Akram, Javed; Eghrari, Allen O; Riazuddin, S Amer

    2016-01-01

    The aim of this study is to identify the molecular basis of autosomal recessive congenital cataracts (arCC) in a large consanguineous pedigree. All participating individuals underwent a detailed ophthalmic examination. Each patient's medical history, particularly of cataracts and other ocular abnormalities, was compiled from available medical records and interviews with family elders. Blood samples were donated by all participating family members and used to extract genomic DNA. Genetic analysis was performed to rule out linkage to known arCC loci and genes. Whole-exome sequencing libraries were prepared and paired-end sequenced. A large deletion was found that segregated with arCC in the family, and chromosome walking was conducted to estimate the proximal and distal boundaries of the deletion mutation. Exclusion and linkage analysis suggested linkage to a region of chromosome 6p24 harboring GCNT2 (glucosaminyl (N-acetyl) transferase 2) with a two-point logarithm of odds score of 5.78. PCR amplifications of the coding exons of GCNT2 failed in individuals with arCC, and whole-exome data analysis revealed a large deletion on chromosome 6p in the region harboring GCNT2. Chromosomal walking using multiple primer pairs delineated the extent of the deletion to approximately 190 kb. Interestingly, a failure to amplify a junctional fragment of the deletion break strongly suggests an insertion in addition to the large deletion. Here, we report a novel insertion/deletion mutation at the GCNT2 locus that is responsible for congenital cataracts in a large consanguineous family.

  9. Caffeine intake by patients with autosomal dominant polycystic kidney disease

    International Nuclear Information System (INIS)

    Vendramini, L.C.; Nishiura, J.L.; Baxmann, A.C.; Heilberg, I.P.

    2012-01-01

    Because caffeine may induce cyst and kidney enlargement in autosomal dominant polycystic kidney disease (ADPKD), we evaluated caffeine intake and renal volume using renal ultrasound in ADPKD patients. Caffeine intake was estimated by the average of 24-h dietary recalls obtained on 3 nonconsecutive days in 102 ADPKD patients (68 females, 34 males; 39 ± 12 years) and compared to that of 102 healthy volunteers (74 females, 28 males; 38 ± 14 years). The awareness of the need for caffeine restriction was assessed. Clinical and laboratory data were obtained from the medical records of the patients. Mean caffeine intake was significantly lower in ADPKD patients versus controls (86 vs 134 mg/day), and 63% of the ADPKD patients had been previously aware of caffeine restriction. Caffeine intake did not correlate with renal volume in ADPKD patients. There were no significant differences between the renal volumes of patients in the highest and lowest tertiles of caffeine consumption. Finally, age-adjusted multiple linear regression revealed that renal volume was associated with hypertension, chronic kidney disease stage 3 and the time since diagnosis, but not with caffeine intake. The present small cross-sectional study indicated a low level of caffeine consumption by ADPKD patients when compared to healthy volunteers, which was most likely due to prior awareness of the need for caffeine restriction. Within the range of caffeine intake observed by ADPKD patients in this study (0-471 mg/day), the renal volume was not directly associated with caffeine intake

  10. Genes and Mutations Causing Autosomal Dominant Retinitis Pigmentosa

    Science.gov (United States)

    Daiger, Stephen P.; Bowne, Sara J.; Sullivan, Lori S.

    2015-01-01

    Retinitis pigmentosa (RP) has a prevalence of approximately one in 4000; 25%–30% of these cases are autosomal dominant retinitis pigmentosa (adRP). Like other forms of inherited retinal disease, adRP is exceptionally heterogeneous. Mutations in more than 25 genes are known to cause adRP, more than 1000 mutations have been reported in these genes, clinical findings are highly variable, and there is considerable overlap with other types of inherited disease. Currently, it is possible to detect disease-causing mutations in 50%–75% of adRP families in select populations. Genetic diagnosis of adRP has advantages over other forms of RP because segregation of disease in families is a useful tool for identifying and confirming potentially pathogenic variants, but there are disadvantages too. In addition to identifying the cause of disease in the remaining 25% of adRP families, a central challenge is reconciling clinical diagnosis, family history, and molecular findings in patients and families. PMID:25304133

  11. Caffeine intake by patients with autosomal dominant polycystic kidney disease

    Energy Technology Data Exchange (ETDEWEB)

    Vendramini, L.C.; Nishiura, J.L.; Baxmann, A.C.; Heilberg, I.P. [Disciplina de Nefrologia, Departamento de Medicina, Universidade Federal de São Paulo, São Paulo, SP (Brazil)

    2012-07-20

    Because caffeine may induce cyst and kidney enlargement in autosomal dominant polycystic kidney disease (ADPKD), we evaluated caffeine intake and renal volume using renal ultrasound in ADPKD patients. Caffeine intake was estimated by the average of 24-h dietary recalls obtained on 3 nonconsecutive days in 102 ADPKD patients (68 females, 34 males; 39 ± 12 years) and compared to that of 102 healthy volunteers (74 females, 28 males; 38 ± 14 years). The awareness of the need for caffeine restriction was assessed. Clinical and laboratory data were obtained from the medical records of the patients. Mean caffeine intake was significantly lower in ADPKD patients versus controls (86 vs 134 mg/day), and 63% of the ADPKD patients had been previously aware of caffeine restriction. Caffeine intake did not correlate with renal volume in ADPKD patients. There were no significant differences between the renal volumes of patients in the highest and lowest tertiles of caffeine consumption. Finally, age-adjusted multiple linear regression revealed that renal volume was associated with hypertension, chronic kidney disease stage 3 and the time since diagnosis, but not with caffeine intake. The present small cross-sectional study indicated a low level of caffeine consumption by ADPKD patients when compared to healthy volunteers, which was most likely due to prior awareness of the need for caffeine restriction. Within the range of caffeine intake observed by ADPKD patients in this study (0-471 mg/day), the renal volume was not directly associated with caffeine intake.

  12. Preimplantation Genetic Diagnosis Counseling in Autosomal Dominant Polycystic Kidney Disease.

    Science.gov (United States)

    Murphy, Erin L; Droher, Madeline L; DiMaio, Miriam S; Dahl, Neera K

    2018-03-30

    Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary forms of chronic kidney disease. Mutations within PKD1 or PKD2 lead to innumerable fluid-filled cysts in the kidneys and in some instances, end-stage renal disease (ESRD). Affected individuals have a 50% chance of passing the mutation to each of their offspring. Assisted reproductive technology using preimplantation genetic diagnosis (PGD) allows these individuals to reduce this risk to 1% to 2%. We assess the disease burden of 8 individuals with ADPKD who have undergone genetic testing in preparation for PGD. Clinical features that predict high risk for progression to ESRD in patients with ADPKD include genotype, early onset of hypertension, a urologic event before age 35 years, and a large height-adjusted total kidney volume. Patients may have a family history of intracranial aneurysms or complications involving hepatic cysts, which may further influence the decision to pursue PGD. We also explore the cost, risks, and benefits of using PGD. All patients with ADPKD of childbearing potential, regardless of risk for progression to ESRD or risk for a significant disease burden, will likely benefit from genetic counseling. Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  13. Autosomal dominant familial erythrocytosis due to autonomous erythropoietin production

    International Nuclear Information System (INIS)

    Distelhorst, C.W.; Wagner, D.S.; Goldwasser, E.; Adamson, J.W.

    1981-01-01

    A family is described in which four members spanning three consecutive generations have erythrocytosis associated with a normal hemoglobin oxygen affinity. When bone marrow from one affected family member was cultured in vitro, erythroid colonies formed only when erythropoietin was added to the culture. Serum erythropoietin, measured by radioimmunoassay, was significantly elevated above normal in each of the affected family members. Bioassayable erythropoietin was detected in the urine of two of the three affected family members. In two of the affected family members, erythropoietin was measured in serum by radioimmunoassay and in urine by bioassay before and for 4 days following an isovolemic phlebotomy, which reduced the red cell mass by 20%. Neither serum nor urinary erythropoietin levels changed following phlebotomy. The erythrocytosis in this family appears to be secondary to inappropriately increased erythropoietin production unassociated with a decrease in the blood oxygen-carrying capacity. This is the first instance in which autonomous erythropoietin production appears to be inherited on an autosomal dominant basis

  14. Is Autosomal Dominant Polycystic Kidney Disease Becoming a Pediatric Disorder?

    Directory of Open Access Journals (Sweden)

    Stéphanie De Rechter

    2017-12-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD affects 1 in 400 to 1,000 live births, making it the most common monogenic cause of renal failure. Although no definite cure is available yet, it is important to affect disease progression by influencing modifiable factors such as hypertension and proteinuria. Besides this symptomatic management, the only drug currently recommended in Europe for selected adult patients with rapid disease progression, is the vasopressin receptor antagonist tolvaptan. However, the question remains whether these preventive interventions should be initiated before extensive renal damage has occurred. As renal cyst formation and expansion begins early in life, frequently in utero, ADPKD should no longer be considered an adult-onset disease. Moreover, the presence of hypertension and proteinuria in affected children has been reported to correlate well with disease severity. Until now, it is controversial whether children at-risk for ADPKD should be tested for the presence of the disease, and if so, how this should be done. Herein, we review the spectrum of pediatric ADPKD and discuss the pro and contra of testing at-risk children and the challenges and unmet needs in pediatric ADPKD care.

  15. Autosomal dominant cyclic hematopoiesis: Genetics, phenotype, and natural history

    Energy Technology Data Exchange (ETDEWEB)

    Palmer, S.E.; Stephens, K.; Dale, D.C. [Univ. of Washington, Seattle, WA (United States)

    1994-09-01

    Autosomal dominant cyclic hematopoiesis (ADCH; cyclic neutropenia) is a rare disorder manifested by transient neutropenia that recurs every three weeks. To facilitate mapping the ADCH gene by genetic linkage analysis, we studied 9 ADCH families with 42 affected individuals. Pedigrees revealed AD inheritance with no evidence for decreased penetrance. Similar intra- and interfamilial variable expression was observed, with no evidence to support heterogeneity. At least 3 families displayed apparent new mutations. Many adults developed chronic neutropenia, while offspring always cycled during childhood. Children displayed recurrent oral ulcers, gingivitis, lymphadenopathy, fever, and skin and other infections with additional symptoms. Interestingly, there were no cases of neonatal infection. Some children required multiple hospitalizations for treatment. Four males under age 18 died of Clostridium sepsis following necrotizing enterocolitis; all had affected mothers. No other deaths due to ADCH were found; most had improvement of symptoms and infections as adults. Adults experienced increased tooth loss prior to age 30 (16 out of 27 adults, with 9 edentulous). No increase in myelodysplasia, malignancy, or congenital anomalies was observed. Recombinant G-CSF treatment resulted in dramatic improvement of symptoms and infections. The results suggest that ADCH is not a benign disorder, especially in childhood, and abdominal pain requires immediate evaluation. Diagnosis of ADCH requires serial blood counts in the proband and at least one CBC in relatives to exclude similar disorders. Genetic counseling requires specific histories as well as CBCs of each family member at risk to determine status regardless of symptom history, especially to assess apparent new mutations.

  16. Subjective memory complaints in preclinical autosomal dominant Alzheimer disease.

    Science.gov (United States)

    Norton, Daniel J; Amariglio, Rebecca; Protas, Hillary; Chen, Kewei; Aguirre-Acevedo, Daniel C; Pulsifer, Brendan; Castrillon, Gabriel; Tirado, Victoria; Munoz, Claudia; Tariot, Pierre; Langbaum, Jessica B; Reiman, Eric M; Lopera, Francisco; Sperling, Reisa A; Quiroz, Yakeel T

    2017-10-03

    To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD). We examined self-reported and study partner-based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing. Self-reported SMC were greater in carriers than noncarriers ( p = 0.02). Study partner-based SMC did not differ between groups ( p = 0.21), but in carriers increased with age ( r = 0.66, p < 0.001) and decreased with hippocampal volume ( r = -0.35, p = 0.08). Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset. © 2017 American Academy of Neurology.

  17. Prenatal diagnosis of recurrent autosomal dominant osteogenesis imperfecta associated with unaffected parents and paternal gonadal mosaicism

    Directory of Open Access Journals (Sweden)

    Chih-Ping Chen

    2013-03-01

    Conclusion: Recurrent autosomal dominant OI may occur in the offspring of unaffected parents with parental gonadal mosaicism. Genetic counseling of recurrent autosomal dominant OI should include a thorough mutational analysis of the family members, and mutational analysis of the sperm may detect paternal gonadal mosaicism for the mutation.

  18. Chorioretinal dysplasia-microcephaly-mental retardation syndrome : Another family with autosomal dominant inheritance

    NARCIS (Netherlands)

    Hordijk, R; VandeLogt, F; Houtman, WA; VanEssen, AJ

    1996-01-01

    We describe a boy and his father with the chorioretinal dysplasia-microcephaly-mental retardation syndrome (CDMMS). Our report extends the phenotypic spectrum of autosomal dominant CDMMS by describing microphthalmia for the first time in an autosomal dominant family. The boy was also severely

  19. Molecular and cellular pathogenesis of autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    A.P. Bastos

    2011-07-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is one of the most common human life-threatening monogenic disorders. The disease is characterized by bilateral, progressive renal cystogenesis and cyst and kidney enlargement, often leading to end-stage renal disease, and may include extrarenal manifestations. ADPKD is caused by mutation in one of two genes, PKD1 and PKD2, which encode polycystin-1 (PC1 and polycystin-2 (PC2, respectively. PC2 is a non-selective cation channel permeable to Ca2+, while PC1 is thought to function as a membrane receptor. The cyst cell phenotype includes increased proliferation and apoptosis, dedifferentiation, defective planar polarity, and a secretory pattern associated with extracellular matrix remodeling. The two-hit model for cyst formation has been recently extended by the demonstration that early gene inactivation leads to rapid and diffuse development of renal cysts, while inactivation in adult life is followed by focal and late cyst formation. Renal ischemia/reperfusion, however, can function as a third hit, triggering rapid cyst development in kidneys with Pkd1 inactivation induced in adult life. The PC1-PC2 complex behaves as a sensor in the primary cilium, mediating signal transduction via Ca2+ signaling. The intracellular Ca2+ homeostasis is impaired in ADPKD, being apparently responsible for the cAMP accumulation and abnormal cell proliferative response to cAMP. Activated mammalian target for rapamycin (mTOR and cell cycle dysregulation are also significant features of PKD. Based on the identification of pathways altered in PKD, a large number of preclinical studies have been performed and are underway, providing a basis for clinical trials in ADPKD and helping the design of future trials.

  20. Oculopharyngeal Weakness, Hypophrenia, Deafness, and Impaired Vision: A Novel Autosomal Dominant Myopathy with Rimmed Vacuoles

    Directory of Open Access Journals (Sweden)

    Ting Chen

    2016-01-01

    Conclusions: We reported a novel autosomal dominant myopathy with rimmed vacuoles characterized by dysarthria, dysphagia, external ophthalmoplegia, limb weakness, hypophrenia, deafness, and impaired vision, but the causative gene has not been found and needs further study.

  1. A newly recognized autosomal dominant limb girdle muscular dystrophy with cardiac involvement

    NARCIS (Netherlands)

    van der Kooi, A. J.; Ledderhof, T. M.; de Voogt, W. G.; Res, C. J.; Bouwsma, G.; Troost, D.; Busch, H. F.; Becker, A. E.; de Visser, M.

    1996-01-01

    Sixty-five members of three families with limb girdle muscular dystrophy (LGMD) underwent neurological, cardiological, and ancillary investigations. Thirty-five individuals were diagnosed as having slowly progressive autosomal dominant LGMD. Symmetrical weakness started in the proximal lower limb

  2. Imaging of the Macula Indicates Early Completion of Structural Deficit in Autosomal-Dominant Optic Atrophy

    DEFF Research Database (Denmark)

    Rönnbäck, Cecilia; Milea, Dan; Larsen, Michael

    2013-01-01

    Optical coherence tomography (OCT) enables 3-dimensional imaging of the retina, including the layer of ganglion cells that supplies the optic nerve with its axons. We tested OCT as means of diagnosing and phenotyping autosomal-dominant optic atrophy (ADOA)....

  3. An 11-Year-Old Child with Autosomal Dominant Polycystic Kidney Disease Who Presented with Nephrolithiasis

    Directory of Open Access Journals (Sweden)

    Fatih Firinci

    2012-01-01

    Full Text Available Patients with autosomal dominant polycystic kidney disease become symptomatic and are diagnosed usually at adulthood. The rate of nephrolithiasis in these patients is 5–10 times the rate in the general population, and both anatomic and metabolic abnormalities play role in the formation of renal stones. However, nephrolithiasis is rare in childhood age group. In this paper, an 11-year-old child with autosomal dominant polycystic kidney disease presenting with nephrolithiasis is discussed.

  4. Autosomal dominant spastic paraplegia with peripheral neuropathy maps to chr12q23-24.

    Science.gov (United States)

    Schüle, R; Bonin, M; Dürr, A; Forlani, S; Sperfeld, A D; Klimpe, S; Mueller, J C; Seibel, A; van de Warrenburg, B P; Bauer, P; Schöls, L

    2009-06-02

    Hereditary spastic paraplegias (HSP) are genetically exceedingly heterogeneous. To date, 37 genetic loci for HSP have been described (SPG1-41), among them 16 loci for autosomal dominant disease. Notwithstanding, further genetic heterogeneity is to be expected in HSP, as various HSP families do not link to any of the known HSP loci. In this study, we aimed to map the disease locus in a German family segregating autosomal dominant complicated HSP. A genome-wide linkage analysis was performed using the GeneChip Mapping 10Kv2.0 Xba Array containing 10,204 SNP markers. Suggestive loci were further analyzed by mapping of microsatellite markers. One locus on chromosome 12q23-24, termed SPG36, was confirmed by high density microsatellite fine mapping with a significant LOD score of 3.2. SPG36 is flanked by markers D12S318 and D12S79. Linkage to SPG36 was excluded in >20 additional autosomal dominant HSP families. Candidate genes were selected and sequenced. No disease-causing mutations were identified in the coding regions of ATXN2, HSPB8, IFT81, Myo1H, UBE3B, and VPS29. SPG36 is complicated by a sensory and motor neuropathy; it is therefore the eighth autosomal dominant subtype of complicated HSP. We report mapping of a new locus for autosomal dominant hereditary spastic paraplegia (HSP) (SPG36) on chromosome 12q23-24 in a German family with autosomal dominant HSP complicated by peripheral neuropathy.

  5. Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal Dominant Polycystic Kidney Disease

    Science.gov (United States)

    2017-09-01

    AWARD NUMBER: W81XWH-15-1-0419 TITLE: Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal Dominant Polycystic Kidney Disease...COVERED 1 Sep 2016 - 31 Aug 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal...inappropriate cell growth, fluid secretion, and dysregulation of cellular energy metabolism. The enzyme AMPK regulates a number of cellular pathways, including

  6. Clinical and Radiological Findings of Autosomal Dominant Osteopetrosis Type II: A Case Report

    Directory of Open Access Journals (Sweden)

    Priyanka Kant

    2013-01-01

    Full Text Available Osteopetrosis is a rare inherited genetic disease characterized by sclerosis of the skeleton caused by the absence or malfunction of osteoclasts. Three distinct forms of the disease have been recognized, autosomal dominant osteopetrosis being the most common. Autosomal dominant osteopetrosis exhibits a heterogeneous trait with milder symptoms, often at later childhood or adulthood. The aim of this case report is to present the clinical and radiographic features of a 35-year-old female patient with autosomal dominant osteopetrosis type II who exhibited features of chronic generalised periodontitis, and the radiographs revealed generalised osteosclerosis and hallmark radiographic features of ADO type II, that is, “bone-within-bone appearance” and “Erlenmeyer-flask deformity.”

  7. Management of pain in autosomal dominant polycystic kidney disease and anatomy of renal innervation.

    Science.gov (United States)

    Tellman, Matthew W; Bahler, Clinton D; Shumate, Ashley M; Bacallao, Robert L; Sundaram, Chandru P

    2015-05-01

    Chronic pain is a prominent feature of autosomal dominant polycystic kidney disease that is difficult to treat and manage, often resulting in a decrease in quality of life. Understanding the underlying anatomy of renal innervation and the various etiologies of pain that occur in autosomal dominant polycystic kidney disease can help guide proper treatments to manage pain. Reviewing previously studied treatments for pain in autosomal dominant polycystic kidney disease can help characterize treatment in a stepwise fashion. We performed a literature search of the etiology and management of pain in autosomal dominant polycystic kidney disease and the anatomy of renal innervation using PubMed® and Embase® from January 1985 to April 2014 with limitations to human studies and English language. Pain occurs in the majority of patients with autosomal dominant polycystic kidney disease due to renal, hepatic and mechanical origins. Patients may experience different types of pain which can make it difficult to clinically confirm its etiology. An anatomical and histological evaluation of the complex renal innervation helps in understanding the mechanisms that can lead to renal pain. Understanding the complex nature of renal innervation is essential for surgeons to perform renal denervation. The management of pain in autosomal dominant polycystic kidney disease should be approached in a stepwise fashion. Acute causes of renal pain must first be ruled out due to the high incidence in autosomal dominant polycystic kidney disease. For chronic pain, nonopioid analgesics and conservative interventions can be used first, before opioid analgesics are considered. If pain continues there are surgical interventions such as renal cyst decortication, renal denervation and nephrectomy that can target pain produced by renal or hepatic cysts. Chronic pain in patients with autosomal dominant polycystic kidney disease is often refractory to conservative, medical and other noninvasive treatments

  8. Genotype-phenotype correlation in FMF patients: A "non classic" recessive autosomal or "atypical" dominant autosomal inheritance?

    Science.gov (United States)

    Procopio, V; Manti, S; Bianco, G; Conti, G; Romeo, A; Maimone, F; Arrigo, T; Cutrupi, M C; Salpietro, C; Cuppari, C

    2018-01-30

    Uncertainty remains on the pathogenetic mechanisms, model of inheritance as well as genotype-phenotype correlation of FMF disease. To investigate the impact of genetic factors on the FMF phenotype and the disease inheritance model. A total of 107 FMF patients were enrolled. Patients were diagnosed clinically. All patients underwent genetic analysis of the FMF locus on 16p13.3. 9 distinct mutations were detected. Specifically, the 85.98% of patients showed a heterozygous genotype. The most common genotypes were p.Met680Ile/wt and p.Met694Val/wt. The most frequent clinical findings were fever, abdominal pain, joint pain, thoracic pain, and erysipelas-like erythema. Analysis of clinical data did not detect any significant difference in clinical phenotype among heterozygous, homozygous as well as compound homozygous subjects, further supporting the evidence that, contrary to the recessive autosomal inheritance, heterozygous patients fulfilled the criteria of clinical FMF. Moreover, subjects with p.Met694Val/wt and p.Met680Ile/wt genotype reported the most severe clinical phenotype. p.Ala744Ser/wt, p.Glu148Gln/Met680Ile, p.Met680Ile/Met680Ile, p.Met680Ile/Met694Val, p.Pro369Ser/wt, p.Met694Ile/wt, p.Glu148Gln/Glu148Gln, p.Lys695Arg/wt resulted in 100% pathogenicity. The existence of a "non classic" autosomal recessive inheritance as well as of an "atypical" dominant autosomal inheritance with incomplete penetrance and variable expressivity cannot be excluded in FMF. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. CLPB Variants Associated with Autosomal-Recessive Mitochondrial Disorder with Cataract, Neutropenia, Epilepsy, and Methylglutaconic Aciduria

    DEFF Research Database (Denmark)

    Saunders, Carol; Smith, Laurie; Wibrand, Flemming

    2015-01-01

    of type IV 3-MGA-uria characterized by cataracts, severe psychomotor regression during febrile episodes, epilepsy, neutropenia with frequent infections, and death in early childhood. Four of the individuals were of Greenlandic descent, and one was North American, of Northern European and Asian descent...

  10. Genomic deletions in OPA1 in Danish patients with autosomal dominant optic atrophy

    DEFF Research Database (Denmark)

    Almind, Gitte J; Grønskov, Karen; Milea, Dan

    2011-01-01

    Autosomal dominant optic atrophy (ADOA, Kjer disease, MIM #165500) is the most common form of hereditary optic neuropathy. Mutations in OPA1 located at chromosome 3q28 are the predominant cause for ADOA explaining between 32 and 89% of cases. Although deletions of OPA1 were recently reported...

  11. Autosomal dominant spastic paraplegia with peripheral neuropathy maps to chr12q23-24.

    NARCIS (Netherlands)

    Schule, R.; Bonin, M.; Durr, A.; Forlani, S.; Sperfeld, A.D.; Klimpe, S.; Mueller, J.C.; Seibel, A.; Warrenburg, B.P.C. van de; Bauer, P.; Schols, L.

    2009-01-01

    OBJECTIVE: Hereditary spastic paraplegias (HSP) are genetically exceedingly heterogeneous. To date, 37 genetic loci for HSP have been described (SPG1-41), among them 16 loci for autosomal dominant disease. Notwithstanding, further genetic heterogeneity is to be expected in HSP, as various HSP

  12. A novel mutation in the ELOVL4 gene causes autosomal dominant Stargardt-like macular dystrophy.

    NARCIS (Netherlands)

    Maugeri, A.; Meire, F.; Hoyng, C.B.; Vink, C.W.; Regemorter, N. van; Karan, G.; Yang, Z.; Cremers, F.P.M.; Zhang, K.

    2004-01-01

    PURPOSE: To conduct clinical and genetic studies in a European family with autosomal dominant Stargardt-like macular dystrophy (adSTGD-like MD) and to investigate the functional consequences of a novel ELOVL4 mutation. METHODS: Ophthalmic examination and mutation screening by direct sequencing of

  13. Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal Dominant Polycystic Kidney Disease

    Science.gov (United States)

    2017-09-01

    Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most prevalent genetic disease, affecting at least 600,000 Americans . It is characterized...Pennathur, Michigan Metabolomics and Obesity Center (MMOC) at U. Michigan and statistical consultation from Dr. K. Abebe at U. Pittsburgh. Cell

  14. Current novel-gene-finding strategy for autosomal-dominant hypercholesterolaemia needs refinement

    NARCIS (Netherlands)

    Fouchier, Sigrid W.; Hutten, Barbara A.; Defesche, Joep C.

    2015-01-01

    Autosomal-dominant hypercholesterolaemia (ADH) is a heterogeneous common disorder, and uncovering the molecular determinants that underlie ADH is a major focus of cardiovascular research. However, despite rapid technical advances, efforts to identify novel ADH genes have yet not been very successful

  15. Plasma lipoprotein(a) levels in patients with homozygous autosomal dominant hypercholesterolemia

    NARCIS (Netherlands)

    Sjouke, Barbara; Yahya, Reyhana; Tanck, Michael W. T.; Defesche, Joep C.; de Graaf, Jacqueline; Wiegman, Albert; Kastelein, John J. P.; Mulder, Monique T.; Hovingh, G. Kees; Roeters van Lennep, Jeanine E.

    2017-01-01

    Patients with autosomal dominant hypercholesterolemia (ADH), caused by mutations in either low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9) are characterized by high low-density lipoprotein cholesterol levels and in some

  16. Plasma lipoprotein(a) levels in patients with homozygous autosomal dominant hypercholesterolemia

    NARCIS (Netherlands)

    Sjouke, B.; Yahya, R.; Tanck, M.W.T.; Defesche, J.C.; Graaf, J. de; Wiegman, A.; Kastelein, J.J.; Mulder, M.T.; Hovingh, G.K.; Roeters van Lennep, J.E.

    2017-01-01

    BACKGROUND: Patients with autosomal dominant hypercholesterolemia (ADH), caused by mutations in either low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin-kexin type 9 (PCSK9) are characterized by high low-density lipoprotein cholesterol levels and

  17. A new mutation causing autosomal dominant periodic fever syndrome in a Danish family

    DEFF Research Database (Denmark)

    Weyhreter, Heike; Schwartz, Marianne; Kristensen, Tim D

    2003-01-01

    We describe four members in a family of 8 individuals over 3 generations with the autosomal dominant inherited periodic fever syndrome tumor necrosis factor receptor-associated periodic syndrome (TRAPS). The patients had recurrent episodes of fever, abdominal pain, arthritis, and rash. We examined...

  18. EDAR mutation in autosomal dominant hypohidrotic ectodermal dysplasia in two Swedish families

    Directory of Open Access Journals (Sweden)

    Schmitt-Egenolf Marcus

    2006-11-01

    Full Text Available Abstract Background Hypohidrotic ectodermal dysplasia (HED is a genetic disorder characterized by defective development of teeth, hair, nails and eccrine sweat glands. Both autosomal dominant and autosomal recessive forms of HED have previously been linked to mutations in the ectodysplasin 1 anhidrotic receptor (EDAR protein that plays an important role during embryogenesis. Methods The coding DNA sequence of the EDAR gene was analyzed in two large Swedish three-generational families with autosomal dominant HED. Results A non-sense C to T mutation in exon 12 was identified in both families. This disease-specific mutation changes an arginine amino acid in position 358 of the EDAR protein into a stop codon (p.Arg358X, thereby truncating the protein. In addition to the causative mutation two polymorphisms, not associated with the HED disorder, were also found in the EDAR gene. Conclusion The finding of the p.Arg358X mutation in the Swedish families is the first corroboration of a previously described observation in an American family. Thus, our study strengthens the role of this particular mutation in the aetiology of autosomal dominant HED and confirms the importance of EDAR for the development of HED.

  19. Autosomal recessive congenital cataract in captive-bred vervet monkeys (Chlorocebus aethiops).

    Science.gov (United States)

    Magwebu, Zandisiwe E; Abdul-Rasool, Sahar; Seier, Jürgen V; Chauke, Chesa G

    2018-04-01

    The aim of the study was to evaluate the genetic predisposition of congenital cataract in a colony of captive-bred vervet monkeys. Four congenital cataract genes: glucosaminyl (N-acetyl) transferase 2 (GCNT2), heat shock transcription factor 4 (HSF4), crystallin alpha A (CRYAA) and lens intrinsic membrane protein-2 (LIM2) were screened, sequenced and analysed for possible genetic variants in 36 monkeys. Gene expression was also evaluated in these genes. Fifteen sequence variants were identified in the coding regions of three genes (GCNT2, HSF4 and CRYAA). Of these variations, only three were missense mutations (M258V, V16I and S24N) and identified in the GCNT2 transcripts A, B and C, respectively, which resulted in a downregulated gene expression. Although the three missense mutations in GCNT2 have a benign effect, a possibility exists that the candidate genes (GCNT2, HSF4 and CRYAA) might harbour mutations that are responsible for total congenital cataract. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. The congenital "ant-egg" cataract phenotype is caused by a missense mutation in connexin46

    DEFF Research Database (Denmark)

    Hansen, Lars; Yao, Wenliang; Eiberg, Hans

    2006-01-01

    "Ant-egg" cataract is a rare, distinct variety of congenital/infantile cataract that was reported in a large Danish family in 1967. This cataract phenotype is characterized by ant-egg-like bodies embedded in the lens in a laminar configuration and is inherited as an autosomal dominant trait. We r...

  1. A curious fact: Photic sneeze reflex. Autosomical dominant compelling helio-ophthalmic outburst syndrome.

    Science.gov (United States)

    Sevillano, C; Parafita-Fernández, A; Rodriguez-Lopez, V; Sampil, M; Moraña, N; Viso, E; Cores, F J

    2016-07-01

    To assess ocular involvement in the pathophysiology of autosomal dominant compelling helio-ophthalmic outburst syndrome (ACHOOs). An interview was conducted with a Caucasian family that showed clinical features of ACHOOs. Twelve of them had photic reflex and were recruited. A complete eye evaluation was made. A dominant autosomal inheritance with mild penetrance was demonstrated, with 67% of the studied subjects showing some degree of prominent corneal nerves. No other eye changes were found. Prominent corneal nerves may be associated with ACHOOs. The other eye structures studied do not seem to play a role in ACHOOs. Further studies are needed to understand the physiology of the ACHOOs. Copyright © 2016 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.

  2. [Clinical and molecular study in a family with autosomal dominant hypohidrotic ectodermal dysplasia].

    Science.gov (United States)

    Callea, Michele; Cammarata-Scalisi, Francisco; Willoughby, Colin E; Giglio, Sabrina R; Sani, Ilaria; Bargiacchi, Sara; Traficante, Giovanna; Bellacchio, Emanuele; Tadini, Gianluca; Yavuz, Izzet; Galeotti, Angela; Clarich, Gabriella

    2017-02-01

    Hypohidrotic ectodermal dysplasia (HED) is a rare disease characterized by deficiency in development of structure derived from the ectoderm and is caused by mutations in the genes EDA, EDAR, or EDARADD. Phenotypes caused by mutations in these three may exhibit similar clinical features, explained by a common signaling pathway. Mutations in EDA gene cause X linked HED, which is the most common form. Mutations in EDAR and EDARADD genes cause autosomal dominant and recessive form of HED. The most striking clinical findings in HED are hypodontia, hypotrichosis and hypohidrosis that can lead to episodes of hyperthermia. We report on clinical findings in a child with HED with autosomal dominant inheritance pattern with a heterozygous mutation c.1072C>T (p.Arg358X) in the EDAR gene. A review of the literature with regard to other cases presenting the same mutation has been carried out and discussed. Sociedad Argentina de Pediatría.

  3. Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal Dominant Polycystic Kidney Disease

    Science.gov (United States)

    2016-09-01

    pathways that are involved in cyst development and expansion. These experiments will make use of cultured ADPKD cells and a mouse model of ADPKD to...AWARD NUMBER: W81XWH-15-1-0420 TITLE: Cellular Energy Pathways as Novel Targets for the Therapy of Autosomal Dominant Polycystic Kidney Disease...PRINCIPAL INVESTIGATOR: Kenneth R. Hallows, MD, PhD, FASN CONTRACTING ORGANIZATION: University of Southern California Los Angeles, CA 90089-0701

  4. Molecular Diagnostics in Autosomal Dominant Polycystic Kidney Disease: Utility and Limitations

    Science.gov (United States)

    Zhao, Xiao; Paterson, Andrew D.; Zahirieh, Alireza; He, Ning; Wang, Kairong; Pei, York

    2008-01-01

    Background and objectives: Gene-based mutation screening is now available and has the potential to provide diagnostic confirmation or exclusion of autosomal dominant polycystic kidney disease. This study illustrates its utility and limitations in the clinical setting. Design, setting, participants, & measurements: Using a molecular diagnostic service, genomic DNA of one affected individual from each study family was screened for pathologic PKD1 and PKD2 mutations. Bidirectional sequencing was performed to identify sequence variants in all exons and splice junctions of both genes and to confirm the specific mutations in other family members. In two multiplex families, microsatellite markers were genotyped at both PDK1 and PKD2 loci, and pair-wise and multipoint linkage analysis was performed. Results: Three of five probands studied were referred for assessment of renal cystic disease without a family history of autosomal dominant polycystic kidney disease, and two others were younger at-risk members of families with autosomal dominant polycystic kidney disease being evaluated as living-related kidney donors. Gene-based mutation screening identified pathogenic mutations that provided confirmation or exclusion of disease in three probands, but in the other two, only unclassified variants were identified. In one proband in which mutation screening was indeterminate, DNA linkage studies provided strong evidence for disease exclusion. Conclusions: Gene-based mutation screening or DNA linkage analysis should be considered in individuals in whom the diagnosis of autosomal dominant polycystic kidney disease is uncertain because of a lack of family history or equivocal imaging results and in younger at-risk individuals who are being evaluated as living-related kidney donors. PMID:18077784

  5. Acute abdomen and ascites as presenting features of autosomal dominant polycystic kidney disease

    OpenAIRE

    Chaudhary, Sanjay; Qian, Qi

    2012-01-01

    We describe a patient with sudden onset of abdominal pain and ascites, leading to the diagnosis of autosomal dominant polycystic kidney disease (ADPKD). Her presentation was consistent with acute liver cyst rupture as the cause of her acute illness. A review of literature on polycystic liver disease in patients with ADPKD and current management strategies are presented. This case alerts physicians that ADPKD could occasionally present as an acute abdomen; cyst rupture related to ADPKD may be ...

  6. A new variant of spondylometaphyseal dysplasia with autosomal dominant mode of inheritance.

    OpenAIRE

    García-Castro, J M; Isales-Forsythe, C M; Díaz de Garau, P

    1982-01-01

    Clinical and radiographic evaluation of an infant boy and his father revealed findings suggesting a new variant of spondylometaphyseal dysplasia with an apparently autosomal dominant mode of inheritance. The main clinical findings included short stature and marked ligamentous laxity in the infant. X-ray findings included severe and peculiar multiple metaphyseal involvement and striking vertebral undermineralisation in the infant, and platyspondyly in the father. However, all the epiphyses wer...

  7. Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME: Probable first family from India

    Directory of Open Access Journals (Sweden)

    Chandra Mohan Sharma

    2014-01-01

    Full Text Available Autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME is an extremely rare syndrome characterized by familial occurrence of postural and action-induced tremors of the hands but showing electrophysiologic findings of cortical reflex myoclonus. Patients also have cognitive decline and tonic-clonic seizures, often precipitated by sleep deprivation or photic stimulation. We describe probably the first family from India of this ill-defined syndrome.

  8. The role of noise and positive feedback in the onset of autosomal dominant diseases

    Directory of Open Access Journals (Sweden)

    Bosl William J

    2010-06-01

    Full Text Available Abstract Background Autosomal dominant (AD diseases result when a single mutant or non-functioning gene is present on an autosomal chromosome. These diseases often do not emerge at birth. There are presently two prevailing theories explaining the expression of AD diseases. One explanation originates from the Knudson two-hit theory of hereditary cancers, where loss of heterozygosity or occurrence of somatic mutations impairs the function of the wild-type copy. While these somatic second hits may be sufficient for stable disease states, it is often difficult to determine if their occurrence necessarily marks the initiation of disease progression. A more direct consequence of a heterozygous genetic background is haploinsufficiency, referring to a lack of sufficient gene function due to reduced wild-type gene copy number; however, haploinsufficiency can involve a variety of additional mechanisms, such as noise in gene expression or protein levels, injury and second hit mutations in other genes. In this study, we explore the possible contribution to the onset of autosomal dominant diseases from intrinsic factors, such as those determined by the structure of the molecular networks governing normal cellular physiology. Results First, simple models of single gene insufficiency using the positive feedback loops that may be derived from a three-component network were studied by computer simulation using Bionet software. The network structure is shown to affect the dynamics considerably; some networks are relatively stable even when large stochastic variations in are present, while others exhibit switch-like dynamics. In the latter cases, once the network switches over to the disease state it remains in that state permanently. Model pathways for two autosomal dominant diseases, AD polycystic kidney disease and mature onset diabetes of youth (MODY were simulated and the results are compared to known disease characteristics. Conclusions By identifying the

  9. DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome

    DEFF Research Database (Denmark)

    White, Janson; Mazzeu, Juliana F; Hoischen, Alexander

    2015-01-01

    Robinow syndrome is a genetically heterogeneous disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features and for which both autosomal-recessive and autosomal-dominant inheritance patterns have been described. Causative variants in the non-canonical ...

  10. Characterization of Cat-2t, a radiation-induced dominant cataract mutation in mice

    International Nuclear Information System (INIS)

    Graw, J.; Bors, W.; Gopinath, P.M.; Merkle, S.; Michel, C.; Reitmeir, P.; Schaeffer, E.S.; Summer, K.H.; Wulff, A.

    1990-01-01

    A dominant cataract mutation was detected recently among the offspring of x-ray-irradiated male mice. The mutation, which causes total lens opacity, has provisionally been designated by the gene symbol Cat-2t. In the lenses of heterozygous and homozygous Cat-2t mutants, the epithelial and fiber cells were swollen and the lens capsule was ruptured. The histologic analysis demonstrated a complete destruction of the cellular organization of the lens, which might be caused by its altered developmental processes. The data derived from biochemical investigations indicate that biochemistry of the cataractous Cat-2t lenses is affected: the osmotic state as indicated by the increased water content and increased Na(+)-K(+)-adenosinetriphosphatase (ATPase) activity; the energy state as indicated by the decreased adenosine triphosphate (ATP) concentration; and the redox state as indicated by the enhanced content of oxidized glutathione. Additionally, the lenticular protein composition is altered because of the presence of vimentin in the water-soluble fraction. This cannot be explained by the enhanced crosslinking activity of transglutaminase. The changes of the osmotic, energy, and redox states are considered to be secondary in relation to the altered lenticular development. In contrast, the variations concerning vimentin and transglutaminase might be a biochemical indication of the changed development. Possible similarities to other dominantly expressed murine cataract mutants are discussed

  11. C-terminal truncations in human 3 '-5 ' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

    NARCIS (Netherlands)

    Richards, Anna; van den Maagdenberg, Arn M. J. M.; Jen, Joanna C.; Kavanagh, David; Bertram, Paula; Spitzer, Dirk; Liszewski, M. Kathryn; Barilla-LaBarca, Maria-Louise; Terwindt, Gisela M.; Kasai, Yumi; McLellan, Mike; Grand, Mark Gilbert; Vanmolkot, Kaate R. J.; de Vries, Boukje; Wan, Jijun; Kane, Michael J.; Mamsa, Hafsa; Schaefer, Ruth; Stam, Anine H.; Haan, Joost; Paulus, T. V. M. de Jong; Storimans, Caroline W.; van Schooneveld, Mary J.; Oosterhuis, Jendo A.; Gschwendter, Andreas; Dichgans, Martin; Kotschet, Katya E.; Hodgkinson, Suzanne; Hardy, Todd A.; Delatycki, Martin B.; Hajj-Ali, Rula A.; Kothari, Parul H.; Nelson, Stanley F.; Frants, Rune R.; Baloh, Robert W.; Ferrari, Michel D.; Atkinson, John P.

    Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle- age onset. In nine families, we identified heterozygous C- terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease

  12. Vasopressin, Copeptin, and Renal Concentrating Capacity in Patients with Autosomal Dominant Polycystic Kidney Disease without Renal Impairment

    NARCIS (Netherlands)

    Zittema, Debbie; Boertien, Wendy E.; van Beek, Andre P.; Dullaart, Robin P. F.; Franssen, Casper F. M.; de Jong, Paul E.; Meijer, Esther; Gansevoort, Ron T.

    Background and objectives Autosomal dominant polycystic kidney disease (ADPKD) is the most prevalent hereditary renal disease, characterized by cyst formation in the kidneys leading to end stage kidney failure. It is clinically acknowledged that ADPKD patients have impaired urine concentrating

  13. Kidney Function and Plasma Copeptin Levels in Healthy Kidney Donors and Autosomal Dominant Polycystic Kidney Disease Patients

    NARCIS (Netherlands)

    Zittema, Debbie; van den Berg, Else; Meijer, Esther; Boertien, Wendy E.; Muller Kobold, Anneke C.; Franssen, Casper F. M.; de Jong, Paul E.; Bakker, Stephan J. L.; Navis, Gerjan; Gansevoort, Ron T.

    Background and objectives Plasma copeptin, a marker of arginine vasopressin, is elevated in patients with autosomal dominant polycystic kidney disease and predicts disease progression. It is unknown whether elevated copeptin levels result from decreased kidney clearance or as compensation for

  14. Diverging longitudinal changes in astrocytosis and amyloid PET in autosomal dominant Alzheimer's disease.

    Science.gov (United States)

    Rodriguez-Vieitez, Elena; Saint-Aubert, Laure; Carter, Stephen F; Almkvist, Ove; Farid, Karim; Schöll, Michael; Chiotis, Konstantinos; Thordardottir, Steinunn; Graff, Caroline; Wall, Anders; Långström, Bengt; Nordberg, Agneta

    2016-03-01

    Alzheimer's disease is a multifactorial dementia disorder characterized by early amyloid-β, tau deposition, glial activation and neurodegeneration, where the interrelationships between the different pathophysiological events are not yet well characterized. In this study, longitudinal multitracer positron emission tomography imaging of individuals with autosomal dominant or sporadic Alzheimer's disease was used to quantify the changes in regional distribution of brain astrocytosis (tracer (11)C-deuterium-L-deprenyl), fibrillar amyloid-β plaque deposition ((11)C-Pittsburgh compound B), and glucose metabolism ((18)F-fluorodeoxyglucose) from early presymptomatic stages over an extended period to clinical symptoms. The 52 baseline participants comprised autosomal dominant Alzheimer's disease mutation carriers (n = 11; 49.6 ± 10.3 years old) and non-carriers (n = 16; 51.1 ± 14.2 years old; 10 male), and patients with sporadic mild cognitive impairment (n = 17; 61.9 ± 6.4 years old; nine male) and sporadic Alzheimer's disease (n = 8; 63.0 ± 6.5 years old; five male); for confidentiality reasons, the gender of mutation carriers is not revealed. The autosomal dominant Alzheimer's disease participants belonged to families with known mutations in either presenilin 1 (PSEN1) or amyloid precursor protein (APPswe or APParc) genes. Sporadic mild cognitive impairment patients were further divided into (11)C-Pittsburgh compound B-positive (n = 13; 62.0 ± 6.4; seven male) and (11)C-Pittsburgh compound B-negative (n = 4; 61.8 ± 7.5 years old; two male) groups using a neocortical standardized uptake value ratio cut-off value of 1.41, which was calculated with respect to the cerebellar grey matter. All baseline participants underwent multitracer positron emission tomography scans, cerebrospinal fluid biomarker analysis and neuropsychological assessment. Twenty-six of the participants underwent clinical and imaging follow-up examinations after 2.8 ± 0.6 years. By using linear

  15. Mutations in DNMT1 cause autosomal dominant cerebellar ataxia, deafness and narcolepsy

    DEFF Research Database (Denmark)

    Winkelmann, Juliane; Lin, Ling; Schormair, Barbara

    2012-01-01

    to HDAC2. It is also highly expressed in immune cells and required for the differentiation of CD4+ into T regulatory cells. Mutations in exon 20 of this gene were recently reported to cause hereditary sensory neuropathy with dementia and hearing loss (HSAN1). Our mutations are all located in exon 21......Autosomal dominant cerebellar ataxia, deafness and narcolepsy (ADCA-DN) is characterized by late onset (30-40 years old) cerebellar ataxia, sensory neuronal deafness, narcolepsy-cataplexy and dementia. We performed exome sequencing in five individuals from three ADCA-DN kindreds and identified DNMT...

  16. Acute abdomen and ascites as presenting features of autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Chaudhary, Sanjay; Qian, Qi

    2012-12-27

    We describe a patient with sudden onset of abdominal pain and ascites, leading to the diagnosis of autosomal dominant polycystic kidney disease (ADPKD). Her presentation was consistent with acute liver cyst rupture as the cause of her acute illness. A review of literature on polycystic liver disease in patients with ADPKD and current management strategies are presented. This case alerts physicians that ADPKD could occasionally present as an acute abdomen; cyst rupture related to ADPKD may be considered in the differential diagnoses of acute abdomen.

  17. A rare cardiac manifestation in autosomal-dominant polycystic kidney disease

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    Meriam Hajji

    2017-01-01

    Full Text Available Autosomal-dominant polycystic kidney disease (ADPKD is a systemic disorder associated with various extrarenal complications. There is little information regarding the occurrence and distribution of cardiovascular abnormalities during the course of ADPKD. The major cardiovascular complications of ADPKD include valvulopathies and vascular ectasia. Aneurysm of the atrial septum (ASA is a very rare manifestation in ADPKD. A 37-year-old woman who was diagnosed with ADPKD was admitted to our hospital for advanced renal failure. Pelvic computed tomography revealed multiple variable-sized cysts in both kidneys. Trans-thoracic echocardiography showed ASA while the patient was completely asymptomatic.

  18. Health-related quality of life across all stages of autosomal dominant polycystic kidney disease

    DEFF Research Database (Denmark)

    Eriksson, Daniel; Karlsson, Linda; Eklund, Oskar

    2017-01-01

    BACKGROUND: A limited number of studies have assessed health-related quality of life (HRQoL) in autosomal dominant polycystic kidney disease (ADPKD). Results to date have been conflicting and studies have generally focused on patients with later stages of the disease. This study aimed to assess...... stages 4-5 and patients on dialysis. Progressive disease predominately had an impact on physical health, whereas mental health showed less variation between stages of the disease. A substantial loss in quality of life was observed as patients progressed to CKD stages 4-5. CONCLUSIONS: Later stages...

  19. Autosomal dominant polycystic kidney disease: recent advances in clinical management [version 1; referees: 2 approved

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    Zhiguo Mao

    2016-08-01

    Full Text Available The first clinical descriptions of autosomal dominant polycystic kidney disease (ADPKD go back at least 500 years to the late 16th century. Advances in understanding disease presentation and pathophysiology have mirrored the progress of clinical medicine in anatomy, pathology, physiology, cell biology, and genetics. The identification of PKD1 and PKD2, the major genes mutated in ADPKD, has stimulated major advances, which in turn have led to the first approved drug for this disorder and a fresh reassessment of patient management in the 21st century. In this commentary, we consider how clinical management is likely to change in the coming decade.

  20. New autosomal dominant syndrome reminiscent of Coffin-Siris syndrome and Brachymorphism-Onychodysplasia-Dysphalangism syndrome.

    Science.gov (United States)

    Elliott, A M; Teebi, A S

    2000-01-01

    We report a man and his two daughters (one stillborn) with an apparently unique constellation of anomalies including fifth finger/toe terminal phalanx and nail hypoplasia. The craniofacial manifestations include large boxy head, round face, hypertelorism with downslanting palpebral fissures and wide mouth. Other manifestations include brachydactyly, fifth finger clinodactyly and ventricular septal defect. Intelligence is normal. The resemblance to Coffin-Siris, Brachymorphism-Onychodysplasia-Dysphalangism and DOOR syndromes is discussed and we concluded that this family probably represents a new autosomal dominant syndrome.

  1. Three novel GJB2 (connexin 26) variants associated with autosomal dominant syndromic and nonsyndromic hearing loss.

    Science.gov (United States)

    DeMille, Desiree; Carlston, Colleen M; Tam, Oliver H; Palumbos, Janice C; Stalker, Heather J; Mao, Rong; Zori, Roberto T; Viskochil, David H; Park, Albert H; Carey, John C

    2018-04-01

    Connexin 26 (Cx26), encoded by the GJB2 gene, is a key protein involved in the formation of gap junctions in epithelial organs including the inner ear and palmoplantar epidermis. Pathogenic variants in GJB2 are responsible for approximately 50% of inherited sensorineural deafness. The majority of these variants are associated with autosomal recessive inheritance; however, rare reports of dominantly co-segregating variants have been published. Since we began offering GJB2 testing in 2003, only about 2% of detected GJB2 variants from our laboratory have been classified as dominant. Here we report three novel dominant GJB2 variants (p.Thr55Ala, p.Gln57_Pro58delinsHisSer, and p.Trp44Gly); two associated with syndromic sensorineural hearing loss and one with nonsyndromic hearing loss. In the kindred with the p.Thr55Ala variant, the proband and his father present with only leukonychia as a cutaneous finding of their syndromic hearing loss. This phenotype has been previously documented in conjunction with palmoplantar hyperkeratosis, but isolated leukonychia is a novel finding likely associated with the unique threonine to alanine change at codon 55 (other variants at this codon have been reported in cases of nonsyndromic hearing loss). This report contributes to the short list of GJB2 variants associated with autosomal dominant hearing loss, highlights the variability of skin and nail findings associated with such cases, and illustrates the occurrence of both syndromic and nonsyndromic presentations with changes in the same gene. © 2018 Wiley Periodicals, Inc.

  2. Identification and molecular modelling of a mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11)

    NARCIS (Netherlands)

    Luijendijk, M.W.J.; Wijk, E. van; Bischoff, A.M.L.C.; Krieger, E.; Huygen, P.L.M.; Pennings, R.J.E.; Brunner, H.G.; Cremers, C.W.R.J.; Cremers, F.P.M.; Kremer, J.M.J.

    2004-01-01

    Myosin VIIA is an unconventional myosin that has been implicated in Usher syndrome type 1B, atypical Usher syndrome, non-syndromic autosomal recessive hearing impairment (DFNB2) and autosomal dominant hearing impairment (DFNA11). Here, we present a family with non-syndromic autosomal dominant

  3. Identification and molecular modelling of a mutation in the motor head domain of myosin VIIA in a family with autosomal dominant hearing impairment (DFNA11).

    NARCIS (Netherlands)

    Luijendijk, M.W.J.; Wijk, E. van; Bischoff, A.M.L.C.; Krieger, E.; Huygen, P.L.M.; Pennings, R.J.E.; Brunner, H.G.; Cremers, C.W.R.J.; Cremers, F.P.M.; Kremer, J.M.J.

    2004-01-01

    Myosin VIIA is an unconventional myosin that has been implicated in Usher syndrome type 1B, atypical Usher syndrome, non-syndromic autosomal recessive hearing impairment (DFNB2) and autosomal dominant hearing impairment (DFNA11). Here, we present a family with non-syndromic autosomal dominant

  4. Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer's Disease: Results from the DIAN Study Group.

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    Yi Su

    Full Text Available Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer's Network (DIAN, an autosomal dominant Alzheimer's disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time. White matter referencing improved statistical power in the detecting longitudinal changes in relative tracer retention; however, the reason for this improvement is unclear and requires further investigation. Full dynamic acquisition and kinetic modeling improved statistical power although it may add cost and time. Several technical variations to amyloid burden quantification were examined in this study. Partial volume correction emerged as the strategy that most consistently improved statistical power for the detection of both longitudinal changes and across-group differences. For the autosomal dominant Alzheimer's disease population with PiB imaging, utilizing brainstem as a reference region with partial volume correction may be optimal for current interventional trials. Further investigation of technical issues in quantitative amyloid imaging in different study populations using different amyloid imaging tracers is warranted.

  5. Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer’s Disease: Results from the DIAN Study Group

    Science.gov (United States)

    Su, Yi; Blazey, Tyler M.; Owen, Christopher J.; Christensen, Jon J.; Friedrichsen, Karl; Joseph-Mathurin, Nelly; Wang, Qing; Hornbeck, Russ C.; Ances, Beau M.; Snyder, Abraham Z.; Cash, Lisa A.; Koeppe, Robert A.; Klunk, William E.; Galasko, Douglas; Brickman, Adam M.; McDade, Eric; Ringman, John M.; Thompson, Paul M.; Saykin, Andrew J.; Ghetti, Bernardino; Sperling, Reisa A.; Johnson, Keith A.; Salloway, Stephen P.; Schofield, Peter R.; Masters, Colin L.; Villemagne, Victor L.; Fox, Nick C.; Förster, Stefan; Chen, Kewei; Reiman, Eric M.; Xiong, Chengjie; Marcus, Daniel S.; Weiner, Michael W.; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L. S.

    2016-01-01

    Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer’s Network (DIAN), an autosomal dominant Alzheimer’s disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB) PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time. White matter referencing improved statistical power in the detecting longitudinal changes in relative tracer retention; however, the reason for this improvement is unclear and requires further investigation. Full dynamic acquisition and kinetic modeling improved statistical power although it may add cost and time. Several technical variations to amyloid burden quantification were examined in this study. Partial volume correction emerged as the strategy that most consistently improved statistical power for the detection of both longitudinal changes and across-group differences. For the autosomal dominant Alzheimer’s disease population with PiB imaging, utilizing brainstem as a reference region with partial volume correction may be optimal for current interventional trials. Further investigation of technical issues in quantitative amyloid imaging in different study populations using different amyloid imaging tracers is warranted. PMID:27010959

  6. Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.

    Science.gov (United States)

    Rinaldi, Carlo; Schmidt, Thomas; Situ, Alan J; Johnson, Janel O; Lee, Philip R; Chen, Ke-Lian; Bott, Laura C; Fadó, Rut; Harmison, George H; Parodi, Sara; Grunseich, Christopher; Renvoisé, Benoît; Biesecker, Leslie G; De Michele, Giuseppe; Santorelli, Filippo M; Filla, Alessandro; Stevanin, Giovanni; Dürr, Alexandra; Brice, Alexis; Casals, Núria; Traynor, Bryan J; Blackstone, Craig; Ulmer, Tobias S; Fischbeck, Kenneth H

    2015-05-01

    The family of genes implicated in hereditary spastic paraplegias (HSPs) is quickly expanding, mostly owing to the widespread availability of next-generation DNA sequencing methods. Nevertheless, a genetic diagnosis remains unavailable for many patients. To identify the genetic cause for a novel form of pure autosomal dominant HSP. We examined and followed up with a family presenting to a tertiary referral center for evaluation of HSP for a decade until August 2014. Whole-exome sequencing was performed in 4 patients from the same family and was integrated with linkage analysis. Sanger sequencing was used to confirm the presence of the candidate variant in the remaining affected and unaffected members of the family and screen the additional patients with HSP. Five affected and 6 unaffected participants from a 3-generation family with pure adult-onset autosomal dominant HSP of unknown genetic origin were included. Additionally, 163 unrelated participants with pure HSP of unknown genetic cause were screened. Mutation in the neuronal isoform of carnitine palmitoyl-transferase (CPT1C) gene. We identified the nucleotide substitution c.109C>T in exon 3 of CPT1C, which determined the base substitution of an evolutionarily conserved Cys residue for an Arg in the gene product. This variant strictly cosegregated with the disease phenotype and was absent in online single-nucleotide polymorphism databases and in 712 additional exomes of control participants. We showed that CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene known to be mutated in pure HSPs. The mutation, as indicated by nuclear magnetic resonance spectroscopy studies, alters the protein conformation and reduces the mean (SD) number (213.0 [46.99] vs 81.9 [14.2]; P lipid droplets on overexpression in cells. We also observed a reduction of mean (SD) lipid droplets in primary cortical neurons

  7. Fibroblast Growth Factor 23 and Kidney Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

    Science.gov (United States)

    Chonchol, Michel; Gitomer, Berenice; Isakova, Tamara; Cai, Xuan; Salusky, Isidro; Pereira, Renata; Abebe, Kaleab; Torres, Vicente; Steinman, Theodor I; Grantham, Jared J; Chapman, Arlene B; Schrier, Robert W; Wolf, Myles

    2017-09-07

    Increases in fibroblast growth factor 23 precede kidney function decline in autosomal dominant polycystic kidney disease; however, the role of fibroblast growth factor 23 in autosomal dominant polycystic kidney disease has not been well characterized. We measured intact fibroblast growth factor 23 levels in baseline serum samples from 1002 participants in the HALT-PKD Study A ( n =540; mean eGFR =91±17 ml/min per 1.73 m 2 ) and B ( n =462; mean eGFR =48±12 ml/min per 1.73 m 2 ). We used linear mixed and Cox proportional hazards models to test associations between fibroblast growth factor 23 and eGFR decline, percentage change in height-adjusted total kidney volume, and composite of time to 50% reduction in eGFR, onset of ESRD, or death. Median (interquartile range) intact fibroblast growth factor 23 was 44 (33-56) pg/ml in HALT-PKD Study A and 69 (50-93) pg/ml in Study B. In adjusted models, annualized eGFR decline was significantly faster in the upper fibroblast growth factor 23 quartile (Study A: quartile 4, -3.62; 95% confidence interval, -4.12 to -3.12 versus quartile 1, -2.51; 95% confidence interval, -2.71 to -2.30 ml/min per 1.73 m 2 ; P for trend kidney volume in adjusted models (quartile 4, 6.76; 95% confidence interval, 5.57 to 7.96 versus quartile 1, 6.04; 95% confidence interval, 5.55 to 6.54; P for trend =0.03). In Study B, compared with the lowest quartile, the highest fibroblast growth factor 23 quartile was associated with elevated risk for the composite outcome (hazard ratio, 3.11; 95% confidence interval, 1.84 to 5.25). Addition of fibroblast growth factor 23 to a model of annualized decline in eGFR≥3.0 ml/min per 1.73 m 2 did not improve risk prediction. Higher serum fibroblast growth factor 23 concentration was associated with kidney function decline, height-adjusted total kidney volume percentage increase, and death in patients with autosomal dominant polycystic kidney disease. However, fibroblast growth factor 23 did not substantially

  8. Novel Presenting Phenotype in a Child With Autosomal Dominant Best's Vitelliform Macular Dystrophy.

    Science.gov (United States)

    Abdalla, Yasmine F; De Salvo, Gabriella; Elsahn, Ahmad; Self, James E

    2017-07-01

    Best's macular dystrophy (BMD) usually manifests with visual failure in the first or second decade of life; however, there is a large variability in expressivity of the disease, and some patients have no manifestation other than a pathological electro-oculogram (EOG). Autosomal dominant Best's vitelliform macular dystrophy (AD-BVMD) has a very specific phenotype that varies with the stage of the disease. In recent years, the authors have seen description of another clinical entity known as autosomal recessive BMD. Herein, the authors describe a 5-year-old girl referred from a peripheral hospital for investigation with a positive family history of BMD. Clinical findings included best-corrected visual acuity of 0.325 and 0.300 in the right and left eyes, respectively, by Sonksen logMar test, full color vision, normal orthoptic examination, and a small degree of hyperopia consistent with age. Macular optical coherence tomography (OCT) showed intraretinal fluid cysts and EOG showed reduced Arden ratio. Genetic testing was done for the proband and her father, who were found to be heterozygous for c.37C>T p. (Arg13Cys). The proband's younger sister will be reviewed and followed up once of age. The authors identified a new phenotype of AD-BVMD; although this is a single patient, more young children with BMD can now be scanned with the availability of hand-held OCT with better knowledge of the phenotype. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:580-585.]. Copyright 2017, SLACK Incorporated.

  9. [Cardiac tamponade as first manifestation in Mediterranean fever with autosomal dominant form].

    Science.gov (United States)

    Sánchez Ferrer, F; Martinez Villar, M; Fernández Bernal, A; Martín de Lara, I; Paya Elorza, I

    2015-01-01

    Familial Mediterranean fever (FMF) is a hereditary disease characterized by brief, recurring and self-limited episodes of fever and pain with inflammation, of one or several serous (peritoneum, pleura, pericardium, synovial or vaginal tunic of the testicle). Amyloidosis is its more important complication and the principal reason of death in the cases in which it appears. Diagnosis is based on the clinic and is confirmed by genetic tests. The treatment with Colchicine (0,02-0,03 mg/kg/day) prevents the recurrence of FMF attacks and the development of secondary (AA) amyloidosis. We report a case of a 13-year-old child in which FMF was diagnosed after several coincidental episodes with fever, pericarditis and cardiac tamponade. The genetic confirmation showed an autosomal dominant inheritance that is less frecuent than the recesive form, in this disease. Copyright © 2013 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

  10. Recurrent acute pancreatitis and cholangitis in a patient with autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    Kambiz Yazdanpanah

    2013-01-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is an inherited disorder associated with multiple cyst formation in the different organs. Development of pancreatic cyst in ADPKD is often asymptomatic and is associated with no complication. A 38-year-old man with ADPKD was presented with six episodes of acute pancreatitis and two episodes of cholangitis in a period of 12 months. Various imaging studies revealed multiple renal, hepatic and pancreatic cysts, mild ectasia of pancreatic duct, dilation of biliary system and absence of biliary stone. He was managed with conservative treatment for each attack. ADPKD should be considered as a potential risk factor for recurrent acute and/or chronic pancreatitis and cholangitis.

  11. Autosomal dominant type of endosteal hyperostosis with unusual manifestations of sclerosis of the jaw bones

    Energy Technology Data Exchange (ETDEWEB)

    Nakamura, Takashi; Yamada, Naoyuki; Nonaka, Ryosuke; Sasaki, Motomasa

    1987-01-01

    We report three cases of autosomal dominant type endosteal hyperostosis which occurred in one Japanese family. A new pattern of sclerotic changes in the jaw bones is evident. In all members of the family there was a symmetrical thickening of the diaphyseal cortices of the long bones. The affected bones were only minimally widened and the epiphyses and metaphyses were spared. Endosteal sclerosis of the neurocranium was present with loss of the diploe. The sclerotic changes included enlargement and mottled sclerosis of both the maxilla and mandible, with multiple embedded teeth and odontomas. The ramus of the mandible was spared. Severe sclerosis of the jaw bones was present only in a 28-year-old women. The 2-year-son showed only focal sclerosis in the mandible, and his grandmother had minimal changes in the skeleton.

  12. Novel LMNA Mutation in a Taiwanese Family with Autosomal Dominant Emery-Dreifuss Muscular Dystrophy

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    Wen-Chen Liang

    2007-01-01

    Full Text Available Emery-Dreifuss muscular dystrophy (EDMD is characterized by early-onset contractures, slowly progressive weakness, and muscle wasting in humeroperoneal muscles, and adult-onset cardiomyopathy with conduction block. We analyzed blood samples from an EDMD family, including a mother and two daughters, and found a novel mutation in codon 520 in exon 9 of the lamin A/C (LMNA gene, resulting in a substitution of tryptophan (W by glycine (G in all three patients. The mother died after a stroke-like episode at the age of 43. The elder sister received pacemaker implantation, which improved symptoms of exercise intolerance and dizziness. These cases illustrate the necessity of correct diagnosis, evaluation, and follow-up of cardiac problems due to the wide clinical spectrum and high prevalence of cardiac conduction block in patients with autosomal dominant EDMD. [J Formos Med Assoc 2007;106(2 Suppl:S27-S31

  13. Autosomal-dominant non-autoimmune hyperthyroidism presenting with neuromuscular symptoms.

    Science.gov (United States)

    Elgadi, Aziz; Arvidsson, C-G; Janson, Annika; Marcus, Claude; Costagliola, Sabine; Norgren, Svante

    2005-08-01

    Neuromuscular presentations are common in thyroid disease, although the mechanism is unclear. In the present study, we investigated the pathogenesis in a boy with autosomal-dominant hyperthyroidism presenting with neuromuscular symptoms. The TSHr gene was investigated by direct sequencing. Functional properties of the mutant TSHr were investigated during transient expression in COS-7 cells. Family members were investigated by clinical and biochemical examinations. Sequence analysis revealed a previously reported heterozygous missense mutation Glycine 431 for Serine in the first transmembrane segment, leading to an increased specific constitutive activity. Three additional affected family members carried the same mutation. There was no indication of autoimmune disorder. All symptoms disappeared upon treatment with thacapzol and L-thyroxine and subsequent subtotal thyroidectomy. The data imply that neuromuscular symptoms can be caused by excessive thyroid hormone levels rather than by autoimmunity.

  14. Rare co-occurrence of osteogenesis imperfecta type I and autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Hoefele, Julia; Mayer, Karin; Marschall, Christoph; Alberer, Martin; Klein, Hanns-Georg; Kirschstein, Martin

    2016-11-01

    There are several clinical reports about the co-occurrence of autosomal dominant polycystic kidney disease (ADPKD) and connective tissue disorders. A simultaneous occurrence of osteogenesis imperfecta (OI) type I and ADPKD has not been observed so far. This report presents the first patient with OI type I and ADPKD. Mutational analysis of PKD1 and COL1A1 in the index patient revealed a heterozygous mutation in each of the two genes. Mutational analysis of the parents indicated the mother as a carrier of the PKD1 mutation and the father as a carrier of the COL1A1 mutation. The simultaneous occurrence of both disorders has an estimated frequency of 3.5:100 000 000. In singular cases, ADPKD can occur in combination with other rare disorders, e.g. connective tissue disorders.

  15. Prenatal diagnosis of autosomal dominant hereditary spastic paraplegia (SPG4) using direct mutation detection

    DEFF Research Database (Denmark)

    Nielsen, Jørgen E; Koefoed, Pernille; Kjaergaard, Susanne

    2004-01-01

    OBJECTIVE: To present a report on prenatal diagnosis using direct SPG4 gene analysis in a family with autosomal dominant hereditary spastic paraplegia (AD-HSP). METHODS: Genetic linkage and haplotype analysis were previously carried out with chromosome 2p markers. DNA was obtained from affected...... individuals, the affected father, the mother, and fetal DNA from an ongoing pregnancy by chorionic villus sampling (CVS) in the first trimester. The spastin gene (SPG4) was completely sequenced. RESULTS: A novel 832insGdelAA frameshift mutation, predicted to cause loss of functional protein, was identified...... in the affected father and in the fetal DNA. CONCLUSIONS: This is the first report on direct prenatal diagnosis of chromosome 2p-linked AD-HSP (SPG4). In addition, we report a novel SPG4-combined small insertion/deletion mutation in exon 5, which may be the first SPG4 mutational hot spot....

  16. A stepwise approach for effective management of chronic pain in autosomal-dominant polycystic kidney disease.

    Science.gov (United States)

    Casteleijn, Niek F; Visser, Folkert W; Drenth, Joost P H; Gevers, Tom J G; Groen, Gerbrand J; Hogan, Marie C; Gansevoort, Ron T

    2014-09-01

    Chronic pain, defined as pain existing for >4-6 weeks, affects >60% of patients with autosomal-dominant polycystic disease (ADPKD). It can have various causes, indirectly or directly related to the increase in kidney and liver volume in these patients. Chronic pain in ADPKD patients is often severe, impacting physical activity and social relationships, and frequently difficult to manage. This review provides an overview of pathophysiological mechanisms that can lead to pain and discusses the sensory innervation of the kidneys and the upper abdominal organs, including the liver. In addition, the results of a systematic literature search of ADPKD-specific treatment options are presented. Based on pathophysiological knowledge and evidence derived from the literature an argumentative stepwise approach for effective management of chronic pain in ADPKD is proposed. © The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  17. Late onset autosomal dominant cerebellar ataxia a family description and linkage analysis with the hla system

    Directory of Open Access Journals (Sweden)

    Walter O. Arruda

    1991-09-01

    Full Text Available A family suffering an autosomal dominant form of late onset hereditary cerebellar ataxia is described. Eight affected family members were personally studied, and data from another four were obtained through anamnesis. The mean age of onset was 37.1±5.4 years (27-47 years. The clinical picture consisted basically of a pure ataxic cerebellar syndrome. CT-scan disclosed diffuse cerebellar atrophy with relative sparing of the brainstem (and no involvement of supratentorial structures. Neurophysiological studies (nerve conduction, VEP and BAEP were normal. Twenty-six individuals were typed for HLA histocompatibility antigens. Lod scores were calculated with the computer program LINKMAP. Close linkage of the ataxia gene with the HLA system in this family could be excluded - 0==0,02, z=(-2,17 - and the overall analysis of the lod scores suggest another chromossomal location than chromosome 6.

  18. [A family with autosomal dominant temporal lobe epilepsy accompanied by motor and sensory neuropathy].

    Science.gov (United States)

    Matsuoka, Takeshi; Furuya, Hirokazu; Ikezoe, Koji; Murai, Hiroyuki; Ohyagi, Yasumasa; Yoshiura, Takashi; Sasaki, Masayuki; Tobimatsu, Syozo; Kira, Jun-ichi

    2004-01-01

    We report a 20-year-old man with temporal lobe epilepsy (TLE) accompanied by hereditary motor and sensory neuropathy (HMSN). He had experienced complex partial seizures (CPS), which started with a nausea-like feeling, followed by loss of consciousness and automatism, since he was 6 years old. The frequency of attacks was at first decreased by phenytoin. However, attacks increased again when he was 18 years old. On admission, neurological examination showed mild weakness of the toes, pes cavus, hammer toe and mildly impaired vibratory sensation in his legs. Ten people in four generations of his family showed a history of epilepsy in the autosomal dominant inheritance form. His younger sister and mother had a history of epilepsy accompanied with pes cavus, hammer toe, weakness of toe and finger extension and mildly impaired vibratory sensation as well. Direct sequencing of the glioma-inactivated leucine-rich gene (LGI1), in which several mutations were reported in patients with familial lateral temporal lobe epilepsy, showed no specific mutation in this family. On consecutive video-EEG monitoring, paroxysmal rhythmic activity was confirmed in his left fronto-temporal region when he showed automatism, and then a generalized slow burst activity was detected when he lost consciousness. For his seizures, TLE with secondary generalization was diagnosed. In the nerve conduction study, delayed nerve conduction, distal motor latency and decreased amplitudes of the compound muscle action potentials (CMAP) of bilateral peroneal nerves were observed, indicating the existence of mild axonal degeneration. Based on these data, we consider that this family to be a new phenotype of autosomal dominant TLE accompanied by motor and sensory neuropathy.

  19. Longitudinal Assessment of Left Ventricular Mass in Autosomal Dominant Polycystic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Taimur Dad

    2018-05-01

    Full Text Available Introduction: The high burden of cardiovascular morbidity and mortality in autosomal dominant polycystic kidney disease (ADPKD is related to development of hypertension and left ventricular hypertrophy. Blood pressure reduction has been shown to reduce left ventricular mass in ADPKD; however, moderators and predictors of response to lower blood pressure are unknown. Methods: This was a post hoc cohort analysis of HALT PKD study A, a randomized placebo controlled trial examining the effect of low blood pressure and single versus dual renin−angiotensin blockade in early ADPKD. Participants were hypertensive ADPKD patients 15 to 49 years of age with estimated glomerular filtration rate (eGFR > 60 ml/min per 1.73 m2 across 7 centers in the United States. Predictors included age, sex, baseline eGFR, systolic blood pressure, total kidney volume, serum potassium, and urine sodium, potassium, albumin, and aldosterone. Outcome was left ventricular mass index (LVMI measured using 1.5-T magnetic resonance imaging at months 0, 24, 48, and 60. Results: Reduction in LVMI was associated with higher baseline systolic blood pressure and larger kidney volume regardless of blood pressure control group assignment (P < 0.001 for both. Male sex and baseline eGFR were associated with a positive annual slope in LVMI (P < 0.001 and P = 0.07, respectively. Conclusion: Characteristics associated with higher risk of progression in ADPKD, including higher systolic blood pressure, larger kidney volume, and lower eGFR are associated with improvement in LVMI with intensive blood pressure control, whereas male sex is associated with a smaller slope of reduction in LVMI. Keywords: autosomal dominant polycystic kidney disease, hypertension, left ventricular hypertrophy, left ventricular mass index

  20. Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia

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    Huang Lijia

    2012-09-01

    Full Text Available Abstract Background Congenital nonprogressive spinocerebellar ataxia is characterized by early gross motor delay, hypotonia, gait ataxia, mild dysarthria and dysmetria. The clinical presentation remains fairly stable and may be associated with cerebellar atrophy. To date, only a few families with autosomal dominant congenital nonprogressive spinocerebellar ataxia have been reported. Linkage to 3pter was demonstrated in one large Australian family and this locus was designated spinocerebellar ataxia type 29. The objective of this study is to describe an unreported Canadian family with autosomal dominant congenital nonprogressive spinocerebellar ataxia and to identify the underlying genetic causes in this family and the original Australian family. Methods and Results Exome sequencing was performed for the Australian family, resulting in the identification of a heterozygous mutation in the ITPR1 gene. For the Canadian family, genotyping with microsatellite markers and Sanger sequencing of ITPR1 gene were performed; a heterozygous missense mutation in ITPR1 was identified. Conclusions ITPR1 encodes inositol 1,4,5-trisphosphate receptor, type 1, a ligand-gated ion channel that mediates calcium release from the endoplasmic reticulum. Deletions of ITPR1 are known to cause spinocerebellar ataxia type 15, a distinct and very slowly progressive form of cerebellar ataxia with onset in adulthood. Our study demonstrates for the first time that, in addition to spinocerebellar ataxia type 15, alteration of ITPR1 function can cause a distinct congenital nonprogressive ataxia; highlighting important clinical heterogeneity associated with the ITPR1 gene and a significant role of the ITPR1-related pathway in the development and maintenance of the normal functions of the cerebellum.

  1. De Novo GMNN Mutations Cause Autosomal-Dominant Primordial Dwarfism Associated with Meier-Gorlin Syndrome.

    Science.gov (United States)

    Burrage, Lindsay C; Charng, Wu-Lin; Eldomery, Mohammad K; Willer, Jason R; Davis, Erica E; Lugtenberg, Dorien; Zhu, Wenmiao; Leduc, Magalie S; Akdemir, Zeynep C; Azamian, Mahshid; Zapata, Gladys; Hernandez, Patricia P; Schoots, Jeroen; de Munnik, Sonja A; Roepman, Ronald; Pearring, Jillian N; Jhangiani, Shalini; Katsanis, Nicholas; Vissers, Lisenka E L M; Brunner, Han G; Beaudet, Arthur L; Rosenfeld, Jill A; Muzny, Donna M; Gibbs, Richard A; Eng, Christine M; Xia, Fan; Lalani, Seema R; Lupski, James R; Bongers, Ernie M H F; Yang, Yaping

    2015-12-03

    Meier-Gorlin syndrome (MGS) is a genetically heterogeneous primordial dwarfism syndrome known to be caused by biallelic loss-of-function mutations in one of five genes encoding pre-replication complex proteins: ORC1, ORC4, ORC6, CDT1, and CDC6. Mutations in these genes cause disruption of the origin of DNA replication initiation. To date, only an autosomal-recessive inheritance pattern has been described in individuals with this disorder, with a molecular etiology established in about three-fourths of cases. Here, we report three subjects with MGS and de novo heterozygous mutations in the 5' end of GMNN, encoding the DNA replication inhibitor geminin. We identified two truncating mutations in exon 2 (the 1(st) coding exon), c.16A>T (p.Lys6(∗)) and c.35_38delTCAA (p.Ile12Lysfs(∗)4), and one missense mutation, c.50A>G (p.Lys17Arg), affecting the second-to-last nucleotide of exon 2 and possibly RNA splicing. Geminin is present during the S, G2, and M phases of the cell cycle and is degraded during the metaphase-anaphase transition by the anaphase-promoting complex (APC), which recognizes the destruction box sequence near the 5' end of the geminin protein. All three GMNN mutations identified alter sites 5' to residue Met28 of the protein, which is located within the destruction box. We present data supporting a gain-of-function mechanism, in which the GMNN mutations result in proteins lacking the destruction box and hence increased protein stability and prolonged inhibition of replication leading to autosomal-dominant MGS. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  2. Autosomal dominant distal myopathy due to a novel ACTA1 mutation.

    Science.gov (United States)

    Liewluck, Teerin; Sorenson, Eric J; Walkiewicz, Magdalena A; Rumilla, Kandelaria M; Milone, Margherita

    2017-08-01

    Mutations in skeletal muscle α-actin 1-encoding gene (ACTA1) cause autosomal dominant or recessive myopathies with marked clinical and pathological heterogeneity. Patients typically develop generalized or limb-girdle pattern of weakness, but recently a family with scapuloperoneal myopathy was reported. We describe a father and 2 children with childhood-to-juvenile onset distal myopathy, carrying a novel dominant ACTA1 variant, c.757G>C (p.Gly253Arg). Father had delayed motor development and developed significant proximal weakness later in life; he was initially misdiagnosed as having spinal muscular atrophy based on electromyographic findings. His children had predominant anterior distal leg and finger extensor involvement. Nemaline rods were abundant on the daughter's biopsy, absent on the father's initial biopsy, and extremely rare on the father's subsequent biopsy a decade later. The father's second biopsy also showed myofibrillar pathology and rare fibers with actin filament aggregates. The present family expands the spectrum of actinopathy to include a distal myopathy. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. The Genetics of Hybrid Male Sterility Between the Allopatric Species Pair Drosophila persimilis and D. pseudoobscura bogotana: Dominant Sterility Alleles in Collinear Autosomal Regions

    OpenAIRE

    Chang, Audrey S.; Noor, Mohamed A. F.

    2007-01-01

    F1 hybrid male sterility is thought to result from interactions between loci on the X chromosome and dominant-acting loci on the autosomes. While X-linked loci that contribute to hybrid male sterility have been precisely localized in many animal taxa, their dominant autosomal interactors have been more difficult to localize precisely and/or have been shown to be of relatively smaller effect. Here, we identified and mapped at least four dominant autosomal factors contributing to hybrid male st...

  4. Autosomal dominant cutis laxa with progeroid features due to a novel, de novo mutation in ALDH18A1.

    Science.gov (United States)

    Bhola, Priya T; Hartley, Taila; Bareke, Eric; Boycott, Kym M; Nikkel, Sarah M; Dyment, David A

    2017-06-01

    De novo dominant mutations in the aldehyde dehydrogenase 18 family member A1 (ALDH18A1) gene have recently been shown to cause autosomal dominant cutis laxa with progeroid features (MIM 616603). To date, all de novo dominant mutations have been found in a single highly conserved amino acid residue at position p.Arg138. We report an 8-year-old male with a clinical diagnosis of autosomal dominant cutis laxa (ADCL) with progeroid features and a novel de novo missense mutation in ALDH18A1 (NM_002860.3: c.377G>A (p.Arg126His)). This is the first report of an individual with ALDH18A1-ADCL due to a substitution at a residue other than p.Arg138. Knowledge of the complete spectrum of dominant-acting mutations that cause this rare syndrome will have implications for molecular diagnosis and genetic counselling of these families.

  5. Autosomal-dominant Leber Congenital Amaurosis Caused by a Heterozygous CRX Mutation in a Father and Son.

    Science.gov (United States)

    Arcot Sadagopan, Karthikeyan; Battista, Robert; Keep, Rosanne B; Capasso, Jenina E; Levin, Alex V

    2015-06-01

    Leber congenital amaurosis (LCA) is most often an autosomal recessive disorder. We report a father and son with autosomal dominant LCA due to a mutation in the CRX gene. DNA screening using an allele specific assay of 90 of the most common LCA-causing variations in the coding sequences of AIPL1, CEP290, CRB1, CRX, GUCY2D, RDH12 and RPE65 was performed on the father. Automated DNA sequencing of his son examining exon 3 of the CRX gene was subsequently performed. Both father and son have a heterozygous single base pair deletion of an adenine at codon 153 in the coding sequence of the CRX gene resulting in a frameshift mutation. Mutations involving the CRX gene may demonstrate an autosomal dominant inheritance pattern for LCA.

  6. Autosomal dominant cerebellar ataxia type I: A review of the phenotypic and genotypic characteristics

    Directory of Open Access Journals (Sweden)

    Fujioka Shinsuke

    2011-05-01

    Full Text Available Abstract Type I autosomal dominant cerebellar ataxia (ADCA is a type of spinocerebellar ataxia (SCA characterized by ataxia with other neurological signs, including oculomotor disturbances, cognitive deficits, pyramidal and extrapyramidal dysfunction, bulbar, spinal and peripheral nervous system involvement. The global prevalence of this disease is not known. The most common type I ADCA is SCA3 followed by SCA2, SCA1, and SCA8, in descending order. Founder effects no doubt contribute to the variable prevalence between populations. Onset is usually in adulthood but cases of presentation in childhood have been reported. Clinical features vary depending on the SCA subtype but by definition include ataxia associated with other neurological manifestations. The clinical spectrum ranges from pure cerebellar signs to constellations including spinal cord and peripheral nerve disease, cognitive impairment, cerebellar or supranuclear ophthalmologic signs, psychiatric problems, and seizures. Cerebellar ataxia can affect virtually any body part causing movement abnormalities. Gait, truncal, and limb ataxia are often the most obvious cerebellar findings though nystagmus, saccadic abnormalities, and dysarthria are usually associated. To date, 21 subtypes have been identified: SCA1-SCA4, SCA8, SCA10, SCA12-SCA14, SCA15/16, SCA17-SCA23, SCA25, SCA27, SCA28 and dentatorubral pallidoluysian atrophy (DRPLA. Type I ADCA can be further divided based on the proposed pathogenetic mechanism into 3 subclasses: subclass 1 includes type I ADCA caused by CAG repeat expansions such as SCA1-SCA3, SCA17, and DRPLA, subclass 2 includes trinucleotide repeat expansions that fall outside of the protein-coding regions of the disease gene including SCA8, SCA10 and SCA12. Subclass 3 contains disorders caused by specific gene deletions, missense mutation, and nonsense mutation and includes SCA13, SCA14, SCA15/16, SCA27 and SCA28. Diagnosis is based on clinical history, physical

  7. A novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia linked to a mutation in the human insulin receptor gene

    DEFF Research Database (Denmark)

    Højlund, Kurt; Hansen, Torben; Lajer, Maria

    2004-01-01

    a missense mutation (Arg1174Gln) in the tyrosine kinase domain of the insulin receptor gene that cosegregated with the disease phenotype (logarithm of odds [LOD] score 3.21). In conclusion, we report a novel syndrome of autosomal-dominant hyperinsulinemic hypoglycemia. The findings demonstrate...

  8. A three-generation family with idiopathic facial palsy suggesting an autosomal dominant inheritance with high penetrance

    DEFF Research Database (Denmark)

    Larsen, Christian Grønhøj; Gyldenløve, Mette; Jønch, Aia Elise

    2015-01-01

    Idiopathic facial palsy (IFP), also known as Bell's palsy, is a common neurologic disorder, but recurrent and familial forms are rare. This case series presents a three-generation family with idiopathic facial palsy. The mode of inheritance of IFP has previously been suggested as autosomal dominant...

  9. Autosomal-dominant polycystic kidney disease (ADPKD) : executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

    NARCIS (Netherlands)

    Chapman, Arlene B.; Devuyst, Olivier; Eckardt, Kai-Uwe; Gansevoort, Ron T.; Harris, Tess; Horie, Shigeo; Kasiske, Bertram L.; Odland, Dwight; Pei, York; Perrone, Ronald D.; Pirson, Yves; Schrier, Robert W.; Torra, Roser; Torres, Vicente E.; Watnick, Terry; Wheeler, David C.

    Autosomal-dominant polycystic kidney disease (ADPKD) affects up to 12 million individuals and is the fourth most common cause for renal replacement therapy worldwide. There have been many recent advances in the understanding of its molecular genetics and biology, and in the diagnosis and management

  10. Mutations in POGLUT1, Encoding Protein O-Glucosyltransferase 1, Cause Autosomal-Dominant Dowling-Degos Disease

    DEFF Research Database (Denmark)

    Basmanav, F Buket; Oprisoreanu, Ana-Maria; Pasternack, Sandra M

    2014-01-01

    Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To ident...

  11. Rationale and Design of a Clinical Trial Investigating Tolvaptan Safety and Efficacy in Autosomal Dominant Polycystic Kidney Disease

    NARCIS (Netherlands)

    Torres, Vicente E.; Devuyst, Olivier; Chapman, Arlene B.; Gansevoort, Ron T.; Perrone, Ronald D.; Ouyang, John; Blais, Jaime D.; Czerwiec, Frank S.; Sergeyeva, Olga

    Background: In TEMPO 3: 4, the vasopressin V2-receptor antagonist tolvaptan slowed kidney growth and function decline in autosomal dominant polycystic kidney disease (ADPKD) patients with relatively preserved kidney function. Methods: Prospective, phase 3b, multi-center, randomized-withdrawal,

  12. Mutation spectrum in the large GTPase dynamin 2, and genotype-phenotype correlation in autosomal dominant centronuclear myopathy

    DEFF Research Database (Denmark)

    Böhm, Johann; Biancalana, Valérie; Dechene, Elizabeth T

    2012-01-01

    Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzym...

  13. A peculiar autosomal dominant macular dystrophy caused by an asparagine deletion at codon 169 in the peripherin/RDS gene

    NARCIS (Netherlands)

    van Lith-Verhoeven, Janneke J. C.; van den Helm, Bellinda; Deutman, August F.; Bergen, Arthur A. B.; Cremers, Frans P. M.; Hoyng, Carel B.; de Jong, Paulus T. V. M.

    2003-01-01

    Objective: To describe the clinical and genetic findings in a family with a peculiar autosomal dominant macular dystrophy with peripheral deposits. Methods: All family members underwent an ophthalmic examination, and their genomic DNA was screened for mutations in the human retinal degeneration slow

  14. Tolvaptan and Kidney Pain in Patients With Autosomal Dominant Polycystic Kidney Disease : Secondary Analysis From a Randomized Controlled Trial

    NARCIS (Netherlands)

    Casteleijn, Niek F.; Blais, Jaime D.; Chapman, Arlene B.; Czerwiec, Frank S.; Devuyst, Olivier; Higashihara, Eiji; Leliveld, Anna M.; Ouyang, John; Perrone, Ronald D.; Torres, Vicente E.; Gansevoort, Ron T.

    Background: Kidney pain is a common complication in patients with autosomal dominant polycystic kidney disease (ADPKD), and data from the TEMPO 3: 4 trial suggested that tolvaptan, a vasopressin V2 receptor antagonist, may have a positive effect on kidney pain in this patient group. Because pain is

  15. Health-related quality of life across all stages of autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Eriksson, Daniel; Karlsson, Linda; Eklund, Oskar; Dieperink, Hans; Honkanen, Eero; Melin, Jan; Selvig, Kristian; Lundberg, Johan

    2017-12-01

    A limited number of studies have assessed health-related quality of life (HRQoL) in autosomal dominant polycystic kidney disease (ADPKD). Results to date have been conflicting and studies have generally focused on patients with later stages of the disease. This study aimed to assess HRQoL in ADPKD across all stages of the disease, from patients with early chronic kidney disease (CKD) to patients with end-stage renal disease. A study involving cross-sectional patient-reported outcomes and retrospective clinical data was undertaken April-December 2014 in Denmark, Finland, Norway and Sweden. Patients were enrolled into four mutually exclusive stages of the disease: CKD stages 1-3; CKD stages 4-5; transplant recipients; and dialysis patients. Overall HRQoL was generally highest in patients with CKD stages 1-3, followed by transplant recipients, patients with CKD stages 4-5 and patients on dialysis. Progressive disease predominately had an impact on physical health, whereas mental health showed less variation between stages of the disease. A substantial loss in quality of life was observed as patients progressed to CKD stages 4-5. Later stages of ADPKD are associated with reduced physical health. The value of early treatment interventions that can delay progression of the disease should be considered. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.

  16. Molecular Typing of Staphylococcus aureus Isolated from Patients with Autosomal Dominant Hyper IgE Syndrome

    Directory of Open Access Journals (Sweden)

    Inka Sastalla

    2017-06-01

    Full Text Available Autosomal dominant hyper IgE syndrome (AD-HIES is a primary immunodeficiency caused by a loss-of-function mutation in the Signal Transducer and Activator of Transcription 3 (STAT3. This immune disorder is clinically characterized by increased susceptibility to cutaneous and sinopulmonary infections, in particular with Candida and Staphylococcus aureus. It has recently been recognized that the skin microbiome of patients with AD-HIES is altered with an overrepresentation of certain Gram-negative bacteria and Gram-positive staphylococci. However, these alterations have not been characterized at the species- and strain-level. Since S. aureus infections are influenced by strain-specific expression of virulence factors, information on colonizing strain characteristics may provide insights into host-pathogen interactions and help guide management strategies for treatment and prophylaxis. The aim of this study was to determine whether the immunodeficiency of AD-HIES selects for unique strains of colonizing S. aureus. Using multi-locus sequence typing (MLST, protein A (spa typing, and PCR-based detection of toxin genes, we performed a detailed analysis of the S. aureus isolates (n = 13 found on the skin of twenty-one patients with AD-HIES. We found a low diversity of sequence types, and an abundance of strains that expressed methicillin resistance, Panton-Valentine leukocidin (PVL, and staphylococcal enterotoxins K and Q (SEK, SEQ. Our results indicate that patients with AD-HIES may often carry antibiotic-resistant strains that harbor key virulence factors.

  17. Blood Pressure and Intracranial Aneurysms in Autosomal Dominant Polycystic Kidney Disease

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    Mariusz Niemczyk

    2014-12-01

    Full Text Available Background/Aims: Autosomal dominant polycystic kidney disease (ADPKD is correlated with an increased frequency of both intracranial aneurysms (ICANs, and arterial hypertension (AH. The aim of our study was to search for the association between blood pressure (BP and ICANs in ADPKD patients. Methods: Sixty-eight adult, pre-dialysis phase ADPKD patients underwent both screening for ICANs with magnetic resonance angiography of the brain, and ambulatory blood pressure monitoring (ABPM. Results: ICANs were diagnosed in 10 patients (ICAN(+ group, while in 58 were not (ICAN(- group. The nighttime maximum diastolic blood pressure (DBP, maximum increase in DBP from measurement to measurement (positive delta of DBP at night, and the standard deviation of the daytime mean arterial pressure were significantly higher in ICAN(+ compared to ICAN(- patients. Additionally, in a subgroup of patients after 45 years-of-age, ICAN(+ patients had significantly higher maximum 24-hour and daytime systolic blood pressure, maximum 24-hour, daytime, nighttime DBP, maximum daytime and nighttime positive delta of DBP compared to ICAN(- cases. Conclusions: Development of ICANs in hypertensive ADPKD patients is accompanied with higher values of some BP parameters measured by ABPM. Hypertensive ADPKD patients with substantial fluctuations in BP assessed by ABPM, especially those after 45 years-of-age, should become candidates for screening for ICANs.

  18. The value of intrarenal resistive index in autosomal dominant polycystic kidney disease

    International Nuclear Information System (INIS)

    Lee, Young Rae; Lee, Kyu Beck; Park, Hae Won

    1998-01-01

    The purpose of this study was to determine the value of the intrarenal resistive index(RI), measured by Doppler sonography, in order to assess intrarenal vascular resistance in autosomal dominant polycystic kidney disease (ADPKD) patients. In 26 patients with ADPKD, RI was measured by Doppler sonography and correlated with the presence of hypertension, renal function (creatinine clearance) and anatomical renal severity index (RSI), thus indicating renal morphologic abnormalities during Bmode sonography. RI was significantly higher in 18 hypertensive ADPKD patients (0.64±0.65) (Mean±1SD;range:0.52-0.74) than in eight normotensive patients (0.59± 0.50) (0.48-0.64) (p<0.05). Statistically significant inverse correlation was found between RI values and creatinine clearance (r=3D-0.45, p<0.05), and statistically significant correlation was found between RI values and RSI, indicating the degree of renal parenchymal involvement. RI correlates with the development of hypertension, renal function and renal morphologic abnormality scoring by RSI during B-mode Doppler sonography, and measured in this way may thus be used to assess renal vascular resistance in ADPKD patients.=20

  19. Mutation spectrum of the rhodopsin gene among patients with autosomal dominant retinitis pigmentosa

    International Nuclear Information System (INIS)

    Dryja, T.P.; Han, L.B.; Cowley, G.S.; McGee, T.L.; Berson, E.L.

    1991-01-01

    The authors searched for point mutations in every exon of the rhodopsin gene in 150 patients from separate families with autosomal dominant retinitis pigmentosa. Including the 4 mutations the authors reported previously, they found a total of 17 different mutations that correlate with the disease. Each of these mutations is a single-base substitution corresponding to a single amino acid substitution. Based on current models for the structure of rhodopsin, 3 of the 17 mutant amino acids are normally located on the cytoplasmic side of the protein, 6 in transmembrane domains, and 8 on the intradiscal side. Forty-three of the 150 patients (29%) carry 1 of these mutations, and no patient has more than 1 mutation. In every family with a mutation so far analyzed, the mutation cosegregates with the disease. They found one instance of a mutation in an affected patient that was absent in both unaffected parents (i.e., a new germ-line mutation), indicating that some isolate cases of retinitis pigmentosa carry a mutation of the rhodopsin gene

  20. "An evil heritage": interview study of pain and autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Heiwe, Susanne; Bjuke, Monica

    2009-09-01

    Pain is a common problem for patients with autosomal dominant polycystic kidney disease (ADPKD). Knowledge about patients' experience of the pain, pain management, and pain's effect on everyday life is, however, limited. In clinical practice there is a need to improve the care of these patients. To be able to do so, information about how the disease and its pain affect the patients is required. This study explores patients' experience of living with ADPKD and its pain. The findings are based on in-depth semistructured interviews. The participants were 22 patients with ADPKD. The data were transcribed and analyzed by using phenomenology. Findings showed that the patients experienced limitations in their everyday life due to inexplicable and unpredictable pain and fatigue. Also, pain management was experienced as suboptimal and pain was seldom discussed at health care appointments. Emotional distress concerning the hereditary nature of the disease was also present. Health care providers need to increase their focus on pain and pain management to reduce the disease's intrusion in patients' everyday life. Also, patients and people in the patients' immediate surroundings need to be given information and education about the disease and its pain as well as the opportunity to talk about their worries concerning heredity. By implementing the findings of the present study when meeting a patient with ADPKD, improved patient satisfaction and health-related quality of life could be accomplished.

  1. Treatment of Persistent Gross Hematuria with Tranexamic Acid in Autosomal Dominant Polycystic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Qing Yao

    2017-04-01

    Full Text Available Background/Aims: In this retrospective study we aimed to compare the effect of tranexamic acid (TXA vs etamsylate, two hemostatic agents, on hematuria duration in autosomal dominant polycystic kidney disease (ADPKD patients with persistent gross hematuria. Methods: This is a retrospective study of 40 patients with ADPKD and macroscopic hematuria. 20 patients receiving TXA and snake venom blood clotting enzyme injection were compared with 20 matched patients receiving etamsylate and snake venom blood clotting enzyme injection. The primary outcome was hematuria duration and the secondary outcomes were blood transfusion requirements and adverse events. Results: The hematuria duration was shorter in the TXA group compared with the etamsylate group (4[3-5] d vs 7[6-10] d, P<0.001. The volume of blood transfusion tended to be less in the TXA group than in the etamsylate group (300±115 ml vs 486±195 ml, P=0.12, and the number of patients needing a blood transfusion also tended to be lower [20% (4/20 vs 35% (7/20, P=0.29]. TXA and etamsylate were equally well tolerated and no serious adverse events were observed in both groups. Conclusions: Our study indicates that TXA treatment was more effective than etamsylate in stopping bleeding in ADPKD patients with persistent gross hematuria.

  2. Overview of autosomal dominant polycystic kidney disease in the south of Spain

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    Ana Isabel Morales García

    2018-03-01

    Full Text Available Introduction: Although autosomal dominant polycystic kidney disease is the most common hereditary kidney disease, available data tend to be limited to after initiation of renal replacement therapy. Objective: To ascertain an overview of autosomal dominant polycystic kidney disease within the health area of Granada in southern Spain. Materials and methods: From January 2007 to December 2016, we collected clinical, family and demographic information about all patients with autosomal dominant polycystic kidney disease, irrespective of whether or not they were treated with RRT, in the Granada health area. The computer software SPSS 15.0 and GenoPro were used. Results: 50.6% of the 1107 diagnosed patients were men. 99.1% were Caucasian and 4–6 generations/family were studied. The geographical distribution was heterogeneous. There was no family history in 2.43%. The mean age of diagnosis was 34.0 ± 17.80 years and the diagnosis was made after having offspring in 57.7% of cases. The main reason for diagnosis was family history (46.4%. The mean age of initiation of renal replacement therapy was 54.2 ± 11.05 years. 96.3% of the deceased had some degree of renal failure at the time of death. The mean age of death was 60.9 ± 14.10 years, the main cause of death being unknown in 33.5% of cases, followed by cardiovascular (27.8%. Conclusions: Cases and families were concentrated in certain geographical areas and a significant number of individuals were undiagnosed prior to cardiovascular death or diagnosed late after reproduction. Given that there is currently no curative treatment, the primary prevention strategy of preimplantation genetic diagnosis should play a leading role. Resumen: Introducción: La poliquistosis renal autosómica dominante es la enfermedad renal hereditaria más frecuente aunque los datos disponibles generalmente son tras el inicio del tratamiento renal sustitutivo. Objetivo: Conocer la situaci

  3. High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease.

    Science.gov (United States)

    Pottier, C; Hannequin, D; Coutant, S; Rovelet-Lecrux, A; Wallon, D; Rousseau, S; Legallic, S; Paquet, C; Bombois, S; Pariente, J; Thomas-Anterion, C; Michon, A; Croisile, B; Etcharry-Bouyx, F; Berr, C; Dartigues, J-F; Amouyel, P; Dauchel, H; Boutoleau-Bretonnière, C; Thauvin, C; Frebourg, T; Lambert, J-C; Campion, D

    2012-09-01

    Performing exome sequencing in 14 autosomal dominant early-onset Alzheimer disease (ADEOAD) index cases without mutation on known genes (amyloid precursor protein (APP), presenilin1 (PSEN1) and presenilin2 (PSEN2)), we found that in five patients, the SORL1 gene harbored unknown nonsense (n=1) or missense (n=4) mutations. These mutations were not retrieved in 1500 controls of same ethnic origin. In a replication sample, including 15 ADEOAD cases, 2 unknown non-synonymous mutations (1 missense, 1 nonsense) were retrieved, thus yielding to a total of 7/29 unknown mutations in the combined sample. Using in silico predictions, we conclude that these seven private mutations are likely to have a pathogenic effect. SORL1 encodes the Sortilin-related receptor LR11/SorLA, a protein involved in the control of amyloid beta peptide production. Our results suggest that besides the involvement of the APP and PSEN genes, further genetic heterogeneity, involving another gene of the same pathway is present in ADEOAD.

  4. Genetic linkage of autosomal dominant progressive supranuclear palsy to 1q31.1.

    Science.gov (United States)

    Ros, Raquel; Gómez Garre, Pilar; Hirano, Michio; Tai, Yen F; Ampuero, Israel; Vidal, Lídice; Rojo, Ana; Fontan, Aurora; Vazquez, Ana; Fanjul, Samira; Hernandez, Jaime; Cantarero, Susana; Hoenicka, Janet; Jones, Alison; Ahsan, R Laila; Pavese, Nicola; Piccini, Paola; Brooks, David J; Perez-Tur, Jordi; Nyggard, Torbjorn; de Yébenes, Justo G

    2005-05-01

    Progressive supranuclear palsy (PSP) is a disorder of unknown pathogenesis. Familial clusters of PSP have been reported related to mutations of protein tau. We report the linkage of a large Spanish family with typical autosomal dominant PSP to a new locus in chromosome 1. Four members of this family had typical PSP, confirmed by neuropathology in one case. At least five ancestors had similar disease. Other members of the family have incomplete phenotypes. The power of the linkage analysis was increased by detecting presymptomatic individuals with 18F-fluoro-dopa and 18F-deoxyglucose positron emission tomography. We screened the human genome with 340 polymorphic markers and we enriched the areas of interest with additional markers. The disease status was defined according to the clinical and positron emission tomography data. We excluded linkage to the tau gene in chromosome 17. PSP was linked, in this family, to one area of 3.4 cM in chromosome 1q31.1, with a maximal multipoint < OD score of +3.53. This area contains at least three genes, whose relevance in PSP is unknown. We expect to further define the gene responsible for PSP, which could help to understand the pathogenesis of this disease and to design effective treatment.

  5. Epidemiologic analysis of families with isolated anorectal malformations suggests high prevalence of autosomal dominant inheritance.

    Science.gov (United States)

    Dworschak, Gabriel C; Zwink, Nadine; Schmiedeke, Eberhard; Mortazawi, Kiarasch; Märzheuser, Stefanie; Reinshagen, Konrad; Leonhardt, Johannes; Gómez, Barbara; Volk, Patrick; Rißmann, Anke; Jenetzky, Ekkehart; Reutter, Heiko

    2017-12-13

    Anorectal malformations (ARM) are rare abnormalities that occur in approximately 1 in 3000 live births with around 40% of patients presenting with isolated forms. Multiple familial cases reported, suggest underlying genetic factors that remain largely unknown. The recurrence in relatives is considered rare, however transmission rates of ARM by affected parents have never been determined before. The inheritance pattern of ARM was investigated in our database of patients with isolated ARM. Within our cohort of 327 patients with isolated ARM we identified eight adult patients from eight families who had in total 16 children with their healthy spouse. Of these ten had ARM, resulting in a recurrence risk of approximately one in two live births (10 of 16; 62%). From 226 families with 459 siblings we found two affected siblings in five families. Hence, the recurrence risk of ARM among siblings is approximately one in 92 live births (5 of 459; 1.0%). Comparing the observed recurrence risk in our cohort with the prevalence in the general population, we see a 1500-fold increase in recurrence risk for offspring and a 32-fold increase if a sibling is affected. The recurrence risk of approximately 62% indicates an autosomal dominant mode of inheritance. Reliable figures on recurrence of ARM are becoming increasingly important since improved surgical techniques are able to maintain sexual function resulting in more offspring of patients with ARM. These data allow more precise counseling of families with ARM and support the need for genetic studies.

  6. Autosomal dominant polycystic kidney disease caused by somatic and germline mosaicism.

    Science.gov (United States)

    Tan, A Y; Blumenfeld, J; Michaeel, A; Donahue, S; Bobb, W; Parker, T; Levine, D; Rennert, H

    2015-04-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a heterogeneous genetic disorder caused by loss of function mutations of PKD1 or PKD2 genes. Although PKD1 is highly polymorphic and the new mutation rate is relatively high, the role of mosaicism is incompletely defined. Herein, we describe the molecular analysis of ADPKD in a 19-year-old female proband and her father. The proband had a PKD1 truncation mutation c.10745dupC (p.Val3584ArgfsX43), which was absent in paternal peripheral blood lymphocytes (PBL). However, very low quantities of this mutation were detected in the father's sperm DNA, but not in DNA from his buccal cells or urine sediment. Next generation sequencing (NGS) analysis determined the level of this mutation in the father's PBL, buccal cells and sperm to be ∼3%, 4.5% and 10%, respectively, consistent with somatic and germline mosaicism. The PKD1 mutation in ∼10% of her father's sperm indicates that it probably occurred early in embryogenesis. In ADPKD cases where a de novo mutation is suspected because of negative PKD gene testing of PBL, additional evaluation with more sensitive methods (e.g. NGS) of the proband PBL and paternal sperm can enhance detection of mosaicism and facilitate genetic counseling. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Autosomal dominant tubulointerstitial kidney disease caused by uromodulin mutations: seek and you will find.

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    Raffler, Gabriele; Zitt, Emanuel; Sprenger-Mähr, Hannelore; Nagel, Mato; Lhotta, Karl

    2016-04-01

    Uromodulin (UMOD)-associated kidney disease belongs to the group of autosomal dominant interstitial kidney diseases and is caused by mutations in the UMOD gene. Affected patients present with hyperuricemia, gout, and progressive renal failure. The disease is thought to be very rare but is probably underdiagnosed. Two index patients from two families with tubulointerstitial nephropathy and hyperuricemia were examined, including blood and urine chemistry, ultrasound, and mutation analysis of the UMOD gene. In addition, other available family members were studied. In a 46-year-old female patient with a fractional excretion of uric acid of 3 %, analysis of the UMOD gene revealed a p.W202S missense mutation. The same mutation was found in her 72-year-old father, who suffers from gout and end-stage renal disease. The second index patient was a 47-year-old female with chronic kidney disease and gout for more than 10 years. Her fractional uric acid excretion was 3.5 %. Genetic analysis identified a novel p.H250Q UMOD mutation that was also present in her 12-year-old son, who had normal renal function and uric acid levels. In patients suffering from chronic tubulointerstitial nephropathy, hyperuricemia, and a low fractional excretion of uric acid mutation, analysis of the UMOD gene should be performed to diagnose UMOD-associated kidney disease.

  8. Isolated autosomal dominant growth hormone deficiency: an evolving pituitary deficit? A multicenter follow-up study.

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    Mullis, Primus E; Robinson, Iain C A F; Salemi, Souzan; Eblé, Andrée; Besson, Amélie; Vuissoz, Jean-Marc; Deladoey, Johnny; Simon, Dominique; Czernichow, Paul; Binder, Gerhard

    2005-04-01

    Four distinct familial types of isolated GH deficiency have been described so far, of which type II is the autosomal dominant inherited form. It is mainly caused by mutations within the first 6 bp of intervening sequence 3. However, other splice site and missense mutations have been reported. Based on in vitro experiments and transgenic animal data, there is strong evidence that there is a wide variability in phenotype in terms of the severity of GH deficiency. Therefore, we studied a total of 57 subjects belonging to 19 families suffering from different splice site as well as missense mutations within the GH-1 gene. The subjects presenting with a splice site mutation within the first 2 bp of intervening sequence 3 (5'IVS +1/+2 bp) leading to a skipping of exon 3 were found to be more likely to present in the follow-up with other pituitary hormone deficiencies. In addition, although the patients with missense mutations have previously been reported to be less affected, a number of patients presenting with the P89L missense GH form, showed some pituitary hormone impairment. The development of multiple hormonal deficiencies is not age dependent, and there is a clear variability in onset, severity, and progression, even within the same families. The message of clinical importance from these studies is that the pituitary endocrine status of all such patients should continue to be monitored closely over the years because further hormonal deficiencies may evolve with time.

  9. A recurrent deletion mutation in OPA1 causes autosomal dominant optic atrophy in a Chinese family

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    Zhang, Liping; Shi, Wei; Song, Liming; Zhang, Xiao; Cheng, Lulu; Wang, Yanfang; Ge, Xianglian; Li, Wei; Zhang, Wei; Min, Qingjie; Jin, Zi-Bing; Qu, Jia; Gu, Feng

    2014-11-01

    Autosomal dominant optic atrophy (ADOA) is the most frequent form of hereditary optic neuropathy and occurs due to the degeneration of the retinal ganglion cells. To identify the genetic defect in a family with putative ADOA, we performed capture next generation sequencing (CNGS) to screen known retinal disease genes. However, six exons failed to be sequenced by CNGS in optic atrophy 1 gene (OPA1). Sequencing of those exons identified a 4 bp deletion mutation (c.2983-1_2985del) in OPA1. Furthermore, we sequenced the transcripts of OPA1 from the patient skin fibroblasts and found there is six-nucleotide deletion (c.2984-c.2989, AGAAAG). Quantitative-PCR and Western blotting showed that OPA1 mRNA and its protein expression have no obvious difference between patient skin fibroblast and control. The analysis of protein structure by molecular modeling suggests that the mutation may change the structure of OPA1 by formation of an alpha helix protruding into an existing pocket. Taken together, we identified an OPA1 mutation in a family with ADOA by filling the missing CNGS data. We also showed that this mutation affects the structural intactness of OPA1. It provides molecular insights for clinical genetic diagnosis and treatment of optic atrophy.

  10. Autosomal dominant hypoparathyroidism caused by germline mutation in GNA11: phenotypic and molecular characterization.

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    Li, Dong; Opas, Evan E; Tuluc, Florin; Metzger, Daniel L; Hou, Cuiping; Hakonarson, Hakon; Levine, Michael A

    2014-09-01

    Most cases of autosomal dominant hypoparathyroidism (ADH) are caused by gain-of-function mutations in CASR or dominant inhibitor mutations in GCM2 or PTH. Our objectives were to identify the genetic basis for ADH in a multigenerational family and define the underlying disease mechanism. Here we evaluated a multigenerational family with ADH in which affected subjects had normal sequences in these genes and were shorter than unaffected family members. We collected clinical and biochemical data from 6 of 11 affected subjects and performed whole-exome sequence analysis on DNA from two affected sisters and their affected father. Functional studies were performed after expression of wild-type and mutant Gα11 proteins in human embryonic kidney-293-CaR cells that stably express calcium-sensing receptors. Whole-exome-sequencing followed by Sanger sequencing revealed a heterozygous mutation, c.179G>T; p.R60L, in GNA11, which encodes the α-subunit of G11, the principal heterotrimeric G protein that couples calcium-sensing receptors to signal activation in parathyroid cells. Functional studies of Gα11 R60L showed increased accumulation of intracellular concentration of free calcium in response to extracellular concentration of free calcium with a significantly decreased EC50 compared with wild-type Gα11. By contrast, R60L was significantly less effective than the oncogenic Q209L form of Gα11 as an activator of the MAPK pathway. Compared to subjects with CASR mutations, patients with GNA11 mutations lacked hypercalciuria and had normal serum magnesium levels. Our findings indicate that the germline gain-of-function mutation of GNA11 is a cause of ADH and implicate a novel role for GNA11 in skeletal growth.

  11. Autosomal dominant pseudohypoaldosteronism type 1 with a novel splice site mutation in MR gene

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    Kaito Hiroshi

    2009-11-01

    Full Text Available Abstract Background Autosomal dominant pseudohypoaldosteronism type 1 (PHA1 is a rare inherited condition that is characterized by renal resistance to aldosterone as well as salt wasting, hyperkalemia, and metabolic acidosis. Renal PHA1 is caused by mutations of the human mineralcorticoid receptor gene (MR, but it is a matter of debate whether MR mutations cause mineralcorticoid resistance via haploinsufficiency or dominant negative mechanism. It was previously reported that in a case with nonsense mutation the mutant mRNA was absent in lymphocytes because of nonsense mediated mRNA decay (NMD and therefore postulated that haploinsufficiency alone can give rise to the PHA1 phenotype in patients with truncated mutations. Methods and Results We conducted genomic DNA analysis and mRNA analysis for familial PHA1 patients extracted from lymphocytes and urinary sediments and could detect one novel splice site mutation which leads to exon skipping and frame shift result in premature termination at the transcript level. The mRNA analysis showed evidence of wild type and exon-skipped RT-PCR products. Conclusion mRNA analysis have been rarely conducted for PHA1 because kidney tissues are unavailable for this disease. However, we conducted RT-PCR analysis using mRNA extracted from urinary sediments. We could demonstrate that NMD does not fully function in kidney cells and that haploinsufficiency due to NMD with premature termination is not sufficient to give rise to the PHA1 phenotype at least in this mutation of our patient. Additional studies including mRNA analysis will be needed to identify the exact mechanism of the phenotype of PHA.

  12. Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease.

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    Wang, Fen; Gordon, Brian A; Ryman, Davis C; Ma, Shengmei; Xiong, Chengjie; Hassenstab, Jason; Goate, Alison; Fagan, Anne M; Cairns, Nigel J; Marcus, Daniel S; McDade, Eric; Ringman, John M; Graff-Radford, Neill R; Ghetti, Bernardino; Farlow, Martin R; Sperling, Reisa; Salloway, Steve; Schofield, Peter R; Masters, Colin L; Martins, Ralph N; Rossor, Martin N; Jucker, Mathias; Danek, Adrian; Förster, Stefan; Lane, Christopher A S; Morris, John C; Benzinger, Tammie L S; Bateman, Randall J

    2015-09-01

    To investigate the associations of cerebral amyloidosis with concurrent cognitive performance and with longitudinal cognitive decline in asymptomatic and symptomatic stages of autosomal dominant Alzheimer disease (ADAD). Two hundred sixty-three participants enrolled in the Dominantly Inherited Alzheimer Network observational study underwent neuropsychological evaluation as well as PET scans with Pittsburgh compound B. One hundred twenty-one participants completed at least 1 follow-up neuropsychological evaluation. Four composite cognitive measures representing global cognition, episodic memory, language, and working memory were generated using z scores from a battery of 13 standard neuropsychological tests. General linear mixed-effects models were used to investigate the relationship between baseline cerebral amyloidosis and baseline cognitive performance and whether baseline cerebral amyloidosis predicts cognitive change over time (mean follow-up 2.32 years ± 0.92, range 0.89-4.19) after controlling for estimated years from expected symptom onset, APOE ε4 allelic status, and education. In asymptomatic mutation carriers, amyloid burden was not associated with baseline cognitive functioning but was significantly predictive of longitudinal decline in episodic memory. In symptomatic mutation carriers, cerebral amyloidosis was correlated with worse baseline performance in multiple cognitive composites and predicted greater decline over time in global cognition, working memory, and Mini-Mental State Examination. Cerebral amyloidosis predicts longitudinal episodic memory decline in presymptomatic ADAD and multidomain cognitive decline in symptomatic ADAD. These findings imply that amyloidosis in the brain is an indicator of early cognitive decline and provides a useful outcome measure for early assessment and prevention treatment trials. © 2015 American Academy of Neurology.

  13. A novel OPA1 mutation in a Chinese family with autosomal dominant optic atrophy

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    Zhang, Juanjuan; Yuan, Yimin; Lin, Bing; Feng, Hao; Li, Yan [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China); Dai, Xianning; Zhou, Huihui [Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, Zhejiang (China); Dong, Xujie [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China); Liu, Xiao-Ling, E-mail: lxl@mail.eye.ac.cn [School of Ophthalmology and Optometry, Wenzhou Medical College, Wenzhou 325027, Zhejiang (China); Guan, Min-Xin, E-mail: min-xin.guan@cchmc.org [Attardi Institute of Mitochondrial Biomedicine and Zhejiang Provincial Key Laboratory of Medical Genetics, School of Life Sciences, Wenzhou Medical College, Wenzhou 325035, Zhejiang (China); Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang 310012 (China); Division of Human Genetics, Cincinnati Children' s Hospital Medical Center, OH 45229 (United States)

    2012-03-23

    Highlights: Black-Right-Pointing-Pointer We report the characterization of a four-generation large Chinese family with ADOA. Black-Right-Pointing-Pointer We find a new heterozygous mutation c.C1198G in OPA1 gene which may be a novel pathogenic mutation in this pedigree. Black-Right-Pointing-Pointer We do not find any mitochondrial DNA mutations associated with optic atrophy. Black-Right-Pointing-Pointer Other factors may also contribute to the phenotypic variability of ADOA in this pedigree. -- Abstract: A large four-generation Chinese family with autosomal dominant optic atrophy (ADOA) was investigated in the present study. Eight of the family members were affected in this pedigree. The affected family members exhibited early-onset and progressive visual impairment, resulting in mild to profound loss of visual acuity. The average age-at-onset was 15.9 years. A new heterozygous mutation c.C1198G was identified by sequence analysis of the 12th exon of the OPA1 gene. This mutation resulted in a proline to alanine substitution at codon 400, which was located in an evolutionarily conserved region. This missense mutation in the GTPase domain was supposed to result in a loss of function for the encoded protein and act through a dominant negative effect. No other mutations associated with optic atrophy were found in our present study. The c.C1198G heterozygous mutation in the OPA1 gene may be a novel key pathogenic mutation in this pedigree with ADOA. Furthermore, additional nuclear modifier genes, environmental factors, and psychological factors may also contribute to the phenotypic variability of ADOA in this pedigree.

  14. A novel OPA1 mutation in a Chinese family with autosomal dominant optic atrophy

    International Nuclear Information System (INIS)

    Zhang, Juanjuan; Yuan, Yimin; Lin, Bing; Feng, Hao; Li, Yan; Dai, Xianning; Zhou, Huihui; Dong, Xujie; Liu, Xiao-Ling; Guan, Min-Xin

    2012-01-01

    Highlights: ► We report the characterization of a four-generation large Chinese family with ADOA. ► We find a new heterozygous mutation c.C1198G in OPA1 gene which may be a novel pathogenic mutation in this pedigree. ► We do not find any mitochondrial DNA mutations associated with optic atrophy. ► Other factors may also contribute to the phenotypic variability of ADOA in this pedigree. -- Abstract: A large four-generation Chinese family with autosomal dominant optic atrophy (ADOA) was investigated in the present study. Eight of the family members were affected in this pedigree. The affected family members exhibited early-onset and progressive visual impairment, resulting in mild to profound loss of visual acuity. The average age-at-onset was 15.9 years. A new heterozygous mutation c.C1198G was identified by sequence analysis of the 12th exon of the OPA1 gene. This mutation resulted in a proline to alanine substitution at codon 400, which was located in an evolutionarily conserved region. This missense mutation in the GTPase domain was supposed to result in a loss of function for the encoded protein and act through a dominant negative effect. No other mutations associated with optic atrophy were found in our present study. The c.C1198G heterozygous mutation in the OPA1 gene may be a novel key pathogenic mutation in this pedigree with ADOA. Furthermore, additional nuclear modifier genes, environmental factors, and psychological factors may also contribute to the phenotypic variability of ADOA in this pedigree.

  15. Progression of autosomal dominant kidney disease: measurement of the stage transitions of chronic kidney disease

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    Christopher M Blanchette

    2015-04-01

    Full Text Available Background: Autosomal dominant polycystic kidney disease (ADPKD is a progressive genetic disorder characterized by the development of numerous kidney cysts that result in kidney failure. Little is known regarding the key patient characteristics and utilization of healthcare resources for ADPKD patients along the continuum of disease progression. This observational study was designed to describe the characteristics of ADPKD patients and compare them with those of patients with other chronic kidney diseases. Methods: This retrospective cohort study involved patients with a claim for ADPKD or PKD unspecified from 1/1/2000–2/28/2013 and ≥6 months of previous continuous enrollment (baseline within a large database of administrative claims in the USA. A random sample of chronic kidney disease (CKD patients served as comparators. For a subset of ADPKD patients who had only a diagnosis code of unspecified PKD, abstraction of medical records was undertaken to estimate the proportion of patients who had medical chart-confirmed ADPKD. In patients with linked electronic laboratory data, the estimated glomerular filtration rate was calculated via serum creatinine values to determine CKD stage at baseline and during follow-up. Proportions of patients transitioning to another stage and the mean age at transition were calculated. Results: ADPKD patients were, in general, younger and had fewer physician visits, but had more specific comorbidities at observation start compared with CKD patients. ADPKD patients had a longer time in the milder stages and longer duration before recorded transition to a more severe stage compared with CKD patients. Patients with ADPKD at risk of rapid progression had a shorter time-to-end-stage renal disease than patients with CKD and ADPKD patients not at risk, but stage duration was similar between ADPKD patients at risk and those not at risk. Conclusions: These results suggest that distribution of patients by age at transition

  16. Branched-chain amino acids enhance cyst development in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Yamamoto, Junya; Nishio, Saori; Hattanda, Fumihiko; Nakazawa, Daigo; Kimura, Toru; Sata, Michio; Makita, Minoru; Ishikawa, Yasunobu; Atsumi, Tatsuya

    2017-08-01

    Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney and liver cysts. The mammalian target of rapamycin (mTOR) cascade is one of the important pathways regulating cyst growth in ADPKD. Branched-chain amino acids (BCAAs), including leucine, play a crucial role to activate mTOR pathway. Therefore, we administered BCAA dissolved in the drinking water to Pkd1 flox/flox :Mx1-Cre (cystic) mice from four to 22 weeks of age after polyinosinic-polycytidylic acid-induced conditional Pkd1 knockout at two weeks of age. The BCAA group showed significantly greater kidney/body weight ratio and higher cystic index in both the kidney and liver compared to the placebo-treated mice. We found that the L-type amino acid transporter 1 that facilitates BCAA entry into cells is strongly expressed in cells lining the cysts. We also found increased cyst-lining cell proliferation and upregulation of mTOR and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways in the BCAA group. In vitro, we cultured renal epithelial cell lines from Pkd1 null mice with or without leucine. Leucine was found to stimulate cell proliferation, as well as activate mTOR and MAPK/ERK pathways in these cells. Thus, BCAA accelerated disease progression by mTOR and MAPK/ERK pathways. Hence, BCAA may be harmful to patients with ADPKD. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

  17. The role of nicotinic acetylcholine receptors in autosomal dominant nocturnal frontal lobe epilepsy.

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    Andrea eBecchetti

    2015-02-01

    Full Text Available Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE is a focal epilepsy with attacks typically arising in the frontal lobe during non rapid eye movement (NREM sleep. It is characterized by clusters of complex and stereotyped hypermotor seizures, frequently accompanied by sudden arousals. Cognitive and psychiatric symptoms may be also observed. Approximately 12% of the ADNFLE families carry mutations on genes coding for subunits of the heteromeric neuronal nicotinic receptors (nAChRs. This is consistent with the widespread expression of these receptors, particularly the α4β2* subtype, in the neocortex and thalamus. However, understanding how mutant nAChRs lead to partial frontal epilepsy is far from being straightforward because of the complexity of the cholinergic regulation in both developing and mature brains. The relation with the sleep-waking cycle must be also explained. We discuss some possible pathogenetic mechanisms in the light of recent advances about the nAChR role in prefrontal regions as well as the studies carried out in murine models of ADNFLE. Functional evidence points to alterations in prefrontal GABA release, and the synaptic unbalance probably arises during the cortical circuit maturation. Although most of the available functional evidence concerns mutations on nAChR subunit genes, other genes have been recently implicated in the disease, such as KCNT1 (coding for a Na+-dependent K+ channel, DEPD5 (Dishevelled, Egl-10 and Pleckstrin Domain-containing protein 5, and CRH (Corticotropin-Releasing Hormone. Overall, the uncertainties about both the etiology and the pathogenesis of ADNFLE point to the current gaps in our knowledge the regulation of neuronal networks in the cerebral cortex.

  18. Screening for Unruptured Intracranial Aneurysms in Autosomal Dominant Polycystic Kidney Disease: A Survey of 420 Nephrologists.

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    Adrien Flahault

    Full Text Available Despite a high prevalence of intracranial aneurysm (ICA in autosomal dominant polycystic kidney disease (ADPKD, rupture events are rare. The current recommendations for ICA screening are based on expert opinions and studies with low levels of evidence.The aim of our study was to describe the attitudes of practicing nephrologists in Europe towards screening for ICA using magnetic resonance angiography (MRA.We conducted a web-based survey among 1315 European French-speaking nephrologists and nephrology residents. An anonymous, electronic questionnaire including 24 independent questions related to ICA screening modalities, indications and participant profiles was sent by email between September and December 2014. Four hundred and twenty nephrologists (mostly from France participated, including 31 nephrology residents; the response rate was 32%.Systematic screening for ICA was advocated by 28% of the nephrologists. A family history of ICA rupture, sudden death, stroke and migraine were consensual indications for screening (> 90% of the panel. In other clinical situations largely not covered by the recommendations (pregnancy, nephrectomy, kidney transplantation, cardiac or hepatic surgery, uncontrolled hypertension, lack of familial ADPKD history, at-risk activity, tobacco use, the attitudes towards screening were highly divergent. ICA screening was influenced by nephrologists experience with ADPKD and by their practice setting. The majority of participants (57% would not repeat a normal ICA screening. Only a few participants (22% knew that non-contrast MRA was the reference diagnostic tool for ICA screening, whereas most participants thought that contrast enhancement was necessary to screen for ICA. The results from the nephrology residents were analyzed separately and yielded similar results.This practice survey revealed that most nephrologists follow the current recommendations for the initial screening of ICAs. However, more than a quarter of the

  19. Prevalence of autosomal dominant polycystic kidney disease in the European Union.

    Science.gov (United States)

    Willey, Cynthia J; Blais, Jaime D; Hall, Anthony K; Krasa, Holly B; Makin, Andrew J; Czerwiec, Frank S

    2017-08-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of end-stage renal disease, but estimates of its prevalence vary by >10-fold. The objective of this study was to examine the public health impact of ADPKD in the European Union (EU) by estimating minimum prevalence (point prevalence of known cases) and screening prevalence (minimum prevalence plus cases expected after population-based screening). A review of the epidemiology literature from January 1980 to February 2015 identified population-based studies that met criteria for methodological quality. These examined large German and British populations, providing direct estimates of minimum prevalence and screening prevalence. In a second approach, patients from the 2012 European Renal Association‒European Dialysis and Transplant Association (ERA-EDTA) Registry and literature-based inflation factors that adjust for disease severity and screening yield were used to estimate prevalence across 19 EU countries (N = 407 million). Population-based studies yielded minimum prevalences of 2.41 and 3.89/10 000, respectively, and corresponding estimates of screening prevalences of 3.3 and 4.6/10 000. A close correspondence existed between estimates in countries where both direct and registry-derived methods were compared, which supports the validity of the registry-based approach. Using the registry-derived method, the minimum prevalence was 3.29/10 000 (95% confidence interval 3.27-3.30), and if ADPKD screening was implemented in all countries, the expected prevalence was 3.96/10 000 (3.94-3.98). ERA-EDTA-based prevalence estimates and application of a uniform definition of prevalence to population-based studies consistently indicate that the ADPKD point prevalence is <5/10 000, the threshold for rare disease in the EU. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.

  20. Identification of novel mutations in Chinese Hans with autosomal dominant polycystic kidney disease

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    Yu Chaowen

    2011-12-01

    Full Text Available Abstract Background Autosomal dominant polycystic kidney disease (ADPKD is the most common inherited renal disease with an incidence of 1 in 400 to 1000. The disease is genetically heterogeneous, with two genes identified: PKD1 (16p13.3 and PKD2 (4q21. Molecular diagnosis of the disease in at-risk individuals is complicated due to the structural complexity of PKD1 gene and the high diversity of the mutations. This study is the first systematic ADPKD mutation analysis of both PKD1 and PKD2 genes in Chinese patients using denaturing high-performance liquid chromatography (DHPLC. Methods Both PKD1 and PKD2 genes were mutation screened in each proband from 65 families using DHPLC followed by DNA sequencing. Novel variations found in the probands were checked in their family members available and 100 unrelated normal controls. Then the pathogenic potential of the variations of unknown significance was examined by evolutionary comparison, effects of amino acid substitutions on protein structure, and effects of splice site alterations using online mutation prediction resources. Results A total of 92 variations were identified, including 27 reported previously. Definitely pathogenic mutations (ten frameshift, ten nonsense, two splicing defects and one duplication were identified in 28 families, and probably pathogenic mutations were found in an additional six families, giving a total detection level of 52.3% (34/65. About 69% (20/29 of the mutations are first reported with a recurrent mutation rate of 31%. Conclusions Mutation study of PKD1 and PKD2 genes in Chinese Hans with ADPKD may contribute to a better understanding of the genetic diversity between different ethnic groups and enrich the mutation database. Besides, evaluating the pathogenic potential of novel variations should also facilitate the clinical diagnosis and genetic counseling of the disease.

  1. Psychiatric comorbidities in patients from seven families with autosomal dominant cortical tremor, myoclonus, and epilepsy.

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    Coppola, Antonietta; Caccavale, Carmela; Santulli, Lia; Balestrini, Simona; Cagnetti, Claudia; Licchetta, Laura; Esposito, Marcello; Bisulli, Francesca; Tinuper, Paolo; Provinciali, Leandro; Minetti, Carlo; Zara, Federico; Striano, Pasquale; Striano, Salvatore

    2016-03-01

    The objective of this report was to assess the psychiatric comorbidity in a group of patients affected by autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME). Reliable and validated psychodiagnostic scales including the BDI (Beck Depression Inventory), STAI-Y1 and 2 (State-Trait Anxiety Inventory - Y; 1 and 2), MMPI-2 (Minnesota Multiphasic Personality Inventory - 2), and QoLIE-31 (Quality of Life in Epilepsy Inventory - 31) were administered to 20 patients with ADCME, 20 patients with juvenile myoclonic epilepsy (JME), and 20 healthy controls. There was a higher prevalence of mood disorders in patients with ADCME compared to patients with JME and healthy controls, particularly depression (p=0.035 and p=0.017, respectively) and state anxiety (p=0.024 and p=0.019, respectively). Trait anxiety was not different from JME (p=0.102) but higher than healthy controls (p=0.017). The myoclonus score positively correlated with both state (rho: 0.58, p=0.042) and trait anxiety (rho: 0.65, p=0.011). These psychiatric features were also often associated with pathological traits of personality: paranoid (OR: 25.7, p=0.003), psychasthenia (OR: 7.0, p=0.023), schizophrenia (OR: 8.5, p=0.011), and hypomania (OR: 5.5, p=0.022). Finally, in patients with ADCME, decreased quality of life correlated with these psychiatric symptoms. Patients with ADCME show a significant psychiatric burden that impairs their quality of life. A comprehensive psychiatric evaluation should be offered at the time of diagnosis to detect these comorbidities and to treat them. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation.

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    Tenhola, Sirpa; Voutilainen, Raimo; Reyes, Monica; Toiviainen-Salo, Sanna; Jüppner, Harald; Mäkitie, Outi

    2016-09-01

    Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and inappropriately low PTH concentrations. ADH type 1 is caused by activating mutations in the calcium-sensing receptor (CASR), a G-protein-coupled receptor signaling through α11 (Gα11) and αq (Gαq) subunits. Heterozygous activating mutations in GNA11, the gene encoding Gα11, underlie ADH type 2. This study describes disease characteristics in a family with ADH caused by a gain-of-function mutation in GNA11. A three-generation family with seven members (3 adults, 4 children) presenting with ADH. Biochemical parameters of calcium metabolism, clinical, genetic and brain imaging findings were analyzed. Sanger sequencing revealed a heterozygous GNA11 missense mutation (c.1018G>A, p.V340M) in all seven hypocalcemic subjects, but not in the healthy family members (n=4). The adult patients showed clinical symptoms of hypocalcemia, while the children were asymptomatic. Plasma ionized calcium ranged from 0.95 to 1.14mmol/L, yet plasma PTH was inappropriately low for the degree of hypocalcemia. Serum 25OHD was normal. Despite hypocalcemia 1,25(OH)2D and urinary calcium excretion were inappropriately in the reference range. None of the patients had nephrocalcinosis. Two adults and one child (of the two MRI scanned children) had distinct intracranial calcifications. All affected subjects had short stature (height s.d. scores ranging from -3.4 to -2.3 vs -0.5 in the unaffected children). The identified GNA11 mutation results in biochemical abnormalities typical for ADH. Additional features, including short stature and early intracranial calcifications, cosegregated with the mutation. These findings may indicate a wider role for Gα11 signaling besides calcium regulation. © 2016 European Society of Endocrinology.

  3. Phenotypic diversity in autosomal-dominant cone-rod dystrophy elucidated by adaptive optics retinal imaging.

    Science.gov (United States)

    Song, Hongxin; Rossi, Ethan A; Stone, Edwin; Latchney, Lisa; Williams, David; Dubra, Alfredo; Chung, Mina

    2018-01-01

    Several genes causing autosomal-dominant cone-rod dystrophy (AD-CRD) have been identified. However, the mechanisms by which genetic mutations lead to cellular loss in human disease remain poorly understood. Here we combine genotyping with high-resolution adaptive optics retinal imaging to elucidate the retinal phenotype at a cellular level in patients with AD-CRD harbouring a defect in the GUCA1A gene. Nine affected members of a four-generation AD-CRD pedigree and three unaffected first-degree relatives underwent clinical examinations including visual acuity, fundus examination, Goldmann perimetry, spectral domain optical coherence tomography and electroretinography. Genome-wide scan followed by bidirectional sequencing was performed on all affected participants. High-resolution imaging using a custom adaptive optics scanning light ophthalmoscope (AOSLO) was performed for selected participants. Clinical evaluations showed a range of disease severity from normal fundus appearance in teenaged patients to pronounced macular atrophy in older patients. Molecular genetic testing showed a mutation in in GUCA1A segregating with disease. AOSLO imaging revealed that of the two teenage patients with mild disease, one had severe disruption of the photoreceptor mosaic while the other had a normal cone mosaic. AOSLO imaging demonstrated variability in the pattern of cone and rod cell loss between two teenage cousins with early AD-CRD, who had similar clinical features and had the identical disease-causing mutation in GUCA1A . This finding suggests that a mutation in GUCA1A does not lead to the same degree of AD-CRD in all patients. Modifying factors may mitigate or augment disease severity, leading to different retinal cellular phenotypes. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  4. Effec Of Low Protein Diet On Chronic Renal Failure Due To Autosomal Dominant Polycystic Kidney Disease

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    Terukuni Ideura

    2012-06-01

    Full Text Available There are few reports about therapeutic effects of low protein diet on the progression of chronic renal failure due to autosomal dominant polycystic kidney disease (ADPKD, although the disease is common.The annual incidence rate for end-stage renal disease caused by ADPKD is around 6 per million.In this retrospective study in one center, ten chronic renal failure patients due to ADPKD with creatinine clearnce of 17.0±3.3 mL/min /1.73 m2 and serum creatinine (Cr level of 4.4±0.7 mg/dL were studied for 40 months after the introduction of severe low protein diet (SLPD (0.48±0.03 g/kgBW/day without supplementation of essential amino acids or keto-analogues. Dietary protein intake was estimated by urea appearance rate from 24hr urine sample according to Mitch-Maroni's formula. The results clearly showed that ▵1/Cr/month(×10−3 was significantly suppressed from 5.8±0.9 to 2.0±0.6 following the introduction of SLPD (p<0.02. Furthermore, BUN/Cr ratio decreased from 10.4±0.02 to 7.3±0.02 (p<0.01. Mean blood pressure (mmHg remained unchanged; 92±3 vs 89±3 (ns, and urinary protein excretion (g/day did not change; 0.6±0.2 vs 0.6±0.1 (ns. There were no significant differences between body mass index, serum albumin, transferrin and hemoglobin levels as the indices of nutritional state before and after the introduction of SLPD.In conclusion, SLPD was effective in suppressing the progression of further decline in renal function due to ADPKD under nutritionally safety condition in this cohort.

  5. Lysine methyltransferase SMYD2 promotes cyst growth in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Li, Linda Xiaoyan; Fan, Lucy X; Zhou, Julie Xia; Grantham, Jared J; Calvet, James P; Sage, Julien; Li, Xiaogang

    2017-06-30

    Autosomal dominant polycystic kidney disease (ADPKD) is driven by mutations in PKD1 and PKD2 genes. Recent work suggests that epigenetic modulation of gene expression and protein function may play a role in ADPKD pathogenesis. In this study, we identified SMYD2, a SET and MYND domain protein with lysine methyltransferase activity, as a regulator of renal cyst growth. SMYD2 was upregulated in renal epithelial cells and tissues from Pkd1-knockout mice as well as in ADPKD patients. SMYD2 deficiency delayed renal cyst growth in postnatal kidneys from Pkd1 mutant mice. Pkd1 and Smyd2 double-knockout mice lived longer than Pkd1-knockout mice. Targeting SMYD2 with its specific inhibitor, AZ505, delayed cyst growth in both early- and later-stage Pkd1 conditional knockout mouse models. SMYD2 carried out its function via methylation and activation of STAT3 and the p65 subunit of NF-κB, leading to increased cystic renal epithelial cell proliferation and survival. We further identified two positive feedback loops that integrate epigenetic regulation and renal inflammation in cyst development: SMYD2/IL-6/STAT3/SMYD2 and SMYD2/TNF-α/NF-κB/SMYD2. These pathways provide mechanisms by which SMYD2 might be induced by cyst fluid IL-6 and TNF-α in ADPKD kidneys. The SMYD2 transcriptional target gene Ptpn13 also linked SMYD2 to other PKD-associated signaling pathways, including ERK, mTOR, and Akt signaling, via PTPN13-mediated phosphorylation.

  6. Radiologic and clinical bronchiectasis associated with autosomal dominant polycystic kidney disease.

    Directory of Open Access Journals (Sweden)

    Teng Moua

    Full Text Available BACKGROUND: Polycystin 1 and 2, the protein abnormalities associated with autosomal dominant polycystic kidney disease (ADPKD, are also found in airway cilia and smooth muscle cells. There is evidence of increased radiologic bronchiectasis associated with ADPKD, though the clinical and functional implications of this association are unknown. We hypothesized an increased prevalence of both radiologic and clinical bronchiectasis is associated with APDKD as compared to non-ADPKD chronic kidney disease (CKD controls. MATERIALS AND METHODS: A retrospective case-control study was performed at our institution involving consecutive ADPKD and non-ADPKD chronic kidney disease (CKD patients seen over a 13 year period with both chest CT and PFT. CTs were independently reviewed by two blinded thoracic radiologists. Manually collected clinical data included symptoms, smoker status, transplant history, and PFT findings. RESULTS: Ninety-two ADPKD and 95 non-ADPKD CKD control patients were compared. Increased prevalence of radiologic bronchiectasis, predominantly mild lower lobe disease, was found in ADPKD patients compared to CKD control (19 vs. 9%, P = 0.032, OR 2.49 (CI 1.1-5.8. After adjustment for covariates, ADPKD was associated with increased risk of radiologic bronchiectasis (OR 2.78 (CI 1.16-7.12. Symptomatic bronchiectasis occurred in approximately a third of ADPKD patients with radiologic disease. Smoking was associated with increased radiologic bronchiectasis in ADPKD patients (OR 3.59, CI 1.23-12.1. CONCLUSIONS: Radiological bronchiectasis is increased in patients with ADPKD particularly those with smoking history as compared to non-ADPKD CKD controls. A third of such patients have symptomatic disease. Bronchiectasis should be considered in the differential in ADPKD patients with respiratory symptoms and smoking history.

  7. Attitudes in Patients with Autosomal Dominant Polycystic Kidney Disease Toward Prenatal Diagnosis and Preimplantation Genetic Diagnosis.

    Science.gov (United States)

    Swift, Oscar; Vilar, Enric; Rahman, Belinda; Side, Lucy; Gale, Daniel P

    2016-12-01

    No recommendations currently exist regarding implementation of both prenatal diagnosis and preimplantation genetic diagnosis (PGD) for autosomal dominant polycystic kidney disease (ADPKD). This study evaluated attitudes in ADPKD patients with either chronic kidney disease (CKD) stages I-IV or end-stage renal failure (ESRF) toward prenatal diagnosis and PGD. Ninety-six ADPKD patients were recruited from an outpatient clinic, wards, and dialysis units. Thirty-eight patients had ESRF and 58 had CKD stages I-IV. Participants were given an information sheet on prenatal diagnosis and PGD and subsequently completed a questionnaire. The median age of participants was 51.5 years. Seventeen percent of ADPKD patients with CKD and 18% of ADPKD patients with ESRF would consider prenatal diagnosis and termination of pregnancy for ADPKD. Fifty percent with CKD would have opted for PGD (or might consider it in the future) were it available and funded by the UK National Health Service, compared to 63% in the ESRF group (p = 0.33). Sixty-nine percent in the CKD group and 68% in the ESRF group believed that PGD should be offered to other patients. There was a spectrum of attitudes among this cohort. A proportion of patients believe that PGD should be made available to prospective parents with this disease. The discrepancy between the low proportion (17% CKD, 18% ESRF) who would consider prenatal diagnosis and termination of pregnancy and the higher number who hypothetically express an intention or wish to access PGD (50% CKD and 63% ESRF) indicates far greater acceptability for diagnostic methods that occur before embryo implantation. It is not known how the development of methods to identify patients whose renal function is likely to decline rapidly and treatments altering the natural history of ADPKD will affect these attitudes.

  8. Nephrotic Syndrome and Idiopathic Membranous Nephropathy Associated with Autosomal-Dominant Polycystic Kidney Disease

    Science.gov (United States)

    Peces, Ramón; Martínez-Ara, Jorge; Peces, Carlos; Picazo, Mariluz; Cuesta-López, Emilio; Vega, Cristina; Azorín, Sebastián; Selgas, Rafael

    2011-01-01

    We report the case of a 38-year-old male with autosomal-dominant polycystic kidney disease (ADPKD) and concomitant nephrotic syndrome secondary to membranous nephropathy (MN). A 3-month course of prednisone 60 mg daily and losartan 100 mg daily resulted in resistance. Treatment with chlorambucil 0.2 mg/kg daily, low-dose prednisone, plus an angiotensin-converting enzyme inhibitor (ACEI) and an angiotensin II receptor blocker (ARB) for 6 weeks resulted in partial remission of his nephrotic syndrome for a duration of 10 months. After relapse of the nephrotic syndrome, a 13-month course of mycophenolate mofetil (MFM) 2 g daily and low-dose prednisone produced complete remission for 44 months. After a new relapse, a second 24-month course of MFM and low-dose prednisone produced partial to complete remission of proteinuria with preservation of renal function. Thirty-six months after MFM withdrawal, complete remission of nephrotic-range proteinuria was maintained and renal function was preserved. This case supports the idea that renal biopsy is needed for ADPKD patients with nephrotic-range proteinuria in order to exclude coexisting glomerular disease and for appropriate treatment/prevention of renal function deterioration. To the best of our knowledge, this is the first reported case of nephrotic syndrome due to MN in a patient with ADPKD treated with MFM, with remission of proteinuria and preservation of renal function after more than 10 years. Findings in this patient also suggest that MFM might reduce cystic cell proliferation and fibrosis, preventing progressive renal scarring with preservation of renal function. PMID:21552769

  9. Nephrotic Syndrome and Idiopathic Membranous Nephropathy Associated with Autosomal-Dominant Polycystic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Ramón Peces

    2011-01-01

    Full Text Available We report the case of a 38-year-old male with autosomal-dominant polycystic kidney disease (ADPKD and concomitant nephrotic syndrome secondary to membranous nephropathy (MN. A 3-month course of prednisone 60 mg daily and losartan 100 mg daily resulted in resistance. Treatment with chlorambucil 0.2 mg/kg daily, low-dose prednisone, plus an angiotensin-converting enzyme inhibitor (ACEI and an angiotensin II receptor blocker (ARB for 6 weeks resulted in partial remission of his nephrotic syndrome for a duration of 10 months. After relapse of the nephrotic syndrome, a 13-month course of mycophenolate mofetil (MFM 2 g daily and low-dose prednisone produced complete remission for 44 months. After a new relapse, a second 24-month course of MFM and low-dose prednisone produced partial to complete remission of proteinuria with preservation of renal function. Thirty-six months after MFM withdrawal, complete remission of nephrotic-range proteinuria was maintained and renal function was preserved. This case supports the idea that renal biopsy is needed for ADPKD patients with nephrotic-range proteinuria in order to exclude coexisting glomerular disease and for appropriate treatment/prevention of renal function deterioration. To the best of our knowledge, this is the first reported case of nephrotic syndrome due to MN in a patient with ADPKD treated with MFM, with remission of proteinuria and preservation of renal function after more than 10 years. Findings in this patient also suggest that MFM might reduce cystic cell proliferation and fibrosis, preventing progressive renal scarring with preservation of renal function.

  10. Affected parent sex and severity of autosomal dominant polycystic kidney disease: a retrospective cohort study
.

    Science.gov (United States)

    Nowak, Kristen L; Chonchol, Michel; You, Zhiying; Gupta, Malika; Gitomer, Berenice

    2018-03-01

    Parental inheritance may differentially affect autosomal dominant polycystic kidney disease (-ADPKD) severity via genetic imprinting or in utero epigenetic modifications; however, evidence is inconsistent. We conducted a longitudinal retrospective cohort study to assess the association between sex of the affected parent and time to hypertension diagnosis, end-stage renal disease (ESRD), and death in patients with the PKD1 genotype. 814 individuals who participated in research at the University of Colorado were studied. Kaplan-Meier survival analysis was performed. The predictor was parental sex, and outcomes were diagnosis of hypertension, progression to ESRD, and death. We also examined associations in four strata according to affected parent and participant sex, as previous studies have reported earlier onset of ESRD in males compared to females. The median follow-up for each outcome was as follows: hypertension, 30 (interquartile range (IQR): 18, 37); ESRD, 43 (IQR: 31, 52), death 39 (IQR: 25, 52) years of age. Among affected offspring in the entire cohort, there was no difference in hypertension diagnosis (p = 0.97) or progression to ESRD (p = 0.79) according to affected parent sex; however, participants with an affected mother were more likely to die than participants with an affected father (p father (p < 0.01) but not when the affected parent was the mother (p ≥ 0.11). Our results are largely in contrast to the hypothesis that severity of ADPKD is worse with maternal inheritance of disease.
.

  11. Iron Supplementation Associated With Loss of Phenotype in Autosomal Dominant Hypophosphatemic Rickets.

    Science.gov (United States)

    Kapelari, Klaus; Köhle, Julia; Kotzot, Dieter; Högler, Wolfgang

    2015-09-01

    Autosomal dominant hypophosphatemic rickets (ADHR) is the only hereditary disorder of renal phosphate wasting in which patients may regain the ability to conserve phosphate. Low iron status plays a role in the pathophysiology of ADHR. This study reports of a girl with ADHR, iron deficiency, and a paternal history of hypophosphatemic rickets that resolved without treatment. The girl's biochemical phenotype resolved with iron supplementation. A 26-month-old girl presented with typical features of hypophosphatemic rickets, short stature (79 cm; -2.82 SDS), and iron deficiency. Treatment with elemental phosphorus and calcitriol improved her biochemical profile and resolved the rickets. The girl's father had presented with rickets at age 11 months but never received medication. His final height was reduced (154.3 cm; -3.51 SDS), he had undergone corrective leg surgery and had an adult normal phosphate, fibroblast growth factor 23, and iron status. Father and daughter were found to have a heterozygous mutation in exon 3 of the FGF23 gene (c.536G>A, p.Arg179Gln), confirming ADHR. Withdrawal of rickets medication was attempted off and on iron supplementation. Withdrawal of rickets medication in the girl was unsuccessful in the presence of low-normal serum iron levels at age 5.6 years but was later successful in the presence of high-normal serum iron levels following high-dose iron supplementation. We report an association between iron supplementation and a complete loss of biochemical ADHR phenotype, allowing withdrawal of rickets medication. Experience from this case suggests that reduction and withdrawal of rickets medication should be attempted only after iron status has been optimized.

  12. Autosomal dominant polycystic kidney disease in a family with mosaicism and hypomorphic allele.

    Science.gov (United States)

    Reiterová, Jana; Štekrová, Jitka; Merta, Miroslav; Kotlas, Jaroslav; Elišáková, Veronika; Lněnička, Petr; Korabečná, Marie; Kohoutová, Milada; Tesař, Vladimír

    2013-03-15

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited kidney disease that results in renal failure. ADPKD is a systemic disorder with cysts and connective tissue abnormalities involving many organs. ADPKD caused by mutations in PKD1 gene is significantly more severe than the cases caused by PKD2 gene mutations. The large intra-familial variability of ADPKD highlights a role for genetic background. Here we report a case of ADPKD family initially appearing unlinked to the PKD1 or PKD2 loci and the influence of mosaicism and hypomorphic allele on the variability of the clinical course of the disease. A grandmother with the PKD1 gene mutation in mosaicism (p.Val1105ArgfsX4) and with mild clinical course of ADPKD (end stage renal failure at the age of 77) seemed to have ADPKD because of PKD2 gene mutation. On the other hand, her grandson had a severe clinical course (end stage renal disease at the age of 45) in spite of the early treatment of mild hypertension. There was found by mutational analysis of PKD genes that the severe clinical course was caused by PKD1 gene frameshifting mutation inherited from his father and mildly affected grandmother in combination with inherited hypomorphic PKD1 allele with described missense mutation (p.Thr2250Met) from his clinically healthy mother. The sister with two cysts and with PKD1 hypomorphic allele became the kidney donor to her severely affected brother. We present the first case of ADPKD with the influence of mosaicism and hypomorphic allele of the PKD1 gene on clinical course of ADPKD in one family. Moreover, this report illustrates the role of molecular genetic testing in assessing young related kidney donors for patients with ADPKD.

  13. Relationship between intracranial aneurysms and the severity of autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Yoshida, Hiroki; Higashihara, Eiji; Maruyama, Keisuke; Nutahara, Kikuo; Nitatori, Toshiaki; Miyazaki, Isao; Shiokawa, Yoshiaki

    2017-12-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disease characterized by the progressive enlargement of innumerable renal cysts. Although the association of intracranial aneurysms (ICANs) with ADPKD is well known, the relationship between the ICAN and the disease severity including total kidney volume (TKV) and estimated glomerular filtration rate (eGFR) is poorly understood. We screened 265 patients with ADPKD (mean age, 48.8 years; range, 14.9-88.3 years) with MR angiography. The patients with a past history related to ICANs were excluded from the study. The incidence and characteristics of ICAN in patients with ADPKD were evaluated. TKV was measured by volumetric analyses of MR imaging. We detected 65 ICANs in 49 patients (37 women and 12 men, mean age, 52.7 years; range, 20.4-86 years). The incidence of ICANs was 18.5% and female patients had was higher incidence (23.1%) than male patients (11.4%) (p = 0.02). An age of those with ICANs was significantly higher than those without (p = 0.006), and the cumulative risk of diagnosis of ICANs increased with age. TKV was significantly larger in those with ICANs than those without (p = 0.001), but eGFR was not different between two groups (p = 0.07). By multivariate analyses, only TKV was significantly related to the development of ICANs (p = 0.02). The incidence of ICANs increased with age, was higher in females, and correlated with kidney enlargement in patients with ADPKD. Necessity of screening ICANs would be particularly high in elderly women with large kidneys.

  14. Autosomal dominant polycystic kidney disease: Study of clinical characteristics in an Indian population

    Directory of Open Access Journals (Sweden)

    Sanjay Vikrant

    2017-01-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is the most common hereditary form of kidney disease. Clinical data on this multisystem disorder are scarce from developing countries. We conducted a prospective observational study of the clinical profile of ADPKD patients at a single center over a period of six years. A total of 208 patients were studied. Majority were male (60.6% and the mean age was 45.8 ± 14.5 years. About 61.5% had early stage (Stages 1-3 of chronic kidney disease (CKD and 38.5% had advanced CKD (Stages 4 and 5. Clinical features observed included pain abdomen (46.2%, nocturia (65.9%, hematuria (21.6%, nephrolithiasis (38.9%, urinary tract infection (UTI (38.9%, hypertension (69.5%, and raised serum creatinine (54.3%. The prevalence of nocturia, hypertension, and renal dysfunction showed a significant increase with age (P = 0.001. Extrarenal manifestations were polycystic liver disease in 77 patients (37%, cysts in pancreas in two (1%, and stroke in three (1.5% (hemorrhage in 2 and infarct in 1. There was significantly higher prevalence of hypertension (P = 0.027 and nephrolithiasis (P = 0.044 in males compared to females. Ninety-two patients (44.2% had a positive family history for ADPKD. Fifteen (7.2% had kidney failure at the diagnosis of ADPKD, were hospitalized, and underwent emergency dialysis. A total of 20 patients (9.6% developed end-stage kidney disease during the study period. The age at diagnosis was higher, and there was a high prevalence of hypertension, nocturia, abdominal pain, nephrolithiasis, UTI, and renal dysfunction in Indian ADPKD patients.

  15. Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients

    OpenAIRE

    Trender-Gerhard , Iris; Sweeney , Mary G; Schwingenschuh , Petra; Mir , Pablo; Edwards , Mark J; Gerhard , Alexander; Polke , James M; Hanna , Mike G; Davis , Mary B; Wood , Nick W; Bhatia , Kailash P

    2009-01-01

    Abstract An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1) is the most common cause of dopa-responsive dystonia (DRD). A classic phenotype of young-onset lower limb dystonia, diurnal fluctuations, and excellent response to levodopa has been well recognized in association with GCH1 mutations, and rare atypical presentations have been reported. However, a number of clinical issues remain unresolved including phenot...

  16. Autosomal dominant hereditary spastic paraplegia with axonal sensory motor polyneuropathy maps to chromosome 21q 22.3.

    Science.gov (United States)

    Peddareddygari, Leema Reddy; Hanna, Philip A; Igo, Robert P; Luo, Yuqun A; Won, Sungho; Hirano, Michio; Grewal, Raji P

    2016-01-01

    Hereditary spastic paraplegia (HSP) are a genetically and clinically heterogeneous group of disorders. At present, 19 autosomal dominant loci for HSP have been mapped. We ascertained an American family of European descent segregating an autosomal dominant HSP associated with peripheral neuropathy. A genome wide scan was performed with 410 microsatellite repeat marker (Weber lab screening set 16) and following linkage and haplotype analysis, fine mapping was performed. Established genes or loci for HSP were excluded by direct sequencing or haplotype analysis. All established loci for HSP were excluded. Fine mapping suggested a locus on chromosome 21q22.3 flanked by markers D21S1411 and D21S1446 with a maximum logarithm of odds score of 2.05 and was supported by haplotype analysis. A number of candidate genes in this region were analyzed and no disease-producing mutations were detected. We present the clinical and genetic analysis of an American family with autosomal dominant HSP with axonal sensory motor polyneuropathy mapping to a novel locus on chromosome 21q22.3 designated SPG56.

  17. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy resulting in stroke in an 11-year-old male

    DEFF Research Database (Denmark)

    Granild-Jensen, Jakob Bie; Jensen, Uffe Birk; Schwartz, Marianne

    2009-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the Notch3 gene on chromosome 19. The condition manifests itself clinically typically in the third to fifth decade with migraine and recurrent episodes of stroke or trans......Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is caused by mutations in the Notch3 gene on chromosome 19. The condition manifests itself clinically typically in the third to fifth decade with migraine and recurrent episodes of stroke...... or transient ischaemic attacks. We report the case of an 11-year-old male with CADASIL resulting in stroke with right hemiparesis and dysphasia. Acute magnetic resonance imaging suggested infarction in the left hemisphere; magnetic resonance angiography revealed calibre variation of the intracerebral arteries...... of CADASIL, with an autosomal dominant pattern. The diagnosis of CADASIL was confirmed by the finding of the known mutation of the Notch3 gene running in the family. With treatment in a neurorehabilitation centre the patient recovered most of his functions with only discrete fine-motor and cognitive sequelae...

  18. A novel IMPDH1 mutation (Arg231Pro) in a family with a severe form of autosomal dominant retinitis pigmentosa.

    Science.gov (United States)

    Grover, Sandeep; Fishman, Gerald A; Stone, Edwin M

    2004-10-01

    To define ophthalmic findings in a family with autosomal dominant retinitis pigmentosa and a novel IMPDH1 gene mutation. Genetic and observational family study. Sixteen affected members of a family with autosomal dominant retinitis pigmentosa. Ophthalmic examination, including best-corrected visual acuity (VA), slit-lamp biomicroscopy, direct and indirect ophthalmoscopy, Goldmann kinetic perimetry, and electroretinography were performed. Deoxyribonucleic acid single-strand conformation polymorphism (SSCP) analysis was done. Abnormal polymerase chain reaction products identified by SSCP analysis were sequenced bidirectionally. All affected patients had the onset of night blindness within the first decade of life. Ocular findings were characterized by diffuse retinal pigmentary degenerative changes, marked restriction of peripheral visual fields, severe loss of VA, nondetectable electroretinography amplitudes, and a high frequency of posterior subcapsular lens opacities. Affected members were observed to harbor a novel IMPDH1 gene mutation. A novel IMPDH1 gene mutation (Arg231Pro) was associated with a severe form of autosomal dominant retinitis pigmentosa. Families affected with a severe form of this genetic subtype should be investigated for a mutation in the IMPDH1 gene.

  19. Magnetic resonance imaging of posterior pituitary for evaluation of the neurohypophyseal function in idiopathic and autosomal dominant neurohypophyseal diabetes insipidus

    International Nuclear Information System (INIS)

    Ozata, M.; Tayfun, C.; Kurtaran, K.; Yetkin, I.; Beyhan, Z.; Corakci, A.; Caglayan, S.; Alemdaroglu, A.; Guendogan, M.A.

    1997-01-01

    We investigated the role of MR imaging for evaluation of the functional status of the neurohypophyseal system in both idiopathic central diabetes insipidus (DI) and familial autosomal dominant neurohypophyseal DI. The patients and family with DI were analyzed retrospectively for the presence or absence of posterior pituitary gland hyperintense signal on MR images. A total of 19 adult patients with idiopathic central DI, 7 members of a family with autosomal dominant DI and 20 control subjects were included in the study. Diagnosis of idiopathic DI was based on the presence of central DI in the absence of any alteration that is known to be responsible for DI. The patients were studied retrospectively and the morphology and intensity of the posterior lobe by MR imaging was assessed by blinded reading. In all patients with idiopathic central DI and the affected members of the family, the posterior bright signal was absent while the stalk was normal on MR images. In contrast, normal posterior pituitary bright signal and stalk were found in unaffected members of the family and all control subjects. We conclude that MR imaging of the posterior pituitary lobe can be used to evaluate the functional status of the neurohypophyseal system in idiopathic central DI and familial autosomal dominant DI. (orig.). With 3 figs., 1 tab

  20. Iron Modifies Plasma FGF23 Differently in Autosomal Dominant Hypophosphatemic Rickets and Healthy Humans

    Science.gov (United States)

    Peacock, Munro; Gray, Amie K.; Padgett, Leah R.; Hui, Siu L.; Econs, Michael J.

    2011-01-01

    Context: In autosomal dominant hypophosphatemic rickets (ADHR), fibroblast growth factor 23 (FGF23) resists cleavage, causing increased plasma FGF23 levels. The clinical phenotype includes variable onset during childhood or adulthood and waxing/waning of hypophosphatemia. Delayed onset after puberty in females suggests iron status may be important. Objective: Studies were performed to test the hypothesis that plasma C-terminal and intact FGF23 concentrations are related to serum iron concentrations in ADHR. Design and Setting: Cross-sectional and longitudinal studies of ADHR and a cross-sectional study in healthy subjects were conducted at an academic medical center. Participants: Participants included 37 subjects with ADHR mutations from four kindreds and 158 healthy adult controls. Main Outcome Measure: The relationships of serum iron concentrations with plasma C-terminal and intact FGF23 concentrations were evaluated. Results: Serum phosphate and 1,25-dihydroxyvitamin D correlated negatively with C-terminal FGF23 and intact FGF23 in ADHR but not in controls. Serum iron was negatively correlated to both C-terminal FGF23 (r = −0.386; P < 0.05) and intact FGF23 (r = −0.602; P < 0.0001) in ADHR. However, control subjects also demonstrated a negative relationship of serum iron with C-terminal FGF23 (r = −0.276; P < 0.001) but no relationship with intact FGF23. Longitudinally in ADHR subjects, C-terminal FGF23 and intact FGF23 concentrations changed negatively with iron concentrations (P < 0.001 and P = 0.055, respectively), serum phosphate changed negatively with C-terminal FGF23 and intact FGF23 (P < 0.001), and there was a positive relationship between serum iron and phosphate (P < 0.001). Conclusions: Low serum iron is associated with elevated FGF23 in ADHR. However, in controls, low serum iron was also associated with elevated C-terminal FGF23, but not intact FGF23, suggesting cleavage maintains homeostasis despite increased FGF23 expression. PMID:21880793

  1. Berberine slows cell growth in autosomal dominant polycystic kidney disease cells

    International Nuclear Information System (INIS)

    Bonon, Anna; Mangolini, Alessandra; Pinton, Paolo; Senno, Laura del; Aguiari, Gianluca

    2013-01-01

    Highlights: •Berberine at appropriate doses slows cell proliferation in ADPKD cystic cells. •Reduction of cell growth by berberine occurs by inhibition of ERK and p70-S6 kinase. •Higher doses of berberine cause an overall cytotoxic effect. •Berberine overdose induces apoptotic bodies formation and DNA fragmentation. •Antiproliferative properties of this drug make it a new candidate for ADPKD therapy. -- Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary monogenic disorder characterized by development and enlargement of kidney cysts that lead to loss of renal function. It is caused by mutations in two genes (PKD1 and PKD2) encoding for polycystin-1 and polycystin-2 proteins which regulate different signals including cAMP, mTOR and EGFR pathways. Abnormal activation of these signals following PC1 or PC2 loss of function causes an increased cell proliferation which is a typical hallmark of this disease. Despite the promising findings obtained in animal models with targeted inhibitors able to reduce cystic cell growth, currently, no specific approved therapy for ADPKD is available. Therefore, the research of new more effective molecules could be crucial for the treatment of this severe pathology. In this regard, we have studied the effect of berberine, an isoquinoline quaternary alkaloid, on cell proliferation and apoptosis in human and mouse ADPKD cystic cell lines. Berberine treatment slows cell proliferation of ADPKD cystic cells in a dose-dependent manner and at high doses (100 μg/mL) it induces cell death in cystic cells as well as in normal kidney tubule cells. However, at 10 μg/mL, berberine reduces cell growth in ADPKD cystic cells only enhancing G 0 /G 1 phase of cell cycle and inhibiting ERK and p70-S6 kinases. Our results indicate that berberine shows a selected antiproliferative activity in cellular models for ADPKD, suggesting that this molecule and similar natural compounds could open new opportunities

  2. FDG-PET/CT in autosomal dominant polycystic kidney disease patients with suspected cyst infection.

    Science.gov (United States)

    Pijl, Jordy Pieter; Glaudemans, Andor W J M; Slart, Riemer H J A; Kwee, Thomas Christian

    2018-04-13

    Purpose: To determine the value of 18 F-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT) for diagnosing renal or hepatic cyst infection in patients with autosomal dominant polycystic kidney disease (ADPKD). Methods: This retrospective single-center study included all patients with ADPKD who underwent FDG-PET/CT because of suspected cyst infection between 2010 and 2017. Results: Thirty FDG-PET/CT scans of thirty individual patients were included, of which 19 were positive for cyst infection. According to a previously established clinical and biochemical reference standard, FDG-PET/CT achieved sensitivity of 88.9%, specificity of 75.0%, positive predictive value of 84.2%, and negative predictive value of 81.8% for the diagnosis of cyst infection. In 5 cases, FDG-PET/CT suggested a different pathologic process that explained the symptoms, including pneumonia ( n = 1), generalized peritonitis ( n = 1), pancreatitis ( n = 1), colitis ( n = 1), and cholangitis ( n = 1). Total duration of hospital stay and duration between FDG-PET/CT scan and hospital discharge of patients with an FDG-PET/CT scan positive for cyst infection were significantly longer than those with a negative scan ( P = 0.005 and P = 0.009, respectively). Creatinine levels were significantly higher in patients with an FDG-PET/CT scan positive for cyst infection than in patients with a negative scan ( P = 0.015). Other comparisons of clinical parameters (age, gender, presence of fever (>38.5°C) for more than 3 days, abdominal pain, history of solid organ transplantation and nephrectomy, immune status), laboratory values (C-reactive protein level (CRP), leukocyte count, estimated glomerular filtration rate), and microbiologic results (blood and urine cultures) were not significantly different ( P = 0.13-1.00) between FDG-PET/CT-positive and -negative patients. Conclusion: FDG-PET/CT is a useful and recommendable (upfront) imaging modality for the evaluation of

  3. Two novel mutations of CLCN7 gene in Chinese families with autosomal dominant osteopetrosis (type II).

    Science.gov (United States)

    Zheng, Hui; Shao, Chong; Zheng, Yan; He, Jin-Wei; Fu, Wen-Zhen; Wang, Chun; Zhang, Zhen-Lin

    2016-07-01

    Autosomal dominant osteopetrosis type II (ADO-II) is a heritable bone disorder characterized by osteosclerosis, predominantly involving the spine (vertebral end-plate thickening, or rugger-jersey spine), the pelvis ("bone-within-bone" structures) and the skull base. Chloride channel 7 (CLCN7) has been reported to be the causative gene. In this study, we aimed to identify the pathogenic mutation in four Chinese families with ADO-II. All 25 exons of the CLCN7 gene, including the exon-intron boundaries, were amplified and sequenced directly in four probands from the Chinese families with ADO-II. The mutation site was then identified in other family members and 250 healthy controls. In family 1, a known missense mutation c.296A>G in exon 4 of CLCN7 was identified in the proband, resulting in a tyrosine (UAU) to cysteine (UGU) substitution at p.99 (Y99C); the mutation was also identified in his affected father. In family 2, a novel missense mutation c.865G>C in exon 10 was identified in the proband, resulting in a valine (GUC) to leucine (CUC) substitution at p.289 (V289L); the mutation was also identified in her healthy mother and sister. In family 3, a novel missense mutation c.1625C>T in exon 17 of CLCN7 was identified in the proband, resulting in an alanine (GCG) to valine (GUG) substitution at p.542 (A542V); the mutation was also identified in her father. In family 4, a hot spot, R767W (c.2299C>T, CGG>TGG), in exon 24 was found in the proband which once again proved the susceptibility of the site or the similar genetic background in different races. Moreover, two novel mutations, V289L and A542V, occurred at a highly conserved position, found by a comparison of the protein sequences from eight vertebrates, and were predicted to have a pathogenic effect by PolyPhen-2 software, which showed "probably damaging" with a score of approximately 1. These mutation sites were not identified in 250 healthy controls. Our present findings suggest that the novel missense

  4. Berberine slows cell growth in autosomal dominant polycystic kidney disease cells

    Energy Technology Data Exchange (ETDEWEB)

    Bonon, Anna; Mangolini, Alessandra [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy); Pinton, Paolo [Department of Morphology, Surgery and Experimental Medicine, Section of General Pathology, University of Ferrara, 44121 Ferrara (Italy); Senno, Laura del [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy); Aguiari, Gianluca, E-mail: dsn@unife.it [Department of Biomedical and Specialty Surgical Sciences, University of Ferrara, 44121 Ferrara (Italy)

    2013-11-22

    Highlights: •Berberine at appropriate doses slows cell proliferation in ADPKD cystic cells. •Reduction of cell growth by berberine occurs by inhibition of ERK and p70-S6 kinase. •Higher doses of berberine cause an overall cytotoxic effect. •Berberine overdose induces apoptotic bodies formation and DNA fragmentation. •Antiproliferative properties of this drug make it a new candidate for ADPKD therapy. -- Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary monogenic disorder characterized by development and enlargement of kidney cysts that lead to loss of renal function. It is caused by mutations in two genes (PKD1 and PKD2) encoding for polycystin-1 and polycystin-2 proteins which regulate different signals including cAMP, mTOR and EGFR pathways. Abnormal activation of these signals following PC1 or PC2 loss of function causes an increased cell proliferation which is a typical hallmark of this disease. Despite the promising findings obtained in animal models with targeted inhibitors able to reduce cystic cell growth, currently, no specific approved therapy for ADPKD is available. Therefore, the research of new more effective molecules could be crucial for the treatment of this severe pathology. In this regard, we have studied the effect of berberine, an isoquinoline quaternary alkaloid, on cell proliferation and apoptosis in human and mouse ADPKD cystic cell lines. Berberine treatment slows cell proliferation of ADPKD cystic cells in a dose-dependent manner and at high doses (100 μg/mL) it induces cell death in cystic cells as well as in normal kidney tubule cells. However, at 10 μg/mL, berberine reduces cell growth in ADPKD cystic cells only enhancing G{sub 0}/G{sub 1} phase of cell cycle and inhibiting ERK and p70-S6 kinases. Our results indicate that berberine shows a selected antiproliferative activity in cellular models for ADPKD, suggesting that this molecule and similar natural compounds could open new

  5. A novel missense mutation in the CLCN7 gene linked to benign autosomal dominant osteopetrosis: a case series

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    Rashid Ban Mousa

    2013-01-01

    Full Text Available Abstract Introduction Osteopetrosis is a rare inherited genetic disease characterized by sclerosis of the skeleton. The absence or malfunction of osteoclasts is found to be strongly associated with the disease evolution. Currently, four clinically distinct forms of the disease have been recognized: the infantile autosomal recessive osteopetrosis, the malignant and the intermediate forms, and autosomal dominant osteopetrosis, type I and type II forms. The autosomal recessive types are the most severe forms with symptoms in very early childhood, whereas the autosomal dominant classes exhibit a heterogeneous trait with milder symptoms, often at later childhood or adulthood. Case presentation Case 1 is the 12-year-old daughter (index patient of an Iraqi-Kurdish family who, at the age of eight years, was diagnosed clinically to have mild autosomal dominant osteopetrosis. Presently, at 12-years old, she has severe complications due to the disease progression. In addition, the same family previously experienced the death of a female child in her late childhood. The deceased child had been misdiagnosed, at that time, with thalassemia major. In this report, we extended our investigation to identify the type of the inheritance patterns of osteopetrosis using molecular techniques, because consanguineous marriages exist within the family history. We have detected one heterozygous mutation in exon 15 of the Chloride Channel 7 gene in the index patient (Case 1, whereas other mutations were not detected in the associated genes TCIRG1, OSTM1, RANK, and RANKL. The missense mutation (CGG>TGG located in exon 15 (c.1225C>T of the Chloride Channel 7 gene changed the amino acid position 409 from arginine to tryptophan (p.R409W, c.1225C>T. Case 2 is the 16-year-old son (brother of the index patient of the same family who was diagnosed clinically with mild autosomal dominant osteopetrosis. We have identified the same heterozygous mutation in exon 15 of the Chloride

  6. A novel missense mutation in the CLCN7 gene linked to benign autosomal dominant osteopetrosis: a case series.

    Science.gov (United States)

    Rashid, Ban Mousa; Rashid, Nawshirwan Gafoor; Schulz, Ansgar; Lahr, Georgia; Nore, Beston Faiek

    2013-01-09

    Osteopetrosis is a rare inherited genetic disease characterized by sclerosis of the skeleton. The absence or malfunction of osteoclasts is found to be strongly associated with the disease evolution. Currently, four clinically distinct forms of the disease have been recognized: the infantile autosomal recessive osteopetrosis, the malignant and the intermediate forms, and autosomal dominant osteopetrosis, type I and type II forms. The autosomal recessive types are the most severe forms with symptoms in very early childhood, whereas the autosomal dominant classes exhibit a heterogeneous trait with milder symptoms, often at later childhood or adulthood. Case 1 is the 12-year-old daughter (index patient) of an Iraqi-Kurdish family who, at the age of eight years, was diagnosed clinically to have mild autosomal dominant osteopetrosis. Presently, at 12-years old, she has severe complications due to the disease progression. In addition, the same family previously experienced the death of a female child in her late childhood. The deceased child had been misdiagnosed, at that time, with thalassemia major. In this report, we extended our investigation to identify the type of the inheritance patterns of osteopetrosis using molecular techniques, because consanguineous marriages exist within the family history. We have detected one heterozygous mutation in exon 15 of the Chloride Channel 7 gene in the index patient (Case 1), whereas other mutations were not detected in the associated genes TCIRG1, OSTM1, RANK, and RANKL. The missense mutation (CGG>TGG) located in exon 15 (c.1225C>T) of the Chloride Channel 7 gene changed the amino acid position 409 from arginine to tryptophan (p.R409W, c.1225C>T).Case 2 is the 16-year-old son (brother of the index patient) of the same family who was diagnosed clinically with mild autosomal dominant osteopetrosis. We have identified the same heterozygous mutation in exon 15 of the Chloride channel 7 gene in this patient (Case 2). The missense

  7. Autosomal dominant epidermodysplasia verruciformis lacking a known EVER1 or EVER2 mutation

    OpenAIRE

    McDermott, David H.; Gammon, Bryan; Snijders, Peter J.; Mbata, Ihunanya; Phifer, Beth; Hartley, A. Howland; Lee, Chyi-Chia Richard; Murphy, Philip M.; Hwang, Sam T.

    2009-01-01

    Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to infection with specific human papillomavirus (HPV) serotypes. EV is a genetically heterogeneous disease, and autosomal recessive and X-linked inheritance patterns have been reported. Nonsense mutations in the genes EVER1 and EVER2 have been identified in over 75% of cases. We present EV in a father and son with typical histologic and clinical findings that occur in the absence of mutation...

  8. An autopsy case of vertebrobasilar dolichoectasia under hemodialysis due to autosomal dominant polycystic kidney disease

    OpenAIRE

    Nakagawa, Shiori; Furuichi, Kengo; Sagara, Akihiro; Shinozaki, Yasuyuki; Kitajima, Shinji; Toyama, Tadashi; Hara, Akinori; Iwata, Yasunori; Sakai, Norihiko; Shimizu, Miho; Matsui, Kazuhiro; Kaneko, Shuichi; Toyama, Tatsuhiko; Wada, Takashi

    2015-01-01

    A 60-year-old male with end-stage kidney disease due to autosomal polycystic kidney disease began maintenance hemodialysis in 2005. A brain CT scan showed dilatation of left vertebral artery, basilar artery, bilateral post cerebral artery, and middle cerebral artery. At the time, he was diagnosed as vertebrobasilar dolichoectasia. He was once admitted to our hospital for ischemic stroke. After discharge, he was treated with anticoagulant agent from 2010 to 2012 without any new stroke events. ...

  9. Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer’s disease

    Science.gov (United States)

    Franzmeier, Nicolai; Düzel, Emrah; Jessen, Frank; Buerger, Katharina; Levin, Johannes; Duering, Marco; Dichgans, Martin; Haass, Christian; Suárez-Calvet, Marc; Fagan, Anne M; Paumier, Katrina; Benzinger, Tammie; Masters, Colin L; Morris, John C; Perneczky, Robert; Janowitz, Daniel; Catak, Cihan; Wolfsgruber, Steffen; Wagner, Michael; Teipel, Stefan; Kilimann, Ingo; Ramirez, Alfredo; Rossor, Martin; Jucker, Mathias; Chhatwal, Jasmeer; Spottke, Annika; Boecker, Henning; Brosseron, Frederic; Falkai, Peter; Fliessbach, Klaus; Heneka, Michael T; Laske, Christoph; Nestor, Peter; Peters, Oliver; Fuentes, Manuel; Menne, Felix; Priller, Josef; Spruth, Eike J; Franke, Christiana; Schneider, Anja; Kofler, Barbara; Westerteicher, Christine; Speck, Oliver; Wiltfang, Jens; Bartels, Claudia; Araque Caballero, Miguel Ángel; Metzger, Coraline; Bittner, Daniel; Weiner, Michael; Lee, Jae-Hong; Salloway, Stephen; Danek, Adrian; Goate, Alison; Schofield, Peter R; Bateman, Randall J; Ewers, Michael

    2018-01-01

    Abstract Patients with Alzheimer’s disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer’s pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer’s disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer’s disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer’s disease, 55 controls from the Dominantly Inherited Alzheimer’s Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer’s disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer’s disease and cerebrospinal fluid tau levels in sporadic Alzheimer’s disease cases. In both autosomal dominant and sporadic Alzheimer’s disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer’s disease, a significant left frontal cortex connectivity

  10. Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody

    NARCIS (Netherlands)

    Hopkins, Paul N.; Defesche, Joep; Fouchier, Sigrid W.; Bruckert, Eric; Luc, Gérald; Cariou, Bertrand; Sjouke, Barbara; Leren, Trond P.; Harada-Shiba, Mariko; Mabuchi, Hiroshi; Rabès, Jean-Pierre; Carrié, Alain; van Heyningen, Charles; Carreau, Valérie; Farnier, Michel; Teoh, Yee P.; Bourbon, Mafalda; Kawashiri, Masa-Aki; Nohara, Atsushi; Soran, Handrean; Marais, A. David; Tada, Hayato; Abifadel, Marianne; Boileau, Catherine; Chanu, Bernard; Katsuda, Shoji; Kishimoto, Ichiro; Lambert, Gilles; Makino, Hisashi; Miyamoto, Yoshihiro; Pichelin, Matthieu; Yagi, Kunimasa; Yamagishi, Masakazu; Zair, Yassine; Mellis, Scott; Yancopoulos, George D.; Stahl, Neil; Mendoza, Johanna; Du, Yunling; Hamon, Sara; Krempf, Michel; Swergold, Gary D.

    2015-01-01

    Background Patients with PCSK9 gene gain of function (GOF) mutations have a rare form of autosomal dominant hypercholesterolemia. However, data examining their clinical characteristics and geographic distribution are lacking. Furthermore, no randomized treatment study in this population has been

  11. Rationale and design of the RESOLVE trial: lanreotide as a volume reducing treatment for polycystic livers in patients with autosomal dominant polycystic kidney disease.

    NARCIS (Netherlands)

    Gevers, T.J.G.; Chrispijn, M.; Wetzels, J.F.M.; Drenth, J.P.H.

    2012-01-01

    BACKGROUND: A large proportion of patients with autosomal dominant polycystic kidney disease (ADPKD) suffers from polycystic liver disease. Symptoms arise when liver volume increases. The somatostatin analogue lanreotide has proven to reduce liver volume in patients with polycystic liver disease.

  12. External Ocular Manifestations in Autosomal Dominant Dystrophic Epidermolysis Bullosa; a Case Report

    Directory of Open Access Journals (Sweden)

    Manizheh Mahdavi

    2008-11-01

    Full Text Available

    PURPOSE: To present a case of autosomal dominant dystrophic epidermolysis bullosa with symblepharon formation due to eye rubbing. CASE REPORT: A 10-year-old girl suffering from blistering and ulcerative lesions of the trunk and palms and dystrophic nails since childhood was referred to our clinic with a symblepharon connecting the medial portion of the right upper lid to the superonasal quadrant of the cornea. The central cornea in both eyes exhibited mild subepithelial opacification. She had history of eye rubbing due to foreign body sensation in the right eye, resulting in red eye and blister-like conjunctival lesions since three years ago. She had previously undergone surgical symblepharon removal leading to more severe recurrence of the condition. CONCLUSION: Dominant dystrophic epidermolysis bullosa may be accompanied by external ocular manifestations. Protection of the eye from minor trauma such as rubbing may help prevent ocular complications.

  1. Clinical and molecular analysis of the enamelin gene ENAM in Colombian families with autosomal dominant amelogenesis imperfecta

    Directory of Open Access Journals (Sweden)

    Sandra Gutiérrez

    2012-01-01

    Full Text Available In this study, we analyzed the phenotype, clinical characteristics and presence of mutations in the enamelin gene ENAM in five Colombian families with autosomal dominant amelogenesis imperfecta (ADAI. 22 individuals (15 affected and seven unaffected belonging to five Colombian families with ADAI and eight individuals (three affected and five unaffected belonging to three Colombian families with autosomal recessive amelogenesis imperfecta (ARAI that served as controls for molecular alterations and inheritance patterns were studied. Clinical, radiographic and genetic evaluations were done in all individuals. Eight exons and three intron-exon boundaries were sequenced for mutation analysis. Two of the five families with ADAI had the hypoplasic phenotype, two had the hypocalcified phenotype and one had the hypomaturative phenotype. Anterior open bite and mandibular retrognathism were the most frequent skeletal abnormalities in the families with ADAI. No mutations were found. These findings suggest that ADAI in these Colombian families was unrelated to previously described mutations in the ENAM gene. These results also indicate that other regions not included in this investigation, such as the promoter region, introns and other genes should be considered as potential ADAI candidates.

  2. A paradoxical presentation of rickets and secondary osteomyelitis of the jaw in Type II autosomal dominant osteopetrosis: Rare case reports.

    Science.gov (United States)

    Jayachandran, S; Kumar, M Suresh

    2016-01-01

    Osteopetrosis is a rare genetic bone disorder arising due to a defect in the differentiation or function of osteoclast which results in a generalized increase in bone mass. Osteomyelitis is one of the most common complications because of decreased bone marrow function and compromised blood supply. Radiologist plays a vital role in diagnosing osteopetrosis. Here, we present two cases of autosomal dominant osteopetrosis Type II (ADO II) with secondary osteomyelitis changes which were reported to our department. One of these two cases presented with secondary osteomyelitis in both maxilla and mandible and features of rickets, which is very rarely seen in ADO II. To the best of our knowledge, the presentation of rickets with ADO is the first of its kind to be reported. In this paper, we describe the clinical and radiological features leading to the diagnosis of ADO in these two patients. Further, a review of the literature regarding ADO is discussed.

  3. Dystrophic Epidermolysis Bullosa in Pregnancy: A Case Report of the Autosomal Dominant Subtype and Review of the Literature

    Directory of Open Access Journals (Sweden)

    Nicole Colgrove

    2014-01-01

    Full Text Available Epidermolysis bullosa (EB is a group of inherited blistering skin diseases that vary widely in their pathogenesis and severity. There are three main categories of EB: simplex, junctional, and dystrophic. This classification is based on the level of tissue separation within the basement membrane zone and this is attributed to abnormalities of individual or several anchoring proteins that form the interlocking network spanning from the epidermis to the dermis underneath. Dystrophic EB results from mutations in COL7A1 gene coding for type VII collagen leading to blister formation within the dermis. Diagnosis ultimately depends on the patient’s specific genetic mutation, but initial diagnosis can be made from careful examination and history taking. We present a pregnant patient known to have autosomal dominant dystrophic EB and discuss the obstetrical and neonatal outcome. The paper also reviews the current English literature on this rare skin disorder.

  4. The French series of autosomal dominant early onset Alzheimer's disease cases: mutation spectrum and cerebrospinal fluid biomarkers.

    Science.gov (United States)

    Wallon, David; Rousseau, Stéphane; Rovelet-Lecrux, Anne; Quillard-Muraine, Muriel; Guyant-Maréchal, Lucie; Martinaud, Olivier; Pariente, Jérémie; Puel, Michèle; Rollin-Sillaire, Adeline; Pasquier, Florence; Le Ber, Isabelle; Sarazin, Marie; Croisile, Bernard; Boutoleau-Bretonnière, Claire; Thomas-Antérion, Catherine; Paquet, Claire; Moreaud, Olivier; Gabelle, Audrey; Sellal, François; Sauvée, Mathilde; Laquerrière, Annie; Duyckaerts, Charles; Delisle, Marie-Bernadette; Streichenberger, Nathalie; Lannes, Béatrice; Frebourg, Thierry; Hannequin, Didier; Campion, Dominique

    2012-01-01

    We describe 56 novel autosomal dominant early-onset Alzheimer disease (ADEOAD) families with PSEN1, PSEN2, and AβPP mutations or duplications, raising the total of families with mutations on known genes to 111 (74 PSEN1, 8 PSEN2, 16 AβPP, and 13 AβPP duplications) in the French series. In 33 additional families (23% of the series), the genetic determinism remained uncharacterized after this screening. Cerebrospinal fluid (CSF) biomarker levels were obtained for patients of 58 families (42 with known mutations and 16 without genetic characterization). CSF biomarkers profile was consistent with an AD diagnosis in 90% of families carrying mutations on known genes. In families without mutation, CSF biomarkers were consistent with AD diagnosis in 14/16 cases. Overall, these results support further genetic heterogeneity in the determinism of ADEOAD and suggest that other major genes remain to be characterized.

  5. Cerebro-costo-mandibular syndrome in a father and a female fetus: early prenatal ultrasonographic diagnosis and autosomal dominant transmission.

    Science.gov (United States)

    Morin, G; Gekas, J; Naepels, P; Gondry, J; Devauchelle, B; Testelin, S; Sevestre, H; Thépôt, F; Mathieu, M

    2001-10-01

    Ultrasonography in a female fetus revealed cystic cervical hygroma, severe micrognathia, and vertebral and upper limb anomalies suggestive of cerebro-costo-mandibular syndrome (CCMS) which was diagnosed ultrasonographically at 16 weeks' gestation. The father is affected and presents with a Pierre Robin sequence, short stature and typical costovertebral anomalies. CCMS is a rare and severe disorder. The high frequency of sporadic cases, vertical transmission, and the excess of sibs affected via horizontal transmission suggest dominant autosomal mutation with possible germinal mosaicism. The vertical familial case detailed in the present report is a reminder of the high risk when one parent or one sibling is affected and the extreme variability of phenotype and costal ossification. Early prenatal ultrasound diagnosis is possible in a severely affected fetus. Copyright 2001 John Wiley & Sons, Ltd.

  6. Autosomal dominant mesomandibular fibro-osseous dysplasia: a self-resolving inherited fibro-osseous lesion of the jaws

    Directory of Open Access Journals (Sweden)

    Ioannis eKoutlas

    2012-12-01

    Full Text Available A hereditary congenital condition characterized by a fibro-osseous lesion sharing some features with fibrous dysplasia and affecting the middle aspect of the mandible is presented. The condition was initially described as congenital monostotic fibrous dysplasia in two siblings, a male and a female. However, there is sufficient evidence that the disorder is autosomal dominant since it has been encountered in two of four children, both males, of the female propositus and one child, a boy, of the male propositus. All patients presented at birth or right after birth with enlargement of the middle part of the mandible. Radiographs from affected individuals have shown mesomandibular enlargement with irregular trabeculation akin of ground-glass appearance. Histologically, samples from all patients revealed woven bone proliferation in a cellular fibroblastic stroma. Interestingly, the originally described siblings, now in their 30s, have no evidence of jaw lesions either radiographically or clinically, thus indicating that the condition is self-limiting or self-resolving. An autosomal dominant mode of inheritance with apparent male predilection is favored. The molecular basis of this condition is currently unknown. However, the location of the lesions in the middle aspect of the mandible suggests dysregulation of Bone Morphogenetic Protein signaling since BMPs regulate mandibular morphogenesis in utero, particularly in the medial region as well as postnatal bone remodeling. Immunohistochemical evaluation for a BMP-binding protein Twisted Gastrulation revealed mosaic pattern of staining, with some cells, including osteoclasts, strongly stained and others exhibiting faint or no staining, thus supporting active regulation of BMP signaling within the lesion. Future investigations will determine if dysregulation of BMP signaling plays a causative role or rather reflects secondary activation of repair mechanisms and/or bone remodeling.

  7. Characterization of macular structure and function in two Swedish families with genetically identified autosomal dominant retinitis pigmentosa

    Science.gov (United States)

    Abdulridha-Aboud, Wissam; Kjellström, Ulrika; Andréasson, Sten

    2016-01-01

    Purpose To study the phenotype in two families with genetically identified autosomal dominant retinitis pigmentosa (adRP) focusing on macular structure and function. Methods Clinical data were collected at the Department of Ophthalmology, Lund University, Sweden, for affected and unaffected family members from two pedigrees with adRP. Examinations included optical coherence tomography (OCT), full-field electroretinography (ffERG), and multifocal electroretinography (mfERG). Molecular genetic screening was performed for known mutations associated with adRP. Results The mode of inheritance was autosomal dominant in both families. The members of the family with a mutation in the PRPF31 (p.IVS6+1G>T) gene had clinical features characteristic of RP, with severely reduced retinal rod and cone function. The degree of deterioration correlated well with increasing age. The mfERG showed only centrally preserved macular function that correlated well with retinal thinning on OCT. The family with a mutation in the RHO (p.R135W) gene had an extreme intrafamilial variability of the phenotype, with more severe disease in the younger generations. OCT showed pathology, but the degree of morphological changes was not correlated with age or with the mfERG results. The mother, with a de novo mutation in the RHO (p.R135W) gene, had a normal ffERG, and her retinal degeneration was detected merely with the reduced mfERG. Conclusions These two families demonstrate the extreme inter- and intrafamilial variability in the clinical phenotype of adRP. This is the first Swedish report of the clinical phenotype associated with a mutation in the PRPF31 (p.IVS6+1G>T) gene. Our results indicate that methods for assessment of the central retinal structure and function may improve the detection and characterization of the RP phenotype. PMID:27212874

  8. Mutation in the novel nuclear-encoded mitochondrial protein CHCHD10 in a family with autosomal dominant mitochondrial myopathy.

    Science.gov (United States)

    Ajroud-Driss, Senda; Fecto, Faisal; Ajroud, Kaouther; Lalani, Irfan; Calvo, Sarah E; Mootha, Vamsi K; Deng, Han-Xiang; Siddique, Nailah; Tahmoush, Albert J; Heiman-Patterson, Terry D; Siddique, Teepu

    2015-01-01

    Mitochondrial myopathies belong to a larger group of systemic diseases caused by morphological or biochemical abnormalities of mitochondria. Mitochondrial disorders can be caused by mutations in either the mitochondrial or nuclear genome. Only 5% of all mitochondrial disorders are autosomal dominant. We analyzed DNA from members of the previously reported Puerto Rican kindred with an autosomal dominant mitochondrial myopathy (Heimann-Patterson et al. 1997). Linkage analysis suggested a putative locus on the pericentric region of the long arm of chromosome 22 (22q11). Using the tools of integrative genomics, we established chromosome 22 open reading frame 16 (C22orf16) (later designated as CHCHD10) as the only high-scoring mitochondrial candidate gene in our minimal candidate region. Sequence analysis revealed a double-missense mutation (R15S and G58R) in cis in CHCHD10 which encodes a coiled coil-helix-coiled coil-helix protein of unknown function. These two mutations completely co-segregated with the disease phenotype and were absent in 1,481 Caucasian and 80 Hispanic (including 32 Puerto Rican) controls. Expression profiling showed that CHCHD10 is enriched in skeletal muscle. Mitochondrial localization of the CHCHD10 protein was confirmed using immunofluorescence in cells expressing either wild-type or mutant CHCHD10. We found that the expression of the G58R, but not the R15S, mutation induced mitochondrial fragmentation. Our findings identify a novel gene causing mitochondrial myopathy, thereby expanding the spectrum of mitochondrial myopathies caused by nuclear genes. Our findings also suggest a role for CHCHD10 in the morphologic remodeling of the mitochondria.

  9. Clinical results from low-level laser therapy in patients with autosomal dominant cone-rod dystrophy

    Science.gov (United States)

    Koev, K.; Avramov, L.; Borissova, E.

    2018-03-01

    The objective of this study is to examine long-term effects of low-level laser therapy (LLLT) in patients with autosomal dominant cone-rod dystrophy (CRDs). A He-Ne Laser with continuous emission at 633 nm (01 mW/cm2) was used on five patients with autosomal dominant pedigree of Romani origin with non-syndromic CRDs. The laser radiation was applied transpupillary to the macula six times for three minutes every other day. The experiment was conducted for a period of three years. The clinical evaluation included best corrected visual acuity determination, funduscopy, Humphrey perimetry, Farnsworth Hue-28 color testing, fluorescein angiography, and full-field electroretinogram (ERG). All affected individuals presented reduced visual acuity (0.01 – 0.4) and photophobia. The funduscopic examination and fluorescein angiography revealed advanced changes including bone spicule-like pigment deposits in the midperiphery and the macular area, along with retinal atrophy, narrowing of the vessels, and waxy optic discs. The visual fields demonstrated central scotoma. The electrophysiologic examination of the patients detected an abnormal cone-rod ERG (20 – 30 μV) with photopic amplitudes more markedly reduced than the scotopic. Flicker responses were missing and Farnsworth Hue-28 test found protanopia. There was a statistically significant increase in the visual acuity (p<0.001, end of study versus baseline) for CRDs patients for the period of three years after the treatment with LLLT. Following the LLLT, the central absolute scotoma in CRDs was reduced, as was the prevalence of metamorphopsia in CRDs. This study shows that LLLT may prove be a novel long-lasting therapeutic option for both forms of CRDs. It is a highly effective treatment resulting in a long-term improvement of the visual acuity.

  10. Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis.

    Science.gov (United States)

    Saroja, Aralikatte Onkarappa; Naik, Karkal Ravishankar; Nalini, Atcharayam; Gayathri, Narayanappa

    2013-10-01

    Bethlem myopathy and Ullrich congenital muscular dystrophy form a spectrum of collagenopathies caused by genetic mutations encoding for any of the three subunits of collagen VI. Bethlem phenotype is relatively benign and is characterized by proximal dominant myopathy, keloids, contractures, distal hyperextensibility, and follicular hyperkeratosis. Three patients from a single family were diagnosed to have Bethlem myopathy based on European Neuromuscular Centre Bethlem Consortium criteria. Affected father and his both sons had slowly progressive proximal dominant weakness and recurrent falls from the first decade. Both children aged 18 and 20 years were ambulant at presentation. All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy. Creatinine kinase was mildly elevated and electromyography revealed myopathic features. Muscle imaging revealed severe involvement of glutei and vasti with "central shadow" in rectus femoris. Muscle biopsy in the father showed dystrophic changes with normal immmunostaining for collagen VI, sarcoglycans, and dysferlin.

  11. Epiphyseal osteochondromas with autosomal dominant inheritance and multiple parosteal bone proliferations

    International Nuclear Information System (INIS)

    Fahmy, Mohamed A.L.; Pandey, Tarun

    2008-01-01

    The familial cases of dysplasia epiphysealis hemimelica (DEH), or Trevor's disease, are thought to represent dominant carpotarsal osteochondromatosis (DCO). Only three families affected by DCO have been reported so far in the literature. We report a fourth family: a 10-year-old girl, her father, and his cousin. Unlike the other reported cases of DCO this family had no carpal or upper limb epiphyseal osteochondromas and many of the other reported associations. The only consistent associated finding in our cases was the presence of multiple parosteal osteochondromatous proliferations. The findings of our cases are, therefore, unique in many ways. These cases may represent a variant of dominant carpotarsal osteochondromatosis or may represent a new entity. (orig.)

  12. Bethlem myopathy: An autosomal dominant myopathy with flexion contractures, keloids, and follicular hyperkeratosis

    Directory of Open Access Journals (Sweden)

    Aralikatte Onkarappa Saroja

    2013-01-01

    Full Text Available Bethlem myopathy and Ullrich congenital muscular dystrophy form a spectrum of collagenopathies caused by genetic mutations encoding for any of the three subunits of collagen VI. Bethlem phenotype is relatively benign and is characterized by proximal dominant myopathy, keloids, contractures, distal hyperextensibility, and follicular hyperkeratosis. Three patients from a single family were diagnosed to have Bethlem myopathy based on European Neuromuscular Centre Bethlem Consortium criteria. Affected father and his both sons had slowly progressive proximal dominant weakness and recurrent falls from the first decade. Both children aged 18 and 20 years were ambulant at presentation. All had flexion contractures, keloids, and follicular hyperkeratosis without muscle hypertrophy. Creatinine kinase was mildly elevated and electromyography revealed myopathic features. Muscle imaging revealed severe involvement of glutei and vasti with "central shadow" in rectus femoris. Muscle biopsy in the father showed dystrophic changes with normal immmunostaining for collagen VI, sarcoglycans, and dysferlin.

  13. Epiphyseal osteochondromas with autosomal dominant inheritance and multiple parosteal bone proliferations

    Energy Technology Data Exchange (ETDEWEB)

    Fahmy, Mohamed A.L. [Razi Orthopedic Hospital, Consultant Orthopedic Surgeon, P.O. Box 4235, Safat (Kuwait); Pandey, Tarun [University of Arkansas for Medical Sciences (UAMS), Department of Radiology, Little Rock, AR (United States)

    2008-01-15

    The familial cases of dysplasia epiphysealis hemimelica (DEH), or Trevor's disease, are thought to represent dominant carpotarsal osteochondromatosis (DCO). Only three families affected by DCO have been reported so far in the literature. We report a fourth family: a 10-year-old girl, her father, and his cousin. Unlike the other reported cases of DCO this family had no carpal or upper limb epiphyseal osteochondromas and many of the other reported associations. The only consistent associated finding in our cases was the presence of multiple parosteal osteochondromatous proliferations. The findings of our cases are, therefore, unique in many ways. These cases may represent a variant of dominant carpotarsal osteochondromatosis or may represent a new entity. (orig.)

  14. Somatic and germline mosaicism for a mutation of the PHEX gene can lead to genetic transmission of X-linked hypophosphatemic rickets that mimics an autosomal dominant trait.

    Science.gov (United States)

    Goji, Katsumi; Ozaki, Kayo; Sadewa, Ahmad H; Nishio, Hisahide; Matsuo, Masafumi

    2006-02-01

    Familial hypophosphatemic rickets is usually transmitted as an X-linked dominant disorder (XLH), although autosomal dominant forms have also been observed. Genetic studies of these disorders have identified mutations in PHEX and FGF23 as the causes of X-linked dominant disorder and autosomal dominant forms, respectively. The objective of the study was to describe the molecular genetic findings in a family affected by hypophosphatemic rickets with presumed autosomal dominant inheritance. We studied a family in which the father and the elder of his two daughters, but not the second daughter, were affected by hypophosphatemic rickets. The pedigree interpretation of the family suggested that genetic transmission of the disorder occurred as an autosomal dominant trait. Direct nucleotide sequencing of FGF23 and PHEX revealed that the elder daughter was heterozygous for an R567X mutation in PHEX, rather than FGF23, suggesting that the genetic transmission occurred as an X-linked dominant trait. Unexpectedly, the father was heterozygous for this mutation. Single-nucleotide primer extension and denaturing HPLC analysis of the father using DNA from single hair roots revealed that he was a somatic mosaic for the mutation. Haplotype analysis confirmed that the father transmitted the genotypes for 18 markers on the X chromosome equally to his two daughters. The fact that the father transmitted the mutation to only one of his two daughters indicated that he was a germline mosaic for the mutation. Somatic and germline mosaicism for an X-linked dominant mutation in PHEX may mimic autosomal dominant inheritance.

  15. Mutational analysis in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD): Identification of five mutations in the PKD1 gene.

    Science.gov (United States)

    Abdelwahed, Mayssa; Hilbert, Pascale; Ahmed, Asma; Mahfoudh, Hichem; Bouomrani, Salem; Dey, Mouna; Hachicha, Jamil; Kamoun, Hassen; Keskes-Ammar, Leila; Belguith, Neïla

    2018-05-31

    Autosomal Dominant Polycystic Kidney Disease (ADPKD), the most frequent genetic disorder of the kidneys, is characterized by a typical presenting symptoms include cysts development in different organs and a non-cysts manifestations. ADPKD is caused by mutations in PKD1 or PKD2 genes. In this study, we aimed to search for molecular causative defects among PKD1 and PKD2 genes. Eighteen patients were diagnosed based on renal ultrasonography and renal/extra-renal manifestations. Then, Sanger sequencing was performed for PKD1 and PKD2 genes. Multiplex Ligation dependent Probe Amplification method (MLPA) methods was performed for both PKD genes. Mutational analysis of the PKD2 gene revealed the absence of variants and no deletions or duplications of both PKD genes were detected. But three novels mutations i.e. p.S463C exon 7; c. c.11156+2T>C IVS38 and c.8161-1G>A IVS22 and two previously reported c.1522T>C exon 7 and c.412C>T exon 4 mutations in the PKD1 gene were detected. Bioinformatics tools predicted that the novel variants have a pathogenic effects on splicing machinery, pre-mRNA secondary structure and stability and protein stability. Our results highlighted molecular features of Tunisian patients with ADPKD and revealed novel variations that can be utilized in clinical diagnosis and in the evaluation of living kidney donor. To the best of our knowledge, this is the first report of Autosomal Polycystic Kidney Disease in Tunisia. Copyright © 2017. Published by Elsevier B.V.

  16. Autosomal dominant inheritance of Williams-Beuren syndrome in a father and son with haploinsufficiency for FKBP6.

    Science.gov (United States)

    Metcalfe, Kay; Simeonov, Emil; Beckett, William; Donnai, Dian; Tassabehji, May

    2005-04-01

    Williams-Beuren syndrome (WBS) is a neurodevelopmental microdeletion disorder that usually occurs sporadically due to its location within a highly repetitive genomic region that is unstable and prone to unequal cross-over during meiosis. The consequential loss of chromosomal material includes approximately 1.5 Mb of DNA at 7q11.23. Whilst cases of dominant inheritance have been described in the literature, there have been few reports of molecular confirmation and none have carried out detailed genotyping. We describe a Bulgarian father and son with WBS detected by fluorescent in situ hybridisation (with an elastin gene probe) and loss of heterozygosity mapping using microsatellite markers located in the critical region. These individuals appear to have a common WBS heterozygous deletion, confirming the expected dominant transmission and adding to the few familial cases reported. The deletion includes the gene FKBP6 which has recently been shown to play a role in homologous chromosome pairing in meiosis and male fertility in mouse models. Homozygous Fkbp6 -/- male mice are infertile and our data suggests that haploinsufficiency for FKBP6 does not appear to preclude male fertility in WBS, although male infertility involving this gene has the potential to follow the mouse model as a human autosomal recessive condition.

  17. Impaired Cleavage of Preproinsulin Signal Peptide Linked to Autosomal-Dominant Diabetes

    Science.gov (United States)

    Liu, Ming; Lara-Lemus, Roberto; Shan, Shu-ou; Wright, Jordan; Haataja, Leena; Barbetti, Fabrizio; Guo, Huan; Larkin, Dennis; Arvan, Peter

    2012-01-01

    Recently, missense mutations upstream of preproinsulin’s signal peptide (SP) cleavage site were reported to cause mutant INS gene-induced diabetes of youth (MIDY). Our objective was to understand the molecular pathogenesis using metabolic labeling and assays of proinsulin export and insulin and C-peptide production to examine the earliest events of insulin biosynthesis, highlighting molecular mechanisms underlying β-cell failure plus a novel strategy that might ameliorate the MIDY syndrome. We find that whereas preproinsulin-A(SP23)S is efficiently cleaved, producing authentic proinsulin and insulin, preproinsulin-A(SP24)D is inefficiently cleaved at an improper site, producing two subpopulations of molecules. Both show impaired oxidative folding and are retained in the endoplasmic reticulum (ER). Preproinsulin-A(SP24)D also blocks ER exit of coexpressed wild-type proinsulin, accounting for its dominant-negative behavior. Upon increased expression of ER–oxidoreductin-1, preproinsulin-A(SP24)D remains blocked but oxidative folding of wild-type proinsulin improves, accelerating its ER export and increasing wild-type insulin production. We conclude that the efficiency of SP cleavage is linked to the oxidation of (pre)proinsulin. In turn, impaired (pre)proinsulin oxidation affects ER export of the mutant as well as that of coexpressed wild-type proinsulin. Improving oxidative folding of wild-type proinsulin may provide a feasible way to rescue insulin production in patients with MIDY. PMID:22357960

  18. Spectrum of sonographic changes in hereditary motor and sensory neuropathy with autosomal dominant and X-linked inheritance

    Directory of Open Access Journals (Sweden)

    E. S. Naumova

    2016-01-01

    Full Text Available Background. In the recent years interest towards nerve sonography has largely increased, specifically in terms of differentiating types of hereditary motor and sensory neuropathy (HMSN. The diagnostic possibilities of high-resolution ultrasound (HRUS compared to standard neurophysiological tools in the peripheral nerve disorders is still a matter of debate.Objectives. Analysis of quantitative and qualitative ultrasound changes of limb nerves in patients with HMSN type 1 and its comparison with anthropometric and nerve conduction study data.Materials and methods. 44 HMSN patients were analyzed: 16 men, mean age 35,9 ± 6,8 years; 16 (37 % with autosomal dominant type 1А, 11 (25 % – with 1В type and 17 (38 % with Х-linked inheritance. Control group included 44 subjects, 16 male; mean age 35,9 ± 6,8 years. HRUS parameters were analyzed bilaterally on the selected levels: cross-sectional area (CSA, visual cross sectional and longitudinal patterns of the median and ulnar nerves, C5, C6, C7 spinal nerves, tibial, peroneal and sciatic nerves. HRUS parameters were compared to standard anthropometric data, nerve conduction velocity and CMAP amplitude.Results. In all HMSN cases CSA was enlarged compared to healthy controls. Greater changes were found in patients with autosomal dominant inheritance. CSA enlargement in С5, С6, С7 spinal nerves was found in patients with HMSN 1A, С6, С7 – in HMSN 1В, С6 – in HMSN 1X, confirming the necessity to include those nerves in the sonographic protocol in patients with HMSN. Three qualitative cross sectional and longitudinal patterns of the investigated arm nerves were identified, distinct for each of the HMSN type. Absence of significant differences in CSA of the upper limb nerves among analyzed types of HMSN makes it unreliable as the differential parameter, opposite to the defined sonographic patterns. Methodological issues and absence of significant quantitative and qualitative data

  19. Autosomal dominant hypercalciuria in a mouse model due to a mutation of the epithelial calcium channel, TRPV5.

    Directory of Open Access Journals (Sweden)

    Nellie Y Loh

    Full Text Available Hypercalciuria is a major cause of nephrolithiasis, and is a common and complex disorder involving genetic and environmental factors. Identification of genetic factors for monogenic forms of hypercalciuria is hampered by the limited availability of large families, and to facilitate such studies, we screened for hypercalciuria in mice from an N-ethyl-N-nitrosourea mutagenesis programme. We identified a mouse with autosomal dominant hypercalciuria (HCALC1. Linkage studies mapped the Hcalc1 locus to a 11.94 Mb region on chromosome 6 containing the transient receptor potential cation channel, subfamily V, members 5 (Trpv5 and 6 (Trpv6 genes. DNA sequence analysis of coding regions, intron-exon boundaries and promoters of Trpv5 and Trpv6 identified a novel T to C transition in codon 682 of TRPV5, mutating a conserved serine to a proline (S682P. Compared to wild-type littermates, heterozygous (Trpv5(682P/+ and homozygous (Trpv5(682P/682P mutant mice had hypercalciuria, polyuria, hyperphosphaturia and a more acidic urine, and ∼10% of males developed tubulointerstitial nephritis. Trpv5(682P/682P mice also had normal plasma parathyroid hormone but increased 1,25-dihydroxyvitamin D(3 concentrations without increased bone resorption, consistent with a renal defect for the hypercalciuria. Expression of the S682P mutation in human embryonic kidney cells revealed that TRPV5-S682P-expressing cells had a lower baseline intracellular calcium concentration than wild-type TRPV5-expressing cells, suggesting an altered calcium permeability. Immunohistological studies revealed a selective decrease in TRPV5-expression from the renal distal convoluted tubules of Trpv5(682P/+ and Trpv5(682P/682P mice consistent with a trafficking defect. In addition, Trpv5(682P/682P mice had a reduction in renal expression of the intracellular calcium-binding protein, calbindin-D(28K, consistent with a specific defect in TRPV5-mediated renal calcium reabsorption. Thus, our findings

  20. Feasibility of measuring renal blood flow by phase-contrast magnetic resonance imaging in patients with autosomal dominant polycystic kidney disease

    NARCIS (Netherlands)

    Spithoven, E. M.; Meijer, E.; Borns, C.; Boertien, W. E.; Gaillard, C. A. J. M.; Kappert, P.; Greuter, M. J. W.; van der Jagt, E.; Vart, P.; de Jong, P. E.; Gansevoort, R. T.

    Renal blood flow (RBF) has been shown to predict disease progression in autosomal dominant polycystic kidney disease (ADPKD). We investigated the feasibility and accuracy of phase-contrast RBF by MRI (RBFMRI) in ADPKD patients with a wide range of estimated glomerular filtration rate (eGFR) values.

  1. C-terminal truncations in human 3'-5' DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy

    NARCIS (Netherlands)

    Richards, Anna; van den Maagdenberg, Arn M. J. M.; Jen, Joanna C.; Kavanagh, David; Bertram, Paula; Spitzer, Dirk; Liszewski, M. Kathryn; Barilla-LaBarca, Maria-Louise; Terwindt, Gisela M.; Kasai, Yumi; McLellan, Mike; Grand, Mark Gilbert; Vanmolkot, Kaate R. J.; de Vries, Boukje; Wan, Jijun; Kane, Michael J.; Mamsa, Hafsa; Schäfer, Ruth; Stam, Anine H.; Haan, Joost; de Jong, Paulus T. V. M.; Storimans, Caroline W.; van Schooneveld, Mary J.; Oosterhuis, Jendo A.; Gschwendter, Andreas; Dichgans, Martin; Kotschet, Katya E.; Hodgkinson, Suzanne; Hardy, Todd A.; Delatycki, Martin B.; Hajj-Ali, Rula A.; Kothari, Parul H.; Nelson, Stanley F.; Frants, Rune R.; Baloh, Robert W.; Ferrari, Michel D.; Atkinson, John P.

    2007-01-01

    Autosomal dominant retinal vasculopathy with cerebral leukodystrophy is a microvascular endotheliopathy with middle-age onset. In nine families, we identified heterozygous C-terminal frameshift mutations in TREX1, which encodes a 3'-5' exonuclease. These truncated proteins retain exonuclease

  2. Induced pluripotent stem cells derived from a patient with autosomal dominant familial neurohypophyseal diabetes insipidus caused by a variant in the AVP gene

    DEFF Research Database (Denmark)

    Toustrup, Lise Bols; Zhou, Yan; Kvistgaard, Helene

    2017-01-01

    Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is caused by variants in the arginine vasopressin (AVP) gene. Here we report the generation of induced pluripotent stem cells (iPSCs) from a 42-year-old man carrying an adFNDI causing variant in exon 1 of the AVP gene using...

  3. Feasibility of measuring renal blood flow by phase-contrast magnetic resonance imaging in patients with autosomal dominant polycystic kidney disease

    NARCIS (Netherlands)

    Spithoven, Edwin M.; Meijer, E.; Borns, C.; Boertien, W. E.; Gaillard, C. A. J. M.; Kappert, P.; Greuter, Marcel J W; van der Jagt, E.; Vart, P.; de Jong, P. E.; Gansevoort, Ron T.

    Renal blood flow (RBF) has been shown to predict disease progression in autosomal dominant polycystic kidney disease (ADPKD). We investigated the feasibility and accuracy of phase-contrast RBF by MRI (RBFMRI) in ADPKD patients with a wide range of estimated glomerular filtration rate (eGFR)

  4. Chronic Kidney Pain in Autosomal Dominant Polycystic Kidney Disease : A Case Report of Successful Treatment by Catheter-Based Renal Denervation

    NARCIS (Netherlands)

    Casteleijn, Niek F.; de Jager, Rosa L.; Neeleman, M. Peer; Blankestijn, Peter J.; Gansevoort, Ron T.

    Chronic pain is a common concern in patients with autosomal dominant polycystic kidney disease (ADPKD). We report what to our knowledge is the first catheter-based renal denervation procedure in a patient with ADPKD resulting in successful management of chronic pain. The patient was a 43-year-old

  5. White matter pathology and disconnection in the frontal lobe in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).

    Science.gov (United States)

    Craggs, Lucinda J L; Yamamoto, Yumi; Ihara, Masafumi; Fenwick, Richard; Burke, Matthew; Oakley, Arthur E; Roeber, Sigrun; Duering, Marco; Kretzschmar, Hans; Kalaria, Raj N

    2014-08-01

    Magnetic resonance imaging indicates diffuse white matter (WM) changes are associated with cognitive impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We examined whether the distribution of axonal abnormalities is related to microvascular pathology in the underlying WM. We used post-mortem brains from CADASIL subjects and similar age cognitively normal controls to examine WM axonal changes, microvascular pathology, and glial reaction in up to 16 different regions extending rostro-caudally through the cerebrum. Using unbiased stereological methods, we estimated length densities of affected axons immunostained with neurofilament antibody SMI32. Standard immunohistochemistry was used to assess amyloid precursor protein immunoreactivity per WM area. To relate WM changes to microvascular pathology, we also determined the sclerotic index (SI) in WM arterioles. The degree of WM pathology consistently scored higher across all brain regions in CADASIL subjects (Pneurones connecting to targets in the subcortical structures. © 2013 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.

  6. Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations.

    Science.gov (United States)

    Wang, Xia; Charng, Wu-Lin; Chen, Chun-An; Rosenfeld, Jill A; Al Shamsi, Aisha; Al-Gazali, Lihadh; McGuire, Marianne; Mew, Nicholas Ah; Arnold, Georgianne L; Qu, Chunjing; Ding, Yan; Muzny, Donna M; Gibbs, Richard A; Eng, Christine M; Walkiewicz, Magdalena; Xia, Fan; Plon, Sharon E; Lupski, James R; Schaaf, Christian P; Yang, Yaping

    2017-04-01

    ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL1 in the Philadelphia chromosome of leukemia cancer cells. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants cosegregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found to occur de novo or cosegregate with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in a sixth individual (family 4). We overexpressed the mutant constructs in HEK 293T cells and observed increased tyrosine phosphorylation, suggesting increased ABL1 kinase activities associated with both the p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and experimental findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans and developmental defects in Abl1 knockout mice, suggest that ABL1 has an important role during organismal development.

  7. Germline mutations in ABL1 cause an autosomal dominant syndrome characterized by congenital heart defects and skeletal malformations

    Science.gov (United States)

    Wang, Xia; Charng, Wu-Lin; Chen, Chun-An; Rosenfeld, Jill A.; Shamsi, Aisha Al; Al-Gazali, Lihadh; McGuire, Marianne; Mew, Nicholas Ah; Arnold, Georgianne L.; Qu, Chunjing; Ding, Yan; Muzny, Donna M.; Gibbs, Richard A.; Eng, Christine M.; Walkiewicz, Magdalena; Xia, Fan; Plon, Sharon E.; Lupski, James R.; Schaaf, Christian P.; Yang, Yaping

    2017-01-01

    ABL1 is a proto-oncogene well known as part of the fusion gene BCR-ABL in the Philadelphia chromosome of leukemia cancer cells1. Inherited germline ABL1 changes have not been associated with genetic disorders. Here we report ABL1 germline variants co-segregating with an autosomal dominant disorder characterized by congenital heart disease, skeletal abnormalities, and failure to thrive. The variant c.734A>G (p.Tyr245Cys) was found as de novo or co-segregating with disease in five individuals (families 1-3). Additionally, a de novo c.1066G>A (p.Ala356Thr) variant was identified in the sixth individual (family 4). We overexpressed the mutant constructs in HEK 293T cells and observed increased tyrosine phosphorylation, suggesting increased ABL1 kinase activities associated with both p.Tyr245Cys and p.Ala356Thr substitutions. Our clinical and laboratory findings, together with previously reported teratogenic effects of selective BCR-ABL inhibitors in humans2-5 and developmental defects in Abl1 knock-out mice6,7, suggest ABL1 plays an important role during organismal development. PMID:28288113

  8. High prevalence of mutations affecting the splicing process in a Spanish cohort with autosomal dominant retinitis pigmentosa

    Science.gov (United States)

    Ezquerra-Inchausti, Maitane; Barandika, Olatz; Anasagasti, Ander; Irigoyen, Cristina; López de Munain, Adolfo; Ruiz-Ederra, Javier

    2017-01-01

    Retinitis pigmentosa is the most frequent group of inherited retinal dystrophies. It is highly heterogeneous, with more than 80 disease-causing genes 27 of which are known to cause autosomal dominant RP (adRP), having been identified. In this study a total of 29 index cases were ascertained based on a family tree compatible with adRP. A custom panel of 31 adRP genes was analysed by targeted next-generation sequencing using the Ion PGM platform in combination with Sanger sequencing. This allowed us to detect putative disease-causing mutations in 14 out of the 29 (48.28%) families analysed. Remarkably, around 38% of all adRP cases analysed showed mutations affecting the splicing process, mainly due to mutations in genes coding for spliceosome factors (SNRNP200 and PRPF8) but also due to splice-site mutations in RHO. Twelve of the 14 mutations found had been reported previously and two were novel mutations found in PRPF8 in two unrelated patients. In conclusion, our results will lead to more accurate genetic counselling and will contribute to a better characterisation of the disease. In addition, they may have a therapeutic impact in the future given the large number of studies currently underway based on targeted RNA splicing for therapeutic purposes. PMID:28045043

  9. Clinical characterization of a novel calcium sensing receptor genetic alteration in a Greek patient with autosomal dominant hypocalcemia type 1.

    Science.gov (United States)

    Papadopoulou, Anna; Gole, Evangelia; Melachroinou, Katerina; Trangas, Theoni; Bountouvi, Evaggelia; Papadimitriou, Anastasios

    2017-04-01

    Autosomal dominant hypocalcemia (ADH) is a rare familial or sporadic syndrome associated with activating mutations in the calcium sensing receptor (CaSR) gene. The aim of this study was to assess the functional significance of a novel CaSR mutation and, moreover, to present the clinical characteristics and the bone mineral density (BMD) progression from early childhood to late puberty in a patient with ADH. Genetic analysis of the CaSR gene was performed in a patient who presented in the neonatal period with hypocalcemic seizures and biochemical features of ADH. The functional impact of the novel mutation identified was assessed in cultured HEK 293T cells, transfected with either the wild type (WT) or mutant CaSR, by evaluating intracellular calcium ([Ca2+]i) influx after stimulation with extracellular calcium (Ca2+). Several BMD measurements were performed during the patient's follow-up until late puberty. A novel CaSR mutation (p.L123S) was identified, which, as demonstrated by functional analysis, renders CaSR more sensitive to extracellular changes of Ca2+ compared with the WT, although the difference is not statistically significant. BMD measurements, from early childhood to late puberty, revealed high normal to elevated BMD. We present the first Greek patient, to our knowledge, with sporadic ADH due to a novel gain-of-function mutation of the CaSR gene.

  10. Recurrent Skin and Lung Infections in Autosomal Dominant Hyper IgE Syndrome with Transactivation Domain STAT3 Mutation

    Directory of Open Access Journals (Sweden)

    Chad J. Cooper

    2014-01-01

    Full Text Available Background. Hyper IgE is a rare systemic disease characterized by the clinical triad of high serum levels of IgE (>2000 IU/mL, eczema, and recurrent staphylococcal skin and lung infections. The presentation of hyper IgE syndrome is highly variable, which makes it easy to confuse the diagnosis with that of severe atopy or other rare immunodeficiency disorders. Case Report. A 23-year-old Hispanic presented with history of frequent respiratory and gastrointestinal infections as a child and multiple episodes of skin and lung infections (abscess with Staphylococcus aureus throughout his adult life. He had multiple eczematous lesions and folliculitis over his entire body, oral/esophageal candidiasis, and retention of his primary teeth. The IgE was elevated (>5000 IU/mL. Genetic mutation analysis revealed a mutation affecting the transactivation domain of the STAT3 gene. Conclusion. The hallmark of hyper IgE syndrome is serum IgE of >2000 IU/mL. Hyper IgE syndrome is a genetic disorder that is either autosomal dominant or recessive. A definite diagnosis can be made with genetic mutation analysis, and in this case, it revealed a very rare finding of the transactivation domain STAT3 mutation. Hyper IgE syndrome is a challenge for clinicians in establishing a diagnosis in suspected cases.

  11. Percutaneous Nephrolithotomy in Autosomal Dominant Polycystic Kidney Disease: Is it Different from Percutaneous Nephrolithotomy in Normal Kidney?

    Science.gov (United States)

    Singh, Vishwajeet; Sinha, Rahul Janak; Gupta, Dheeraj Kumar

    2013-08-01

    Nephrolithiasis has been reported in 20-28% of patients, of whom 50% are symptomatic for stone disease and 20% require definite urologic intervention. The management of nephrolithiasis includes oral alkali dissolution therapy, extracorporeal shock wave lithotripsy and surgical treatment. In such patients, percutaneous nephrolithotomy (PNL) as a method of stone treatment has been reported in few cases with limited experience. The aim of this study is to present our experience of PNL in autosomal dominant polycystic kidney disease (ADPKD) and assessing the outcome results. From 2002 to 2011, 22 patients (26 renal units) suffering from ADPKD with stone were managed by PNL. Demographic characteristics, operative parameters and postoperative complications were recorded and analysed. The overall success rate of PNL was 82.1% and PNL with extracorporeal shock wave lithotripsy for clinically significant residual fragments was 92.85% respectively. The hematuria required blood transfusion (n = 9), postoperative fever due to cyst infection (n = 4) and paralytic ileus (n = 3) were recorded. The PNL in ADPKD PNL is safe and effective but have more postoperative complications such as bleeding requiring transfusions, fever due to cyst infection and paralytic ileus.

  12. Type II autosomal dominant osteopetrosis: radiological features in two families containing five members with asymptomatic and uncomplicated disease

    Energy Technology Data Exchange (ETDEWEB)

    Fotiadou, Anastasia; Kiriakou, Vera; Tsitouridis, Ioannis [Papageorgiou Hospital, Radiology Department, Thessaloniki (Greece); Arvaniti, Maria [Genimatas Hospital, Radiology Department, Thessaloniki (Greece)

    2009-10-15

    In this study we analysed the imaging patterns in two families containing five members with asymptomatic and uncomplicated autosomal dominant osteopetrosis (ADO II), and we report new and uncommon radiological manifestations. These findings might be useful in the context of reducing the incidence of fractures and other orthopaedic complications. Diffuse pelvic sclerosis on radiographs was observed incidentally in two patients. Both cases were asymptomatic, and the patients had never suffered a fracture. The suggestion of ADO II was raised. A detailed medical history, an imaging survey, and a haematological study were obtained so that other rare causes of osteosclerosis could be ruled out. No genetic study was conducted. All their first-degree relatives were also examined. Bony sclerosis was observed in five patients, and the radiological findings were analysed. A not previously reported thickening of the skull base without cranial nerve palsy or optic nerve atrophy was revealed in all patients. Scoliosis was present in three of them. This has been reported previously only once in ADO II. No lower limb deformity was detected. This study provided information on the pattern of radiological features in familial asymptomatic ADO II. These data on new and rare imaging findings will increase the diagnostic awareness of physicians and will guide a thorough investigation of the entire family. This might result in a consequent decrease in the incidence of fractures and other orthopaedic complications. (orig.)

  13. Type II autosomal dominant osteopetrosis: radiological features in two families containing five members with asymptomatic and uncomplicated disease

    International Nuclear Information System (INIS)

    Fotiadou, Anastasia; Kiriakou, Vera; Tsitouridis, Ioannis; Arvaniti, Maria

    2009-01-01

    In this study we analysed the imaging patterns in two families containing five members with asymptomatic and uncomplicated autosomal dominant osteopetrosis (ADO II), and we report new and uncommon radiological manifestations. These findings might be useful in the context of reducing the incidence of fractures and other orthopaedic complications. Diffuse pelvic sclerosis on radiographs was observed incidentally in two patients. Both cases were asymptomatic, and the patients had never suffered a fracture. The suggestion of ADO II was raised. A detailed medical history, an imaging survey, and a haematological study were obtained so that other rare causes of osteosclerosis could be ruled out. No genetic study was conducted. All their first-degree relatives were also examined. Bony sclerosis was observed in five patients, and the radiological findings were analysed. A not previously reported thickening of the skull base without cranial nerve palsy or optic nerve atrophy was revealed in all patients. Scoliosis was present in three of them. This has been reported previously only once in ADO II. No lower limb deformity was detected. This study provided information on the pattern of radiological features in familial asymptomatic ADO II. These data on new and rare imaging findings will increase the diagnostic awareness of physicians and will guide a thorough investigation of the entire family. This might result in a consequent decrease in the incidence of fractures and other orthopaedic complications. (orig.)

  14. Mutation Spectrum in the Large GTPase Dynamin 2, and Genotype–Phenotype Correlation in Autosomal Dominant Centronuclear Myopathy

    Science.gov (United States)

    Böhm, Johann; Biancalana, Valérie; DeChene, Elizabeth T.; Bitoun, Marc; Pierson, Christopher R.; Schaefer, Elise; Karasoy, Hatice; Dempsey, Melissa A.; Klein, Fabrice; Dondaine, Nicolas; Kretz, Christine; Haumesser, Nicolas; Poirson, Claire; Toussaint, Anne; Greenleaf, Rebecca S.; Barger, Melissa A.; Mahoney, Lane J.; Kang, Peter B.; Zanoteli, Edmar; Vissing, John; Witting, Nanna; Echaniz-Laguna, Andoni; Wallgren-Pettersson, Carina; Dowling, James; Merlini, Luciano; Oldfors, Anders; Ousager, Lilian Bomme; Melki, Judith; Krause, Amanda; Jern, Christina; Oliveira, Acary S. B.; Petit, Florence; Jacquette, Aurélia; Chaussenot, Annabelle; Mowat, David; Leheup, Bruno; Cristofano, Michele; Aldea, Juan José Poza; Michel, Fabrice; Furby, Alain; Llona, Jose E. Barcena; Van Coster, Rudy; Bertini, Enrico; Urtizberea, Jon Andoni; Drouin-Garraud, Valérie; Béroud, Christophe; Prudhon, Bernard; Bedford, Melanie; Mathews, Katherine; Erby, Lori A. H.; Smith, Stephen A.; Roggenbuck, Jennifer; Crowe, Carol A.; Spitale, Allison Brennan; Johal, Sheila C.; Amato, Anthony A.; Demmer, Laurie A.; Jonas, Jessica; Darras, Basil T.; Bird, Thomas D.; Laurino, Mercy; Welt, Selman I.; Trotter, Cynthia; Guicheney, Pascale; Das, Soma; Mandel, Jean-Louis; Beggs, Alan H.; Laporte, Jocelyn

    2012-01-01

    Centronuclear myopathy (CNM) is a genetically heterogeneous disorder associated with general skeletal muscle weakness, type I fiber predominance and atrophy, and abnormally centralized nuclei. Autosomal dominant CNM is due to mutations in the large GTPase dynamin 2 (DNM2), a mechanochemical enzyme regulating cytoskeleton and membrane trafficking in cells. To date, 40 families with CNM-related DNM2 mutations have been described, and here we report 60 additional families encompassing a broad genotypic and phenotypic spectrum. In total, 18 different mutations are reported in 100 families and our cohort harbors nine known and four new mutations, including the first splice-site mutation. Genotype–phenotype correlation hypotheses are drawn from the published and new data, and allow an efficient screening strategy for molecular diagnosis. In addition to CNM, dissimilar DNM2 mutations are associated with Charcot–Marie–Tooth (CMT) peripheral neuropathy (CMTD1B and CMT2M), suggesting a tissue-specific impact of the mutations. In this study, we discuss the possible clinical overlap of CNM and CMT, and the biological significance of the respective mutations based on the known functions of dynamin 2 and its protein structure. Defects in membrane trafficking due to DNM2 mutations potentially represent a common pathological mechanism in CNM and CMT. PMID:22396310

  15. Effects of Lacunar Infarctions on Cognitive Impairment in Patients with Cerebral Autosomal-Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

    Science.gov (United States)

    Choi, Jay Chol; Kang, Sa-Yoon; Kang, Ji-Hoon; Na, Hae Ri; Park, Ji-Kang

    2011-01-01

    Background and Purpose Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited microangiopathy caused by mutations in the Notch3 gene. Although previous studies have shown an association between lacunar infarction and cognitive impairment, the relationship between MRI parameters and cognition remains unclear. In this study we investigated the influence of MRI parameters on cognitive impairment in CADASIL. Methods We applied a prospective protocol to 40 patients. MRI analysis included the normalized volume of white-matter hyperintensities (nWMHs), number of lacunes, and number of cerebral microbleeds. Cognition was assessed with the aid of psychometric tests [Mini-Mental State Examination (MMSE), Alzheimer's Disease Assessment Scale-cognition (ADAS-cog), Trail-Making Test, and Stroop interference (Stroop IF)]. Results A multivariate regression analysis revealed that the total number of lacunes influenced the performance in the MMSE, ADAS-cog, and Stroop IF, while nWMHs had a strong univariate association with ADAS-cog and Stroop IF scores. However, this association disappeared in the multivariate analysis. Conclusions These findings demonstrate that the number of lacunes is the main predictive factor of cognitive impairment in CADASIL. PMID:22259617

  16. Hydrops fetalis and pulmonary lymphangiectasia due to FOXC2 mutation: an autosomal dominant hereditary lymphedema syndrome with variable expression.

    Science.gov (United States)

    de Bruyn, Gwendolyn; Casaer, Alexandra; Devolder, Katrien; Van Acker, Geert; Logghe, Hilde; Devriendt, Koen; Cornette, Luc

    2012-03-01

    Non-immune hydrops fetalis may find its origin within genetically determined lymphedema syndromes, caused by mutations in FOXC2 and SOX-18. We describe a newborn girl, diagnosed with non-immune hydrops fetalis at a gestational age of 30 weeks. Family history revealed the presence of an autosomal dominant late-onset form of lymphedema of the lower limbs in her father, associated with an aberrant implantation of the eyelashes in some individuals. The newborn, hydropic girl suffered from severe pulmonary lymphangiectasia, resulting in terminal respiratory failure at the age of 3 months. Genetic analysis in both the father and the newborn girl demonstrated a heterozygous FOXC2 mutation, i.e., c.939C>A, p.Tyr313X. Her two older sisters are currently asymptomatic and the parents decided not to test them for the FOXC2 mutation. Patients with a mutation in the FOXC2 transcription factor usually show lower limb lymphedema with onset at or after puberty, together with distichiasis. However, the eye manifestations can be very mild and easily overlooked. The association between FOXC2 mutation and neonatal hydrops resulting in terminal respiratory failure is not reported so far. Therefore, in sporadic patients diagnosed with non-immune hydrops fetalis, lymphangiogenic genes should be systematically screened for mutations. In addition, all cases of fetal edema must prompt a thorough analysis of the familial pedigree, in order to detect familial patterns and to facilitate adequate antenatal counseling.

  17. A de novo mutation in KCNN3 associated with autosomal dominant idiopathic non-cirrhotic portal hypertension.

    Science.gov (United States)

    Koot, Bart G P; Alders, Marielle; Verheij, Joanne; Beuers, Ulrich; Cobben, Jan M

    2016-04-01

    Non-cirrhotic portal hypertension is characterized by histopathological abnormalities in the liver, mostly affecting small intrahepatic portal veins that cause portal hypertension in the absence of cirrhosis. It can be secondary to coagulation disorders or toxic agents. However, most cases are idiopathic non-cirrhotic portal hypertension (INCPH) and familial cases are rare. We report a family in which a father and three of his four children conceived with three different mothers are affected by INCPH. Whole exome and Sanger sequencing showed the father to have a de novo single nucleotide substitution c.1348G>C in the KCNN3 gene that was transmitted to all three of his affected offspring. The KCNN3 gene encodes small conductance calcium-activated potassium (SK) channel 3. SK channels are involved in the regulation of arterial and venous vascular tone by causing smooth muscle relaxation on activation. No data exist on the expression and function of SK channels in portal veins. The autosomal dominant inheritance in this unique pedigree and the single de novo mutation identified, strongly suggests that KCNN3 mutations have a pathogenetic role in INCPH. Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  18. A Case of New Familiar Genetic Variant of Autosomal Dominant Polycystic Kidney Disease-2: A Case Study.

    Science.gov (United States)

    Litvinchuk, Tetiana; Tao, Yunxia; Singh, Ruchi; Vasylyeva, Tetyana L

    2015-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is characterized by renal cyst formation due to mutations in genes coding for polycystin-1 [PKD1 (85-90% of cases), on ch 16p13.3] and polycystin-2 [PKD2 (10-15% of cases), on ch 4q13-23] and PKD3 gene (gene unmapped). It is also associated with TSC2/PKD1 contiguous gene syndrome. ADPKD is usually inherited, but new mutations without a family history occur in approximately 10% of the cases. A 17-year-old boy was followed up for bilateral cystic kidney disease, hypertension, and obesity since he was 13 years old. The diagnosis was an accidental finding during abdominal CT at age 13 to rule out appendicitis. A renal ultrasonogram also demonstrated a multiple bilateral cysts. Because of parental history of bilateral renal cysts, PKD1 and PKD2, genetic testing was ordered. Results showed, PKD2 variant 1:3 bp deletion of TGT; nucleotide position: 1602-1604; codon position: 512-513; mRNA reading frame maintained. The same mutation was later identified in his father. A smaller number of patients have a defect in the PKD2 locus on chromosome 4 (resulting in PKD2 disease). There are no known published cases on this familiar genetic variant of ADPKD-2 cystic kidney disease. In this case, the disease is present unusually early in life.

  19. Clinical and ERG data in a family with autosomal dominant RP and Pro-347-Arg mutation in the rhodopsin gene.

    Science.gov (United States)

    Niemeyer, G; Trüb, P; Schinzel, A; Gal, A

    1992-01-01

    In a family with autosomal dominant retinitis pigmentosa, documented over six generations, a previously undescribed point mutation in the rhodopsin gene could be identified. The mutation found in the six affected members examined but in none of the controls, including healthy members of the family, was a point mutation in codon 347 predicting a substitution of the amino acid arginine for proline, designated Pro-347-Arg. Six affected members from two generations were examined clinically and with ganzfeld rod and cone electroretinography. The cone and, more dramatically, the rod electroretinograms were reduced to residual b-wave amplitudes or were non-detectable as early as ages 18 to 22 years. The Pro-347-Arg mutation resulted in a subjectively and clinically homogeneous phenotype: early onset of night blindness before age 11, relatively preserved usable visual fields until about age 30, blindness at ages 40 to 60, and change from an initial apparently sine pigmento to a hyperpigmented and atrophic fundus picture between 30 and 50 years of age.

  20. Insights into cellular and molecular basis for urinary tract infection in autosomal-dominant polycystic kidney disease.

    Science.gov (United States)

    Gao, Chao; Zhang, Long; Zhang, Ye; Wallace, Darren P; Lopez-Soler, Reynold I; Higgins, Paul J; Zhang, Wenzheng

    2017-11-01

    Urinary tract infection (UTI) is a broad term referring to an infection of the kidneys, ureters, bladder, and/or urethra. Because of its prevalence, frequent recurrence, and rising resistance to antibiotics, UTI has become a challenge in clinical practice. Autosomal-dominant polycystic kidney disease (ADPKD) is the most common monogenic disorder of the kidney and is characterized by the growth of fluid-filled cysts in both kidneys. Progressive cystic enlargement, inflammation, and interstitial fibrosis result in nephron loss with subsequent decline in kidney function. ADPKD patients frequently develop UTI; however, the cellular and molecular mechanisms responsible for the high UTI incidence in ADPKD patients remain virtually unaddressed. Emerging evidence suggests that α-intercalated cells (α-ICs) of the collecting ducts function in the innate immune defense against UTI. α-ICs inhibit bacterial growth by acidifying urine and secreting neutrophil gelatinase-associated lipocalin (NGAL) that chelates siderophore-containing iron. It is necessary to determine, therefore, if ADPKD patients with recurrent UTI have a reduced number and/or impaired function of α-ICs. Identification of the underlying cellular and molecular mechanisms may lead to the development of novel strategies to reduce UTI in ADPKD. Copyright © 2017 the American Physiological Society.

  1. The Value of Pre-Screening in the Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease Trial.

    Science.gov (United States)

    Rios-Romenets, S; Giraldo-Chica, M; López, H; Piedrahita, F; Ramos, C; Acosta-Baena, N; Muñoz, C; Ospina, P; Tobón, C; Cho, W; Ward, M; Langbaum, J B; Tariot, P N; Reiman, E M; Lopera, F

    2018-01-01

    The Alzheimer's Prevention Initiative (API) Autosomal Dominant Alzheimer's Disease (ADAD) trial evaluates the anti-amyloid-β antibody crenezumab in cognitively unimpaired persons who, based on genetic background and age, are at high imminent risk of clinical progression, and provides a powerful test of the amyloid hypothesis. The Neurosciences Group of Antioquia implemented a pre-screening process with the goals of decreasing screen failures and identifying participants most likely to adhere to trial requirements of the API ADAD trial in cognitively unimpaired members of Presenilin1 E280A mutation kindreds. The pre-screening failure rate was 48.2%: the primary reason was expected inability to comply with the protocol, chiefly due to work requirements. More carriers compared to non-carriers, and more males compared to females, failed pre-screening. Carriers with illiteracy or learning/comprehension difficulties failed pre-screening more than non-carriers. With the Colombian API Registry and our prescreening efforts, we randomized 169 30-60 year-old cognitively unimpaired carriers and 83 non-carriers who agreed to participate in the trial for at least 60 months. Our findings suggest multiple benefits of implementing a pre-screening process for enrolling prevention trials in ADAD.

  2. Type III Bartter-like syndrome in an infant boy with Gitelman syndrome and autosomal dominant familial neurohypophyseal diabetes insipidus.

    Science.gov (United States)

    Brugnara, Milena; Gaudino, Rossella; Tedeschi, Silvana; Syrèn, Marie-Louise; Perrotta, Silverio; Maines, Evelina; Zaffanello, Marco

    2014-09-01

    We report the case of an infant boy with polyuria and a familial history of central diabetes insipidus. Laboratory blood tests disclosed hypokalemia, metabolic alkalosis, hyperreninemia, and hyperaldosteronism. Plasma magnesium concentration was slightly low. Urine analysis showed hypercalciuria, hyposthenuria, and high excretion of potassium. Such findings oriented toward type III Bartter syndrome (BSIII). Direct sequencing of the CLCNKB gene revealed no disease-causing mutations. The water deprivation test was positive. Magnetic resonance imaging showed a lack of posterior pituitary hyperintensity. Finally, direct sequencing of the AVP-NPII gene showed a point mutation (c.1884G>A) in a heterozygous state, confirming an autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI). This condition did not explain the patient's phenotype; thus, we investigated for Gitelman syndrome (GS). A direct sequencing of the SLC12A3 gene showed c.269A>C and c.1205C>A new mutations. In conclusion, the patient had a genetic combination of GS and adFNDI with a BSIII-like phenotype.

  3. High-Resolution En Face Images of Microcystic Macular Edema in Patients with Autosomal Dominant Optic Atrophy

    Directory of Open Access Journals (Sweden)

    Kiyoko Gocho

    2013-01-01

    Full Text Available The purpose of this study was to investigate the characteristics of microcystic macular edema (MME determined from the en face images obtained by an adaptive optics (AO fundus camera in patients with autosomal dominant optic atrophy (ADOA and to try to determine the mechanisms underlying the degeneration of the inner retinal cells and RNFL by using the advantage of AO. Six patients from 4 families with ADOA underwent detailed ophthalmic examinations including spectral domain optical coherence tomography (SD-OCT. Mutational screening of all coding and flanking intron sequences of the OPA1 gene was performed by DNA sequencing. SD-OCT showed a severe reduction in the retinal nerve fiber layer (RNFL thickness in all patients. A new splicing defect and two new frameshift mutations with premature termination of the Opa1 protein were identified in three families. A reported nonsense mutation was identified in one family. SD-OCT of one patient showed MME in the inner nuclear layer (INL of the retina. AO images showed microcysts in the en face images of the INL. Our data indicate that AO is a useful method to identify MME in neurodegenerative diseases and may also help determine the mechanisms underlying the degeneration of the inner retinal cells and RNFL.

  4. Cataract Surgery

    Science.gov (United States)

    ... Oncology Oculoplastics/Orbit Refractive Management/Intervention Retina/Vitreous Uveitis Focus On Pediatric Ophthalmology ... Are Cataracts? Pediatric Cataracts Cataract Diagnosis and Treatment Cataract Surgery IOL Implants: Lens Replacement After Cataracts ...

  5. The genetics of hybrid male sterility between the allopatric species pair Drosophila persimilis and D. pseudoobscura bogotana: dominant sterility alleles in collinear autosomal regions.

    Science.gov (United States)

    Chang, Audrey S; Noor, Mohamed A F

    2007-05-01

    F(1) hybrid male sterility is thought to result from interactions between loci on the X chromosome and dominant-acting loci on the autosomes. While X-linked loci that contribute to hybrid male sterility have been precisely localized in many animal taxa, their dominant autosomal interactors have been more difficult to localize precisely and/or have been shown to be of relatively smaller effect. Here, we identified and mapped at least four dominant autosomal factors contributing to hybrid male sterility in the allopatric species pair Drosophila persimilis and D. pseudoobscura bogotana. Using these results, we tested predictions of reduced recombination models of speciation. Consistent with these models, three of the four QTL associated with hybrid male sterility occur in collinear (uninverted) regions of these genomes. Furthermore, these QTL do not contribute significantly to hybrid male sterility in crosses between the sympatric species D. persimilis and D. pseudoobscura pseudoobscura. The autosomal loci identified in this study provide the basis for introgression mapping and, ultimately, for molecular cloning of interacting genes that contribute to F(1) hybrid sterility.

  6. Review Recent progress in identification and characterization of loci associated with sex-linked congenital cataract.

    Science.gov (United States)

    Zhang, D D; Du, J Z; Topolewski, J; Wang, X M

    2016-07-29

    Congenital cataract is a common cause of blindness in children; however, its pathogenesis remains unclear. Genetic factors have been shown to play an important role in the pathogenesis of congenital cataract. The current genetic models of congenital cataract include autosomal dominant, autosomal recessive, and sex-linked inheritance. Sex-linked congenital cataract could be inherited through the X or Y chromosome. Congenital cataract is a symptom associated with several X-linked disorders, including Nance-Horan syndrome, Lowe syndrome, Conradi-Hünermann-Happle syndrome, oculo-facio-cardio-dental syndrome, and Alport syndrome. On the other hand, the mechanism and characteristics of Y-linked congenital cataract remains to be identified. Despite its rarity, sex-linked congenital cataract has been known to seriously affect the quality of life of patients. In this review, we present our current understanding of the genes and loci associated with sex-linked congenital cataract. This could help identify novel approaches for the prevention, early diagnosis, and comprehensive disease treatment.

  7. Mutations in POGLUT1, Encoding Protein O-Glucosyltransferase 1, Cause Autosomal-Dominant Dowling-Degos Disease

    Science.gov (United States)

    Basmanav, F. Buket; Oprisoreanu, Ana-Maria; Pasternack, Sandra M.; Thiele, Holger; Fritz, Günter; Wenzel, Jörg; Größer, Leopold; Wehner, Maria; Wolf, Sabrina; Fagerberg, Christina; Bygum, Anette; Altmüller, Janine; Rütten, Arno; Parmentier, Laurent; El Shabrawi-Caelen, Laila; Hafner, Christian; Nürnberg, Peter; Kruse, Roland; Schoch, Susanne; Hanneken, Sandra; Betz, Regina C.

    2014-01-01

    Dowling-Degos disease (DDD) is an autosomal-dominant genodermatosis characterized by progressive and disfiguring reticulate hyperpigmentation. We previously identified loss-of-function mutations in KRT5 but were only able to detect pathogenic mutations in fewer than half of our subjects. To identify additional causes of DDD, we performed exome sequencing in five unrelated affected individuals without mutations in KRT5. Data analysis identified three heterozygous mutations from these individuals, all within the same gene. These mutations, namely c.11G>A (p.Trp4∗), c.652C>T (p.Arg218∗), and c.798-2A>C, are within POGLUT1, which encodes protein O-glucosyltransferase 1. Further screening of unexplained cases for POGLUT1 identified six additional mutations, as well as two of the above described mutations. Immunohistochemistry of skin biopsies of affected individuals with POGLUT1 mutations showed significantly weaker POGLUT1 staining in comparison to healthy controls with strong localization of POGLUT1 in the upper parts of the epidermis. Immunoblot analysis revealed that translation of either wild-type (WT) POGLUT1 or of the protein carrying the p.Arg279Trp substitution led to the expected size of about 50 kDa, whereas the c.652C>T (p.Arg218∗) mutation led to translation of a truncated protein of about 30 kDa. Immunofluorescence analysis identified a colocalization of the WT protein with the endoplasmic reticulum and a notable aggregating pattern for the truncated protein. Recently, mutations in POFUT1, which encodes protein O-fucosyltransferase 1, were also reported to be responsible for DDD. Interestingly, both POGLUT1 and POFUT1 are essential regulators of Notch activity. Our results furthermore emphasize the important role of the Notch pathway in pigmentation and keratinocyte morphology. PMID:24387993

  8. European ADPKD Forum multidisciplinary position statement on autosomal dominant polycystic kidney disease care: European ADPKD Forum and Multispecialist Roundtable participants.

    Science.gov (United States)

    Harris, Tess; Sandford, Richard; de Coninck, Brenda; Devuyst, Olivier; Drenth, Joost P H; Ecder, Tevfik; Kent, Alastair; Gansevoort, Ron T; Górriz, José Luis; Ong, Albert C M; Pirson, Yves; Torres, Vicente E; Budde, Klemens; Clément, Denis; Derchi, Lorenzo E; Eleftheroudi, Marianna; Levtchenko, Elena; Peters, Dorien; Van Poppel, Hendrik; Vanholder, Raymond

    2017-12-22

    Autosomal dominant polycystic kidney disease (ADPKD) is a chronic, progressive condition characterized by the development and growth of cysts in the kidneys and other organs and by additional systemic manifestations. Individuals with ADPKD should have access to lifelong, multidisciplinary, specialist and patient-centred care involving: (i) a holistic and comprehensive assessment of the manifestations, complications, prognosis and impact of the disease (in physical, psychological and social terms) on the patient and their family; (ii) access to treatment to relieve symptoms, manage complications, preserve kidney function, lower the risk of cardiovascular disease and maintain quality of life; and (iii) information and support to help patients and their families act as fully informed and active partners in care, i.e. to maintain self-management approaches, deal with the impact of the condition and participate in decision-making regarding healthcare policies, services and research. Building on discussions at an international roundtable of specialists and patient advocates involved in ADPKD care, this article sets out (i) the principles for a patient-centred, holistic approach to the organization and delivery of ADPKD care in practice, with a focus on multispecialist collaboration and shared-decision making, and (ii) the rationale and knowledge base for a route map for ADPKD care intended to help patients navigate the services available to them and to help stakeholders and decision-makers take practical steps to ensure that all patients with ADPKD can access the comprehensive multispecialist care to which they are entitled. Further multispecialty collaboration is encouraged to design and implement these services, and to work with patient organizations to promote awareness building, education and research. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.

  9. EFFICACY AND SAFETY OF SIROLIMUS IN REDUCING CYST VOLUME IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

    Directory of Open Access Journals (Sweden)

    Sreelatha Melemadathil

    2016-11-01

    Full Text Available BACKGROUND Autosomal-Dominant Polycystic Kidney Disease is by far the most frequent inherited kidney disease. In White populations, its prevalence ranges from one in 400 to one in 1000 (Gabow 1993. Though the corresponding figure in Blacks is not yet available, the incidence of ESRD due to ADPKD is similar in American Blacks and Whites (Yium et al, 1994. Renoprotective interventions in ADPKD are maximal reduction of blood pressure and proteinuria and limit the effects of additional potential promoters of disease progression such as dyslipidaemia, chronic hyperglycaemia or smoking. At present, there is no definitive treatment for reducing cyst volume and hence disease progression. Sirolimus (Rapamycin is an immunosuppressant mostly used for the management of kidney transplant recipients. This drug by specifically and effectively inhibiting mTOR, exerts antiproliferative and growth inhibiting effects and could be important for the inhibition of cyst progression in ADPKD. MATERIALS AND METHODS It is an interventional randomised open label, active control study for six months. ADPKD type 1 patients between the age of 18 to 60 years with a GFR > 40 mL/min/1.73 m2 were included in the study. RESULTS Total number of subjects enrolled – 60. Patients enrolled in sirolimus arm – 40. Patients enrolled in conventional treatment arm - 20. Patients dropped out due to sirolimus side effects - 5. Patients lost to followup - 1. Patients completed treatment in conventional treatment arm - 20. CONCLUSION Treatment with mTOR inhibitor sirolimus for 6 months was effective in reducing total kidney volume, total renal cyst volume and volume of the largest cyst in patients with ADPKD. There was a small, but significant increase in renal parenchymal volume on treatment with sirolimus. Extending the duration of treatment to one year caused further significant reduction in total kidney volume and cyst volume. Major side effect of sirolimus in our patients was

  10. Urinary proteomic biomarkers for diagnosis and risk stratification of autosomal dominant polycystic kidney disease: a multicentric study.

    Directory of Open Access Journals (Sweden)

    Andreas D Kistler

    Full Text Available Treatment options for autosomal dominant polycystic kidney disease (ADPKD will likely become available in the near future, hence reliable diagnostic and prognostic biomarkers for the disease are strongly needed. Here, we aimed to define urinary proteomic patterns in ADPKD patients, which aid diagnosis and risk stratification. By capillary electrophoresis online coupled to mass spectrometry (CE-MS, we compared the urinary peptidome of 41 ADPKD patients to 189 healthy controls and identified 657 peptides with significantly altered excretion, of which 209 could be sequenced using tandem mass spectrometry. A support-vector-machine based diagnostic biomarker model based on the 142 most consistent peptide markers achieved a diagnostic sensitivity of 84.5% and specificity of 94.2% in an independent validation cohort, consisting of 251 ADPKD patients from five different centers and 86 healthy controls. The proteomic alterations in ADPKD included, but were not limited to markers previously associated with acute kidney injury (AKI. The diagnostic biomarker model was highly specific for ADPKD when tested in a cohort consisting of 481 patients with a variety of renal and extrarenal diseases, including AKI. Similar to ultrasound, sensitivity and specificity of the diagnostic score depended on patient age and genotype. We were furthermore able to identify biomarkers for disease severity and progression. A proteomic severity score was developed to predict height adjusted total kidney volume (htTKV based on proteomic analysis of 134 ADPKD patients and showed a correlation of r = 0.415 (p<0.0001 with htTKV in an independent validation cohort consisting of 158 ADPKD patients. In conclusion, the performance of peptidomic biomarker scores is superior to any other biochemical markers of ADPKD and the proteomic biomarker patterns are a promising tool for prognostic evaluation of ADPKD.

  11. Non-image-forming light driven functions are preserved in a mouse model of autosomal dominant optic atrophy.

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    Georgia Perganta

    Full Text Available Autosomal dominant optic atrophy (ADOA is a slowly progressive optic neuropathy that has been associated with mutations of the OPA1 gene. In patients, the disease primarily affects the retinal ganglion cells (RGCs and causes optic nerve atrophy and visual loss. A subset of RGCs are intrinsically photosensitive, express the photopigment melanopsin and drive non-image-forming (NIF visual functions including light driven circadian and sleep behaviours and the pupil light reflex. Given the RGC pathology in ADOA, disruption of NIF functions might be predicted. Interestingly in ADOA patients the pupil light reflex was preserved, although NIF behavioural outputs were not examined. The B6; C3-Opa1(Q285STOP mouse model of ADOA displays optic nerve abnormalities, RGC dendropathy and functional visual disruption. We performed a comprehensive assessment of light driven NIF functions in this mouse model using wheel running activity monitoring, videotracking and pupillometry. Opa1 mutant mice entrained their activity rhythm to the external light/dark cycle, suppressed their activity in response to acute light exposure at night, generated circadian phase shift responses to 480 nm and 525 nm pulses, demonstrated immobility-defined sleep induction following exposure to a brief light pulse at night and exhibited an intensity dependent pupil light reflex. There were no significant differences in any parameter tested relative to wildtype littermate controls. Furthermore, there was no significant difference in the number of melanopsin-expressing RGCs, cell morphology or melanopsin transcript levels between genotypes. Taken together, these findings suggest the preservation of NIF functions in Opa1 mutants. The results provide support to growing evidence that the melanopsin-expressing RGCs are protected in mitochondrial optic neuropathies.

  12. Cerebral Microbleeds and the Risk of Incident Ischemic Stroke in CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy).

    Science.gov (United States)

    Puy, Laurent; De Guio, François; Godin, Ophélia; Duering, Marco; Dichgans, Martin; Chabriat, Hugues; Jouvent, Eric

    2017-10-01

    Cerebral microbleeds are associated with an increased risk of intracerebral hemorrhage. Recent data suggest that microbleeds may also predict the risk of incident ischemic stroke. However, these results were observed in elderly individuals undertaking various medications and for whom causes of microbleeds and ischemic stroke may differ. We aimed to test the relationship between the presence of microbleeds and incident stroke in CADASIL (Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy)-a severe monogenic small vessel disease known to be responsible for both highly prevalent microbleeds and a high incidence of ischemic stroke in young patients. We assessed microbleeds on baseline MRI in all 378 patients from the Paris-Munich cohort study. Incident ischemic strokes were recorded during 54 months. Survival analyses were used to test the relationship between microbleeds and incident ischemic stroke. Three hundred sixty-nine patients (mean age, 51.4±11.4 years) were followed-up during a median time of 39 months (interquartile range, 19 months). The risk of incident ischemic stroke was higher in patients with microbleeds than in patients without (35.8% versus 19.6%, hazard ratio, 1.87; 95% confidence interval, 1.16-3.01; P =0.009). These results persisted after adjustment for history of ischemic stroke, age, sex, vascular risk factors, and antiplatelet agents use (hazard ratio, 1.89; 95% confidence interval, 1.10-3.26; P =0.02). The presence of microbleeds is an independent risk marker of incident ischemic stroke in CADASIL, emphasizing the need to carefully interpret MRI data. © 2017 American Heart Association, Inc.

  13. Type II autosomal dominant osteopetrosis (Albers-Schönberg disease): clinical and radiological manifestations in 42 patients.

    Science.gov (United States)

    Bénichou, O D; Laredo, J D; de Vernejoul, M C

    2000-01-01

    Type II autosomal dominant osteopetrosis (ADO II, Albers-Schonberg disease) is a genetic condition characterized by generalized osteosclerosis predominating in some skeletal sites such as the spine and pelvis. ADO II is rare, and most available clinical descriptions are based on small numbers of patients. We report the clinical and radiological manifestations in 42 ADO II patients. To our knowledge, this is the largest series reported so far. Our inclusion criterion was presence on radiographs of the spine of vertebral endplate thickening, producing the classic sandwich vertebra appearance. We found various patterns of sandwich vertebra, of which we provide a description to assist physicians in diagnosing ADO II. The classic bone-within-bone appearance was present in most but not all skeletal sites. The radiological penetrance of the disease was high (90%) and increased after 20 years of age. As many as 81% of our patients experienced clinical manifestations. Fractures were common (78% of patients) and healed slowly. Hip osteoarthritis developed in 27% of patients and required arthroplasty in 9 of the 16 affected hips. Nonmandibular osteomyelitis occurred in 4 cases (11%). Twenty-four percent of patients had thoracic or lumbar scoliosis. Orthopedic surgery was performed in 52.8% of patients, of whom half had at least three surgical procedures for internal fracture fixation, arthroplasty, limb deformity correction, or treatment of surgical complications. There was a high rate of surgical complications including nonunion, infection, prosthesis loosening, and intraoperative fractures. Nearly two-thirds of patients (64%) had stomatologic manifestations, including mandibular osteomyelitis in 4 patients (11%). Cranial nerve involvement responsible for hearing loss, bilateral optic atrophy, and/or facial palsy was present in 14 patients but was clearly attributable to ADO II in only 6 cases (16%). This large series sheds new light on several aspects of ADO II, most

  14. Laparoscopic Nephrectomy versus Open Nephrectomy for Patients with Autosomal Dominant Polycystic Kidney Disease: A Systematic Review and Meta-Analysis.

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    Pengyu Guo

    Full Text Available To compare efficacy and safety of laparoscopicnephrectomy (LN versus open nephrectomy (ON in the management of autosomal dominant polycystic kidney disease (ADPKD, we conducted a systematic review and meta-analysis.A systematic search of the electronic databases PubMed, Scopus, and the Cochrane Library was performed up to October 2014. This systematic review was performed based on observational comparative studies that assessed the two techniques. The weighted mean difference (WMD and risk ratio (RR, with their corresponding 95% confidence interval (CI, were calculated to compare continuous and dichotomous variables, respectively.Seven studies were identified, including 195 cases (118 LN/77 ON. Although LN was associated with longer operative time (WMD 30.236, 95%CI 14.541 -45.932, P<0.001 and the specimen might not have been resected as heavy as the ON group (WMD -986.516, 95%CI -1883.24--89.795, P = 0.031, patients in this group might benefit from a shorter length of hospital stay (WMD -3.576, 95%CI 4.976--2.176, P <0.001, less estimated blood loss (WMD -180.245, 95%CI -317.939--42.556, P = 0.010, and lower need of transfusion (RR 0.345, 95%CI 0.183-0.650, P = 0.001. The LN group also had less overall complications (RR 0.545, 95%CI 0.329-0.903, P = 0.018. The need of narcotic analgesics between the two groups might have no significant difference (WMD -54.66, 95%CI -129.76-20.44, P = 0.154.LN for giant symptomatic ADPKD was feasible, safe and efficacious. Morbidity was significantly reduced compared with the open approach. For an experienced laparoscopist, LN might be a better alternative.

  15. Positron-emission computed tomography in cyst infection diagnosis in patients with autosomal dominant polycystic kidney disease.

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    Jouret, François; Lhommel, Renaud; Beguin, Claire; Devuyst, Olivier; Pirson, Yves; Hassoun, Ziad; Kanaan, Nada

    2011-07-01

    Cyst infection remains a challenging issue in patients with autosomal dominant polycystic kidney disease (ADPKD). In most patients, conventional imaging techniques are inconclusive. Isolated observations suggest that (18)fluorodeoxyglucose (¹⁸FDG) positron-emission computed tomography (PET/CT) might help detect cyst infection in ADPKD patients. Comparative assessment of administrative databases from January 2005 to December 2009 identified 27 PET/CT scans performed in 24 ADPKD patients for suspicion of abdominal infection. Cyst infection was definite if confirmed by cyst fluid analysis. Cyst infection was probable if all four of the following criteria were met: temperature of >38°C for >3 days, loin or liver tenderness, C-reactive protein plasma level of >5 mg/dl, and no CT evidence for intracystic bleeding. Episodes with only two or three criteria were grouped as "fever of unknown origin". Thirteen infectious events in 11 patients met all criteria for kidney (n = 3) or liver (n = 10) cyst infection. CT was contributive in only one patient, whereas PET/CT proved cyst infection in 11 patients (84.6%). In addition, 14 episodes of "fever of unknown origin" in 13 patients were recorded. PET/CT identified the source of infection in nine patients (64.3%), including 2 renal cyst infections. Conversely, PET/CT showed no abnormal ¹⁸FDG uptake in 5 patients, including 2 intracystic bleeding. The median delay between the onset of symptoms and PET/CT procedure was 9 days. This retrospective series underscores the usefulness of PET/CT to confirm and locate cyst infection and identify alternative sources of abdominal infection in ADPKD patients.

  16. A novel mutation in PRPF31, causative of autosomal dominant retinitis pigmentosa, using the BGISEQ-500 sequencer

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    Yu Zheng

    2018-01-01

    Full Text Available AIM: To study the genes responsible for retinitis pigmentosa. METHODS: A total of 15 Chinese families with retinitis pigmentosa, containing 94 sporadically afflicted cases, were recruited. The targeted sequences were captured using the Target_Eye_365_V3 chip and sequenced using the BGISEQ-500 sequencer, according to the manufacturer’s instructions. Data were aligned to UCSC Genome Browser build hg19, using the Burroughs Wheeler Aligner MEM algorithm. Local realignment was performed with the Genome Analysis Toolkit (GATK v.3.3.0 IndelRealigner, and variants were called with the Genome Analysis Toolkit Haplotypecaller, without any use of imputation. Variants were filtered against a panel derived from 1000 Genomes Project, 1000G_ASN, ESP6500, ExAC and dbSNP138. In all members of Family ONE and Family TWO with available DNA samples, the genetic variant was validated using Sanger sequencing. RESULTS: A novel, pathogenic variant of retinitis pigmentosa, c.357_358delAA (p.Ser119SerfsX5 was identified in PRPF31 in 2 of 15 autosomal-dominant retinitis pigmentosa (ADRP families, as well as in one, sporadic case. Sanger sequencing was performed upon probands, as well as upon other family members. This novel, pathogenic genotype co-segregated with retinitis pigmentosa phenotype in these two families. CONCLUSION: ADRP is a subtype of retinitis pigmentosa, defined by its genotype, which accounts for 20%-40% of the retinitis pigmentosa patients. Our study thus expands the spectrum of PRPF31 mutations known to occur in ADRP, and provides further demonstration of the applicability of the BGISEQ500 sequencer for genomics research.

  17. A novel mutation in PRPF31, causative of autosomal dominant retinitis pigmentosa, using the BGISEQ-500 sequencer

    Science.gov (United States)

    Zheng, Yu; Wang, Hai-Lin; Li, Jian-Kang; Xu, Li; Tellier, Laurent; Li, Xiao-Lin; Huang, Xiao-Yan; Li, Wei; Niu, Tong-Tong; Yang, Huan-Ming; Zhang, Jian-Guo; Liu, Dong-Ning

    2018-01-01

    AIM To study the genes responsible for retinitis pigmentosa. METHODS A total of 15 Chinese families with retinitis pigmentosa, containing 94 sporadically afflicted cases, were recruited. The targeted sequences were captured using the Target_Eye_365_V3 chip and sequenced using the BGISEQ-500 sequencer, according to the manufacturer's instructions. Data were aligned to UCSC Genome Browser build hg19, using the Burroughs Wheeler Aligner MEM algorithm. Local realignment was performed with the Genome Analysis Toolkit (GATK v.3.3.0) IndelRealigner, and variants were called with the Genome Analysis Toolkit Haplotypecaller, without any use of imputation. Variants were filtered against a panel derived from 1000 Genomes Project, 1000G_ASN, ESP6500, ExAC and dbSNP138. In all members of Family ONE and Family TWO with available DNA samples, the genetic variant was validated using Sanger sequencing. RESULTS A novel, pathogenic variant of retinitis pigmentosa, c.357_358delAA (p.Ser119SerfsX5) was identified in PRPF31 in 2 of 15 autosomal-dominant retinitis pigmentosa (ADRP) families, as well as in one, sporadic case. Sanger sequencing was performed upon probands, as well as upon other family members. This novel, pathogenic genotype co-segregated with retinitis pigmentosa phenotype in these two families. CONCLUSION ADRP is a subtype of retinitis pigmentosa, defined by its genotype, which accounts for 20%-40% of the retinitis pigmentosa patients. Our study thus expands the spectrum of PRPF31 mutations known to occur in ADRP, and provides further demonstration of the applicability of the BGISEQ500 sequencer for genomics research. PMID:29375987

  18. Autosomal-dominant chronic mucocutaneous candidiasis with STAT1-mutation can be complicated with chronic active hepatitis and hypothyroidism.

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    Hori, Tomohiro; Ohnishi, Hidenori; Teramoto, Takahide; Tsubouchi, Kohji; Naiki, Takafumi; Hirose, Yoshinobu; Ohara, Osamu; Seishima, Mariko; Kaneko, Hideo; Fukao, Toshiyuki; Kondo, Naomi

    2012-12-01

    To describe a case of autosomal-dominant (AD)-chronic mucocutaneous candidiasis (CMC) with a signal transducer and activator of transcription (STAT) 1 gene mutation, and some of the important complications of this disease such as chronic hepatitis. We present a 23-year-old woman with CMC, chronic active hepatitis, and hypothyroidism. Her father also had CMC. We performed several immunological analyses of blood and liver samples, and searched for gene mutations for CMC in the patient and her father. We identified the heterozygous substitution c.821 G > A (p.Arg274Gln) in the STAT1 gene of both the patient and her father. The level of β-glucan induced interferon (IFN)-γ in her blood cells was significantly low. Immunoblot analysis detected serum anti-interleukin (IL)-17 F autoantibody. She was found to have increased (low-titer) antibodies related to her hypothyroidism and hepatitis. Her serum IL-18 levels fluctuated with her AST and ALT levels. Liver biopsy revealed CD68-positive cell infiltration and IL-18 expression in the sinusoidal regions. These results suggest that the chronic active hepatitis in this patient may be exacerbated by the excessive IL-18 accumulation caused by recurrent mucocutaneous fungal infection, and decreased IFN-γ production. AD-CMC is known to be caused by a gain-of-function mutation of the STAT1 gene. Chronic active hepatitis is a rare complication of AD-CMC, with currently unknown pathogenesis. It seems that the clinical phenotype in this patient is modified by autoimmune mechanisms and cytokine dysregulation. AD-CMC can be complicated by various immune disorders including autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy.

  19. Exon sequencing of PKD1 gene in an Iranian patient with autosomal-dominant polycystic kidney disease.

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    Hafizi, Atousa; Khatami, Saeid Reza; Galehdari, Hamid; Shariati, Gholamreza; Saberi, Ali Hossein; Hamid, Mohammad

    2014-07-01

    Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common genetic kidney disorders with the incidence of 1 in 1,000 births. ADPKD is genetically heterogeneous with two genes identified: PKD1 (16p13.3, 46 exons) and PKD2 (4q21, 15 exons). Eighty five percent of the patients with ADPKD have at least one mutation in the PKD1 gene. Genetic studies have demonstrated an important allelic variability among patients, but very few data are known about the genetic variation among Iranian populations. In this study, exon direct sequencing of PKD1 was performed in a seven-year old boy with ADPKD and in his parents. The patient's father was ADPKD who was affected without any kidney dysfunction, and the patient's mother was congenitally missing one kidney. Molecular genetic testing found a mutation in all three members of this family. It was a missense mutation GTG>ATG at position 3057 in exon 25 of PKD1. On the other hand, two novel missense mutations were reported just in the 7-year-old boy: ACA>GCA found in exon 15 at codon 2241 and CAC>AAC found in exon 38 at codon 3710. For checking the pathogenicity of these mutations, exons 15, 25, and 38 of 50 unrelated normal cases were sequenced. our findings suggested that GTG>ATG is a polymorphism with high frequency (60%) as well as ACA>GCA and CAC>AAC are polymorphisms with frequencies of 14% and 22%, respectively in the population of Southwest Iran.

  20. Novel calcium-sensing receptor cytoplasmic tail deletion mutation causing autosomal dominant hypocalcemia: molecular and clinical study.

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    Obermannova, Barbora; Sumnik, Zdenek; Dusatkova, Petra; Cinek, Ondrej; Grant, Michael; Lebl, Jan; Hendy, Geoffrey N

    2016-04-01

    Autosomal dominant hypocalcemia (ADH) is a rare disorder caused by activating mutations of the calcium-sensing receptor (CASR). The treatment of ADH patients with 1α-hydroxylated vitamin D derivatives can cause hypercalciuria leading to nephrocalcinosis. We studied a girl who presented with hypoparathyroidism and asymptomatic hypocalcemia at age 2.5 years. Mutations of CASR were investigated by DNA sequencing. Functional analyses of mutant and WT CASRs were done in transiently transfected human embryonic kidney (HEK293) cells. The proband and her father are heterozygous for an eight-nucleotide deletion c.2703_2710delCCTTGGAG in the CASR encoding the intracellular domain of the protein. Transient expression of CASR constructs in kidney cells in vitro suggested greater cell surface expression of the mutant receptor with a left-shifted extracellular calcium dose-response curve relative to that of the WT receptor consistent with gain of function. Initial treatment of the patient with calcitriol led to increased urinary calcium excretion. Evaluation for mosaicism in the paternal grandparents of the proband was negative. We describe a novel naturally occurring deletion mutation within the CASR that apparently arose de novo in the father of the ADH proband. Functional analysis suggests that the cytoplasmic tail of the CASR contains determinants that regulate the attenuation of signal transduction. Early molecular analysis of the CASR gene in patients with isolated idiopathic hypoparathyroidism is recommended because of its relevance to clinical outcome and treatment choice. In ADH patients, calcium supplementation and low-dose cholecalciferol avoids hypocalcemic symptoms without compromising renal function. © 2016 European Society of Endocrinology.

  1. Variability in clinical phenotypes of PRPF8-linked autosomal dominant retinitis pigmentosa correlates with differential PRPF8/SNRNP200 interactions.

    Science.gov (United States)

    Escher, Pascal; Passarin, Olga; Munier, Francis L; Tran, Viet H; Vaclavik, Veronika

    2018-01-01

    To expand the genotype/phenotype correlations in patients with autosomal dominant retinitis pigmentosa (adRP) harboring PRPF8 variants. Two patients, a father and his daughter, harboring a novel p.PRPF8-Glu2331* variant, underwent ophthalmic examination at 3-year-interval, including fundus photography, fundus autofluorescence, optical coherence tomography, and ISCEV standard full field ERGs. All reported disease-causing PRPF8 variants were collected and localized in the PRPF8 and PRPF8/SNRNP200 protein structures. The p.PRPF8-Glu2331* variant results in a truncated PRPF8 protein lacking the last five C-terminal amino acids and caused in the two patients a severe clinical phenotype, with the macula being affected from the second decade on. All but two adRP-linked variants are located in the last exon 43 encoding the C-terminal tail of the C-terminal PRPF8 Jab1 domain. The p.PRPF8-Ser2118Phe and -Asn2280Lys variants encoded by exons 39 and 42, respectively, are located at the basis of the C-terminal tail. Frame-shift mutations and nonconservative amino acid changes in PRPF8 typically cause severe clinical phenotypes. The conservative missense variant p.PRPF8-Arg2310Lys that is not altering the global charge of the C-terminal tail, and variants located at the basis of the C-terminal tail show milder clinical phenotypes, in accordance with functional data on PRPF8/SNRNP200 interactions in yeast.

  2. Novel BICD2 mutation in a Japanese family with autosomal dominant lower extremity-predominant spinal muscular atrophy-2.

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    Yoshioka, Mieko; Morisada, Naoya; Toyoshima, Daisaku; Yoshimura, Hajime; Nishio, Hisahide; Iijima, Kazumoto; Takeshima, Yasuhiro; Uehara, Tomoko; Kosaki, Kenjiro

    2018-04-01

    The most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogenous and largely remain to be elucidated. We present a father and son with atrophy and weakness of the lower leg muscles since infancy. Genetic studies in this family revealed a novel BICD2 mutation causing autosomal dominant lower extremity-predominant SMA type 2. The proband was the father, aged 30, and the son was aged 3. Both of them were born uneventfully to nonconsanguineous parents. While the father first walked at the age of 19 months, the son was unable to walk at age 3 years. In both, knee and ankle reflexes were absent and sensation was intact. Serum creatine kinase levels were normal. The son showed congenital arthrogryposis and underwent orthopedic corrections for talipes calcaneovalgus. Investigation of the father at the age of 5 years revealed normal results on nerve conduction studies and sural nerve biopsy. Electromyography showed chronic neurogenic change, and muscle biopsy showed features suggestive of denervation. The father was diagnosed clinically with a sporadic distal SMA. Follow-up studies showed very slow progression. Next-generation and Sanger sequencing revealed a deleterious mutation in BICD2: c.1667A>G, p.Tyr556Cys, in this family. BICD2 is a cytoplasmic conserved motor-adaptor protein involved in anterograde and retrograde transport along the microtubules. Next-generation sequencing will further clarify the genetic basis of non-5q SMA. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  3. Novel three-dimensional imaging volumetry in autosomal dominant polycystic kidney disease: comparison with 2D volumetry.

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    Shin, Dongsuk; Lee, Kyu-Beck; Hyun, Young Youl; Lee, Young Rae; Hwang, Young-Hwan; Park, Hayne Cho; Ahn, Curie

    2014-08-01

    Autosomal dominant polycystic kidney disease (ADPKD) volumetry is an important marker for evaluating the progression of disease. Three-dimensional (3D) volumetry is generally more timesaving than 2D volumetry, but its reliability and accuracy are uncertain. Small and large phantoms simulating polycystic kidneys and 20 patients with ADPKD underwent magnetic resonance imaging (MRI) volumetry. We evaluated the total kidney volume (TKV) and total cyst volume (TCV) using a novel 3D volumetry program (XelisTM) and compared 3D volumetry data with the conventional 2D method (the reference volume values). After upload and threshold setting, the other organs surrounding the kidney were removed by picking and sculpting. The novel method involves drawing of the kidney or cyst and automatic measurement of kidney volume and cyst volume in 3D images. The 3D volume estimation of the small and large phantoms differed from the actual values by 6.9% and -8.2%, respectively, for TKV and by 2.1% and 1.4% for TCV. In ADPKD patients, the intra-reader reliability of 3D volumetry was 30 ± 180 mL (1.3 ± 10.3%) and 25 ± 113 mL (1.2 ± 9.4%), respectively, for TKV and TCV. Correlation between 3D volumetry and 2D volumetry of TKV and TCV resulted in a high correlation coefficient and a regression slope approaching 1.00 (r = 0.97 - 0.98). The mean of the volume percentage differences for 3D vs. 2D for TKV : TCV were -6.0 ± 8.9% : 2.0 ± 11.8% in large ADPKD and -16.1 ± 10.4% : 13.2 ± 21.9% in small ADPKD. Our study showed that 3D volumetry has reliability and accuracy compared with 2D volumetry in ADPKD. 3D volumetry is more accurate for TCV and large ADPKD.

  4. Autosomal-dominant GTPCH1-deficient DRD: clinical characteristics and long-term outcome of 34 patients.

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    Trender-Gerhard, I; Sweeney, M G; Schwingenschuh, P; Mir, P; Edwards, M J; Gerhard, A; Polke, J M; Hanna, M G; Davis, M B; Wood, N W; Bhatia, K P

    2009-08-01

    An autosomal dominantly inherited defect in the GCH1 gene that encodes guanosine triphosphate cyclohydrolase 1 (GTPCH1) is the most common cause of dopa-responsive dystonia (DRD). A classic phenotype of young-onset lower-limb dystonia, diurnal fluctuations and excellent response to levodopa has been well recognised in association with GCH1 mutations, and rare atypical presentations have been reported. However, a number of clinical issues remain unresolved including phenotypic variability, long-term response to levodopa and associated non-motor symptoms, and there are limited data on long-term follow-up of genetically proven cases. A detailed clinical evaluation of 34 patients (19 women, 15 men), with confirmed mutations in the GCH1 gene, is presented. The classic phenotype was most frequent (n = 23), with female predominance (F:M = 16:7), and early onset (mean 4.5 years) with involvement of legs. However, a surprisingly large number of patients developed craniocervical dystonia, with spasmodic dysphonia being the predominant symptom in two subjects. A subset of patients, mainly men, presented with either a young-onset (mean 6.8 years) mild DRD variant not requiring treatment (n = 4), or with an adult-onset (mean 37 years) Parkinson disease-like phenotype (n = 4). Two siblings were severely affected with early hypotonia and delay in motor development, associated with compound heterozygous GCH1 gene mutations. The study also describes a number of supplementary features including restless-legs-like symptoms, influence of female sex hormones, predominance of tremor or parkinsonism in adult-onset cases, initial reverse reaction to levodopa, recurrent episodes of depressive disorder and specific levodopa-resistant symptoms (writer's cramp, dysphonia, truncal dystonia). Levodopa was used effectively and safely in 20 pregnancies, and did not cause any fetal abnormalities.

  5. Clinical characteristics and disease predictors of a large Chinese cohort of patients with autosomal dominant polycystic kidney disease.

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    Dongping Chen

    Full Text Available OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD is a relentlessly progressing form of chronic kidney disease for which there is no cure. The aim of this study was to characterize Chinese patients with ADPKD and to identify the factors which predict cyst growth and renal functional deterioration. METHODS: To analyze disease predicting factors we performed a prospective longitudinal observational study in a cohort of 541 Chinese patients with ADPKD and an eGFR ≥ 30 ml/min/1.73 m(2. Patients were followed clinically and radiologically with sequential abdominal magnetic resonance imaging (MRI. Clinical characteristics and laboratory data were related to changes in estimated glomerular filtration rate (eGFR and total kidney volume (TKV. A linear regression model was developed to analyze the factors which determine eGFR and TKV changes. RESULTS: The age range of this unselected cohort ranged from 4 to 77 years. Median follow-up time was 14.3 ± 10.6 months. Although inter-individual differences in eGFR and TKV were large, there was a consistent link between these two parameters. Baseline log10-transformed TKV and urinary protein/creatinine ratio were identified as the major predictors for a faster eGFR decline and were associated with a higher TKV growth rate. Interestingly, a lower thrombocyte count correlated significantly with lower eGFR (r = 0.222 and higher TKV (r = 0.134. CONCLUSIONS: This large cohort of Chinese patients with ADPKD provides unique epidemiological data for comparison with other cohorts of different ethnicity. In Chinese patients we identified a lower thrombocyte count as a significant predictor of disease progression. These results are important for the design of future clinical trials to retard polycystic kidney disease progression.

  6. Prognostic importance of congenital cataract morphology: A case report

    Directory of Open Access Journals (Sweden)

    Çağrı İlhan

    2018-02-01

    Full Text Available Congenital cataract (CC has an important place in pediatric ocular diseases. CCs are different from senile nuclear cataracts in terms of their etiologic, clinic and morphological characteristics. CCs occur many different forms such as non-hereditary isolated cases or autosomal dominant bilateral cases. In addition, many of ocular and systemic diseases can be associated with CC and ophthalmologist should be aware of these potential risks. In this article, we questioned whether the different morphological features of CC have prognostic importance or effect decision of surgery by considering a case of CC.

  7. Identification of IFRD1 variant in a Han Chinese family with autosomal dominant hereditary spastic paraplegia associated with peripheral neuropathy and ataxia.

    Science.gov (United States)

    Lin, Pengfei; Zhang, Dong; Xu, Guangrun; Yan, Chuanzhu

    2018-04-01

    Spinocerebellar ataxias (SCAs) are a group of autosomal dominant, clinically heterogeneous neurodegenerative disorders. SCA18 is a rare autosomal dominant sensory/motor neuropathy with ataxia (OMIM#607458) associated with a single missense variant c.514 A>G in the interferon related developmental regulator 1 (IFRD1) gene previously reported in a five-generation American family of Irish origin. However, to date, there have been no other reports of the IFRD1 mutation to confirm its role in SCA. Here, we report a Han Chinese family with SCA18; the family members presented with a slowly progressing gait ataxia, pyramidal tract signs, and peripheral neuropathy. We identified a missense variant (c.514 A>G, p.I172V) in IFRD1 gene in the family using targeted next-generation sequencing and Sanger direct sequencing with specific primers. Our results suggest that the IFRD1 gene may be the causative allele for SCA18.

  8. Genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of the EVR1 locus on chromosome 11q in a large autosomal dominant pedigree.

    Science.gov (United States)

    Bamashmus, M A; Downey, L M; Inglehearn, C F; Gupta, S R; Mansfield, D C

    2000-04-01

    Familial exudative vitreoretinopathy (FEVR) is associated with mutations in the Norrie disease gene in X linked pedigrees and with linkage to the EVR1 locus at 11q13 in autosomal dominant cases. A large autosomal dominant FEVR family was studied, both clinically and by linkage analysis, to determine whether it differed from the known forms of FEVR. Affected members and obligate gene carriers from this family were examined by slit lamp biomicroscopy, indirect ophthalmoscopy, and in some cases fluorescein angiography. Patient DNAs were genotyped for markers at the EVR1 locus on chromosome 11q13. The clinical evaluation in this family is consistent with previous descriptions of FEVR pedigrees, but linkage analysis proves that it has a form of FEVR genetically distinct from the EVR1 locus on 11q. This proves that there are at least three different loci associated with comparable FEVR phenotypes, a situation similar to that existing for many forms of retinal degeneration.

  9. Diagnostic Algorithm in the Management of Acute Febrile Abdomen in Patients with Autosomal Dominant Polycystic Kidney Disease.

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    Marie Neuville

    Full Text Available Acute febrile abdomen represents a diagnostic challenge in patients with autosomal dominant polycystic kidney disease (ADPKD. Although criteria have been proposed for cyst infection (CyI and hemorrhage (CyH, there is a lack of comparative assessments. Furthermore, distinguishing cystic from non-cystic complications remains problematic.ADPKD patients presenting with abdominal pain and/or fever between 01/2005 and 06/2015 were retrospectively identified in a systematic computerized billing database. CyH was defined as spontaneous intracystic density above 50 Hounsfield units on computed tomography (CT. CyI was definite if confirmed by cyst puncture, and probable if 4 criteria were met: 3-day fever, loin/liver tenderness, C-reactive protein (CRP plasma levels >50mg/L and no CT evidence for CyH. Other episodes were grouped as inflammation of unknown origin (IUO.Among a cohort of 173 ADPKD patients, 101 presented with 205 episodes of abdominal pain (n = 172 and/or fever (n = 33. 20 patients experienced 30 CyH, whereas 16 presented 23 episodes of definite (n = 11 or probable (n = 12 CyI. 35 IUO were observed in 31 patients. Clinically, fever was observed in 7% vs. 100% vs. 66% of CyH, CyI and IUO, respectively. Biologically, CRP cut-off at 70 mg/dl showed 92% sensitivity and 81% specificity in CyI diagnosis. Urine or blood cultures remained sterile in >90% of CyH, but were contributive in 53.4% of CyI and IUO, with a 74.2% prevalence for E. coli. Radiologically, ultrasounds, CT and magnetic resonance diagnosed CyI in 2.6%, 20% and 16.7% of cases, respectively. 18F-FDG positron-emission tomography (PET/CT was done within a median period of 7 days post antibiotics, and significantly changed patient management in 71.4%.This retrospective single-center series underscores the usefulness of clinical-fever-and biological-CRP-parameters, but emphasizes the limitations of bacteriological and radiological investigations in cases of acute febrile abdomen in

  10. Characteristics of intracranial aneurysms in the else kröner-fresenius registry of autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Neumann, Hartmut P H; Malinoc, Angelica; Bacher, Janina; Nabulsi, Zinaida; Ivanovas, Vera; Bruechle, Nadine Ortiz; Mader, Irina; Hoffmann, Michael M; Riegler, Peter; Kraemer-Guth, Annette; Burchardi, Christian; Schaeffner, Elke; Martin, Rodolfo S; Azurmendi, Pablo J; Zerres, Klaus; Jilg, Cordula; Eng, Charis; Gläsker, Sven

    2012-01-01

    Patients who harbor intracranial aneurysms (IAs) run a risk for aneurysm rupture and subsequent subarachnoid hemorrhage which frequently results in permanent deficits or death. Prophylactic treatment of unruptured aneurysms is possible and recommended depending on the size and location of the aneurysm as well as patient age and condition. IAs are major manifestations of autosomal dominant polycystic kidney disease (ADPKD). Current guidelines do not suggest surveillance of IAs in ADPKD except in the setting of family history if IA was known in any relative with ADPKD. Management of IAs in ADPKD is problematic because limited data exist from large studies. We established the Else Kröner-Fresenius Registry for ADPKD in Germany. Clinical data were assessed for age at diagnosis of IAs, stage of renal insufficiency, and number, location and size of IAs as well as family history of cerebral events. Patients with symptomatic or asymptomatic IAs were included. All patients with ADPKD-related IAs were offered mutation scanning of the susceptibility genes for ADPKD, the PKD1 and PKD2 genes. Of 463 eligible ADPKD patients from the population base of Germany, 32 (7%) were found to have IAs, diagnosed at the age of 2-71 years, 19 females and 13 males. Twenty (63%) of these 32 patients were symptomatic, whereas IAs were detected in an asymptomatic stage in 12 patients. IAs were multifocal in 12 and unifocal in 20 patients. In 26 patients (81%), IAs were diagnosed before end-stage renal failure. Twenty-five out of 27 unrelated index cases (93%) had no IAs or cerebral events documented in their relatives with ADPKD. In 16 unrelated index patients and 3 relatives, we detected germline mutations. The mutations were randomly distributed across the PKD1 gene in 14 and the PKD2 gene in 2 index cases. Questionnaires answered for 320/441 ADPKD patients without IAs revealed that only 45/320 (14%) had MR angiography. In ADPKD, rupture of IAs occurs frequently before the start of dialysis

  11. Mutations in Splicing Factor Genes Are a Major Cause of Autosomal Dominant Retinitis Pigmentosa in Belgian Families

    Science.gov (United States)

    Coppieters, Frauke; Roels, Dimitri; De Jaegere, Sarah; Flipts, Helena; De Zaeytijd, Julie; Walraedt, Sophie; Claes, Charlotte; Fransen, Erik; Van Camp, Guy; Depasse, Fanny; Casteels, Ingele; de Ravel, Thomy

    2017-01-01

    Purpose Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition. Methods Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations. Results Molecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5–30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%). Conclusions Overall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular

  12. Autosomal Dominant Tubulointerstitial Kidney Disease: Clinical Presentation of Patients With ADTKD-UMOD and ADTKD-MUC1.

    Science.gov (United States)

    Ayasreh, Nadia; Bullich, Gemma; Miquel, Rosa; Furlano, Mónica; Ruiz, Patricia; Lorente, Laura; Valero, Oliver; García-González, Miguel Angel; Arhda, Nisrine; Garin, Intza; Martínez, Víctor; Pérez-Gómez, Vanessa; Fulladosa, Xavier; Arroyo, David; Martínez-Vea, Alberto; Espinosa, Mario; Ballarín, Jose; Ars, Elisabet; Torra, Roser

    2018-05-18

    Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare underdiagnosed cause of end-stage renal disease (ESRD). ADTKD is caused by mutations in at least 4 different genes: MUC1, UMOD, HNF1B, and REN. Retrospective cohort study. 56 families (131 affected individuals) with ADTKD referred from different Spanish hospitals. Clinical, laboratory, radiologic, and pathologic data were collected, and genetic testing for UMOD, MUC1, REN, and HNF1B was performed. Hyperuricemia, ultrasound findings, renal histology, genetic mutations. Age at ESRD, rate of decline in estimated glomerular filtration rate. ADTKD was diagnosed in 25 families (45%), 9 carried UMOD pathogenic variants (41 affected members), and 16 carried the MUC1 pathogenic mutation c.(428)dupC (90 affected members). No pathogenic variants were identified in REN or HNF1B. Among the 77 individuals who developed ESRD, median age at onset of ESRD was 51 years for those with ADTKD-MUC1 versus 56 years (P=0.1) for those with ADTKD-UMOD. Individuals with the MUC1 duplication presented higher risk for developing ESRD (HR, 2.24; P=0.03). The slope of decline in estimated glomerular filtration rate showed no significant difference between groups (-3.0mL/min/1.73m 2 per year in the ADTKD-UMOD group versus -3.9mL/min/1.73m 2 per year in the ADTKD-MUC1 group; P=0.2). The prevalence of hyperuricemia was significantly higher in individuals with ADTKD-UMOD (87% vs 54%; P=0.006). Although gout occurred more frequently in this group, the difference was not statistically significant (24% vs 7%; P=0.07). Relatively small Spanish cohort. MUC1 analysis limited to cytosine duplication. The main genetic cause of ADTKD in our Spanish cohort is the MUC1 pathogenic mutation c.(428)dupC. Renal survival may be worse in individuals with the MUC1 mutation than in those with UMOD mutations. Clinical presentation does not permit distinguishing between these variants. However, hyperuricemia and gout are more frequent in individuals

  13. Characteristics of Intracranial Aneurysms in the Else Kröner-Fresenius Registry of Autosomal Dominant Polycystic Kidney Disease

    Science.gov (United States)

    Neumann, Hartmut P.H.; Malinoc, Angelica; Bacher, Janina; Nabulsi, Zinaida; Ivanovas, Vera; Bruechle, Nadine Ortiz; Mader, Irina; Hoffmann, Michael M.; Riegler, Peter; Kraemer-Guth, Annette; Burchardi, Christian; Schaeffner, Elke; Martin, Rodolfo S.; Azurmendi, Pablo J.; Zerres, Klaus; Jilg, Cordula; Eng, Charis; Gläsker, Sven

    2012-01-01

    Background Patients who harbor intracranial aneurysms (IAs) run a risk for aneurysm rupture and subsequent subarachnoid hemorrhage which frequently results in permanent deficits or death. Prophylactic treatment of unruptured aneurysms is possible and recommended depending on the size and location of the aneurysm as well as patient age and condition. IAs are major manifestations of autosomal dominant polycystic kidney disease (ADPKD). Current guidelines do not suggest surveillance of IAs in ADPKD except in the setting of family history if IA was known in any relative with ADPKD. Management of IAs in ADPKD is problematic because limited data exist from large studies. Methods We established the Else Kröner-Fresenius Registry for ADPKD in Germany. Clinical data were assessed for age at diagnosis of IAs, stage of renal insufficiency, and number, location and size of IAs as well as family history of cerebral events. Patients with symptomatic or asymptomatic IAs were included. All patients with ADPKD-related IAs were offered mutation scanning of the susceptibility genes for ADPKD, the PKD1 and PKD2 genes. Results Of 463 eligible ADPKD patients from the population base of Germany, 32 (7%) were found to have IAs, diagnosed at the age of 2–71 years, 19 females and 13 males. Twenty (63%) of these 32 patients were symptomatic, whereas IAs were detected in an asymptomatic stage in 12 patients. IAs were multifocal in 12 and unifocal in 20 patients. In 26 patients (81%), IAs were diagnosed before end-stage renal failure. Twenty-five out of 27 unrelated index cases (93%) had no IAs or cerebral events documented in their relatives with ADPKD. In 16 unrelated index patients and 3 relatives, we detected germline mutations. The mutations were randomly distributed across the PKD1 gene in 14 and the PKD2 gene in 2 index cases. Questionnaires answered for 320/441 ADPKD patients without IAs revealed that only 45/320 (14%) had MR angiography. Conclusion In ADPKD, rupture of IAs occurs

  14. Characteristics of Intracranial Aneurysms in the Else Kröner-Fresenius Registry of Autosomal Dominant Polycystic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Hartmut P.H. Neumann

    2012-10-01

    Full Text Available Background: Patients who harbor intracranial aneurysms (IAs run a risk for aneurysm rupture and subsequent subarachnoid hemorrhage which frequently results in permanent deficits or death. Prophylactic treatment of unruptured aneurysms is possible and recommended depending on the size and location of the aneurysm as well as patient age and condition. IAs are major manifestations of autosomal dominant polycystic kidney disease (ADPKD. Current guidelines do not suggest surveillance of IAs in ADPKD except in the setting of family history if IA was known in any relative with ADPKD. Management of IAs in ADPKD is problematic because limited data exist from large studies. Methods: We established the Else Kröner-Fresenius Registry for ADPKD in Germany. Clinical data were assessed for age at diagnosis of IAs, stage of renal insufficiency, and number, location and size of IAs as well as family history of cerebral events. Patients with symptomatic or asymptomatic IAs were included. All patients with ADPKD-related IAs were offered mutation scanning of the susceptibility genes for ADPKD, the PKD1 and PKD2 genes. Results: Of 463 eligible ADPKD patients from the population base of Germany, 32 (7% were found to have IAs, diagnosed at the age of 2–71 years, 19 females and 13 males. Twenty (63% of these 32 patients were symptomatic, whereas IAs were detected in an asymptomatic stage in 12 patients. IAs were multifocal in 12 and unifocal in 20 patients. In 26 patients (81%, IAs were diagnosed before end-stage renal failure. Twenty-five out of 27 unrelated index cases (93% had no IAs or cerebral events documented in their relatives with ADPKD. In 16 unrelated index patients and 3 relatives, we detected germline mutations. The mutations were randomly distributed across the PKD1 gene in 14 and the PKD2 gene in 2 index cases. Questionnaires answered for 320/441 ADPKD patients without IAs revealed that only 45/320 (14% had MR angiography. Conclusion: In ADPKD

  15. Diagnostic Algorithm in the Management of Acute Febrile Abdomen in Patients with Autosomal Dominant Polycystic Kidney Disease.

    Science.gov (United States)

    Neuville, Marie; Hustinx, Roland; Jacques, Jessica; Krzesinski, Jean-Marie; Jouret, François

    2016-01-01

    Acute febrile abdomen represents a diagnostic challenge in patients with autosomal dominant polycystic kidney disease (ADPKD). Although criteria have been proposed for cyst infection (CyI) and hemorrhage (CyH), there is a lack of comparative assessments. Furthermore, distinguishing cystic from non-cystic complications remains problematic. ADPKD patients presenting with abdominal pain and/or fever between 01/2005 and 06/2015 were retrospectively identified in a systematic computerized billing database. CyH was defined as spontaneous intracystic density above 50 Hounsfield units on computed tomography (CT). CyI was definite if confirmed by cyst puncture, and probable if 4 criteria were met: 3-day fever, loin/liver tenderness, C-reactive protein (CRP) plasma levels >50mg/L and no CT evidence for CyH. Other episodes were grouped as inflammation of unknown origin (IUO). Among a cohort of 173 ADPKD patients, 101 presented with 205 episodes of abdominal pain (n = 172) and/or fever (n = 33). 20 patients experienced 30 CyH, whereas 16 presented 23 episodes of definite (n = 11) or probable (n = 12) CyI. 35 IUO were observed in 31 patients. Clinically, fever was observed in 7% vs. 100% vs. 66% of CyH, CyI and IUO, respectively. Biologically, CRP cut-off at 70 mg/dl showed 92% sensitivity and 81% specificity in CyI diagnosis. Urine or blood cultures remained sterile in >90% of CyH, but were contributive in 53.4% of CyI and IUO, with a 74.2% prevalence for E. coli. Radiologically, ultrasounds, CT and magnetic resonance diagnosed CyI in 2.6%, 20% and 16.7% of cases, respectively. 18F-FDG positron-emission tomography (PET)/CT was done within a median period of 7 days post antibiotics, and significantly changed patient management in 71.4%. This retrospective single-center series underscores the usefulness of clinical-fever-and biological-CRP-parameters, but emphasizes the limitations of bacteriological and radiological investigations in cases of acute febrile abdomen in ADPKD

  16. Functional characteristics of three new germline mutations of the thyrotropin receptor gene causing autosomal dominant toxic thyroid hyperplasia

    Energy Technology Data Exchange (ETDEWEB)

    Tonacchera, M.; Van Sande, J.; Cetani, F. [Universite Libre de Bruxelles, Brussels (Belgium)] [and others

    1996-02-01

    We report three unrelated families in which hyperthyroidism associated with thyroid hyperplasia was transmitted in an autosomal dominant fashion, in the absence of signs of autoimmunity. Exon 10 of the TSH receptor gene was directly sequenced after PCR amplification from DNA of peripheral leukocytes. In one family, a C to A transversion resulted in an S505R substitution in the third transmembrane segment; in the second, an A to T transversion caused an N650Y substitution in the sixth transmembrane segment; and in the third family, an A to G transition resulted in an N670S substitution in the seventh transmembrane segment. When expressed by transfection in COS-7 cells, each mutated receptor displayed an increase in constitutive stimulation of cAMP production; no effect on basal accumulation of inositol phosphates (IP) could be detected. In binding studies, cells transfected with wild-type of mutated receptors showed similar levels of expression, with the mutated receptors displaying similar or slightly increased affinity for bovine TSH (bTSH) binding. Cells transfected with S505R and N650Y mutants showed a similar cAMP maximal TSH-stimulated accumulation over the cells transfected with the wild type, whereas N670S transfectants showed a blunted response with an increase in EC{sub 50}. A higher IP response to 100 mU/mL bTSH over that obtained with the wild-type receptor was obtained in cells transfected with N650Y; in contrast, cells transfected with S505R showed a blunted IP production (50% less), and the N670S mutant completely lost the ability to stimulate IP accumulation in response to bTSH. The differential effects of individual mutations on stimulation by bTSH of cAMP or IP accumulation suggest that individual mutant receptors may achieve different active conformations with selective abilities to couple to G{sub s}{alpha} and to G{sub q}{alpha}. 17 refs., 8 figs.

  17. POU4F3 mutation screening in Japanese hearing loss patients: Massively parallel DNA sequencing-based analysis identified novel variants associated with autosomal dominant hearing loss.

    Directory of Open Access Journals (Sweden)

    Tomohiro Kitano

    Full Text Available A variant in a transcription factor gene, POU4F3, is responsible for autosomal dominant nonsyndromic hereditary hearing loss, DFNA15. To date, 14 variants, including a whole deletion of POU4F3, have been reported to cause HL in various ethnic groups. In the present study, genetic screening for POU4F3 variants was carried out for a large series of Japanese hearing loss (HL patients to clarify the prevalence and clinical characteristics of DFNA15 in the Japanese population. Massively parallel DNA sequencing of 68 target candidate genes was utilized in 2,549 unrelated Japanese HL patients (probands to identify genomic variations responsible for HL. The detailed clinical features in patients with POU4F3 variants were collected from medical charts and analyzed. Novel 12 POU4F3 likely pathogenic variants (six missense variants, three frameshift variants, and three nonsense variants were successfully identified in 15 probands (2.5% among 602 families exhibiting autosomal dominant HL, whereas no variants were detected in the other 1,947 probands with autosomal recessive or inheritance pattern unknown HL. To obtain the audiovestibular configuration of the patients harboring POU4F3 variants, we collected audiograms and vestibular symptoms of the probands and their affected family members. Audiovestibular phenotypes in a total of 24 individuals from the 15 families possessing variants were characterized by progressive HL, with a large variation in the onset age and severity with or without vestibular symptoms observed. Pure-tone audiograms indicated the most prevalent configuration as mid-frequency HL type followed by high-frequency HL type, with asymmetry observed in approximately 20% of affected individuals. Analysis of the relationship between age and pure-tone average suggested that individuals with truncating variants showed earlier onset and slower progression of HL than did those with non-truncating variants. The present study showed that variants

  18. Optic atrophy, cataracts, lipodystrophy/lipoatrophy, and peripheral neuropathy caused by a de novo OPA3 mutation

    OpenAIRE

    Bourne, Stephanie C.; Townsend, Katelin N.; Shyr, Casper; Matthews, Allison; Lear, Scott A.; Attariwala, Raj; Lehman, Anna; Wasserman, Wyeth W.; van Karnebeek, Clara; Sinclair, Graham; Vallance, Hilary; Gibson, William T.

    2017-01-01

    We describe a woman who presented with cataracts, optic atrophy, lipodystrophy/lipoatrophy, and peripheral neuropathy. Exome sequencing identified a c.235C > G p.(Leu79Val) variant in the optic atrophy 3 (OPA3) gene that was confirmed to be de novo. This report expands the severity of the phenotypic spectrum of autosomal dominant OPA3 mutations.

  19. Imaging features of tuberous sclerosis complex with autosomal-dominant polycystic kidney disease: a contiguous gene syndrome

    International Nuclear Information System (INIS)

    Back, Susan J.; Andronikou, Savvas; Kilborn, Tracy; Kaplan, Bernard S.; Darge, Kassa

    2015-01-01

    Genes for tuberous sclerosis complex (TSC) type 2 and autosomal-dominant polycystic kidney disease (ADPKD) type 1 are both encoded over a short segment of chromosome 16. When deletions involve both genes, an entity known as the TSC2/ADPKD1 contiguous gene syndrome, variable phenotypes of TSC and ADPKD are exhibited. This syndrome has not been reviewed in the radiology literature. Unlike renal cysts in TSC, cystic disease in TSC2/ADPKD1 contiguous gene syndrome results in hypertension and renal failure. A radiologist might demonstrate polycystic kidney disease before the patient develops other stigmata of TSC. Conversely, in patients with known TSC, enlarged and polycystic kidneys should signal the possibility of the TSC2/ADPKD1 contiguous gene syndrome and not simply TSC. Distinguishing these diagnoses has implications in prognosis, treatment and genetic counseling. To describe the clinical and imaging findings of tuberous sclerosis complex and polycystic kidney disease in seven pediatric patients. We retrospectively reviewed renal and brain imaging of children and young adults with genetically proven or high clinical suspicion for TSC2/ADPKD1 contiguous gene syndrome. We included seven pediatric patients from two referral institutions. Ages ranged from birth to 21 years over the course of imaging. The mean follow-up period was 9 years 8 months (4 years 6 months to 20 years 6 months). No child progressed to end-stage renal disease during this period. Three patients were initially imaged for stigmata of TSC, three for abdominal distension and one for elevated serum creatinine concentration. All patients developed enlarged, polycystic kidneys. The latest available imaging studies demonstrated that in 12 of the 14 kidneys 50% or more of the parenchyma was ultimately replaced by >15 cysts, resulting in significant cortical thinning. The largest cysts in each kidney ranged from 2.4 cm to 9.3 cm. Echogenic lesions were present in 13 of the 14 kidneys, in keeping with

  20. Imaging features of tuberous sclerosis complex with autosomal-dominant polycystic kidney disease: a contiguous gene syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Back, Susan J. [The Children' s Hospital of Philadelphia, Department of Radiology, Philadelphia, PA (United States); Andronikou, Savvas [University of the Witwatersrand, Radiology Department, Faculty of Health Sciences, Johannesburg (South Africa); Kilborn, Tracy [University of Cape Town, Red Cross War Memorial Children' s Hospital, Cape Town (South Africa); Kaplan, Bernard S. [The Children' s Hospital of Philadelphia, Division of Nephrology, Philadelphia, PA (United States); University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA (United States); Darge, Kassa [The Children' s Hospital of Philadelphia, Department of Radiology, Philadelphia, PA (United States); University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA (United States)

    2015-03-01

    Genes for tuberous sclerosis complex (TSC) type 2 and autosomal-dominant polycystic kidney disease (ADPKD) type 1 are both encoded over a short segment of chromosome 16. When deletions involve both genes, an entity known as the TSC2/ADPKD1 contiguous gene syndrome, variable phenotypes of TSC and ADPKD are exhibited. This syndrome has not been reviewed in the radiology literature. Unlike renal cysts in TSC, cystic disease in TSC2/ADPKD1 contiguous gene syndrome results in hypertension and renal failure. A radiologist might demonstrate polycystic kidney disease before the patient develops other stigmata of TSC. Conversely, in patients with known TSC, enlarged and polycystic kidneys should signal the possibility of the TSC2/ADPKD1 contiguous gene syndrome and not simply TSC. Distinguishing these diagnoses has implications in prognosis, treatment and genetic counseling. To describe the clinical and imaging findings of tuberous sclerosis complex and polycystic kidney disease in seven pediatric patients. We retrospectively reviewed renal and brain imaging of children and young adults with genetically proven or high clinical suspicion for TSC2/ADPKD1 contiguous gene syndrome. We included seven pediatric patients from two referral institutions. Ages ranged from birth to 21 years over the course of imaging. The mean follow-up period was 9 years 8 months (4 years 6 months to 20 years 6 months). No child progressed to end-stage renal disease during this period. Three patients were initially imaged for stigmata of TSC, three for abdominal distension and one for elevated serum creatinine concentration. All patients developed enlarged, polycystic kidneys. The latest available imaging studies demonstrated that in 12 of the 14 kidneys 50% or more of the parenchyma was ultimately replaced by >15 cysts, resulting in significant cortical thinning. The largest cysts in each kidney ranged from 2.4 cm to 9.3 cm. Echogenic lesions were present in 13 of the 14 kidneys, in keeping with

  1. Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a mutation in the arginine-vasopressin II gene in four generations of a Korean family

    Directory of Open Access Journals (Sweden)

    Myo-Jing Kim

    2014-12-01

    Full Text Available Autosomal dominant neurohypophyseal diabetes insipidus is a rare form of central diabetes insipidus that is caused by mutations in the vasopressin-neurophysin II (AVP-NPII gene. It is characterized by persistent polydipsia and polyuria induced by deficient or absent secretion of arginine vasopressin (AVP. Here we report a case of familial neurohypophyseal diabetes insipidus in four generations of a Korean family, caused by heterozygous missense mutation in exon 2 of the AVP-NPII gene (c.286G>T. This is the first report of such a case in Korea.

  2. Genotype-phenotype correlation for DFNA22: characterization of non-syndromic, autosomal dominant, progressive sensorineural hearing loss due to MYO6 mutations

    DEFF Research Database (Denmark)

    Topsakal, Vedat; Hilgert, Nele; van Dinther, Joost

    2010-01-01

    Clinical and audiological examination was done in 2 Belgian families with autosomal dominant sensorineural hearing loss (SNHL) linked to DFNA22. Nineteen subjects in family 1 had mild to moderate SNHL starting in the third decade. The hearing loss was characterized by a flat audiogram affecting all......Hz. For all hitherto known DFNA22 families the audiological and clinical characteristics were correlated with the molecular data. This study describes the phenotype of 2 Belgian families with SNHL linked to DFNA22, both with a pathogenic change in the deafness gene MYO6. The phenotypes of all hitherto...

  3. Post transplant urinary tract infection in Autosomal dominant polycystic kidney disease a perpetual diagnostic dilema - 18-fluorodeoxyglucose - Positron emission computerized tomography - A valuable tool

    International Nuclear Information System (INIS)

    Sainaresh, VV; Jain, SH; Patel, HV; Shah, PR; Vanikar, AV; Trivedi, HL

    2011-01-01

    Urinary tract infection (UTI) is the most common infection contracted by renal allograft recipients. In patients of autosomal dominant polycystic kidney disease (ADPKD), cyst infection presents a complex diagnostic and therapeutic challenge especially in the post transplant period. Accurate diagnosis forms the cornerstone in salvaging the graft from potentially catastrophic outcome. We describe a case of xanthogranulomatous pyelonephritis (XPN) in the native kidney in a patient of post transplant ADPKD which presented as frequently relapsing UTI with graft dysfunction where in accurate diagnosis was made possible with the aid of 18-fluorodeoxyglucose (FDG) - Positron emission computerized tomography (PET/CT)

  4. Clinical proof-of-concept trial to assess the therapeutic effect of sirolimus in patients with autosomal dominant polycystic kidney disease: SUISSE ADPKD study

    Directory of Open Access Journals (Sweden)

    Wüthrich Rudolf P

    2007-09-01

    Full Text Available Abstract Background Currently there is no effective treatment available to retard cyst growth and to prevent the progression to end-stage renal failure in patients with autosomal dominant polycystic kidney disease (ADPKD. Evidence has recently been obtained from animal experiments that activation of the mammalian target of rapamycin (mTOR signaling pathway plays a crucial role in cyst growth and renal volume expansion, and that the inhibition of mTOR with rapamycin (sirolimus markedly slows cyst development and renal functional deterioration. Based on these promising results in animals we have designed and initiated the first randomized controlled trial (RCT to examine the effectiveness, safety and tolerability of sirolimus to retard disease progression in ADPKD. Method/design This single center, randomised controlled, open label trial assesses the therapeutic effect, safety and tolerability of the mTOR inhibitor sirolimus (Rapamune® in patients with autosomal dominant polycystic kidney disease and preserved renal function. The primary outcome will be the inhibition of kidney volume growth measured by magnetic resonance imaging (MRI volumetry. Secondary outcome parameters will be preservation of renal function, safety and tolerability of sirolimus. Discussion The results from this proof-of-concept RCT will for the first time show whether treatment with sirolimus effectively retards cyst growth in patients with ADPKD. Trial registration NCT00346918

  5. Mapping of the locus for autosomal dominant amelogenesis imperfecta (AIH2) to a 4-Mb YAC contig on chromosome 4q11-q21

    Energy Technology Data Exchange (ETDEWEB)

    Kaerrman, C.; Holmgren, G.; Forsman, K. [Univ. Hospital, Umea (Sweden)]|[Univ. of Umea (Sweden)] [and others

    1997-01-15

    Amelogenesis imperfecta (Al) is a clinically and genetically heterogeneous group of inherited enamel defects. We recently mapped a locus for autosomal dominant local hypoplastic amelogenesis imperfecta (AIH2) to the long arm of chromosome 4. The disease gene was localized to a 17.6-cM region between the markers D4S392 and D4S395. The albumin gene (ALB), located in the same interval, was a candidate gene for autosomal dominant AI (ADAI) since albumin has a potential role in enamel maturation. Here we describe refined mapping of the AIH2 locus and the construction of marker maps by radiation hybrid mapping and yeast artificial chromosome (YAC)-based sequence tagged site-content mapping. A radiation hybrid map consisting of 11 microsatellite markers in the 5-cM interval between D4S409 and D4S1558 was constructed. Recombinant haplotypes in six Swedish ADAI families suggest that the disease gene is located in the interval between D4S2421 and ALB. ALB is therefore not likely to be the disease-causing gene. Affected members in all six families share the same allele haplotypes, indicating a common ancestral mutation in all families. The AIH2 critical region is less than 4 cM and spans a physical distance of approximately 4 Mb as judged from radiation hybrid maps. A YAC contig over the AIH2 critical region including several potential candidate genes was constructed. 35 refs., 4 figs., 1 tab.

  6. Autosomal dominant HMSN with proximal involvement: new Brazilian cases HMSN autossômica dominante com envolvimento proximal: novos casos brasileiros

    Directory of Open Access Journals (Sweden)

    Cristiane Borges Patroclo

    2009-09-01

    Full Text Available We report four Brazilian siblings with Autosomal Dominant Hereditary Motor Sensory Neuropathy with Proximal Dominant Involvement (HMSN-P, a rare form of HMSN, that was characterized by proximal dominant muscle weakness and atrophy onset after the age of 30 years, fasciculation, arreflexia and sensory disturbances with autosomal dominant inheritance. Electrophysiological study and sural nerve biopsy were in the accordance with axonal sensory motor polyneuropathy and laboratorial analysis disclosed serum lipids and muscle enzymes abnormalities. Our report is the first done by a group outside Japan, where the disease initially seemed to be restricted and stressed the phenotypic variability from the original report.Relatamos os casos de quatro irmãos brasileiros com Neuropatia Sensitivo Motora Hereditária com Envolvimento Proximal Dominante (HMSN-P, uma forma rara de HMSN caracterizada por fraqueza muscular de predomínio proximal e atrofia de instalação após os 30 anos, fasciculações, arreflexia, distúrbios sensitivos e padrão de herança autossômica dominante. Os estudos eletrofisiológicos e de biópsia do nervo sural confirmaram o diagnóstico de polineuropatia sensitivo-motora com padrão lesional axonal. Laboratorialmente foram constatadas anormalidades séricas no metabolismo lipídico e enzimas musculares. Nosso relato é o primeiro feito por um grupo fora do Japão, onde a doença parecia restrita até então e ressalta a variabilidade fenotípica apresentada nos casos Brasileiros.

  7. Autosomal dominant Carvajal plus syndrome due to the novel desmoplakin mutation c.1678A > T (p.Ile560Phe).

    Science.gov (United States)

    Finsterer, Josef; Stöllberger, Claudia; Wollmann, Eva; Dertinger, Susanne; Laccone, Franco

    2016-09-01

    Carvajal syndrome is an autosomal dominant or autosomal recessive disorder, manifesting with dilated cardiomyopathy, woolly hair, and palmoplantar keratoma. Additional manifestations can be occasionally found. Carvajal syndrome may be due to mutations in the desmocollin-2, desmoplakin, or plakophilin-2 gene. We report a family with Carvajal syndrome which additionally presented with hypoacusis, noncompaction, recurrent pharyngeal infections, oligodontia, and recurrent diarrhoea. Father and brother were also affected and had died suddenly, the father despite implantation of a cardioverter defibrillator (ICD). Genetic studies revealed the novel pathogenic mutation c.1678A > T in the desmoplakin gene resulting in the amino acid change Ile to Phe at position 560 in the index case and her brother. The index case underwent ICD implantation recently. Phenotypic manifestations of Carvajal syndrome are even broader than so far anticipated, the number of mutations in the desmoplakin gene responsible for Carvajal syndrome is still increasing, and these patients require implantation of an ICD as soon as their diagnosis is established.

  8. Examination of the presynaptic dopaminergic system using positron emission tomography in a family with autosomal dominant parkinsonism and dementia due to pallido-ponto-nigral degeneration (PPNO)

    International Nuclear Information System (INIS)

    Cordes, M.; Wszolek, Z.K.; Pfeiffer, R.F.; Calne, D.B.

    1993-01-01

    We report positron emission tomography (PET) examinations of presynaptic nigrostriatal dopaminergic function in a large family with an autosomal dominant neuro-degenerative disorder characterized pathologically by pallido-ponto-nigral degeneration, and clinically by parkinsonism, dystonia, paresis of conjugate gaze, apraxia of eyelid opening and closing, pyramidal tract dysfunction, and urinary incontinence. Dopaminergic function was studied and quantified with [ 18 F[-L-6-fluorodopa (6 FD) and PET in five affected patients, 13 individuals at-risk, and 15 similarly aged controls. The rate constant K i (mL/striatum/min) for 6 FD was decreased in all patients. None of the individuals at risk had reduced 6 FD uptake. In fact, three of them had increased values. Repeat scans have revealed a fall in 6 FD uptake in two out of the three with initially high constants. This may reflect a preclinical stage of involvement, but longer observation is necessary. (orig.) [de

  9. Changes in causes of death and risk of cancer in Danish patients with autosomal dominant polycystic kidney didease and end-stage renal disease

    DEFF Research Database (Denmark)

    Ørskov, Bjarne; Feldt-Rasmussen, Bo Friis; Strandgaard, Svend Valdemar

    2012-01-01

    Abstract Background. With the improved prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD), causes of death and the risk of cancer might have changed. This was investigated in a Danish population with ADPKD and end-stage renal disease (ESRD) between 1 January 1993 and 31...... December 2008. Methods. Data were retrieved from three Danish national registries and a total of 823 patients were identified of which 431 had died during the study period. The 16 years were divided into two 8-year periods and the causes of death were divided into six categories: cancer, cardiovascular......, cerebrovascular, infection, other and unknown. Results. Cardiovascular disease was the major cause of death. A multivariate competing risk model comparing the two 8-year periods, adjusted for age at ESRD, gender and treatment modality, showed that deaths from cardiovascular disease decreased by 35% [hazard ratios...

  10. Induced pluripotent stem cells derived from a patient with autosomal dominant familial neurohypophyseal diabetes insipidus caused by a variant in the AVP gene

    Directory of Open Access Journals (Sweden)

    Lise Bols Toustrup

    2017-03-01

    Full Text Available Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI is caused by variants in the arginine vasopressin (AVP gene. Here we report the generation of induced pluripotent stem cells (iPSCs from a 42-year-old man carrying an adFNDI causing variant in exon 1 of the AVP gene using lentivirus-mediated nuclear reprogramming. The iPSCs carried the expected variant in the AVP gene. Furthermore, the iPSCs expressed pluripotency markers; displayed in vitro differentiation potential to the three germ layers and had a normal karyotype consistent with the original fibroblasts. This iPSC line is useful in future studies focusing on the pathogenesis of adFNDI.

  11. Changes in causes of death and risk of cancer in Danish patients with autosomal dominant polycystic kidney didease and end-stage renal disease

    DEFF Research Database (Denmark)

    Ørskov, Bjarne; Sørensen, Vibeke Rømming; Feldt-Rasmussen, Bo Friis

    2012-01-01

    Abstract Background. With the improved prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD), causes of death and the risk of cancer might have changed. This was investigated in a Danish population with ADPKD and end-stage renal disease (ESRD) between 1 January 1993 and 31...... December 2008. Methods. Data were retrieved from three Danish national registries and a total of 823 patients were identified of which 431 had died during the study period. The 16 years were divided into two 8-year periods and the causes of death were divided into six categories: cancer, cardiovascular...... (HR) 0.65, P = 0.008] and deaths from cerebrovascular disease decreased by 69% (HR 0.31, P = 0.0003) from the first to the second time period. There were no significant changes between the time periods in death from cancer, infection, other or unknown. From the first to the second 8-year interval...

  12. Simultaneous Occurence of an Autosomal Dominant Inherited MSX1 Mutation and an X-linked Recessive Inherited EDA Mutation in One Chinese Family with Non-syndromic Oligodontia.

    Science.gov (United States)

    Zhang, Xiao Xia; Wong, Sing Wai; Han, Dong; Feng, Hai Lan

    2015-01-01

    To describe the simultaneous occurence of an autosomal dominant inherited MSX1 mutation and an X-linked recessive inherited EDA mutation in one Chinese family with nonsyndromic oligodontia. Clinical data of characteristics of tooth agenesis were collected. MSX1 and EDA gene mutations were detected in a Chinese family of non-syndromic oligodontia. Mild hypodontia in the parents and severe oligodontia in the son was recorded. A novel missense heterozygous mutation c.517C>A (p.Arg173Ser) was detected in the MSX1 gene in the boy and the father. A homozygous missense mutation c.1001G>A (p.Arg334His) was detected in the EDA gene in the boy and the same mutant occurred heterozygously in the mother. Simultaneous occurence of two different gene mutations with different inheritence patterns, which both caused oligodontia, which occurred in one subject and in one family, was reported.

  13. Autosomal dominant polycystic kidney disease and pain - a review of the disease from aetiology, evaluation, past surgical treatment options to current practice.

    Science.gov (United States)

    Badani, K K; Hemal, A K; Menon, M

    2004-01-01

    Autosomal Dominant Polycystic Kidney Disease (ADPKD), often referred to as "adult" polycystic kidney disease, is one of the commonest hereditary disorders. It affects approximately 4 to 6 million individuals worldwide. The disease progresses to end-stage renal disease and it accounts for 10-15% of patients requiring dialysis in the United States. A comprehensive Medline search for aetiology, evaluation, screening, cellular biology, and treatment was utilized to locate, extract, and synthesize relevant data with respect to this topic. Special attention was focused on urologic literature and surgical textbooks regarding operative treatment of pain associated with ADPKD. Now, patients with ADPKD have more treatment options. More specifically, several therapeutic alternatives are now available for the management of pain in these patients. A recent review of literature supports the performance of open or laparoscopic cyst decortication procedures for control of pain and infection without the worry of causing further renal impairment in those with preserved renal function.

  14. Autosomal dominant precocious osteoarthropathy due to a mutation of the cartilage oligomeric matrix protein (COMP) gene: further expansion of the phenotypic variations of COMP defects

    Energy Technology Data Exchange (ETDEWEB)

    Kawaji, Hiroyuki [Department of Orthopaedic Surgery, Sanyudo Hospital, 6-1-219 Chuou, Yonezawa, Yamagata 992-0045 (Japan); Nishimura, Gen [Department of Radiology, Nasu Chuou Hospital, Tochigi (Japan); Watanabe, Sobei; Sasaki, Akira; Sano, Tokuhisa [Department of Orthopaedic Surgery, Tohoku Kohsei-Nenkin Hospital, Miyagi (Japan); Mabuchi, Akihiko; Ikeda, Toshiyuki; Ikegawa, Shiro [Laboratory for Bone and Joint Diseases, SNP Research Center, Tokyo (Japan); Ohashi, Hirofumi [Division of Medical Genetics, Saitama Children' s Medical Center, Saitama (Japan)

    2002-12-01

    We report on a Japanese family of four generations with an autosomal dominant precocious osteoarthropathy. The cardinal clinical manifestations of affected individuals were painful weight-bearing large joints, which started in late childhood or adolescence. The radiological hallmarks included coxa plana, mild epiphyseal dysplasia of the knee, and round talar domes with tibiotalar slant in childhood, which evolved into degenerative joint diseases in adulthood. The disease phenotype was cosegregated with a mutation of the cartilage oligomeric matrix protein (COMP) gene in the family members, who underwent molecular evaluation. COMP mutations have been reported in a mild form of multiple epiphyseal dysplasia (MED), Ribbing type, as well as allied disorders with more severe manifestations, such as MED Fairbank type and pseudoachondroplasia. Unlike previously reported cases with the Ribbing type, the present patients did not have short stature or brachydactyly. This report expands further the phenotypic variations of COMP defects. (orig.)

  15. Atrofia óptica hereditaria autosómica dominante: A propósito de una familia Dominant autosomal hereditary optical atrophy: Apropos of a family

    Directory of Open Access Journals (Sweden)

    Noel Taboada Lugo

    2004-12-01

    Full Text Available Entre las causas de pérdida insidiosa, bilateral y simétrica de la visión central se deben tener siempre presente las atrofias ópticas heredo degenerativas. La atrofia óptica hereditaria autosómica dominante es la forma más frecuente de atrofia óptica heredofamiliar simple o monosintomática. Se realizó la caracterización clínica de una familia con el diagnóstico de esta discapacidad visual.Among the causes of insidious, bilateral and symmetric loss of the central vision, the hereditary and degenerative optical atrophies should always be taken into account. The dominant autosomal hereditary optical atrophy is the most frequent form of simple or monosymptomatic hereditary family optical atrophy. The clinical characterization of a family with the diagnosis of this visual impairment was made.

  16. Examination of the presynaptic dopaminergic system using positron emission tomography in a family with autosomal dominant parkinsonism and dementia due to pallido-ponto-nigral degeneration (PPNO)

    Energy Technology Data Exchange (ETDEWEB)

    Cordes, M. [Neurodegenerative Disorders Centre, Univ. of British Columbia, Vancouver, BC (Canada)]|[Strahlenklinik und Poliklinik, Universitaetsklinikum Rudolf Virchow, Freie Univ. Berlin (Germany); Wszolek, Z.K. [Neurodegenerative Disorders Centre, Univ. of British Columbia, Vancouver, BC (Canada)]|[Section of Neurology, Univ. of Nebraska Medical Center, Omaha, NE (United States); Pfeiffer, R.F. [Section of Neurology, Univ. of Nebraska Medical Center, Omaha, NE (United States); Calne, D.B. [Neurodegenerative Disorders Centre, Univ. of British Columbia, Vancouver, BC (Canada)

    1993-12-31

    We report positron emission tomography (PET) examinations of presynaptic nigrostriatal dopaminergic function in a large family with an autosomal dominant neuro-degenerative disorder characterized pathologically by pallido-ponto-nigral degeneration, and clinically by parkinsonism, dystonia, paresis of conjugate gaze, apraxia of eyelid opening and closing, pyramidal tract dysfunction, and urinary incontinence. Dopaminergic function was studied and quantified with [{sup 18}F]-L-6-fluorodopa (6 FD) and PET in five affected patients, 13 individuals at-risk, and 15 similarly aged controls. The rate constant K{sub i} (mL/striatum/min) for 6 FD was decreased in all patients. None of the individuals at risk had reduced 6 FD uptake. In fact, three of them had increased values. Repeat scans have revealed a fall in 6 FD uptake in two out of the three with initially high constants. This may reflect a preclinical stage of involvement, but longer observation is necessary. (orig.) [Deutsch] Wir berichten ueber Untersuchungen der praesynaptischen dopaminergen Funktion mit der Positronenemissionstomographie bei einer grossen Familie mit autosomal-dominant vererbtem Parkinsonismus und Demenz. Die Erkrankung ist pathologisch-anatomisch gekennzeichnet durch eine pallido-ponto-nigrale Degeneration. Klinisch bestehen ein Parkinsonismus, Dystonien, eine Apraxie der Augenoeffnung und -schliessung, pyramidale Dysfunktionen und eine Harninkontinenz. Die praesynaptische dopaminerge Funktion wurde untersucht und quantifiziert mittels [{sup 18}F]-L-6-Fluorodopa (6FD) PET bei fuenf erkrankten Patienten, 13 Risikopatienten und 15 Kontrollpersonen vergleichbaren Alters. Die Transportkonstante K{sub i} (ml/Striatum/min) fuer die striatale Aufnahme des Radiotracers war bei allen erkrankten Patienten erniedrigt. Von den 13 Risikopatienten hatte keiner eine reduzierte Aufnahme von 6FD. Drei Risikopatienten zeigten sogar Werte fuer K{sub i}, die oberhalb des Referenzbereiches der Kontrollpersonen lagen

  17. Autosomal dominant hereditary sensory neuropathy with chronic cough and gastro-oesophageal reflux: clinical features in two families linked to chromosome 3p22-p24.

    Science.gov (United States)

    Spring, Penelope J; Kok, Cindy; Nicholson, Garth A; Ing, Alvin J; Spies, Judith M; Bassett, Mark L; Cameron, John; Kerlin, Paul; Bowler, Simon; Tuck, Roger; Pollard, John D

    2005-12-01

    Autosomal dominant hereditary sensory neuropathy (HSN I) is a clinically and genetically heterogeneous group of disorders, and in some families it is due to mutations in the serine palmitoyltransferase (SPTLC1) gene. We have characterized two families with HSN I associated with cough and gastro-oesophageal reflux (GOR). From a large Australian family, 27 individuals and from a smaller family, 11 individuals provided clinical information and blood for genetic analysis. Affected individuals had an adult onset of paroxysmal cough, GOR and distal sensory loss. Cough could be triggered by noxious odours or by pressure in the external auditory canal (Arnold's ear-cough reflex). Other features included throat clearing, hoarse voice, cough syncope and sensorineural hearing loss. Neurophysiological and pathological studies demonstrated a sensory axonal neuropathy. Gastric emptying studies were normal, and autonomic function and sweat tests were either normal or showed distal hypohidrosis. Cough was likely to be due to a combination of denervation hypersensitivity of the upper airways and oesophagus, and prominent GOR. Most affected individuals were shown on 24 h ambulatory oesophageal pH monitoring to have multiple episodes of GOR, closely temporally associated with coughing. Hoarse voice was probably attributable to acid-induced laryngeal damage, and there was no evidence of vocal cord palsy. No other cause for cough was found on most respiratory or otorhinological studies. Linkage to chromosome 3p22-p24 has been found in both families, with no evidence of linkage to loci for known HSN I, autosomal dominant hereditary motor and sensory neuropathy, hereditary GOR or triple A syndrome. These families represent a genetically novel variant of HSN I, with a distinctive cough owing to involvement of the upper aerodigestive tract.

  18. Targeted deletion of the Nesp55 DMR defines another Gnas imprinting control region and provides a mouse model of autosomal dominant PHP-Ib.

    Science.gov (United States)

    Fröhlich, Leopold F; Mrakovcic, Maria; Steinborn, Ralf; Chung, Ung-Il; Bastepe, Murat; Jüppner, Harald

    2010-05-18

    Approximately 100 genes undergo genomic imprinting. Mutations in fewer than 10 imprinted genetic loci, including GNAS, are associated with complex human diseases that differ phenotypically based on the parent transmitting the mutation. Besides the ubiquitously expressed Gsalpha, which is of broad biological importance, GNAS gives rise to an antisense transcript and to several Gsalpha variants that are transcribed from the nonmethylated parental allele. We previously identified two almost identical GNAS microdeletions extending from exon NESP55 to antisense (AS) exon 3 (delNESP55/delAS3-4). When inherited maternally, both deletions are associated with erasure of all maternal GNAS methylation imprints and autosomal-dominant pseudohypoparathyroidism type Ib, a disorder characterized by parathyroid hormone-resistant hypocalcemia and hyperphosphatemia. As for other imprinting disorders, the mechanisms resulting in abnormal GNAS methylation are largely unknown, in part because of a paucity of suitable animal models. We now showed in mice that deletion of the region equivalent to delNESP55/delAS3-4 on the paternal allele (DeltaNesp55(p)) leads to healthy animals without Gnas methylation changes. In contrast, mice carrying the deletion on the maternal allele (DeltaNesp55(m)) showed loss of all maternal Gnas methylation imprints, leading in kidney to increased 1A transcription and decreased Gsalpha mRNA levels, and to associated hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism. Besides representing a murine autosomal-dominant pseudohypoparathyroidism type Ib model and one of only few animal models for imprinted human disorders, our findings suggest that the Nesp55 differentially methylated region is an additional principal imprinting control region, which directs Gnas methylation and thereby affects expression of all maternal Gnas-derived transcripts.

  19. Autosomal dominant inheritance of brain cardiolipin fatty acid abnormality in VM/DK mice: association with hypoxic-induced cognitive insensitivity.

    Science.gov (United States)

    Ta, Nathan L; Jia, Xibei; Kiebish, Michael; Seyfried, Thomas N

    2014-01-01

    Cardiolipin is a complex polyglycerol phospholipid found almost exclusively in the inner mitochondrial membrane and regulates numerous enzyme activities especially those related to oxidative phosphorylation and coupled respiration. Abnormalities in cardiolipin can impair mitochondrial function and bioenergetics. We recently demonstrated that the ratio of shorter chain saturated and monounsaturated fatty acids (C16:0; C18:0; C18:1) to longer chain polyunsaturated fatty acids (C18:2; C20:4; C22:6) was significantly greater in the brains of adult VM/DK (VM) inbred mice than in the brains of C57BL/6 J (B6) mice. The cardiolipin fatty acid abnormalities in VM mice are also associated with alterations in the activity of mitochondrial respiratory complexes. In this study we found that the abnormal brain fatty acid ratio in the VM strain was inherited as an autosomal dominant trait in reciprocal B6 × VM F1 hybrids. To evaluate the potential influence of brain cardiolipin fatty acid composition on cognitive sensitivity, we placed the parental B6 and VM mice and their reciprocal male and female B6VMF1 hybrid mice (3-month-old) in a hypoxic chamber (5 % O2). Cognitive awareness (conscientiousness) under hypoxia was significantly lower in the VM parental mice and F1 hybrid mice (11.4 ± 0.4  and 11.0 ± 0.4 min, respectively) than in the parental B6 mice (15.3 ± 1.4 min), indicating an autosomal dominant inheritance like that of the brain cardiolipin abnormalities. These findings suggest that impaired cognitive awareness under hypoxia is associated with abnormalities in neural lipid composition.

  20. Non-syndromic posterior lenticonus a cause of childhood cataract: evidence for X-linked inheritance.

    Science.gov (United States)

    Russell-Eggitt, I M

    2000-12-01

    When an X-linked pedigree of posterior lenticonus with cataract was identified further evidence for X-linked inheritance of this condition was sought. Forty-three cases of posterior lenticonus were identified from a database of 354 children with cataract. Two children with the X-linked syndromes of Lowe and Nance-Horan and 3 children with Fanconi syndrome have been excluded from further analysis. None of the children was deaf. None of the non-syndromic cases had microcornea. There were 38 cases of non-syndromic posterior lenticonus (approximately 11%). There were 15 children from 13 pedigrees and 23 apparently sporadic cases. Of the 106 cases on the database with unilateral cataract 15 had posterior lenticonus (approximately 14%). Eleven of 13 pedigrees were compatible with X-linked inheritance or autosomal dominant inheritance with variable expression. However, in 2 pedigrees there was father to son transmission. Posterior lenticonus is a common cause of unilateral infantile cataract, but is thought to be a rare cause of bilateral cataracts. This study suggests that posterior lenticonus is responsible for a significant proportion of childhood cataracts (approximately 14% of unilateral and approximately 9% of bilateral cases). Posterior lenticonus is generally thought to occur as a sporadic condition. This study demonstrates that there is a family history of early-onset cataract in a significant number of bilateral cases (approximately 58%).

  1. SLC3A1 and SLC7A9 mutations in autosomal recessive or dominant canine cystinuria: a new classification system.

    Science.gov (United States)

    Brons, A-K; Henthorn, P S; Raj, K; Fitzgerald, C A; Liu, J; Sewell, A C; Giger, U

    2013-01-01

    Cystinuria, one of the first recognized inborn errors of metabolism, has been reported in many dog breeds. To determine urinary cystine concentrations, inheritance, and mutations in the SLC3A1 and SLC7A9 genes associated with cystinuria in 3 breeds. Mixed and purebred Labrador Retrievers (n = 6), Australian Cattle Dogs (6), Miniature Pinschers (4), and 1 mixed breed dog with cystine urolithiasis, relatives and control dogs. Urinary cystinuria and aminoaciduria was assessed and exons of the SLC3A1 and SLC7A9 genes were sequenced from genomic DNA. In each breed, male and female dogs, independent of neuter status, were found to form calculi. A frameshift mutation in SLC3A1 (c.350delG) resulting in a premature stop codon was identified in autosomal-recessive (AR) cystinuria in Labrador Retrievers and mixed breed dogs. A 6 bp deletion (c.1095_1100del) removing 2 threonines in SLC3A1 was found in autosomal-dominant (AD) cystinuria with a more severe phenotype in homozygous than in heterozygous Australian Cattle Dogs. A missense mutation in SLC7A9 (c.964G>A) was discovered in AD cystinuria in Miniature Pinschers with only heterozygous affected dogs observed to date. Breed-specific DNA tests were developed, but the prevalence of each mutation remains unknown. These studies describe the first AD inheritance and the first putative SLC7A9 mutation to cause cystinuria in dogs and expand our understanding of this phenotypically and genetically heterogeneous disease, leading to a new classification system for canine cystinuria and better therapeutic management and genetic control in these breeds. Copyright © 2013 by the American College of Veterinary Internal Medicine.

  2. Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa.

    Science.gov (United States)

    Fischer-Zirnsak, Björn; Escande-Beillard, Nathalie; Ganesh, Jaya; Tan, Yu Xuan; Al Bughaili, Mohammed; Lin, Angela E; Sahai, Inderneel; Bahena, Paulina; Reichert, Sara L; Loh, Abigail; Wright, Graham D; Liu, Jaron; Rahikkala, Elisa; Pivnick, Eniko K; Choudhri, Asim F; Krüger, Ulrike; Zemojtel, Tomasz; van Ravenswaaij-Arts, Conny; Mostafavi, Roya; Stolte-Dijkstra, Irene; Symoens, Sofie; Pajunen, Leila; Al-Gazali, Lihadh; Meierhofer, David; Robinson, Peter N; Mundlos, Stefan; Villarroel, Camilo E; Byers, Peter; Masri, Amira; Robertson, Stephen P; Schwarze, Ulrike; Callewaert, Bert; Reversade, Bruno; Kornak, Uwe

    2015-09-03

    Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively, which both operate in the mitochondrial proline cycle. We report here on eight unrelated individuals born to non-consanguineous families clinically diagnosed with DBS or wrinkly skin syndrome. We found three heterozygous mutations in ALDH18A1 leading to amino acid substitutions of the same highly conserved residue, Arg138 in P5CS. A de novo origin was confirmed in all six probands for whom parental DNA was available. Using fibroblasts from affected individuals and heterologous overexpression, we found that the P5CS-p.Arg138Trp protein was stable and able to interact with wild-type P5CS but showed an altered sub-mitochondrial distribution. A reduced size upon native gel electrophoresis indicated an alteration of the structure or composition of P5CS mutant complex. Furthermore, we found that the mutant cells had a reduced P5CS enzymatic activity leading to a delayed proline accumulation. In summary, recurrent de novo mutations, affecting the highly conserved residue Arg138 of P5CS, cause an autosomal-dominant form of cutis laxa with progeroid features. Our data provide insights into the etiology of cutis laxa diseases and will have immediate impact on diagnostics and genetic counseling. Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  3. Refinement of a locus for autosomal dominant hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) and genetic heterogeneity.

    Science.gov (United States)

    Maeda, Kouji; Kaji, Ryuji; Yasuno, Katsuhito; Jambaldorj, Jamiyansuren; Nodera, Hiroyuki; Takashima, Hiroshi; Nakagawa, Masanori; Makino, Satoshi; Tamiya, Gen

    2007-01-01

    Hereditary motor and sensory neuropathy with proximal dominancy (HMSN-P) is an adult-onset peripheral neurodegenerative disorder which has been reported only in the Okinawa Islands, Japan. The disease locus of "Okinawa-type" HMSN-P has been previously mapped to 3q13.1, with all affected individuals sharing an identical haplotype around the locus, suggesting that the undiscovered causative mutation in HMSN-P originated from a single founder. We have newly found two large families from the western part of Japan within which multiple members developed symptoms similar to those exhibited by HMSN-P patients from Okinawa, with no record of affinal connection between the islands. Using these pedigrees with "Kansai-type" HMSN-P, we carried out a linkage study utilizing eight microsatellite markers and identified a candidate region on 3q13.1 cosegregating with the disease (maximum two-point LOD score of 8.44 at theta=0.0) overlapping with the Okinawa-type HMSN-P locus. However, the disease haplotype shared among all affected members in these families was different from that in the Okinawa kindred, suggesting allelic heterogeneity. Such allelic variation should aid in the identification of the disease-causative gene. Moreover, the allelic heterogeneity of HMSN-P in the Japanese population suggests that HMSN-P may be more common across other ethnic groups, but classified into other disease categories.

  4. Application of Whole Exome Sequencing in Six Families with an Initial Diagnosis of Autosomal Dominant Retinitis Pigmentosa: Lessons Learned

    Science.gov (United States)

    Fernandez-San Jose, Patricia; Liu, Yichuan; March, Michael; Pellegrino, Renata; Golhar, Ryan; Corton, Marta; Blanco-Kelly, Fiona; López-Molina, Maria Isabel; García-Sandoval, Blanca; Guo, Yiran; Tian, Lifeng; Liu, Xuanzhu; Guan, Liping; Zhang, Jianguo; Keating, Brendan; Xu, Xun

    2015-01-01

    This study aimed to identify the genetics underlying dominant forms of inherited retinal dystrophies using whole exome sequencing (WES) in six families extensively screened for known mutations or genes. Thirty-eight individuals were subjected to WES. Causative variants were searched among single nucleotide variants (SNVs) and insertion/deletion variants (indels) and whenever no potential candidate emerged, copy number variant (CNV) analysis was performed. Variants or regions harboring a candidate variant were prioritized and segregation of the variant with the disease was further assessed using Sanger sequencing in case of SNVs and indels, and quantitative PCR (qPCR) for CNVs. SNV and indel analysis led to the identification of a previously reported mutation in PRPH2. Two additional mutations linked to different forms of retinal dystrophies were identified in two families: a known frameshift deletion in RPGR, a gene responsible for X-linked retinitis pigmentosa and p.Ser163Arg in C1QTNF5 associated with Late-Onset Retinal Degeneration. A novel heterozygous deletion spanning the entire region of PRPF31 was also identified in the affected members of a fourth family, which was confirmed with qPCR. This study allowed the identification of the genetic cause of the retinal dystrophy and the establishment of a correct diagnosis in four families, including a large heterozygous deletion in PRPF31, typically considered one of the pitfalls of this method. Since all findings in this study are restricted to known genes, we propose that targeted sequencing using gene-panel is an optimal first approach for the genetic screening and that once known genetic causes are ruled out, WES might be used to uncover new genes involved in inherited retinal dystrophies. PMID:26197217

  5. Recognizing Cataracts

    Science.gov (United States)

    ... age-related cataract. They recommend eating plenty of green leafy vegetables, fruits, nuts and other healthy foods. Also, don’t smoke, because smoking may speed cataract development. To screen for early signs of eye disease, Bishop recommends ...

  6. Medical resource utilization and costs associated with autosomal dominant polycystic kidney disease in the USA: a retrospective matched cohort analysis of private insurer data

    Directory of Open Access Journals (Sweden)

    Knight T

    2015-02-01

    Full Text Available Tyler Knight,1 Caroline Schaefer,1 Holly Krasa,2 Dorothee Oberdhan,2 Arlene Chapman,3 Ronald D Perrone4 1Covance Market Access Services Inc., Gaithersburg, MD, 2Otsuka Pharmaceutical Development and Commercialization, Inc., Rockville, MD, 3Emory University, Atlanta, GA, 4Tufts Medical Center and Tufts University School of Medicine, Boston, MA, USA Background: Autosomal dominant polycystic kidney disease (ADPKD results in kidney cyst development and enlargement, resulting in chronic kidney disease (CKD leading to renal failure. This study sought to determine if ADPKD patients in the early stages of CKD contribute to a sizable economic burden for the US health care system. Methods: This was a retrospective, matched cohort study, reviewing medical resource utilization (MRU and costs for adults in a US private-payer claims database with a diagnosis code of ADPKD (ICD-9-CM 753.13. ADPKD patients were matched by age grouping (0–17, 18–34, 35–44, 45–54, 55–64, and 65+ years and sex to controls to understand the burden of ADPKD. Descriptive statistics on 6-month MRU and costs were assessed by CKD stages, dialysis use, or previous renal transplant. Results: The analysis included ADPKD patients in CKD stages 1–5 (n=316 to n=860, dialysis (n=586, and post-transplant (n=615. Mean ages did not differ across CKD stages (range 43–56 years. Men were the majority in the later stages but the minority in the early stages. The proportion of patients with at least one hospitalization increased with CKD stage, (12% to >40% CKD stage 2 to stage 5, dialysis or post-transplant. The majority had at least one hospital outpatient visit and at least one pharmacy claim. Total 6-month per-patient costs were greater among ADPKD patients than in age-matched and sex-matched healthy non-ADPKD controls (P<0.001 for all comparisons. Conclusion: ADPKD patients with normal kidney function are associated with a significant economic burden to the health care system

  7. Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease : a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice

    NARCIS (Netherlands)

    Gansevoort, Ron T; Arici, Mustafa; Benzing, Thomas; Birn, Henrik; Capasso, Giovambattista; Covic, Adrian; Devuyst, Olivier; Drechsler, Christiane; Eckardt, Kai-Uwe; Emma, Francesco; Knebelmann, Bertrand; Le Meur, Yannick; Massy, Ziad A; Ong, Albert C M; Ortiz, Alberto; Schaefer, Franz; Torra, Roser; Vanholder, Raymond; Więcek, Andrzej; Zoccali, Carmine; Van Biesen, Wim

    Recently, the European Medicines Agency approved the use of the vasopressin V2 receptor antagonist tolvaptan to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adult patients with chronic kidney disease stages 1-3 at

  8. Hepatic Cyst Infection During Use of the Somatostatin Analog Lanreotide in Autosomal Dominant Polycystic Kidney Disease: An Interim Analysis of the Randomized Open-Label Multicenter DIPAK-1 Study

    NARCIS (Netherlands)

    Lantinga, M.A. (Marten A.); D’Agnolo, H.M.A. (Hedwig M. A.); E. Casteleijn (Eric); de Fijter, J.W. (Johan W.); E. Meijer (Esther); A.L. Messchendorp (A. Lianne); D. Peters (Dorien); M. Salih (Mahdi); E.M. Spithoven (Edwin); D. Soonawala (Darius); F.W. Visser (Folkert); Wetzels, J.F.M. (Jack F. M.); R. Zietse (Bob); J.P.H. Drenth (Joost); R.T. Gansevoort (Ron); Drenth, J.P.H.; J.W. de Fijter (Johan); Gansevoort, R.T.; D.J.M. Peters (Dorien J.M.); J.F.M. Wetzels (Jack); Zietse, R.

    2017-01-01

    textabstractIntroduction and Aims: The DIPAK-1 Study investigates the reno- and hepatoprotective efficacy of the somatostatin analog lanreotide compared with standard care in patients with later stage autosomal dominant polycystic kidney disease (ADPKD). During this trial, we witnessed several

  9. Changes in causes of death and risk of cancer in Danish patients with autosomal dominant polycystic kidney disease and end-stage renal disease.

    Science.gov (United States)

    Orskov, Bjarne; Sørensen, Vibeke Rømming; Feldt-Rasmussen, Bo; Strandgaard, Svend

    2012-04-01

    With the improved prognosis in patients with autosomal dominant polycystic kidney disease (ADPKD), causes of death and the risk of cancer might have changed. This was investigated in a Danish population with ADPKD and end-stage renal disease (ESRD) between 1 January 1993 and 31 December 2008. Data were retrieved from three Danish national registries and a total of 823 patients were identified of which 431 had died during the study period. The 16 years were divided into two 8-year periods and the causes of death were divided into six categories: cancer, cardiovascular, cerebrovascular, infection, other and unknown. Cardiovascular disease was the major cause of death. A multivariate competing risk model comparing the two 8-year periods, adjusted for age at ESRD, gender and treatment modality, showed that deaths from cardiovascular disease decreased by 35% [hazard ratios (HR) 0.65, P=0.008] and deaths from cerebrovascular disease decreased by 69% (HR 0.31, P=0.0003) from the first to the second time period. There were no significant changes between the time periods in death from cancer, infection, other or unknown. From the first to the second 8-year interval, the prevalence of cancer increased by 35% (P=0.0002) while the cancer incidence was stable. In Danish patients with ADPKD and ESRD, there was a significant reduction in cardiovascular and cerebrovascular deaths from 1993 to 2008. The prevalence of cancer increased without significant change in cancer incidence or deaths from cancer.

  10. RHO Mutations (p.W126L and p.A346P in Two Japanese Families with Autosomal Dominant Retinitis Pigmentosa

    Directory of Open Access Journals (Sweden)

    Satoshi Katagiri

    2014-01-01

    Full Text Available Purpose. To investigate genetic and clinical features of patients with rhodopsin (RHO mutations in two Japanese families with autosomal dominant retinitis pigmentosa (adRP. Methods. Whole-exome sequence analysis was performed in ten adRP families. Identified RHO mutations for the cosegregation analysis were confirmed by Sanger sequencing. Ophthalmic examinations were performed to evaluate the RP phenotypes. The impact of the RHO mutation on the rhodopsin conformation was examined by molecular modeling analysis. Results. In two adRP families, we identified two RHO mutations (c.377G>T (p.W126L and c.1036G>C (p.A346P, one of which was novel. Complete cosegregation was confirmed for each mutation exhibiting the RP phenotype in both families. Molecular modeling predicted that the novel mutation (p.W126L might impair rhodopsin function by affecting its conformational transition in the light-adapted form. Clinical phenotypes showed that patients with p.W126L exhibited sector RP, whereas patients with p.A346P exhibited classic RP. Conclusions. Our findings demonstrated that the novel mutation (p.W126L may be associated with the phenotype of sector RP. Identification of RHO mutations is a very useful tool for predicting disease severity and providing precise genetic counseling.

  11. Rationale and design of the RESOLVE trial: lanreotide as a volume reducing treatment for polycystic livers in patients with autosomal dominant polycystic kidney disease

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    Gevers Tom JG

    2012-04-01

    Full Text Available Abstract Background A large proportion of patients with autosomal dominant polycystic kidney disease (ADPKD suffers from polycystic liver disease. Symptoms arise when liver volume increases. The somatostatin analogue lanreotide has proven to reduce liver volume in patients with polycystic liver disease. However, this study also included patients with isolated polycystic liver disease (PCLD. The RESOLVE trial aims to assess the efficacy of lanreotide treatment in ADPKD patients with symptomatic polycystic livers. In this study we present the design of the RESOLVE trial. Methods/design This open-label clinical trial evaluates the effect of 6 months of lanreotide in ADPKD patients with symptomatic polycystic livers. Primary outcome is change in liver volume determined by computerised tomography-volumetry. Secondary outcomes are changes in total kidney volume, kidney intermediate volume and renal function. Furthermore, urinary (NGAL, α1-microglobulin, KIM-1, H-FABP, MCP-1 and serum (fibroblast growth factor 23 biomarkers associated with ADPKD disease severity are assessed to investigate whether these biomarkers predict treatment responses to lanreotide. Moreover, safety and tolerability of the drug in ADPKD patients will be assessed. Discussion We anticipate that lanreotide is an effective therapeutic option for ADPKD patients with symptomatic polycystic livers and that this trial aids in the identification of patient related factors that predict treatment response. Trial registration number Clinical trials.gov NCT01354405

  12. Percutaneous Nephrolithotomy under Ultrasound Guidance in Patients with Renal Calculi and Autosomal Dominant Polycystic Kidney Disease: A Report of 11 Cases

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    Xiao Wang

    2017-01-01

    Full Text Available Nephrolithiasis accelerates the renal failure in the patients with ADPKD. In order to evaluate the role of percutaneous nephrolithotomy in management of calculus in these patients, 11 patients with autosomal dominant polycystic kidney disease and renal stones were included in the study. Two patients had bilateral renal stones. All patients were treated by percutaneous nephrolithotomy under ultrasound guidance. 13 percutaneous nephrolithotomy procedures were performed in 1 stage by the urology team under ultrasound guidance. 5 people received second operation with flexible nephroscopy in lateral position. The success rate and morbidity and mortality of the technique and hospital stay were recorded. Results. The puncture procedure was fully successful in all cases. The renal function improved in these patients. 5 patients had moderate fever after the surgery. 5 patients received flexible nephroscopy to take out the residual calculi. 2 persons had ESWL therapy after the surgery. Conclusion. PCNL is an ideal, safe, and effective method to remove the stones from those patients with no definite increase in the risk of complication. The outcome and stone-free rate are satisfactory comparable to the PCNL in the patients without ADPKD.

  13. Autosomal dominant Marfan-like connective-tissue disorder with aortic dilation and skeletal anomaslies not linked to the Fibrillin genes

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    Boileau, C.; Coulon, M.; Alexandre, J.-A.; Junien, C. (Laboratorie Central de Biochimie et de Genetique Moleculaire (France)); Jondeau, G.; Delorme, G.; Dubourg, O.; Bourdarias, J.-P. (CHU Ambroise Pare, Boulogne (France)); Babron, M.-C.; Bonaieti-Pellie, C. (INSERM, Chateau de Longchamp, Paris (France)); Sakai, L. (Shriners' Hospital for Crippled Children, Portland, OR (United States)); Melki, J. (Hopital Necker-Enfants Malades, Paris (France))

    1993-07-01

    The authors describe a large family with a connective-tissue disorder that exhibits some of the skeletal and cardiovascular features seen in Marfan syndrome. However, none of the 19 affected individuals displayed ocular abnormalities and therefore did not comply with recognized criteria for this disease. These patients could alternatively be diagnosed as MASS (mitral valve, aorta, skeleton, and skin) phenotype patients or represent a distinct clinical entity, i.e., a new autosomal dominant connective-tissue disorder. The fibrillin genes located on chromosomes 15 and 5 are clearly involved in the classic form of Marfan syndrome and a clinically related disorder (congenital contractural arachnodactyly), respectively. To test whether one of these genes was also implicated in this French family, the authors performed genetic analyses. Blood samples were obtained for 56 family members, and four polymorphic fibrillin gene markers, located on chromosomes 15 (Fib15) and 5 (Fib5), respectively, were tested. Linkage between the disease allele and the markers of these two genes was excluded with lod scores of [minus]11.39 (for Fib15) and [minus]13.34 (for Fib5), at 0 = .001, indicating that the mutation is at a different locus. This phenotype thus represents a new connective-tissue disorder, overlapping but different from classic Marfan syndrome. 33 refs., 1 fig. 2 tabs.

  14. Polysomnographic and neurometabolic features may mark preclinical autosomal dominant cerebellar ataxia, deafness, and narcolepsy due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1.

    Science.gov (United States)

    Moghadam, Keivan Kaveh; Pizza, Fabio; Tonon, Caterina; Lodi, Raffaele; Carelli, Valerio; Poli, Francesca; Franceschini, Christian; Barboni, Piero; Seri, Marco; Ferrari, Simona; La Morgia, Chiara; Testa, Claudia; Cornelio, Ferdinando; Liguori, Rocco; Winkelmann, Juliane; Lin, Ling; Mignot, Emmanuel; Plazzi, Giuseppe

    2014-05-01

    We aimed to report the clinical picture of two asymptomatic daughters of a patient with autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN) due to a mutation in the DNA (cytosine-5-)-methyltransferase gene, DNMT1. Clinical assessment based on history, neurologic examination, sleep recordings, neurophysiologic neuroimaging, and genetic tests was performed. History and neurologic examination in both subjects were unremarkable. Genetic analysis disclosed in both the paternally-inherited heterozygous point mutation in the DNMT1 gene. Sleep recordings found sleep-onset rapid eye movement periods (SOREMPs) and proton magnetic resonance spectroscopy (MRS) revealed increased cerebellar myoinositol (mI) in both subjects. Auditory and ophthalmologic investigations as well as structural brain magnetic resonance imaging (MRI) scans revealed no abnormalities. The two asymptomatic carriers of the heterozygous DNMT1 mutation for ADCA-DN, a late-onset neurodegenerative disease, presented with SOREMPs associated with an increase of mI in the brain, a marker of glial cell activity and density characteristic of early stages of neurodegenerative diseases. Therefore, SOREMPs may precede the clinical picture of ADCA-DN as an early polysomnographic marker of central nervous system involvement detected by MRS. Copyright © 2014 Elsevier B.V. All rights reserved.

  15. Atypical Association of Ethmoidal Encephalocele and Hydrocephalus in an Adult Patient with Autosomal-Dominant Osteopetrosis Type I (ADO-I): A Case Report.

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    Rossini, Zefferino; Castellani, Carlotta; Borsa, Stefano; Carrabba, Giorgio; Locatelli, Marco; Di Cristofori, Andrea

    2016-05-01

    Osteopetroses are a heterogeneous group of heritable disorders characterized by increased bone density as the result of defective osteoclast-mediated bone resorption. The autosomal-dominant osteopetrosis type I (ADO-I) is defined by the presence of osteosclerosis involving mainly the skull bones, variably associated with compression of the foramina of cranial nerves and vascular structures, hypertelorism, exophthalmos, and less commonly with hydrocephalus, pseudotumor, and Chiari malformation type I. We describe an adult patient with ADO-I presenting with an atypical association of clinical manifestations that required a tailored management. On admission, the patient complained about chronic headache, recurrent sinusitis, and postnasal drip. Findings of the examination didn't show clear signs of increased intracranial pressure, whereas imaging studies revealed thickening of the skull bones and an unexpected fistula associated with anterior ethmoidal meningoencephalocele. Some days after endoscopic transnasal closure of the fistula, a severe hypertensive hydrocephalus developed, which required a prompt ventriculoperitoneal shunt placement, complicated by a diffuse subarachnoid hemorrhage. The 6-month follow-up showed complete recovery. After reviewing the literature, we can confirm that ours was the second case of an adult ADO-I patient associated with anterior ethmoidal meningoencephalocele, the first one needing a combined treatment of the encephalocele and hydrocephalus. Because ADO-I is a rare disease with a wide spectrum of clinical manifestations, our case can represent a prototype for the future management of similar cases. Copyright © 2016. Published by Elsevier Inc.

  16. Exome Sequencing Identifies a Missense Variant in EFEMP1 Co-Segregating in a Family with Autosomal Dominant Primary Open-Angle Glaucoma.

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    Donna S Mackay

    Full Text Available Primary open-angle glaucoma (POAG is a clinically important and genetically heterogeneous cause of progressive vision loss as a result of retinal ganglion cell death. Here we have utilized trio-based, whole-exome sequencing to identify the genetic defect underlying an autosomal dominant form of adult-onset POAG segregating in an African-American family. Exome sequencing identified a novel missense variant (c.418C>T, p.Arg140Trp in exon-5 of the gene coding for epidermal growth factor (EGF containing fibulin-like extracellular matrix protein 1 (EFEMP1 that co-segregated with disease in the family. Linkage and haplotype analyses with microsatellite markers indicated that the disease interval overlapped a known POAG locus (GLC1H on chromosome 2p. The p.Arg140Trp substitution was predicted in silico to have damaging effects on protein function and transient expression studies in cultured cells revealed that the Trp140-mutant protein exhibited increased intracellular accumulation compared with wild-type EFEMP1. In situ hybridization of the mouse eye with oligonucleotide probes detected the highest levels of EFEMP1 transcripts in the ciliary body, cornea, inner nuclear layer of the retina, and the optic nerve head. The recent finding that a common variant near EFEMP1 was associated with optic nerve-head morphology supports the possibility that the EFEMP1 variant identified in this POAG family may be pathogenic.

  17. Aldosterone synthase gene is not a major susceptibility gene for progression of chronic kidney disease in patients with autosomal dominant polycystic kidney disease

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    Gnanasambandan Ramanathan

    2017-01-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is the most common heritable kidney disease and is characterized by bilateral renal cysts. Hypertension is a frequent cause of chronic kidney disease (CKD and mortality in patients with ADPKD. The aldosterone synthase gene polymorphisms of the renin-angiotensin-aldosterone system have been extensively studied as hypertension candidate genes. The present study is aimed to investigate the potential modifier effect of CYP11B2 gene on the progression of CKD in ADPKD. One hundred and two ADPKD patients and 106 healthy controls were recruited based on Ravine inclusion and exclusion criteria. The three tag-SNPs within CYP11B2 gene (rs3802230, rs4543, and rs4544 were genotyped using FRET-based KASPar method. Cochran-Armitage trend test was used to assess the potential associations between these polymorphisms and CKD stages. Mantel- Haenszel stratified analysis was used to explore confounding and interaction effects of these polymorphisms. Of the three tag-SNPs genotyped, rs4544 polymorphism was monomorphic and rs3802230 deviated Hardy-Weinberg equilibrium. The CYP11B2 tag-SNPs did not show significant association with ADPKD or CKD. Further, these polymorphisms did not exhibit confounding effect on the relationship between CKD progression and hypertension. Our results suggest that aldosterone synthase gene is not a major susceptibility gene for progression of CKD in South Indian ADPKD patients.

  18. SPM analysis of brain perfusion SPECT and F-18 FDG PET in the Korean autosomal dominant nocturnal frontal lobe epilepsy family

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    Won, Kyoung Sook; Zeon, Seok Kil

    2004-01-01

    This study attempted to investigate the specific pattern of brain perfusion and glucose metabolism in the Korean autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) family. Using Tc-99m ECD brain perfusion SPECT. we assessed brain perfusion in 6 patients at interictal period and 5 patients at ictal period. Interictal F-18 FDG PET was performed on 6 affected family members. The scans were statistically analyzed by using statistical parametric mapping (SPM99). The data of the affected family members were compared to those of the control subjects. Interictal F-18 FDG PET SPM group analysis showed decreased glucose metabolism over the left middle and superior frontal gyri and the left central regions including the anterior parietal lobe. There was a less pronounced decrease in glucose uptake in the right anterior superior frontal gyrus. Interictal brain perfusion SPECT SPM group analysis showed similar pattern of decreased perfusion compared to those of interictal F-18 FDG PET. Ictal brain perfusion SPECT SPM group analysis revealed increased perfusion over the left pre-and postcentral gyri and less pronounced increased perfusion in the right postcentral gyrus. lnterictal F -18 PET and brain perfusion SPECT SPM group analysis suggest that major abnormalities of ADNFLE family are in the left frontal lobe. These findings may be helpful to elucidate the pathophysiological mechanism of this rare disease entity

  19. A missense mutation in the alpha-actinin 1 gene (ACTN1 is the cause of autosomal dominant macrothrombocytopenia in a large French family.

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    Paul Guéguen

    Full Text Available Inherited thrombocytopenia is a heterogeneous group of disorders characterized by a reduced number of blood platelets. Despite the identification of nearly 20 causative genes in the past decade, approximately half of all subjects with inherited thrombocytopenia still remain unexplained in terms of the underlying pathogenic mechanisms. Here we report a six-generation French pedigree with an autosomal dominant mode of inheritance and the identification of its genetic basis. Of the 55 subjects available for analysis, 26 were diagnosed with isolated macrothrombocytopenia. Genome-wide linkage analysis mapped a 10.9 Mb locus to chromosome 14 (14q22 with a LOD score of 7.6. Candidate gene analysis complemented by targeted next-generation sequencing identified a missense mutation (c.137GA; p.Arg46Gln in the alpha-actinin 1 gene (ACTN1 that segregated with macrothrombocytopenia in this large pedigree. The missense mutation occurred within actin-binding domain of alpha-actinin 1, a functionally critical domain that crosslinks actin filaments into bundles. The evaluation of cultured mutation-harboring megakaryocytes by electron microscopy and the immunofluorescence examination of transfected COS-7 cells suggested that the mutation causes disorganization of the cellular cytoplasm. Our study concurred with a recently published whole-exome sequence analysis of six small Japanese families with congenital macrothrombocytopenia, adding ACTN1 to the growing list of thrombocytopenia genes.

  20. Feasibility of measuring renal blood flow by phase-contrast magnetic resonance imaging in patients with autosomal dominant polycystic kidney disease

    Energy Technology Data Exchange (ETDEWEB)

    Spithoven, E.M.; Meijer, E.; Boertien, W.E.; Gaillard, C.A.J.M.; Jong, P.E. de; Gansevoort, R.T. [University of Groningen, Department of Nephrology, Community and Occupational Medicine, University Medical Center Groningen, PO Box 30.001, RB Groningen (Netherlands); Borns, C.; Kappert, P.; Greuter, M.J.W.; Jagt, E. van der [University of Groningen, Department of Radiology, Community and Occupational Medicine, University Medical Center Groningen, Groningen (Netherlands); Vart, P. [University of Groningen, Department of Health Sciences, Community and Occupational Medicine, University Medical Center Groningen, Groningen (Netherlands)

    2016-03-15

    Renal blood flow (RBF) has been shown to predict disease progression in autosomal dominant polycystic kidney disease (ADPKD). We investigated the feasibility and accuracy of phase-contrast RBF by MRI (RBF{sub MRI}) in ADPKD patients with a wide range of estimated glomerular filtration rate (eGFR) values. First, we validated RBF{sub MRI} measurement using phantoms simulating renal artery hemodynamics. Thereafter, we investigated in a test-set of 21 patients intra- and inter-observer coefficient of variation of RBF{sub MRI}. After validation, we measured RBF{sub MRI} in a cohort of 91 patients and compared the variability explained by characteristics indicative for disease severity for RBF{sub MRI} and RBF measured by continuous hippuran infusion. The correlation in flow measurement using phantoms by phase-contrast MRI was high and fluid collection was high (CCC=0.969). Technical problems that precluded RBF{sub MRI} measurement occurred predominantly in patients with a lower eGFR (34% vs. 16%). In subjects with higher eGFRs, variability in RBF explained by disease characteristics was similar for RBF{sub MRI} compared to RBF{sub Hip,} whereas in subjects with lower eGFRs, this was significantly less for RBF{sub MRI}. Our study shows that RBF can be measured accurately in ADPKD patients by phase-contrast, but this technique may be less feasible in subjects with a lower eGFR. (orig.)

  1. Regional association of pCASL-MRI with FDG-PET and PiB-PET in people at risk for autosomal dominant Alzheimer's disease

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    Lirong Yan

    2018-01-01

    Full Text Available Autosomal dominant Alzheimer's disease (ADAD is a small subset of Alzheimer's disease that is genetically determined with 100% penetrance. It provides a valuable window into studying the course of pathologic processes that leads to dementia. Arterial spin labeling (ASL MRI is a potential AD imaging marker that non-invasively measures cerebral perfusion. In this study, we investigated the relationship of cerebral blood flow measured by pseudo-continuous ASL (pCASL MRI with measures of cerebral metabolism (FDG PET and amyloid deposition (Pittsburgh Compound B (PiB PET. Thirty-one participants at risk for ADAD (age 39±13 years, 19 females were recruited into this study, and 21 of them received both MRI and FDG and PiB PET scans. Considerable variability was observed in regional correlations between ASL-CBF and FDG across subjects. Both regional hypo-perfusion and hypo-metabolism were associated with amyloid deposition. Cross-sectional analyses of each biomarker as a function of the estimated years to expected dementia diagnosis indicated an inverse relationship of both perfusion and glucose metabolism with amyloid deposition during AD development. These findings indicate that neurovascular dysfunction is associated with amyloid pathology, and also indicate that ASL CBF may serve as a sensitive early biomarker for AD. The direct comparison among the three biomarkers provides complementary information for understanding the pathophysiological process of AD.

  2. SPM analysis of brain perfusion SPECT and F-18 FDG PET in the Korean autosomal dominant nocturnal frontal lobe epilepsy family

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    Won, Kyoung Sook; Zeon, Seok Kil [Keimyung University Dongsan Medical Center, Daegu (Korea, Republic of)

    2004-07-01

    This study attempted to investigate the specific pattern of brain perfusion and glucose metabolism in the Korean autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) family. Using Tc-99m ECD brain perfusion SPECT. we assessed brain perfusion in 6 patients at interictal period and 5 patients at ictal period. Interictal F-18 FDG PET was performed on 6 affected family members. The scans were statistically analyzed by using statistical parametric mapping (SPM99). The data of the affected family members were compared to those of the control subjects. Interictal F-18 FDG PET SPM group analysis showed decreased glucose metabolism over the left middle and superior frontal gyri and the left central regions including the anterior parietal lobe. There was a less pronounced decrease in glucose uptake in the right anterior superior frontal gyrus. Interictal brain perfusion SPECT SPM group analysis showed similar pattern of decreased perfusion compared to those of interictal F-18 FDG PET. Ictal brain perfusion SPECT SPM group analysis revealed increased perfusion over the left pre-and postcentral gyri and less pronounced increased perfusion in the right postcentral gyrus. lnterictal F -18 PET and brain perfusion SPECT SPM group analysis suggest that major abnormalities of ADNFLE family are in the left frontal lobe. These findings may be helpful to elucidate the pathophysiological mechanism of this rare disease entity.

  3. A novel mutation in MIP associated with congenital nuclear cataract in a Chinese family.

    Science.gov (United States)

    Wang, Kai Jie; Li, Sha Sha; Yun, Bo; Ma, Wen Xian; Jiang, Tian Ge; Zhu, Si Quan

    2011-01-08

    To identify the underlying genetic defect in a Chinese family affected with autosomal dominant congenital nuclear cataract. A four-generation Chinese family with inherited nuclear cataract phenotype was recruited. Detailed family history and clinical data were recorded. All reported nuclear cataract-related candidate genes were screened for causative mutations by direct DNA sequencing. Effects of amino acid changes on the structure and function of protein were predicted by bioinformatics analysis. All affected individuals in this family showed nuclear cataracts. Sequencing of the candidate genes revealed a heterozygous c.559C>T change in the coding region of the major intrinsic protein (MIP), which caused a substitution of highly conserved arginine by cysteine at codon 187 (p.R187C). This mutation co-segregated with all affected individuals and was not observed in unaffected family members or 110 ethnically matched controls. Bioinformatics analysis showed that the mutation was predicted to affect the function and secondary structure of MIP protein. This study identified a novel disease-causing mutation p.R187C in MIP in a Chinese cataract family, expanding the mutation spectrum of MIP causing congenital cataract.

  4. Feasibility of measuring renal blood flow by phase-contrast magnetic resonance imaging in patients with autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Spithoven, E M; Meijer, E; Borns, C; Boertien, W E; Gaillard, C A J M; Kappert, P; Greuter, M J W; van der Jagt, E; Vart, P; de Jong, P E; Gansevoort, R T

    2016-03-01

    Renal blood flow (RBF) has been shown to predict disease progression in autosomal dominant polycystic kidney disease (ADPKD). We investigated the feasibility and accuracy of phase-contrast RBF by MRI (RBFMRI) in ADPKD patients with a wide range of estimated glomerular filtration rate (eGFR) values. First, we validated RBFMRI measurement using phantoms simulating renal artery hemodynamics. Thereafter, we investigated in a test-set of 21 patients intra- and inter-observer coefficient of variation of RBFMRI. After validation, we measured RBFMRI in a cohort of 91 patients and compared the variability explained by characteristics indicative for disease severity for RBFMRI and RBF measured by continuous hippuran infusion. The correlation in flow measurement using phantoms by phase-contrast MRI was high and fluid collection was high (CCC=0.969). Technical problems that precluded RBFMRI measurement occurred predominantly in patients with a lower eGFR (34% vs. 16%). In subjects with higher eGFRs, variability in RBF explained by disease characteristics was similar for RBFMRI compared to RBFHip, whereas in subjects with lower eGFRs, this was significantly less for RBFMRI. Our study shows that RBF can be measured accurately in ADPKD patients by phase-contrast, but this technique may be less feasible in subjects with a lower eGFR. Renal blood flow (RBF) can be accurately measured by phase-contrast MRI in ADPKD patients. RBF measured by phase-contrast is associated with ADPKD disease severity. RBF measurement by phase-contrast MRI may be less feasible in patients with an impaired eGFR.

  5. Identification of Two Disease-causing Genes TJP2 and GJB2 in a Chinese Family with Unconditional Autosomal Dominant Nonsyndromic Hereditary Hearing Impairment

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    Hong-Yang Wang

    2015-01-01

    Full Text Available Background: There are more than 300 genetic loci that have been found to be related to hereditary hearing impairment (HHI, including 92 causative genes for nonsyndromic hearing loss, among which 34 genes are related to autosomal dominant nonsyndromic HHI (ADNSHHI. Traditional linkage analysis and candidate gene sequencing are not effective at detecting the ADNSHHI, especially for the unconditional families that may have more than one pathogenic cause. This study identified two disease-causing genes TJP2 and GJB2 in a Chinese family with unconditional ADNSHHI. Methods: To decipher the genetic code of a Chinese family (family 686 with ADNSHHI, different gene screening techniques have been performed, including linkage analysis, candidate genes screening, high-throughput sequencing and Sanger sequencing. These techniques were done on samples obtained from this family over a period of 10 years. Results: We identified a pathogenic missense mutation, c. 2081G>A (p.G694E, in TJP2, a gene that plays a crucial role in apoptosis and age-related hearing loss (ARHL. The mutation was co-segregated in this pedigree in all, but not in the two patients who presented with different phenotypes from the other affected family members. In one of the two patients, we confirmed that the compound heterozygosity for p.Y136FNx01 and p.G45E in the GJB2 gene may account for the phenotype shown in this patient. Conclusions: We identified the co-occurrence of two genetic causes in family 686. The possible disease-causing missense mutation of TJP2 in family 686 presents an opportunity for further investigation into ARHL. It is necessary to combine various genes screening methods, especially for some unconventional cases.

  6. Three novel and the common Arg677Ter RP1 protein truncating mutations causing autosomal dominant retinitis pigmentosa in a Spanish population

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    Antiñolo Guillermo

    2006-04-01

    Full Text Available Abstract Background Retinitis pigmentosa (RP, a clinically and genetically heterogeneous group of retinal degeneration disorders affecting the photoreceptor cells, is one of the leading causes of genetic blindness. Mutations in the photoreceptor-specific gene RP1 account for 3–10% of cases of autosomal dominant RP (adRP. Most of these mutations are clustered in a 500 bp region of exon 4 of RP1. Methods Denaturing gradient gel electrophoresis (DGGE analysis and direct genomic sequencing were used to evaluate the 5' coding region of exon 4 of the RP1 gene for mutations in 150 unrelated index adRP patients. Ophthalmic and electrophysiological examination of RP patients and relatives according to pre-existing protocols were carried out. Results Three novel disease-causing mutations in RP1 were detected: Q686X, K705fsX712 and K722fsX737, predicting truncated proteins. One novel missense mutation, Thr752Met, was detected in one family but the mutation does not co-segregate in the family, thereby excluding this amino acid variation in the protein as a cause of the disease. We found the Arg677Ter mutation, previously reported in other populations, in two independent families, confirming that this mutation is also present in a Spanish population. Conclusion Most of the mutations reported in the RP1 gene associated with adRP are expected to encode mutant truncated proteins that are approximately one third or half of the size of wild type protein. Patients with mutations in RP1 showed mild RP with variability in phenotype severity. We also observed several cases of non-penetrant mutations.

  7. Live Donor Renal Transplant With Simultaneous Bilateral Nephrectomy for Autosomal Dominant Polycystic Kidney Disease Is Feasible and Satisfactory at Long-term Follow-up.

    Science.gov (United States)

    Ahmad, Sarwat B; Inouye, Brian; Phelan, Michael S; Kramer, Andrew C; Sulek, Jay; Weir, Matthew R; Barth, Rolf N; LaMattina, John C; Schweitzer, Eugene J; Leeser, David B; Niederhaus, Silke V; Bartlett, Stephen T; Bromberg, Jonathan S

    2016-02-01

    Timing of bilateral nephrectomy (BN) is controversial in patients with refractory symptoms of autosomal dominant polycystic kidney disease (APKD) in need of a renal transplant. Adults who underwent live donor renal transplant (LRT) + simultaneous BN (SBN) from August 2003 to 2013 at a single transplant center (n = 66) were retrospectively compared to a matched group of APKD patients who underwent LRT alone (n = 52). All patients received general health and polycystic kidney symptom surveys. Simultaneous BN increased operative duration, estimated blood loss, transfusions, intravenous fluid, and hospital length of stay. Most common indications for BN were pain, loss of abdominal domain, and early satiety. There were more intraoperative complications for LRT + SBN (6 vs 0, P = 0.03; 2 vascular, 2 splenic, and 1 liver injury; 1 reexploration to adjust graft positioning). There were no differences in Clavien-Dindo grade I or II (39% vs 25%, P = 0.12) or grade III or IV (7.5% vs 5.7%, P = 1.0) complications during the hospital course. There were no surgery-related mortalities. There were no differences in readmission rates (68% vs 48%, P = 0.19) or readmissions requiring procedures (25% vs. 20%, P = 0.51) over 12 months. One hundred percent of LRT + SBN allografts functioned at longer than 1 year for those available for follow-up. Survey response rate was 40% for LRT-alone and 56% for LRT + SBN. One hundred percent of LRT + SBN survey responders were satisfied with their choice of having BN done simultaneously. Excellent outcomes for graft survival, satisfaction, and morbidity suggest that the combined operative approach be preferred for patients with symptomatic APKD to avoid multiple procedures, dialysis, and costs of staged operations.

  8. Profiling conserved biological pathways in Autosomal Dominant Polycystic Kidney Disorder (ADPKD) to elucidate key transcriptomic alterations regulating cystogenesis: A cross-species meta-analysis approach.

    Science.gov (United States)

    Chatterjee, Shatakshee; Verma, Srikant Prasad; Pandey, Priyanka

    2017-09-05

    Initiation and progression of fluid filled cysts mark Autosomal Dominant Polycystic Kidney Disease (ADPKD). Thus, improved therapeutics targeting cystogenesis remains a constant challenge. Microarray studies in single ADPKD animal models species with limited sample sizes tend to provide scattered views on underlying ADPKD pathogenesis. Thus we aim to perform a cross species meta-analysis to profile conserved biological pathways that might be key targets for therapy. Nine ADPKD microarray datasets on rat, mice and human fulfilled our study criteria and were chosen. Intra-species combined analysis was performed after considering removal of batch effect. Significantly enriched GO biological processes and KEGG pathways were computed and their overlap was observed. For the conserved pathways, biological modules and gene regulatory networks were observed. Additionally, Gene Set Enrichment Analysis (GSEA) using Molecular Signature Database (MSigDB) was performed for genes found in conserved pathways. We obtained 28 modules of significantly enriched GO processes and 5 major functional categories from significantly enriched KEGG pathways conserved in human, mice and rats that in turn suggest a global transcriptomic perturbation affecting cyst - formation, growth and progression. Significantly enriched pathways obtained from up-regulated genes such as Genomic instability, Protein localization in ER and Insulin Resistance were found to regulate cyst formation and growth whereas cyst progression due to increased cell adhesion and inflammation was suggested by perturbations in Angiogenesis, TGF-beta, CAMs, and Infection related pathways. Additionally, networks revealed shared genes among pathways e.g. SMAD2 and SMAD7 in Endocytosis and TGF-beta. Our study suggests cyst formation and progression to be an outcome of interplay between a set of several key deregulated pathways. Thus, further translational research is warranted focusing on developing a combinatorial therapeutic

  9. Medical resource utilization and costs associated with autosomal dominant polycystic kidney disease in the USA: a retrospective matched cohort analysis of private insurer data

    Science.gov (United States)

    Knight, Tyler; Schaefer, Caroline; Krasa, Holly; Oberdhan, Dorothee; Chapman, Arlene; Perrone, Ronald D

    2015-01-01

    Background Autosomal dominant polycystic kidney disease (ADPKD) results in kidney cyst development and enlargement, resulting in chronic kidney disease (CKD) leading to renal failure. This study sought to determine if ADPKD patients in the early stages of CKD contribute to a sizable economic burden for the US health care system. Methods This was a retrospective, matched cohort study, reviewing medical resource utilization (MRU) and costs for adults in a US private-payer claims database with a diagnosis code of ADPKD (ICD-9-CM 753.13). ADPKD patients were matched by age grouping (0–17, 18–34, 35–44, 45–54, 55–64, and 65+ years) and sex to controls to understand the burden of ADPKD. Descriptive statistics on 6-month MRU and costs were assessed by CKD stages, dialysis use, or previous renal transplant. Results The analysis included ADPKD patients in CKD stages 1–5 (n=316 to n=860), dialysis (n=586), and post-transplant (n=615). Mean ages did not differ across CKD stages (range 43–56 years). Men were the majority in the later stages but the minority in the early stages. The proportion of patients with at least one hospitalization increased with CKD stage, (12% to >40% CKD stage 2 to stage 5, dialysis or post-transplant). The majority had at least one hospital outpatient visit and at least one pharmacy claim. Total 6-month per-patient costs were greater among ADPKD patients than in age-matched and sex-matched healthy non-ADPKD controls (P<0.001 for all comparisons). Conclusion ADPKD patients with normal kidney function are associated with a significant economic burden to the health care system relative to the general population. Any treatments that delay progression to later stages of CKD may provide potential health care cost offsets. PMID:25759590

  10. Influence of angiotensin converting enzyme (ACE) gene rs4362 polymorphism on the progression of kidney failure in patients with autosomal dominant polycystic kidney disease (ADPKD).

    Science.gov (United States)

    Ramanathan, Gnanasambandan; Ghosh, Santu; Elumalai, Ramprasad; Periyasamy, Soundararajan; Lakkakula, Bhaskar V K S

    2016-06-01

    Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disorder, characterized by the fluid filled cysts in the kidneys leading to end stage renal failure in later years of life. Hypertension is one of the major factors independently contributing to the chronic kidney disease (CKD) progression. The renin-angiotensin aldosterone system (RAAS) genes have been extensively studied as hypertension candidate genes. The aim of the present study was to investigate the role of angiotensin converting enzyme tagging - single nucleotide polymorphisms (ACE tag-SNPs) in progression of CKD in patients with ADPKD. m0 ethods: In the present study six ACE tagSNPs (angiotensin converting enzyme tag single nucleotide polymorphisms) and insertion/deletion (I/D) in 102 ADPKD patients and 106 control subjects were investigated. The tagSNPs were genotyped using FRET-based KASPar method and ACE ID by polymerase chain reaction (PCR) and electrophoresis. Genotypes and haplotypes were compared between ADPKD patients and controls. Univariate and multivariate logistic regression analyses were performed to assess the effect of genotypes and hypertension on CKD advancement. Mantel-Haenszel (M-H) stratified analysis was performed to study the relationship between different CKD stages and hypertension and their interaction. All loci were polymorphic and except rs4293 SNP the remaining loci followed Hardy-Weinberg equilibrium. Distribution of ACE genotypes and haplotypes in controls and ADPKD patients was not significant. A significant linkage disequilibrium (LD) was observed between SNPs forming two LD blocks. The univariate analysis revealed that the age, hypertension, family history of diabetes and ACE rs4362 contributed to the advancement of CKD. The results suggest that the ACE genotypes are effect modifiers of the relationship between hypertension and CKD advancement among the ADPKD patients.

  11. Cyst Ablation Using a Mixture of N-Butyl Cyanoacrylate and Iodized Oil in Patients with Autosomal Dominant Polycystic Kidney Disease: the Long-Term Results

    Energy Technology Data Exchange (ETDEWEB)

    Kim, See Hyung; Kim, Seung Hyup; Cho, Jeong Yeon [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2009-08-15

    We wanted to assess the long-term results of cyst ablation with using N-butyl cyanoacrylate (NBCA) and iodized oil in patients with autosomal dominant polycystic kidney disease (ADPKD) and symptomatic cysts. Cyst ablation using a mixture of NBCA and iodized oil was performed in 99 cysts from 21 patients who had such symptoms as abdominal distension and pain. The collapse or reaccumulation of the ablated cysts after the procedure was assessed during the follow-up period of 36 to 90 months. The treatment effects, including symptom relief, and the clinical data such as the blood pressure and serum creatinine levels were also assessed, together with the complications. The procedure was technically successful in all 99 cysts from the 21 patients. Any procedure-related significant complications were not detected. Seventy-seven of 99 cysts (78%) were successfully collapsed on the follow-up CT. Twenty-two cysts showed reaccumulation during long-term follow-up period. The clinical symptoms were relieved in 17 of the 21 patients (76%). Four of 12 patients (33%) with hypertension and two of six patients (33%) with azotemia were improved. End stage renal disease (ESRD) occurred in six of the 21 patients (28%) during the follow-up period. The mean age of ESRD in our patients was 57 years. The mean time interval for the development of ESRD was 19 months. Ablation using a mixture of NBCA and iodized oil may be an effective, safe method for obtaining symptom relief in patients with ADPKD.

  12. Endothelin 1 gene is not a major modifier of chronic kidney disease advancement among the autosomal dominant polycystic kidney disease patients

    Directory of Open Access Journals (Sweden)

    Annapareddy Shiva Nagendra Reddy

    2016-01-01

    Full Text Available Introduction: Autosomal dominant polycystic kidney disease (ADPKD is characterized by the presence of numerous cysts in the kidney and manifest with various renal and extra-renal complications leading to ESRD. Endothelin may contribute to various renal and extra-renal manifestations pointing to genetic and environmental modifying factors that alter the risk of developing chronic kidney disease (CKD in ADPKD. In the present study we investigated six genes coding for endothelin 1 (EDN1 tagging-single nucleotide polymorphisms (tag-SNPs to unravel the EDN1 gene modifier effect for renal disease progression in ADPKD. Materials and Methods: The tag-SNPs were genotyped using FRET-based KASPar method in 108 ADPKD patients and 119 healthy subjects. Cochran-Armitage trend test was used to determine the association between ADPKD and EDN1 tag-SNPs. Multivariate logistic regression analysis was performed to assess the effect of tag-SNPs on CKD progression. The relationship between different CKD stages and hypertension and their interaction Mantel-Haenszel stratified analysis was performed. Results: All loci are polymorphic and followed Hardy-Weinberg equilibrium. Distribution of EDN1 genotypes and haplotypes in control and ADPKD is not statistically significant. Five SNPs covering 3.4 kb forming single LD block, but the LD was not strong between SNPs. The EDN1 genotypes are not contributing to the CKD advancement among the ADPKD patients. Conclusion: These results suggest that the EDN1 gene is not a major modifier of CKD advancement among ADPKD patients.

  13. Autosomal Dominant STAT3 Deficiency and Hyper-IgE Syndrome Molecular, Cellular, and Clinical Features From a French National Survey

    Science.gov (United States)

    Chandesris, Marie-Olivia; Melki, Isabelle; Natividad, Angels; Puel, Anne; Fieschi, Claire; Yun, Ling; Thumerelle, Caroline; Oksenhendler, Eric; Boutboul, David; Thomas, Caroline; Hoarau, Cyrille; Lebranchu, Yvon; Stephan, Jean-Louis; Cazorla, Celine; Aladjidi, Nathalie; Micheau, Marguerite; Tron, Fran[cedil]cois; Baruchel, Andre; Barlogis, Vincent; Palenzuela, Gilles; Mathey, Catherine; Dominique, Stephane; Body, Gerard; Munzer, Martine; Fouyssac, Fanny; Jaussaud, Rolland; Bader-Meunier, Brigitte; Mahlaoui, Nizar; Blanche, Stephane; Debre, Marianne; Le Bourgeois, Muriel; Gandemer, Virginie; Lambert, Nathalie; Grandin, Virginie; Ndaga, Stephanie; Jacques, Corinne; Harre, Chantal; Forveille, Monique; Alyanakian, Marie-Alexandra; Durandy, Anne; Bodemer, Christine; Suarez, Felipe; Hermine, Olivier; Lortholary, Olivier; Casanova, Jean-Laurent; Fischer, Alain; Picard, Capucine

    2013-01-01

    Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic

  14. Long-term effect of coffee consumption on autosomal dominant polycystic kidneys disease progression: results from the Suisse ADPKD, a Prospective Longitudinal Cohort Study.

    Science.gov (United States)

    Girardat-Rotar, Laura; Puhan, Milo A; Braun, Julia; Serra, Andreas L

    2018-02-01

    Previous in vitro experiments of human polycystic kidney disease (PKD) cells reported that caffeine is a risk factor for the promotion of cyst enlargement in patients with autosomal dominant PKD (ADPKD). The relentless progression of ADPKD inclines the majority of physicians to advocate minimization of caffeine consumption despite the absence of clinical data supporting such a recommendation so far. This is the first clinical study to assess prospectively the association between coffee consumption and disease progression in a longitudinal ADPKD cohort. Information on coffee consumption and disease progression was collected at each follow-up visit using standardized measurement methods. The main model for the outcomes, kidney size (height-adjusted total kidney volume, htTKV) and kidney function (estimated glomerular filtration rate, eGFR), was a linear mixed model. Patients entered the on-going Swiss ADPKD study between 2006 and June 2014 and had at least 1 visit every year. The sample size of the study population was 151 with a median follow-up of 4 visits per patient and a median follow-up time of 4.38 years. After multivariate adjustment for age, smoking, hypertension, sex, body mass index and an interaction term (coffee*visit), coffee drinkers did not have a statistically significantly different kidney size compared to non-coffee drinkers (difference of -33.03 cm 3 height adjusted TKV, 95% confidence interval (CI) from -72.41 to 6.34, p = 0.10). After the same adjustment, there was no statistically significant difference in eGFR between coffee and non-coffee drinkers (2.03 ml/min/1.73 m 2 , 95% CI from -0.31 to 4.31, p = 0.089). Data derived from our prospective longitudinal study do not confirm that drinking coffee is a risk factor for ADPKD progression.

  15. Successful haploidentical donor hematopoietic stem cell transplant and restoration of STAT3 function in an adolescent with autosomal dominant hyper-IgE syndrome.

    Science.gov (United States)

    Patel, N C; Gallagher, J L; Torgerson, T R; Gilman, A L

    2015-07-01

    Autosomal dominant hyper-IgE syndrome (AD-HIES), caused by mutations in Signal Transducer and Activator of Transcription 3 (STAT3) is associated with defective STAT3 signaling and Th17 differentiation and recurrent bacterial and fungal infections. Most patients suffer significant morbidity and premature mortality. Hematopoietic stem cell transplantation (HSCT) has been reported in a small number of cases, with mixed outcomes. We report successful haploidentical donor HSCT in a patient with AD-HIES. Evaluation of lymphocyte subsets, STAT3 signaling, and Th17 cells was performed pre- and post-HSCT. A 14-year old female with AD-HIES developed recurrent methicillin-resistant Staphylococcus aureus (MRSA) abscesses. Immunologic analysis showed elevated IgE (4331 kU/L), absent Th17 cells, and markedly decreased STAT3 phosphorylation in cytokine stimulated peripheral blood mononuclear cells. She had breakthrough abscesses despite clindamycin and trimethoprim-sulfamethoxazole prophylaxis, and developed steroid refractory autoimmune hemolytic anemia. She underwent T-cell depleted haploidentical HSCT from her father following reduced intensity conditioning. She developed one MRSA hand abscess after transplant. Twenty-four months post transplant, she had complete donor chimerism (>95 % donor), normal absolute T cell numbers, and a normal percentage of Th17 cells. IgE was normal at 25 kU/L. She remains well 42 months after transplantation off all antibacterial prophylaxis. Haploidentical HSCT led to successful bone marrow engraftment, normalization of STAT3 signaling in hematopoietic cells, normalization of IgE, and restoration of immune function in this patient with AD-HIES.

  16. A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia

    Science.gov (United States)

    Coutelier, Marie; Blesneac, Iulia; Monteil, Arnaud; Monin, Marie-Lorraine; Ando, Kunie; Mundwiller, Emeline; Brusco, Alfredo; Le Ber, Isabelle; Anheim, Mathieu; Castrioto, Anna; Duyckaerts, Charles; Brice, Alexis; Durr, Alexandra; Lory, Philippe; Stevanin, Giovanni

    2015-01-01

    Hereditary cerebellar ataxias (CAs) are neurodegenerative disorders clinically characterized by a cerebellar syndrome, often accompanied by other neurological or non-neurological signs. All transmission modes have been described. In autosomal-dominant CA (ADCA), mutations in more than 30 genes are implicated, but the molecular diagnosis remains unknown in about 40% of cases. Implication of ion channels has long been an ongoing topic in the genetics of CA, and mutations in several channel genes have been recently connected to ADCA. In a large family affected by ADCA and mild pyramidal signs, we searched for the causative variant by combining linkage analysis and whole-exome sequencing. In CACNA1G, we identified a c.5144G>A mutation, causing an arginine-to-histidine (p.Arg1715His) change in the voltage sensor S4 segment of the T-type channel protein Cav3.1. Two out of 479 index subjects screened subsequently harbored the same mutation. We performed electrophysiological experiments in HEK293T cells to compare the properties of the p.Arg1715His and wild-type Cav3.1 channels. The current-voltage and the steady-state activation curves of the p.Arg1715His channel were shifted positively, whereas the inactivation curve had a higher slope factor. Computer modeling in deep cerebellar nuclei (DCN) neurons suggested that the mutation results in decreased neuronal excitability. Taken together, these data establish CACNA1G, which is highly expressed in the cerebellum, as a gene whose mutations can cause ADCA. This is consistent with the neuropathological examination, which showed severe Purkinje cell loss. Our study further extends our knowledge of the link between calcium channelopathies and CAs. PMID:26456284

  17. Cataract Vision Simulator

    Science.gov (United States)

    ... Oncology Oculoplastics/Orbit Refractive Management/Intervention Retina/Vitreous Uveitis Focus On Pediatric Ophthalmology ... Are Cataracts? Pediatric Cataracts Cataract Diagnosis and Treatment Cataract Surgery IOL Implants: Lens Replacement After Cataracts ...

  18. Inheritance of congenital cataracts and microphthalmia in the Miniature Schnauzer.

    Science.gov (United States)

    Gelatt, K N; Samuelson, D A; Bauer, J E; Das, N D; Wolf, E D; Barrie, K P; Andresen, T L

    1983-06-01

    Congenital cataracts and microphthalmia in the Miniature Schnauzer were inherited as an autosomal recessive trait. Eighteen matings of affected X affected Miniature Schnauzers resulted in 87 offspring with congenital cataracts and microphthalmia (49 males/38 females). Two matings of congenital cataractous and microphthalmic Miniature Schnauzers (2 females) X a normal Miniature Schnauzer (1 male) yielded 11 clinically normal Miniature Schnauzers (7 males/4 females). Eighteen matings of congenital cataractous and microphthalmic Miniature Schnauzers (6 males) X carrier Miniature Schnauzers (9 females) produced 81 offspring; 39 exhibited congenital cataracts and microphthalmia (20 males/19 females) and 42 had clinically normal eyes (17 males/25 females).

  19. Automatic total kidney volume measurement on follow-up magnetic resonance images to facilitate monitoring of autosomal dominant polycystic kidney disease progression.

    Science.gov (United States)

    Kline, Timothy L; Korfiatis, Panagiotis; Edwards, Marie E; Warner, Joshua D; Irazabal, Maria V; King, Bernard F; Torres, Vicente E; Erickson, Bradley J

    2016-02-01

    Renal imaging examinations provide high-resolution information about the anatomic structure of the kidneys and are used to measure total kidney volume (TKV) in autosomal dominant polycystic kidney disease (ADPKD) patients. TKV has become the gold-standard image biomarker for ADPKD progression at early stages of the disease and is used in clinical trials to characterize treatment efficacy. Automated methods to segment the kidneys and measure TKV are desirable because of the long time requirement for manual approaches such as stereology or planimetry tracings. However, ADPKD kidney segmentation is complicated by a number of factors, including irregular kidney shapes and variable tissue signal at the kidney borders. We describe an image processing approach that overcomes these problems by using a baseline segmentation initialization to provide automatic segmentation of follow-up scans obtained years apart. We validated our approach using 20 patients with complete baseline and follow-up T1-weighted magnetic resonance images. Both manual tracing and stereology were used to calculate TKV, with two observers performing manual tracings and one observer performing repeat tracings. Linear correlation and Bland-Altman analysis were performed to compare the different approaches. Our automated approach measured TKV at a level of accuracy (mean difference ± standard error = 0.99 ± 0.79%) on par with both intraobserver (0.77 ± 0.46%) and interobserver variability (1.34 ± 0.70%) of manual tracings. All approaches had excellent agreement and compared favorably with ground-truth manual tracing with interobserver, stereological and automated approaches having 95% confidence intervals ∼ ± 100 mL. Our method enables fast, cost-effective and reproducible quantification of ADPKD progression that will facilitate and lower the costs of clinical trials in ADPKD and other disorders requiring accurate, longitudinal kidney quantification. In addition, it will hasten the routine use of

  20. Cyst infection in hospital-admitted autosomal dominant polycystic kidney disease patients is predominantly multifocal and associated with kidney and liver volume

    Energy Technology Data Exchange (ETDEWEB)

    Balbo, B.E.P. [Divisão de Nefrologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Sapienza, M.T.; Ono, C.R. [Divisão de Medicina Nuclear, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Jayanthi, S.K. [Divisão de Radiologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Dettoni, J.B. [Divisão de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Castro, I.; Onuchic, L.F. [Divisão de Nefrologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

    2014-06-13

    Positron-emission tomography/computed tomography (PET/CT) has improved cyst infection (CI) management in autosomal dominant polycystic kidney disease (ADPKD). The determinants of kidney and/or liver involvement, however, remain uncertain. In this study, we evaluated clinical and imaging factors associated with CI in kidney (KCI) and liver (LCI) in ADPKD. A retrospective cohort study was performed in hospital-admitted ADPKD patients with suspected CI. Clinical, imaging and surgical data were analyzed. Features of infected cysts were evaluated by PET/CT. Total kidney (TKV) and liver (TLV) volumes were measured by CT-derived multiplanar reconstruction. CI was detected in 18 patients who experienced 24 episodes during an interval of 30 months (LCI in 12, KCI in 10 and concomitant infection in 2). Sensitivities of CT, magnetic resonance imaging and PET/CT were 25.0, 71.4, and 95.0%. Dysuria (P<0.05), positive urine culture (P<0.01), and previous hematuria (P<0.05) were associated with KCI. Weight loss (P<0.01) and increased C-reactive protein levels (P<0.05) were associated with LCI. PET/CT revealed that three or more infected cysts were present in 70% of the episodes. TKV was higher in kidney-affected than in LCI patients (AUC=0.91, P<0.05), with a cut-off of 2502 mL (72.7% sensitivity, 100.0% specificity). TLV was higher in liver-affected than in KCI patients (AUC=0.89, P<0.01) with a cut-off of 2815 mL (80.0% sensitivity, 87.5% specificity). A greater need for invasive procedures was observed in LCI (P<0.01), and the overall mortality was 20.8%. This study supports PET/CT as the most sensitive imaging method for diagnosis of cyst infection, confirms the multifocal nature of most hospital-admitted episodes, and reveals an association of kidney and liver volumes with this complication.

  1. Identification and Functional Characterization of a Novel Mutation in the Human Calcium-Sensing Receptor That Co-Segregates With Autosomal-Dominant Hypocalcemia

    Directory of Open Access Journals (Sweden)

    Anne Qvist Rasmussen

    2018-04-01

    Full Text Available The human calcium-sensing receptor (CASR is the key controller of extracellular Cao2+ homeostasis, and different mutations in the CASR gene have been linked to different calcium diseases, such as familial hypocalciuric hypercalcemia, severe hyperparathyroidism, autosomal-dominant hypocalcemia (ADH, and Bartter’s syndrome type V. In this study, two generations of a family with biochemically and clinically confirmed ADH who suffered severe muscle pain, arthralgia, tetany, abdominal pain, and fatigue were evaluated for mutations in the CASR gene. The study comprises genotyping of all family members, functional characterization of a potential mutant receptor by in vitro analysis related to the wild-type receptor to reveal an association between the genotype and phenotype in the affected family members. The in vitro analysis of functional characteristics includes measurements of inositol trisphosphate accumulation, Ca2+ mobilization in response to [Ca2+]o-stimulation and receptor expression. The results reveal a significant leftward shift of inositol trisphosphate accumulation as a result of the “gain-of-function” mutant receptor and surprisingly a normalization of the response in (Ca2+i release in the downstream pathway and additionally the maximal response of (Ca2+i release was significantly decreased compared to the wild type. However, no gross differences were seen in D126V and the D126V/WT CASR dimeric >250 kDa band expression compared to the WT receptor, however, the D126V and D126V/WT CASR immature ~140 kDa species appear to have reduced expression compared to the WT receptor. In conclusion, in this study, a family with a clinical diagnosis of ADH in two generations was evaluated to identify a mutation in the CASR gene and reveal an association between genotype and phenotype in the affected family members. The clinical condition was caused by a novel, activating, missense mutation (D126V in the CASR gene and the in vitro functional

  2. Calcilytic Ameliorates Abnormalities of Mutant Calcium-Sensing Receptor (CaSR) Knock-In Mice Mimicking Autosomal Dominant Hypocalcemia (ADH).

    Science.gov (United States)

    Dong, Bingzi; Endo, Itsuro; Ohnishi, Yukiyo; Kondo, Takeshi; Hasegawa, Tomoka; Amizuka, Norio; Kiyonari, Hiroshi; Shioi, Go; Abe, Masahiro; Fukumoto, Seiji; Matsumoto, Toshio

    2015-11-01

    Activating mutations of calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia (ADH). ADH patients develop hypocalcemia, hyperphosphatemia, and hypercalciuria, similar to the clinical features of hypoparathyroidism. The current treatment of ADH is similar to the other forms of hypoparathyroidism, using active vitamin D3 or parathyroid hormone (PTH). However, these treatments aggravate hypercalciuria and renal calcification. Thus, new therapeutic strategies for ADH are needed. Calcilytics are allosteric antagonists of CaSR, and may be effective for the treatment of ADH caused by activating mutations of CaSR. In order to examine the effect of calcilytic JTT-305/MK-5442 on CaSR harboring activating mutations in the extracellular and transmembrane domains in vitro, we first transfected a mutated CaSR gene into HEK cells. JTT-305/MK-5442 suppressed the hypersensitivity to extracellular Ca(2+) of HEK cells transfected with the CaSR gene with activating mutations in the extracellular and transmembrane domains. We then selected two activating mutations locating in the extracellular (C129S) and transmembrane (A843E) domains, and generated two strains of CaSR knock-in mice to build an ADH mouse model. Both mutant mice mimicked almost all the clinical features of human ADH. JTT-305/MK-5442 treatment in vivo increased urinary cAMP excretion, improved serum and urinary calcium and phosphate levels by stimulating endogenous PTH secretion, and prevented renal calcification. In contrast, PTH(1-34) treatment normalized serum calcium and phosphate but could not reduce hypercalciuria or renal calcification. CaSR knock-in mice exhibited low bone turnover due to the deficiency of PTH, and JTT-305/MK-5442 as well as PTH(1-34) increased bone turnover and bone mineral density (BMD) in these mice. These results demonstrate that calcilytics can reverse almost all the phenotypes of ADH including hypercalciuria and renal calcification, and suggest that calcilytics can become a

  3. Positive Predictive Values of International Classification of Diseases, 10th Revision Coding Algorithms to Identify Patients With Autosomal Dominant Polycystic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Vinusha Kalatharan

    2016-12-01

    Full Text Available Background: International Classification of Diseases, 10th Revision codes (ICD-10 for autosomal dominant polycystic kidney disease (ADPKD is used within several administrative health care databases. It is unknown whether these codes identify patients who meet strict clinical criteria for ADPKD. Objective: The objective of this study is (1 to determine whether different ICD-10 coding algorithms identify adult patients who meet strict clinical criteria for ADPKD as assessed through medical chart review and (2 to assess the number of patients identified with different ADPKD coding algorithms in Ontario. Design: Validation study of health care database codes, and prevalence. Setting: Ontario, Canada. Patients: For the chart review, 201 adult patients with hospital encounters between April 1, 2002, and March 31, 2014, assigned either ICD-10 codes Q61.2 or Q61.3. Measurements: This study measured positive predictive value of the ICD-10 coding algorithms and the number of Ontarians identified with different coding algorithms. Methods: We manually reviewed a random sample of medical charts in London, Ontario, Canada, and determined whether or not ADPKD was present according to strict clinical criteria. Results: The presence of either ICD-10 code Q61.2 or Q61.3 in a hospital encounter had a positive predictive value of 85% (95% confidence interval [CI], 79%-89% and identified 2981 Ontarians (0.02% of the Ontario adult population. The presence of ICD-10 code Q61.2 in a hospital encounter had a positive predictive value of 97% (95% CI, 86%-100% and identified 394 adults in Ontario (0.003% of the Ontario adult population. Limitations: (1 We could not calculate other measures of validity; (2 the coding algorithms do not identify patients without hospital encounters; and (3 coding practices may differ between hospitals. Conclusions: Most patients with ICD-10 code Q61.2 or Q61.3 assigned during their hospital encounters have ADPKD according to the clinical

  4. A postnatal role for embryonic myosin revealed by MYH3 mutations that alter TGFbeta signaling and cause autosomal dominant spondylocarpotarsal synostosis

    NARCIS (Netherlands)

    Zieba, J.; Zhang, W.; Chong, J.X.; Forlenza, K.N.; Martin, J.H.; Heard, K.; Grange, D.K.; Butler, M.G.; Kleefstra, T.; Lachman, R.S.; Nickerson, D.; Regnier, M.; Cohn, D.H.; Bamshad, M.; Krakow, D.

    2017-01-01

    Spondylocarpotarsal synostosis (SCT) is a skeletal disorder characterized by progressive vertebral, carpal and tarsal fusions, and mild short stature. The majority of affected individuals have an autosomal recessive form of SCT and are homozygous or compound heterozygous for nonsense mutations in

  5. Recurrent De Novo Mutations Affecting Residue Arg1 38 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa

    NARCIS (Netherlands)

    Fischer-Zirnsak, Björn; Escande-Beillard, Nathalie; Ganesh, Jaya; Tan, Yu Xuan; Al Bughaili, Mohammed; Lin, Angela E.; Sahai, Inderneel; Bahena, Paulina; Reichert, Sara L.; Loh, Abigail; Wright, Graham D.; Liu, Jaron; Rahikkala, Elisa; Pivnick, Eniko K.; Choudhri, Asim F.; Krüger, Ulrike; Zemojtel, Tomasz; van Ravenswaaij-Arts, Conny; Mostafavi, Roya; Stolte-Dijkstra, Irene; Symoens, Sofie; Pajunen, Leila; Al-Gazali, Lihadh; Meierhofer, David; Robinson, Peter N.; Mundlos, Stefan; Villarroel, Camilo E.; Byers, Peter; Masri, Amira; Robertson, Stephen P.; Schwarze, Ulrike; Callewaert, Bert; Reversade, Bruno; Kornak, Uwe

    2015-01-01

    Progeroid disorders overlapping with De Barsy syndrome (DBS) are collectively denoted as autosomal-recessive cutis laxa type 3 (ARCL3). They are caused by biallelic mutations in PYCR1 or ALDH18A1, encoding pyrroline-5-carboxylate reductase 1 and pyrroline-5-carboxylate synthase (P5CS), respectively,

  6. A Novel Insertion Variant of CRYGD Is Associated with Congenital Nuclear Cataract in a Chinese Family.

    Science.gov (United States)

    Zhuang, Xiaotong; Wang, Lianqing; Song, Zixun; Xiao, Wei

    2015-01-01

    To investigate a novel insertion variant of CRYGD identified in a Chinese family with nuclear congenital cataract. A Chinese family with congenital nuclear cataract was recruited for the mutational screening of candidate genes by direct sequencing. Recombinant N-terminal Myc tagged wildtype or mutant CRYGD was expressed in HEK293T cells. The expression pattern, protein solubility and subcellular distribution were analyzed by western blotting and immunofluorescence. A novel insertion variant, c.451_452insGACT, in CRYGD was identified in the patients. It causes a frameshift and a premature termination of the polypeptide to become Y151*. A significantly reduced solubility was observed for this mutant. Unlike wildtype CRYGD, which existed mainly in the cytoplasm, Y151* was mis-located in the nucleus. We have identified a novel mutation, c.451_452insGACT, in CRYGD, which is associated with nuclear cataract. This is the first insertion mutation of CRYGD found to cause autosomal dominant congenital cataract. The mutant protein, with loss of solubility and localization to the nucleus, is hypothesized to be the major cause of cataract in these patients.

  7. Cataract removal

    Science.gov (United States)

    ... placed into the eye to restore the focusing power of the old lens (cataract). It helps improve ... tests by the ophthalmologist. The doctor will use ultrasound or a laser scanning device to measure your ...

  8. Sex-linked dominant

    Science.gov (United States)

    Inheritance - sex-linked dominant; Genetics - sex-linked dominant; X-linked dominant; Y-linked dominant ... can be either an autosomal chromosome or a sex chromosome. It also depends on whether the trait ...

  9. Etiopathogenesis of cataract: An appraisal

    Directory of Open Access Journals (Sweden)

    Varun B Gupta

    2014-01-01

    Full Text Available Natural eye lens is a crystalline substance to produce a clear passage for light. Cataract is opacity within the clear lens of the eye and is the dominant cause of socio-medical problem i.e., blindness worldwide. The only available treatment of cataract is surgery. However, insufficient surgical facilities in poor and developing countries and post-operative complications inspire researchers to find out other modes of treatment for cataract. In this review, an attempt has been made to appraise various etiological factors of cataract to make their perception clear to build up counterpart treatment. Present study is an assortment of various available literatures and electronic information in view of cataract etiopathogenesis. Various risk factors have been identified in development of cataracts. They can be classified in to genetic factors, ageing (systemic diseases, nutritional and trace metals deficiencies, smoking, oxidative stress etc., traumatic, complicated (inflammatory and degenerative diseases of eye, metabolic (diabetes, galactosemia etc., toxic substances including drugs abuses, alcohol etc., radiation (ultraviolet, electromagnetic waves etc. are implicated as significant risk factors in the development of cataract.

  10. Association of CHMP4B and Autophagy with Micronuclei: Implications for Cataract Formation

    Directory of Open Access Journals (Sweden)

    Antonia P. Sagona

    2014-01-01

    Full Text Available Autophagy is a mechanism of cellular self-degradation that is very important for cellular homeostasis and differentiation. Components of the endosomal sorting complex required for transport (ESCRT machinery are required for endosomal sorting and also for autophagy and the completion of cytokinesis. Here we show that the ESCRT-III subunit CHMP4B not only localizes to normal cytokinetic bridges but also to chromosome bridges and micronuclei, the latter surrounded by lysosomes and autophagosomes. Moreover, CHMP4B can be co-immunoprecipitated with chromatin. Interestingly, a CHMP4B mutation associated with autosomal dominant posterior polar cataract abolishes the ability of CHMP4B to localize to micronuclei. We propose that CHMP4B, through its association with chromatin, may participate in the autophagolysosomal degradation of micronuclei and other extranuclear chromatin. This may have implications for DNA degradation during lens cell differentiation, thus potentially protecting lens cells from cataract development.

  11. The Hereditary Hyperferritinemia-Cataract Syndrome in 2 Italian Families

    Directory of Open Access Journals (Sweden)

    Katia Perruccio

    2013-01-01

    Full Text Available Two 8- and 9-year-old brothers were referred to the Pediatric Oncology Unit, Perugia General Hospital, because of hyperferritinemia. Both had a history of bilateral cataract and epilepsy. Genetic investigation revealed two distinct mutations in iron haemostasis genes; homozygosity for the HFE gene H63D mutation in the younger and heterozygosity in the elder. Both displayed heterozygosity for C33T mutation in the ferritin light chain iron response element. A 7-year-old boy from another family was referred to our unit because of hyperferritinemia. Genetic analyses did not reveal HFE gene mutations. Family history showed that his mother was also affected by hyperferritinemia without HFE gene mutations. Magnetic resonance imaging in the mother was positive for iron overload in the spleen. Cataract was diagnosed in mother and child. Further genetic investigation revealed the C29G mutation of the ferritin light chain iron response element. C33T and C29G mutations in the ferritin light chain iron response element underlie the Hereditary Hyperferritinemia-Cataract Syndrome (HHCS. The HFE gene H63D mutation underlies Hereditary Haemochromatosis (HH, which needs treatment to prevent organ damages by iron overload. HHCS was definitively diagnosed in all three children. HHCS is an autosomal dominant disease characterized by increased L-ferritin production. L-Ferritin aggregates accumulate preferentially in the lens, provoking bilateral cataract since childhood, as unique known organ damage. Epilepsy in one case and the spleen iron overload in another could suggest the misleading diagnosis of HH. Consequently, the differential diagnosis between alterations of iron storage system was essential, particularly in children, and required further genetic investigation.

  12. Genetic linkage analyses and Cx50 mutation detection in a large multiplex Chinese family with hereditary nuclear cataract.

    Science.gov (United States)

    He, Wei; Li, Xin; Chen, Jiajing; Xu, Ling; Zhang, Feng; Dai, Qiushi; Cui, Hao; Wang, Duen-Mei; Yu, Jun; Hu, Songnian; Lu, Shan

    2011-03-01

    The aim of the study was to characterize the underlying mutation in a large multiplex Chinese family with hereditary nuclear cataract. A 6-generation Chinese family having hereditary nuclear cataract was recruited and clinically verified. Blood DNA samples were obtained from 53 available family members. Linkage analyses were performed on the known candidate regions for hereditary cataract with 36 polymorphic microsatellite markers. To identify mutations related to cataract, a direct sequencing approach was applied to a candidate gene residing in our linkage locus. A linkage locus was identified with a maximum 2-point LOD score of 4.31 (recombination fraction = 0) at marker D1S498 and a maximum multipoint LOD score of 5.7 between markers D1S2344 and D1S498 on chromosome 1q21.1, where the candidate gene Cx50 is located. Direct sequencing of Cx50 showed a 139 G to A transition occurred in all affected family members. This transitional mutation resulted in a replacement of aspartic acid by asparagine at residue 47 (D47N) and led to a loss-of-function of the protein. The D47N mutation of Cx50 causes the hereditary nuclear cataract in this family in an autosomal dominant mode of inheritance with incomplete penetrance.

  13. Hyperferritinemia without iron overload in patients with bilateral cataracts: a case series

    Directory of Open Access Journals (Sweden)

    Mumford Andrew

    2011-09-01

    Full Text Available Abstract Introduction Hepatologists and internists often encounter patients with unexplained high serum ferritin concentration. After exclusion of hereditary hemochromatosis and hemosiderosis, rare disorders like hereditary hyperferritinemia cataract syndrome should be considered in the differential diagnosis. This autosomal dominant syndrome, that typically presents with juvenile bilateral cataracts, was first described in 1995 and has an increasing number of recognized molecular defects within a regulatory region of the L-ferritin gene (FTL. Case presentation Two patients (32 and 49-year-old Caucasian men from our ambulatory clinic were suspected as having this syndrome and a genetic analysis was performed. In both patients, sequencing of the FTL 5' region showed previously described mutations within the iron responsive element (FTL c.33 C > A and FTL c.32G > C. Conclusion Hereditary hyperferritinemia cataract syndrome should be considered in all patients with unexplained hyperferritinemia without signs of iron overload, particularly those with juvenile bilateral cataracts. Liver biopsy and phlebotomy should be avoided in this disorder.

  14. Aging and Health: Cataracts

    Science.gov (United States)

    ... Problems Glaucoma Macular Degeneration Join our e-newsletter! Aging & Health A to Z Cataracts Basic Facts & Information ... Are Cataracts? Cataracts are a common result of aging and occur frequently in older people. About one ...

  15. Generation of an induced pluripotent stem cell line, IBMS-iPSC-014-05, from a female autosomal dominant polycystic kidney disease patient carrying a common mutation of R803X in PKD2

    Directory of Open Access Journals (Sweden)

    Ming-Ching Ho

    2017-12-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is one of the most commonly inherited forms of polycystic kidney disease, and is characterized by the growth of numerous cysts in both kidneys. Here we generated an induced pluripotent stem cell (iPSC line from the peripheral blood mononuclear cells (PBMCs of a 63-year-old female ADPKD patient carrying an R803X mutation in the PKD2 gene using the Sendai-virus delivery system. Downstream characterization of these iPSCs showed that they possessed normal karyotyping, were free of genomic integration, retained the disease-causing PKD2 mutation, expressed pluripotency markers and could differentiate into three germ layers.

  16. Looking the Cow in the Eye: Deletion in the NID1 Gene Is Associated with Recessive Inherited Cataract in Romagnola Cattle

    Science.gov (United States)

    Murgiano, Leonardo; Jagannathan, Vidhya; Calderoni, Valerio; Joechler, Monika; Gentile, Arcangelo; Drögemüller, Cord

    2014-01-01

    Cataract is a known condition leading to opacification of the eye lens causing partial or total blindness. Mutations are known to cause autosomal dominant or recessive inherited forms of cataracts in humans, mice, rats, guinea pigs and dogs. The use of large-sized animal models instead of those using mice for the study of this condition has been discussed due to the small size of rodent lenses. Four juvenile-onset cases of bilateral incomplete immature nuclear cataract were recently observed in Romagnola cattle. Pedigree analysis suggested a monogenic autosomal recessive inheritance. In addition to the cataract, one of the cases displayed abnormal head movements. Genome-wide association and homozygosity mapping and subsequent whole genome sequencing of a single case identified two perfectly associated sequence variants in a critical interval of 7.2 Mb on cattle chromosome 28: a missense point mutation located in an uncharacterized locus and an 855 bp deletion across the exon 19/intron 19 border of the bovine nidogen 1 (NID1) gene (c.3579_3604+829del). RT-PCR showed that NID1 is expressed in bovine lenses while the transcript of the second locus was absent. The NID1 deletion leads to the skipping of exon 19 during transcription and is therefore predicted to cause a frameshift and premature stop codon (p.1164fs27X). The truncated protein lacks a C-terminal domain essential for binding with matrix assembly complexes. Nidogen 1 deficient mice show neurological abnormalities and highly irregular crystal lens alterations. This study adds NID1 to the list of candidate genes for inherited cataract in humans and is the first report of a naturally occurring mutation leading to non-syndromic catarct in cattle provides a potential large animal model for human cataract. PMID:25347398

  17. Looking the cow in the eye: deletion in the NID1 gene is associated with recessive inherited cataract in Romagnola cattle.

    Science.gov (United States)

    Murgiano, Leonardo; Jagannathan, Vidhya; Calderoni, Valerio; Joechler, Monika; Gentile, Arcangelo; Drögemüller, Cord

    2014-01-01

    Cataract is a known condition leading to opacification of the eye lens causing partial or total blindness. Mutations are known to cause autosomal dominant or recessive inherited forms of cataracts in humans, mice, rats, guinea pigs and dogs. The use of large-sized animal models instead of those using mice for the study of this condition has been discussed due to the small size of rodent lenses. Four juvenile-onset cases of bilateral incomplete immature nuclear cataract were recently observed in Romagnola cattle. Pedigree analysis suggested a monogenic autosomal recessive inheritance. In addition to the cataract, one of the cases displayed abnormal head movements. Genome-wide association and homozygosity mapping and subsequent whole genome sequencing of a single case identified two perfectly associated sequence variants in a critical interval of 7.2 Mb on cattle chromosome 28: a missense point mutation located in an uncharacterized locus and an 855 bp deletion across the exon 19/intron 19 border of the bovine nidogen 1 (NID1) gene (c.3579_3604+829del). RT-PCR showed that NID1 is expressed in bovine lenses while the transcript of the second locus was absent. The NID1 deletion leads to the skipping of exon 19 during transcription and is therefore predicted to cause a frameshift and premature stop codon (p.1164fs27X). The truncated protein lacks a C-terminal domain essential for binding with matrix assembly complexes. Nidogen 1 deficient mice show neurological abnormalities and highly irregular crystal lens alterations. This study adds NID1 to the list of candidate genes for inherited cataract in humans and is the first report of a naturally occurring mutation leading to non-syndromic catarct in cattle provides a potential large animal model for human cataract.

  18. Cataract surgery in Knobloch syndrome: a case report

    Directory of Open Access Journals (Sweden)

    Bongiovanni CS

    2011-06-01

    Full Text Available Carmen Sílvia Bongiovanni1, Carla Cristina Serra Ferreira1, Ana Paula Silvério Rodrigues1, João Borges Fortes Filho2, Márcia Beatriz Tartarella11Department of Ophthalmology, Congenital Cataract Section, Medical School, Federal University of São Paulo, São Paulo; 2Department of Ophthalmology, Medical School, Federal University of Rio Grande do Sul, Porto Alegre, BrazilAbstract: Knobloch syndrome is an autosomal recessive disorder associated with early-onset ocular abnormalities and central nervous system malformations. Ocular abnormalities are usually severe, and include high myopia, vitreoretinal degeneration, retinal detachment, macular abnormalities, and cataract. The most frequent systemic changes are midline malformations of the brain, ventricular dilation, and occipital encephalocele. Cognitive delay may occur. We report a case of cataract in a child with Knobloch syndrome. Cataract surgery and follow-up are described.Keywords: Knobloch syndrome, cataract, phacoemulsification, vitreous, right eye, left eye, genetic

  19. A novel missense variant (Gln220Arg) of GNB4 encoding guanine nucleotide-binding protein, subunit beta-4 in a Japanese family with autosomal dominant motor and sensory neuropathy.

    Science.gov (United States)

    Miura, Shiroh; Morikawa, Takuya; Fujioka, Ryuta; Noda, Kazuhito; Kosaka, Kengo; Taniwaki, Takayuki; Shibata, Hiroki

    2017-09-01

    Dominant intermediate Charcot-Marie-Tooth disease F (CMTDIF) is an autosomal dominant hereditary form of Charcot-Marie-Tooth disease (CMT) caused by variations in the guanine nucleotide-binding protein, subunit beta-4 gene (GNB4). We examined two Japanese familial cases with CMT. Case 1 was a 49-year-old male whose chief complaint was slowly progressive gait disturbance and limb dysesthesia that appeared at the age of 47. On neurological examination, he showed hyporeflexia or areflexia, distal limb muscle weakness, and distal sensory impairment with lower dominancy. Nerve conduction studies demonstrated demyelinating sensorimotor neuropathy with reduced action potentials in the lower limbs. Case 2 was an 80-year-old man, Case 1's father, who reported difficulty in riding a bicycle at the age of 76. On neurological examination, he showed areflexia in the upper and lower limbs. Distal sensory impairment in the lower limbs was also observed. Nerve conduction studies revealed mainly axonal involvement. Exome sequencing identified a novel heterozygous nonsynonymous variant (NM_021629.3:c.659T > C [p.Gln220Arg]) in GNB4 exon 8, which is known to be responsible for CMT. Sanger sequencing confirmed that both patients are heterozygous for the variation, which causes an amino acid substitution, Gln220Arg, in the highly conserved region of the WD40 domain of GNB4. The frequency of this variant in the Exome Aggregation Consortium Database was 0.000008247, and we confirmed its absence in 502 Japanese control subjects. We conclude that this novel GNB4 variant is causative for CMTDIF in these patients, who represent the first record of the disease in the Japanese population. Copyright © 2017. Published by Elsevier Masson SAS.

  20. Recommendations for the use of tolvaptan in autosomal dominant polycystic kidney disease: a position statement on behalf of the ERA-EDTA Working Groups on Inherited Kidney Disorders and European Renal Best Practice.

    Science.gov (United States)

    Gansevoort, Ron T; Arici, Mustafa; Benzing, Thomas; Birn, Henrik; Capasso, Giovambattista; Covic, Adrian; Devuyst, Olivier; Drechsler, Christiane; Eckardt, Kai-Uwe; Emma, Francesco; Knebelmann, Bertrand; Le Meur, Yannick; Massy, Ziad A; Ong, Albert C M; Ortiz, Alberto; Schaefer, Franz; Torra, Roser; Vanholder, Raymond; Więcek, Andrzej; Zoccali, Carmine; Van Biesen, Wim

    2016-03-01

    Recently, the European Medicines Agency approved the use of the vasopressin V2 receptor antagonist tolvaptan to slow the progression of cyst development and renal insufficiency of autosomal dominant polycystic kidney disease (ADPKD) in adult patients with chronic kidney disease stages 1-3 at initiation of treatment with evidence of rapidly progressing disease. In this paper, on behalf of the ERA-EDTA Working Groups of Inherited Kidney Disorders and European Renal Best Practice, we aim to provide guidance for making the decision as to which ADPKD patients to treat with tolvaptan. The present position statement includes a series of recommendations resulting in a hierarchical decision algorithm that encompasses a sequence of risk-factor assessments in a descending order of reliability. By examining the best-validated markers first, we aim to identify ADPKD patients who have documented rapid disease progression or are likely to have rapid disease progression. We believe that this procedure offers the best opportunity to select patients who are most likely to benefit from tolvaptan, thus improving the benefit-to-risk ratio and cost-effectiveness of this treatment. It is important to emphasize that the decision to initiate treatment requires the consideration of many factors besides eligibility, such as contraindications, potential adverse events, as well as patient motivation and lifestyle factors, and requires shared decision-making with the patient. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.

  1. Síndrome das pernas inquietas com herança autossômica dominante piorada pelo uso de mirtazapina: relato de caso Worsening of autosomal dominant restless legs syndrome after use of mirtazapine: case report

    Directory of Open Access Journals (Sweden)

    Hélio A.G. Teive

    2002-12-01

    Full Text Available Relatamos o caso de uma paciente de 78 anos, com diagnóstico estabelecido de síndrome das pernas inquietas (SPI, de etiologia primária com herança autossômica dominante. A paciente apresentava quadro depressivo associado. Enfatiza-se a piora do quadro clínico da SPI após o uso de anti-depressivo com ação inibidora seletiva da recaptação de serotonina (mirtazapina, com atenuação dos sintomas após a retirada da droga, e a excelente resposta terapêutica com o uso de agonista dopaminérgico (pramipexol em baixa dose.We report the case of a 78 years old female patient with primary restless legs syndrome (RLS with an autosomal dominant pattern of inheritance. In addition, the patient also had depression. We emphasize the worsening of symptoms of RLS after the use of a selective serotonin uptake inhibitor (mirtazapine, with improvement after the drug was discontinued, and an excellent recovery with the use of low dose dopaminergic agonist (pramipexol.

  2. The human dorsal spinocerebellar tract: myelinated fiber spectrum and fiber density in controls, autosomal dominant spinocerebellar atrophy, Huntington's chorea, radiation myelopathy, and diseases with peripheral sensory nerve involvement

    Energy Technology Data Exchange (ETDEWEB)

    Ringelstein, E.B.; Schroeder, J.M.

    1982-01-01

    The human dorsal spinocerebellar tract (DSCT) was evaluated morphometrically in 14 control cases of different age and sex using semithin sections of epon-embedded cross sections from the C3, T5, and T10 segments of the spinal cord. A bimodal fiber spectrum was revealed with one peak at 2-3 microns, and a second, broader peak at about 6-8 microns. Fiber density at C3 was 11,188 fibers/mm2 and at T5, 11,156 fibers/mm2. Regression analysis relating fiber density to age disclosed a highly significant loss of myelinated fibers at T5 amounting to about 2.5% per decade. A severe reduction of fiber density and a distinct change in the fiber spectrum with predominant loss of large myelinated fibers were noted in a case of autosomal dominant spinocerebellar atrophy with late onset, and, to a lesser degree, in a case of Huntington's chorea. A subtotal loss of fibers with a persistent normal distribution of fiber sizes was observed rostral to a focus of severe radiation myelopathy, indicating Wallerian degeneration of large numbers of fibers, and a reduction of fiber diameters caudal to the lesion, suggesting retrograde fiber change. By contrast, no primary or transneural changes in the DSCT were detected in six cases of long-term alcoholism, carcinomatous sensory neuropathy, and neurofibromatosis in spite of the involvement of numerous nerve roots.

  3. Complete Heart Block with Diastolic Heart Failure and Pulmonary Edema Secondary to Enlarging Previously Diagnosed Thrombosed Aneurysm of Sinus of Valsalva in a Patient with History of Autosomal Dominant Polycystic Kidney Disease

    Directory of Open Access Journals (Sweden)

    Sherif Ali Eltawansy

    2015-01-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is associated with vascular aneurysms that can affect any part of the vascular tree, like ascending aorta or coronary arteries. Sinus of Valsalva is known as an anatomical dilation at the root of aorta above the aortic valve and very few cases show aneurysm at that site in patients with ADPKD. Sinus of Valsalva aneurysm (SVA can present with rupture and acute heart failure and infective endocarditis or could be asymptomatic accidentally discovered during cardiac catheterization. We report a case of a 76-year-old male with a unique constellation of cardiovascular anomalies associated with ADPKD. Patient was previously diagnosed with aneurysms affecting ascending aorta, sinus of Valsalva, and coronary arteries. Several years later, he came with complete heart block which was discovered later to be secondary to enlargement of his previously diagnosed thrombosed SVA. His case was complicated with acute heart failure and pulmonary edema. Conclusion. Patients with ADPKD can present with extrarenal manifestations. In our case, aneurysm at sinus of Valsalva was progressively enlarging and presented with complete heart block.

  4. Risk of Japanese carriers of hyperphosphorylated paratarg-7, the first autosomal-dominantly inherited risk factor for hematological neoplasms, to develop monoclonal gammopathy of undetermined significance and multiple myeloma.

    Science.gov (United States)

    Grass, Sandra; Iida, Shinsuke; Wikowicz, Aleksandra; Preuss, Klaus-Dieter; Inagaki, Atsushi; Shimizu, Kazuyuki; Ziepert, Marita; Ueda, Ryuzo; Pfreundschuh, Michael

    2011-03-01

    Hyperphosphorylated paratarg-7 (pP-7) is a frequent target of paraproteins in German patients with monoclonal gammopathy of undetermined significance (MGUS)/multiple myeloma (MM). The frequency of MGUS/MM is lower in Japan than in Europe. As pP-7, the first molecularly defined autosomal-dominant risk factor for any hematological neoplasm, is inherited in a dominant fashion, we determined the incidence of the pP-7 carrier state in a Japanese population, and compared the frequency of pP-7-specific paraproteins and the pP-7 carrier state in Japanese and German patients with MGUS/MM. Peripheral blood from 111 Japanese patients with MGUS/MM and 278 healthy blood donors was analyzed for the pP-7 carrier state by isoelectric focusing and for pP-7-specific antibodies by ELISA. The Japanese group was compared with 252 German MGUS/MM patients and 200 healthy controls. Five of 111 (4.5%) Japanese and 35/252 (13.9%) German IgA/IgG MGUS/MM patients had a pP-7-specific paraprotein (P=0.009). The prevalence of healthy pP-7 carriers in the Japanese study group was 1/278 (0.36%), whereas it was 4/200 in the German group (P=0.166). The relative risk for pP-7 carriers developing MGUS/MM had an odds ratio of 13.1 in the Japanese and 7.9 in the German group. In conclusion, the fraction of pP-7 carriers with a pP-7-specific paraprotein is lower among Japanese than in German patients with MGUS/MM, but pP-7 carriers in both ethnic groups have a high risk of developing MGUS/MM. © 2011 Japanese Cancer Association.

  5. Cerebral autosomal dominant arteriopathy with subcortical infarcts ...

    African Journals Online (AJOL)

    A new finding, to our knowledge, was the normality of visual, somatosensory and auditory evoked potentials. Conclusion. Our study confirms the existence of CADASIL in. South Africa, and also suggests that skin electron microscopy is useful, despite recent reports of its low sensitivity, and that evoked potentials in CADASIL ...

  6. Autosomal dominant non-epidermolytic palmoplantar hyperkeratosis ...

    African Journals Online (AJOL)

    PROF. EZECHUKWU

    2013-08-12

    epidermolytic and the isolated type (NEPPK). The non-volar skin, hair, teeth, nails and other organ systems were not involved. The presence of the disorder in the proband's father and its absence in her paternal grandfather and ...

  7. Cleidocranial Dysplasia with Autosomal Dominant Inheritance Pattern

    African Journals Online (AJOL)

    [3] These patients have the following triad of lesions, which is considered ... Brachycephalic skull with depression in the frontal bone of skull, depressed ... hyper mobility of both shoulders with associated radiographic features. Odontologist is ...

  8. Autosomal dominant transmission of GLUT1 deficiency.

    NARCIS (Netherlands)

    Klepper, J.; Willemsen, M.A.A.P.; Verrips, A.; Guertsen, E.; Herrmann, R.; Kutzick, C.; Florcken, A.; Voit, T.

    2001-01-01

    GLUT1 deficiency is caused by a defect in the facilitative glucose transporter GLUT1. Impaired glucose transport across brain tissue barriers is reflected by hypoglycorrhachia and results in an epileptic encephalopathy with developmental delay and motor disorders. Recently heterozygous mutations in

  9. Autosomal dominant craniosynostosis of the sutura metopica

    NARCIS (Netherlands)

    Hennekam, R. C.; van den Boogaard, M. J.

    1990-01-01

    Trigonocephaly due to craniosynostosis of the sutura metopica was found in two sibs with normal intelligence. Both were microcephalic. The father had a sloping forehead and possibly partial metopic craniosynostosis. The paternal grandfather had a bony ridge at the upper half of the metopic suture

  10. Genetics Home Reference: autosomal dominant vitreoretinochoroidopathy

    Science.gov (United States)

    ... Vitreoretinochoroidopathy Patient Support and Advocacy Resources (2 links) Foundation Fighting Blindness Prevent Blindness: Living Well with Low Vision Scientific Articles on PubMed (1 link) PubMed OMIM ( ...

  11. Autosomal Dominant Polycystic Kidney Disease, incidental finding ...

    African Journals Online (AJOL)

    N.J. Gildenhuys

    2016-06-30

    Jun 30, 2016 ... This case study serves as a learning opportunity and future reference in the cases and management of ... sentation, special investigations, and treatment. The table ... trauma to an abnormal kidney is still a controversial topic. .... running into fence. AP ... He does not have any prior medical or surgical history.

  12. New autosomal recessive faciodigitogenital syndrome.

    OpenAIRE

    Teebi, A S; Naguib, K K; Al-Awadi, S; Al-Saleh, Q A

    1988-01-01

    Most pedigrees of Aarskog's faciodigitogenital syndrome have suggested X linked inheritance. However, sex influenced autosomal dominant inheritance is also a possibility in some families. We describe an Arab family of normal consanguineous parents with five children (three males and two females) with some features of Aarskog syndrome in addition to some unusual hair changes. The possibility that this family represents a distinct previously unrecognised faciodigitogenital syndrome with short s...

  13. Ultrasonographic findings of cataract

    International Nuclear Information System (INIS)

    Choi, Sun Seob; Kim, Yang Soo; Lee, Kwan Seh; Kim, Kun Sang

    1985-01-01

    Examining the eye with high resolution ultrasonography, authors encountered 34 cases (41 eyeballs) of cataract and found out its characteristic ultrasonographic findings, though cataract is easily recognized by physician on inspection. Ultrasonographic findings of cataract were as follows; 1. Thickening of lens due to edema. 2. Demonstration of lens echo in whole circumference. 3. Multiple internal lens echo

  14. Aqueous humor ferritin in hereditary hyperferritinemia cataract syndrome.

    Science.gov (United States)

    Lenzhofer, Markus; Schroedl, Falk; Trost, Andrea; Kaser-Eichberger, Alexandra; Wiedemann, Helmut; Strohmaier, Clemens; Hohensinn, Melchior; Strasser, Michael; Muckenthaler, Martina U; Grabner, Guenther; Aigner, Elmar; Reitsamer, Herbert A

    2015-04-01

    Hereditary hyperferritinemia cataract syndrome (HHCS) is a rare autosomal dominant hereditary disease, characterized by hyperferritinemia but with absence of body iron excess and early onset of bilateral cataracts. Although 5- to 20-fold increased serum ferritin concentrations have been reported in HHCS patients, data of ferritin levels in aqueous humor have not been obtained. We therefore aimed to investigate the ferritin levels in aqueous humor and serum and further present histological and ultrastructural data of the lens. During cataract extraction and intraocular lens implantation, aqueous humor and lens aspirate of a 37-year-old HHCS patient were obtained from both eyes. Ferritin levels in serum and aqueous humor were quantitatively analyzed via immunoassays in the HHCS patient and healthy control subjects (n = 6). Lens aspirate in HHCS was analyzed histologically and at the ultrastructural level. Further, genetic mutation screening by polymerase chain reaction and DNA sequencing in blood was performed. Serum ferritin levels in the control group were 142.2 ± 38.7 μg/L, whereas in the HHCS patient, this parameter was excessively increased (1086 μg/L). Analysis of ferritin in aqueous humor revealed 6.4 ± 3.8 μg/L in normal control subjects and 146.3 μg/L (OD) and 160.4 μg/L (OS) in the HHCS patient. DNA analysis detected a C>A mutation on position +18, a T>G mutation on position +22, a T>C mutation on position +24, and a T>G polymorphism on position +26 in the iron-responsive element of the light-chain ferritin (L-ferritin) gene. In the HHCS patient, a 23-fold (OD) to 25-fold (OS) increased aqueous humor ferritin level was detected. Therefore, the formation of bilateral cataract in HHCS is most likely a result of elevated aqueous humor ferritin. In addition, a novel mutation in this rare disease in the iron-responsive element of L-ferritin gene is reported.

  15. Autosomal dominant anhidrotic ectodermal dysplasia with immunodeficiency caused by a novel NFKBIA mutation, p.Ser36Tyr, presents with mild ectodermal dysplasia and non-infectious systemic inflammation.

    Science.gov (United States)

    Yoshioka, Takakazu; Nishikomori, Ryuta; Hara, Junichi; Okada, Keiko; Hashii, Yoshiko; Okafuji, Ikuo; Nodomi, Seishiro; Kawai, Tomoki; Izawa, Kazushi; Ohnishi, Hidenori; Yasumi, Takahiro; Nakahata, Tatsutoshi; Heike, Toshio

    2013-10-01

    Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) is characterized by hypohidrosis, dental abnormalities, sparse hair, and immunodeficiency. Autosomal dominant (AD)-EDA-ID, caused by a heterozygous mutation within NFKBIA, is very rare and its clinical features remain largely unknown. This study describes a patient with AD-EDA-ID harboring a novel NFKBIA mutation who presented with mild EDA and non-infectious systemic inflammation. The clinical presentation of an AD-EDA-ID patient was described and immunological, genetic, and biochemical analyses were performed, with a focus on nuclear factor kappa B (NF-κB) activation. The patient presented with symptoms of mild EDA-ID, namely sparse hair and hypohidrosis, although a skin biopsy confirmed the presence of sweat glands. There were no dental abnormalities. The patient also suffered from non-infectious inflammation, which responded to systemic corticosteroid therapy; however, the patient remained ill. Immunological analyses revealed reduced Toll-like receptor/IL-1 (TLR/IL-1) and tumor necrosis factor (TNF) receptor family responses to various stimuli. Genetic analysis identified a de novo heterozygous missense mutation, p.Ser36Tyr, in NFKBIA, resulting in defective NFKBIA degradation and impaired NF-κB activation. The patient was diagnosed with AD-EDA-ID and underwent hematopoietic stem cell transplantation. Engraftment was successful, with few signs of acute graft versus host disease. However, the patient suffered hemolytic anemia and thrombocytopenia, and died from a brain hemorrhage due to intractable thrombocytopenia. AD-EDA-ID patients can present with mild ectodermal dysplasia and non-infectious inflammation, rather than with recurrent infections. Also, hematopoietic stem cell transplantation for AD-EDA-ID is still a clinical challenge.

  16. Technical Evaluation: Identification of Pathogenic Mutations in PKD1 and PKD2 in Patients with Autosomal Dominant Polycystic Kidney Disease by Next-Generation Sequencing and Use of a Comprehensive New Classification System.

    Science.gov (United States)

    Kinoshita, Moritoshi; Higashihara, Eiji; Kawano, Haruna; Higashiyama, Ryo; Koga, Daisuke; Fukui, Takafumi; Gondo, Nobuhisa; Oka, Takehiko; Kawahara, Kozo; Rigo, Krisztina; Hague, Tim; Katsuragi, Kiyonori; Sudo, Kimiyoshi; Takeshi, Masahiko; Horie, Shigeo; Nutahara, Kikuo

    2016-01-01

    Genetic testing of PKD1 and PKD2 is expected to play an increasingly important role in determining allelic influences in autosomal dominant polycystic kidney disease (ADPKD) in the near future. However, to date, genetic testing is not commonly employed because it is expensive, complicated because of genetic heterogeneity, and does not easily identify pathogenic variants. In this study, we developed a genetic testing system based on next-generation sequencing (NGS), long-range polymerase chain reaction, and a new software package. The new software package integrated seven databases and provided access to five cloud-based computing systems. The database integrated 241 polymorphic nonpathogenic variants detected in 140 healthy Japanese volunteers aged >35 years, who were confirmed by ultrasonography as having no cysts in either kidney. Using this system, we identified 60 novel and 30 known pathogenic mutations in 101 Japanese patients with ADPKD, with an overall detection rate of 89.1% (90/101) [95% confidence interval (CI), 83.0%-95.2%]. The sensitivity of the system increased to 93.1% (94/101) (95% CI, 88.1%-98.0%) when combined with multiplex ligation-dependent probe amplification analysis, making it sufficient for use in a clinical setting. In 82 (87.2%) of the patients, pathogenic mutations were detected in PKD1 (95% CI, 79.0%-92.5%), whereas in 12 (12.8%) patients pathogenic mutations were detected in PKD2 (95% CI, 7.5%-21.0%); this is consistent with previously reported findings. In addition, we were able to reconfirm our pathogenic mutation identification results using Sanger sequencing. In conclusion, we developed a high-sensitivity NGS-based system and successfully employed it to identify pathogenic mutations in PKD1 and PKD2 in Japanese patients with ADPKD.

  17. A follow-up study of autosomal dominant polycystic kidney disease with intracranial aneurysms using 3.0 T three-dimensional time-of-flight magnetic resonance angiography

    Energy Technology Data Exchange (ETDEWEB)

    Jiang, Tao; Wang, Peng; Qian, Yi [Department of Radiology, Changzheng Hospital, Second Military Medical University, Shanghai (China); Zheng, Xuan [Clinical Nutrition Department of Changhai Hospital, Second Military Medical University, Shanghai (China); Xiao, Liaoyuan [Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai (China); Yu, Shengqiang, E-mail: yushengqiang_cz@163.com [Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai (China); Liu, Shiyuan, E-mail: laijiangtaotao@163.com [Department of Radiology, Changzheng Hospital, Second Military Medical University, Shanghai (China)

    2013-11-01

    Objective: Autosomal dominant polycystic kidney disease (ADPKD) patients have an increased risk for intracranial aneurysms (IAs). Our aim was to screen and follow up the unruptured intracranial aneurysms (UIAs) detected by 3.0 T three-dimensional time-of-flight magnetic resonance angiography (3D-TOF MRA) in patients with ADPKD in order to evaluate the growth of UIAs and the value of 3D-TOF MRA. Methods: From 2011 to 2012, we followed up UIAs detected in 40 ADPKD patients who had MRA examinations with an interval of at least 36 months. All MRA examinations were performed on a 3 T system (Achieva X-Series, Philips Medical Systems) with a Sense-Head-8 receiver head coil. The acquired data sets were transferred to a workstation (EWS, Philips Medical) to perform maximum intensity projection (MIP) and volume rendering (VR) with a specialized software package (Philips Medical). The size of UIAs was determined as the longest diameter in transverse or vertical measurement. UIAs that grew more than 20% were considered as enlarged. Results: Fifty UIAs were found in 40 previously examined ADPKD patients who underwent 3.0 T 3D-TOF MRA follow-ups. No patients ever had treatment before the second examination. The longest diameter of all follow-up UIAs was less than 10 mm and mean diameter was 3.64 ± 2.25 mm. UIAs in only 4 patients (10%) were considered as enlarged. None of the 50 IAs in the 40 ADPKD patients ruptured during the MRA follow-up period. Conclusion: 3.0 T 3D-TOF MRA was feasible for UIAs follow-up in ADPKD patients. The chance of enlargement and rupture of UIAs in ADPKD patients was not higher than in the general population.

  18. A follow-up study of autosomal dominant polycystic kidney disease with intracranial aneurysms using 3.0 T three-dimensional time-of-flight magnetic resonance angiography.

    Science.gov (United States)

    Jiang, Tao; Wang, Peng; Qian, Yi; Zheng, Xuan; Xiao, Liaoyuan; Yu, Shengqiang; Liu, Shiyuan

    2013-11-01

    Autosomal dominant polycystic kidney disease (ADPKD) patients have an increased risk for intracranial aneurysms (IAs). Our aim was to screen and follow up the unruptured intracranial aneurysms (UIAs) detected by 3.0 T three-dimensional time-of-flight magnetic resonance angiography (3D-TOF MRA) in patients with ADPKD in order to evaluate the growth of UIAs and the value of 3D-TOF MRA. From 2011 to 2012, we followed up UIAs detected in 40 ADPKD patients who had MRA examinations with an interval of at least 36 months. All MRA examinations were performed on a 3T system (Achieva X-Series, Philips Medical Systems) with a Sense-Head-8 receiver head coil. The acquired data sets were transferred to a workstation (EWS, Philips Medical) to perform maximum intensity projection (MIP) and volume rendering (VR) with a specialized software package (Philips Medical). The size of UIAs was determined as the longest diameter in transverse or vertical measurement. UIAs that grew more than 20% were considered as enlarged. Fifty UIAs were found in 40 previously examined ADPKD patients who underwent 3.0 T 3D-TOF MRA follow-ups. No patients ever had treatment before the second examination. The longest diameter of all follow-up UIAs was less than 10mm and mean diameter was 3.64 ± 2.25 mm. UIAs in only 4 patients (10%) were considered as enlarged. None of the 50 IAs in the 40 ADPKD patients ruptured during the MRA follow-up period. 3.0 T 3D-TOF MRA was feasible for UIAs follow-up in ADPKD patients. The chance of enlargement and rupture of UIAs in ADPKD patients was not higher than in the general population. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  19. Amino alcohol- (NPS-2143 and quinazolinone-derived calcilytics (ATF936 and AXT914 differentially mitigate excessive signalling of calcium-sensing receptor mutants causing Bartter syndrome Type 5 and autosomal dominant hypocalcemia.

    Directory of Open Access Journals (Sweden)

    Saskia Letz

    Full Text Available Activating calcium sensing receptor (CaSR mutations cause autosomal dominant hypocalcemia (ADH characterized by low serum calcium, inappropriately low PTH and relative hypercalciuria. Four activating CaSR mutations cause additional renal wasting of sodium, chloride and other salts, a condition called Bartter syndrome (BS type 5. Until today there is no specific medical treatment for BS type 5 and ADH. We investigated the effects of different allosteric CaSR antagonists (calcilytics on activating CaSR mutants.All 4 known mutations causing BS type 5 and five ADH mutations were expressed in HEK 293T cells and receptor signalling was studied by measurement of intracellular free calcium in response to extracellular calcium ([Ca2+]o. To investigate the effect of calcilytics, cells were stimulated with 3 mM [Ca2+]o in the presence or absence of NPS-2143, ATF936 or AXT914.All BS type 5 and ADH mutants showed enhanced signalling activity to [Ca2+]o with left shifted dose response curves. In contrast to the amino alcohol NPS-2143, which was only partially effective, the quinazolinone calcilytics ATF936 and AXT914 significantly mitigated excessive cytosolic calcium signalling of all BS type 5 and ADH mutants studied. When these mutants were co-expressed with wild-type CaSR to approximate heterozygosity in patients, ATF936 and AXT914 were also effective on all mutants.The calcilytics ATF936 and AXT914 are capable of attenuating enhanced cytosolic calcium signalling activity of CaSR mutations causing BS type 5 and ADH. Quinazolinone calcilytics might therefore offer a novel treatment option for patients with activating CaSR mutations.

  20. The lens and cataracts.

    Science.gov (United States)

    Matthews, Andrew G

    2004-08-01

    It is conservatively estimated that some form of lens opacity is present in 5% to 7% of horses with otherwise clinically normal eyes.These opacities can range from small epicapsular remnants of the fetal vasculature to dense and extensive cataract. A cataract is defined technically as any opacity or alteration in the optical homogeneity of the lens involving one or more of the following: anterior epithelium, capsule, cortex, or nucleus. In the horse, cataracts rarely involve the entire lens structure (ie, complete cataracts) and are more usually localized to one anatomic landmark or sector of the lens. Complete cataracts are invariably associated with overt and significant visual disability. Focal or incomplete cataracts alone seldom cause any apparent visual dysfunction in affected horses,however.

  1. A γA-Crystallin Mouse Mutant Secc with Small Eye, Cataract and Closed Eyelid.

    Directory of Open Access Journals (Sweden)

    Man Hei Cheng

    Full Text Available Cataract is the most common cause of visual loss in humans. A spontaneously occurred, autosomal dominant mouse mutant Secc, which displayed combined features of small eye, cataract and closed eyelid was discovered in our laboratory. In this study, we identified the mutation and characterized the cataract phenotype of this novel Secc mutant. The Secc mutant mice have eyelids that remain half-closed throughout their life. The mutant lens has a significant reduction in size and with opaque spots clustered in the centre. Histological analysis showed that in the core region of the mutant lens, the fiber cells were disorganized and clefts and vacuoles were observed. The cataract phenotype was evident from new born stage. We identified the Secc mutation by linkage analysis using whole genome microsatellite markers and SNP markers. The Secc locus was mapped at chromosome 1 flanked by SNPs rs3158129 and rs13475900. Based on the chromosomal position, the candidate cataract locus γ-crystallin gene cluster (Cryg was investigated by sequencing. A single base deletion (299delG in exon 3 of Cryga which led to a frame-shift of amino acid sequence from position 91 was identified. As a result of this mutation, the sequences of the 3rd and 4th Greek-key motifs of the γA-crystallin are replaced with an unrelated C-terminal peptide of 75 residues long. Coincidentally, the point mutation generated a HindIII restriction site, allowing the identification of the CrygaSecc mutant allele by RFLP. Western blot analysis of 3-week old lenses showed that the expression of γ-crystallins was reduced in the CrygaSecc mutant. Furthermore, in cell transfection assays using CrygaSecc mutant cDNA expression constructs in 293T, COS-7 and human lens epithelial B3 cell lines, the mutant γA-crystallins were enriched in the insoluble fractions and appeared as insoluble aggregates in the transfected cells. In conclusion, we have demonstrated that the Secc mutation leads to the

  2. Familial co-segregation of Coffin-Lowry syndrome inherited from the mother and autosomal dominant Waardenburg type IV syndrome due to deletion of EDNRB inherited from the father.

    Science.gov (United States)

    Loupe, Jacob; Sampath, Srirangan; Lacassie, Yves

    2014-10-01

    We report an African-American family that was identified after the proposita was referred for diagnostic evaluation at 4½ months with a history of Hirschsprung and dysmorphic features typical of Waardenburg syndrome (WS). Family evaluation revealed that the father had heterochromidia irides and hypertelorism supporting the clinical diagnosis of WS; however, examination of the mother revealed characteristic facial and digital features of Coffin-Lowry syndrome (CLS). Molecular testing of the mother identified a novel 2 bp deletion (c.865_866delCA) in codon 289 of RPS6KA3 leading to a frame-shift and premature termination of translation 5 codons downstream (NM_004586.2:p.Gln289ValfsX5). This deletion also was identified in the proposita and her three sisters with a clinical suspicion of CLS, all of whom as carriers for this X-linked disorder had very subtle manifestations. The molecular confirmation of WS type 4 (Shah-Waardenburg; WS4) was not as straightforward. To evaluate WS types 1-4, multiple sequential molecular tests were requested, including Sanger sequencing of all exons, and deletion/duplication analysis using MLPA for PAX3, MITF, SOX10, EDN3 and EDNRB. Although sequencing did not identify any disease causing variants, MLPA identified a heterozygous deletion of the entire EDNRB in the father. This deletion was also found in the proposita and the oldest child. Since the heterozygous deletion was the only change identified in EDNRB, this family represents one of the few cases of an autosomal dominant inheritance of WS4 involving the endothelin pathway. Altogether, clinical evaluation of the family revealed one child to be positive for WS4 and two positive for CLS, while two children were positive for both diseases simultaneously (including the proposita) while another pair test negative for either disease. This kinship is an example of the coincidence of two conditions co-segregating in one family, with variable phenotypes requiring molecular testing to

  3. Childhood cataract: home to hospital.

    OpenAIRE

    Muhit, MA

    2004-01-01

    Globally, there are 190,000 children who are blind from cataract.1 Cataract in children may be present at birth (congenital cataract) or may appear anytime during the first few years of life (developmental cataract). Childhood cataract is the most common treatable cause of childhood blindness, being responsible for 10-30% of all childhood blindness. A recent national study in Bangladesh showed that 1 in every 3 blind children is unnecessarily blind from congenital/developmental cataract.

  4. Mal de meleda with congenital cataract: A novel case report

    Directory of Open Access Journals (Sweden)

    Anisha Sethi

    2015-01-01

    Full Text Available Mal de meleda (MdM, a rare autosomal recessive genodermatosis is characterized by erythema and hyperkeratosis of the palms and soles with a sharp demarcation and that progress with age (progrediens and extend to the dorsal aspects of the hands and feet (transgrediens. It has been associated with various conditions albeit rarely with congenial cataract. Ocular lens and the skin have the same embryological origins. We hereby present this novel case report of Mal de meleda in association with congenital posterior subcapsular cataract which to the best of our knowledge has not been reported from India before.

  5. Atomic bomb cataracts

    International Nuclear Information System (INIS)

    Shiraeda, Kanji

    1992-01-01

    Eye disturbance caused by atomic bomb radiation can be divided into three groups: direct injury immediately after exposure, eye lesions associated with radiation syndrome, and delayed disturbance. The crystalline lens of the eye is the most radiosensitive. Atomic bomb cataract has been investigated in a number of studies. The first section of this chapter discusses radiation cataract in terms of the incidence and characteristics. The second section deals with atomic bomb cataract, which can be diagnosed based on the four criteria: (1) opacity of the crystalline lens, (2) a history of proximal exposure, (3) lack of eye disease complicating cataract, and (4) non-exposure to radiation other than atomic bombing. The prevalence of cataract and severity of opacity are found to correlate with exposure doses and age at the time of exposure. Furthermore, it is found to correlate with distance from the hypocenter, the condition of shielding, epilation, and the presence or absence or degree of radiation syndrome. (N.K.)

  6. Cataract Surgery in Uveitis

    Directory of Open Access Journals (Sweden)

    Rupesh Agrawal

    2012-01-01

    Full Text Available Cataract surgery in uveitic eyes is often challenging and can result in intraoperative and postoperative complications. Most uveitic patients enjoy good vision despite potentially sight-threatening complications, including cataract development. In those patients who develop cataracts, successful surgery stems from educated patient selection, careful surgical technique, and aggressive preoperative and postoperative control of inflammation. With improved understanding of the disease processes, pre- and perioperative control of inflammation, modern surgical techniques, availability of biocompatible intraocular lens material and design, surgical experience in performing complicated cataract surgeries, and efficient management of postoperative complications have led to much better outcome. Preoperative factors include proper patient selection and counseling and preoperative control of inflammation. Meticulous and careful cataract surgery in uveitic cataract is essential in optimizing the postoperative outcome. Management of postoperative complications, especially inflammation and glaucoma, earlier rather than later, has also contributed to improved outcomes. This manuscript is review of the existing literature and highlights the management pearls in tackling complicated cataract based on medline search of literature and experience of the authors.

  7. Autosomal recessive Charcot-Marie-Tooth neuropathy.

    Science.gov (United States)

    Espinós, Carmen; Calpena, Eduardo; Martínez-Rubio, Dolores; Lupo, Vincenzo

    2012-01-01

    Charcot-Marie-Tooth (CMT) disease, a hereditary motor and sensory neuropathy that comprises a complex group of more than 50 diseases, is the most common inherited neuropathy. CMT is generally divided into demyelinating forms, axonal forms and intermediate forms. CMT is also characterized by a wide genetic heterogeneity with 29 genes and more than 30 loci involved. The most common pattern of inheritance is autosomal dominant (AD), although autosomal recessive (AR) forms are more frequent in Mediterranean countries. In this chapter we give an overview of the associated genes, mechanisms and epidemiology of AR-CMT forms and their associated phenotypes.

  8. Viscoless microincision cataract surgery

    Directory of Open Access Journals (Sweden)

    Guy Sallet

    2008-06-01

    Full Text Available Guy SalletDepartment of Opthamology, Aalsters Stedelijk Ziekenhuis, BelgiumAbstract: A cataract surgery technique is described in which incisions, continuous circular capsulorhexis and hydrodissection are made without the use of any viscoelastics. Two small incisions are created through which the different parts of the procedure can take place, maintaining a stable anterior chamber under continuous irrigation. Subsequent bimanual phacoemulsification can be done through these microincisions. At the end of the procedure, an intraocular lens can be inserted through the self-sealing incision under continuous irrigation. 50 consecutive cataract patients were operated on without the use of viscoelastics and then compared with a group of 50 patients who had been helped with viscoelastics. No difference in outcome, endothelial cell count or pachymetry was noted between the two groups. No intraoperative complication was encountered. Viscoless cataract surgery was a safe procedure with potential advantages.Keywords: ophthalmic visco-surgical device, viscoless cataract surgery, microincision

  9. Solar ultraviolet radiation cataract.

    Science.gov (United States)

    Löfgren, Stefan

    2017-03-01

    Despite being a treatable disease, cataract is still the leading cause for blindness in the world. Solar ultraviolet radiation is epidemiologically linked to cataract development, while animal and in vitro studies prove a causal relationship. However, the pathogenetic pathways for the disease are not fully understood and there is still no perfect model for human age related cataract. This non-comprehensive overview focus on recent developments regarding effects of solar UV radiation wavebands on the lens. A smaller number of fundamental papers are also included to provide a backdrop for the overview. Future studies are expected to further clarify the cellular and subcellular mechanisms for UV radiation-induced cataract and especially the isolated or combined temporal and spatial effects of UVA and UVB in the pathogenesis of human cataract. Regardless of the cause for cataract, there is a need for advances in pharmaceutical or other treatment modalities that do not require surgical replacement of the lens. Copyright © 2016. Published by Elsevier Ltd.

  10. Hypomyelination and congenital cataract: neuroimaging features of a novel inherited white matter disorder

    NARCIS (Netherlands)

    Rossi, A.; Biancheri, R.; Zara, F.; Bruno, C.; Uziel, G.; van der Knaap, M.S.; Minetti, C.; Tortori-Donati, P.

    2008-01-01

    BACKGROUND AND PURPOSE: Hypomyelination and congenital cataract (HCC) is an autosomal recessive white matter disease caused by deficiency of hyccin, a membrane protein implicated in both central and peripheral myelination. We aimed to describe the neuroimaging features of this novel entity.

  11. Acute traumatic cataracts

    International Nuclear Information System (INIS)

    Titelbaum, D.S.; Grossman, R.I.; Lloyd, W.C.; Cohen, E.J.; Atlas, S.W.

    1989-01-01

    This paper reports orbital CT scans of 15 patients with clinically diagnoses traumatic cataracts retrospectively reviewed to determine the presence of radiographically detectable lens abnormalities. Definite lens swelling was clinically observed in a lease five cases. Eleven patients, scanned 4 hours of 3 days after injury, revealed visible and measured decreased CT density of the cataractous lens compared with the normal contralateral lens (average mean difference, 28 HU), suggesting acute lens swelling. In one patient, lens morphologic changes but not HU differences were found, probably due to superimposed hemorrhage. Three patients, scanned 3-8 hours after injury, revealed no detectable lens abnormality. The findings suggest that CT is potentially capable of identifying traumatic cataracts

  12. Radiation and cataract

    International Nuclear Information System (INIS)

    Rehani, M. M.; Vano, E.; Ciraj-Bjelac, O.; Kleiman, N. J.

    2011-01-01

    When this paper was about to go to press, the International Commission on Radiological Protection released a statement recommending a change in the threshold dose for the eye lens and dose limits for eye for occupationally exposed persons. It is clear that the earlier published threshold for radiation cataract is no longer valid. Epidemiological studies among Chernobyl clean-up workers, A bomb survivors, astronauts, residents of contaminated buildings, radiological technicians and recent surveys of staff in interventional rooms indicate that there is an increased incidence of lens opacities at doses below 1 Gy. Nevertheless, eye lens dosimetry is at a primitive stage and needs to be developed further. Despite uncertainties concerning dose threshold and dosimetry, it is possible to significantly reduce the risk of radiation cataract through the use of appropriate eye protection. By increasing awareness among those at risk and better adoption and increased usage of protective measures, radiation cataract can become preventable despite lowering of dose limits. (authors)

  13. Cytomegalovirus Congenital Cataract

    Directory of Open Access Journals (Sweden)

    Ridha Wahyutomo

    2011-06-01

    Full Text Available Cytomegalovirus congenital infection is an infection caused by the the subfamily â Herpesviridae, during pregnancy. The incidence of infections among newborn infants is 1 %. One of the effects of congenitally acquired infection is the congenital cataract. A 6-year-old child complained to have a blurred vision diagnosed with cytomegalovirus congenital cataract. The diagnosis was confirmed by a positive serology testing for Ig M and Ig G CMV. The laboratory test using Giemsa staining to find inclusion bodies and a faster PCR could not be carried out (Sains Medika, 3(1:84-88.

  14. The burden of gestational diabetes mellitus in Jamaican women with a family history of autosomal dominant type 2 diabetes La carga de la diabetes mellitus gestacional en mujeres de Jamaica con antecedentes familiares de diabetes autosómica dominante tipo 2

    Directory of Open Access Journals (Sweden)

    Rachael R. Irving

    2008-02-01

    Full Text Available OBJECTIVES: To determine if Jamaican women of African descent with a family history of early onset autosomal dominant type 2 diabetes have greater odds of developing gestational diabetes mellitus (GDM than those without a family history of the disease. METHODS: A comparative study was conducted of two groups of pregnant Jamaican women: the first with a family history of early onset autosomal dominant type 2 diabetes; the second with no history of the disease. Incidence, odds for developing GDM, and metabolic profiles in first and second trimesters were assessed using SPSS 11.5 (SPSS Inc., Chicago, Illinois, United States. RESULTS: The incidence of GDM was 12.0 % in women with a family history of early onset autosomal dominant type 2 diabetes and 1.5% in women without a family history of the disease (P OBJETIVOS: Determinar si las mujeres jamaicanas de ascendencia africana con antecedentes familiares de inicio temprano de diabetes autosómica dominante tipo 2 tienen mayor probabilidad de desarrollar diabetes mellitus gestacional (DMG que las que no tienen esos antecedentes familiares. MÉTODOS: Se realizó un estudio comparativo con dos grupos de mujeres jamaicanas embarazadas: el primero con mujeres que tenían antecedentes familiares de inicio temprano de diabetes autosómica dominante tipo 2 y el segundo con mujeres sin antecedentes familiares de esa enfermedad. Se empleó el programa SPSS v. 11.5 (SPSS Inc., Chicago, Illinois, Estados Unidos de América para analizar los resultados y calcular la incidencia, la probabilidad de desarrollar DMG y los perfiles metabólicos en el primer y el segundo trimestres de gestación. RESULTADOS: La incidencia de DMG fue de 12,0% en las mujeres con antecedentes familiares de inicio temprano de diabetes autosómica dominante tipo 2 y de 1,5% en las mujeres sin antecedentes familiares de esa enfermedad (P < 0,05. Las mujeres del primer grupo tuvieron nueve veces más probabilidades de desarrollar DMG que las

  15. Cataract surgery among Medicare beneficiaries.

    Science.gov (United States)

    Schein, Oliver D; Cassard, Sandra D; Tielsch, James M; Gower, Emily W

    2012-10-01

    To present descriptive epidemiology of cataract surgery among Medicare recipients in the United States. Cataract surgery performed on Medicare beneficiaries in 2003 and 2004. Medicare claims data were used to identify all cataract surgery claims for procedures performed in the United States in 2003-2004. Standard assumptions were used to limit the claims to actual cataract surgery procedures performed. Summary statistics were created to determine the number of procedures performed for each outcome of interest: cataract surgery rates by age, sex, race and state; surgical volume by facility type and surgeon characteristics; time interval between first- and second-eye cataract surgery. The national cataract surgery rate for 2003-2004 was 61.8 per 1000 Medicare beneficiary person-years. The rate was significantly higher for females and for those aged 75-84 years. After adjustment for age and sex, blacks had approximately a 30% lower rate of surgery than whites. While only 5% of cataract surgeons performed more than 500 cataract surgeries annually, these surgeons performed 26% of the total cataract surgeries. Increasing surgical volume was found to be highly correlated with use of ambulatory surgical centers and reduced time interval between first- and second-eye surgery in the same patient. The epidemiology of cataract surgery in the United States Medicare population documents substantial variation in surgical rates by race, sex, age, and by certain provider characteristics.

  16. Unilateral Autosomal Recessive Anophthalmia in a Patient with Cystic Craniopharyngioma

    Science.gov (United States)

    Kumar, Amandeep; Bansal, Ankit; Garg, Ajay; Sharma, Bhawani S.

    2014-01-01

    Abstract Anophthalmia is a rare ocular malformation. It is a genetically determined disorder and is typically associated with syndromes. However, sporadic nonsyndromic familial as well as non-familial cases of anophthalmia have also been reported. Non-syndromic familial cases are usually bilateral and have been attributed to autosomal recessive, autosomal dominant, and X-linked inheritance patterns. The authors hereby report a rare case of autosomal recessive unilateral anophthalmia in a patient with no other associated congenital anomaly. Patient was operated for craniopharyngioma. The clinical, radiological and intraoperative findings are discussed. PMID:27928292

  17. cataract surgical services

    African Journals Online (AJOL)

    countries of Asia, Africa, and Latin. America (3,4). With an estimated 12,000 bilaterally blind people ... (OMA's). 1 general medical practitioner. Loptometry technician. 1 general nurse and. 3 health assistants. Ocular morbidities cataract and aphakia corneal scarring/phthisis glaucoma refractive errors others. Percent. 52.4.

  18. Connexin mutants and cataracts

    Directory of Open Access Journals (Sweden)

    Eric C Beyer

    2013-04-01

    Full Text Available The lens is a multicellular, but avascular tissue that must stay transparent to allow normal transmission of light and focusing of it on the retina. Damage to lens cells and/or proteins can cause cataracts, opacities that disrupt these processes. The normal survival of the lens is facilitated by an extensive network of gap junctions formed predominantly of connexin46 and connexin50. Mutations of the genes that encode these connexins (GJA3 and GJA8 have been identified and linked to inheritance of cataracts in human families and mouse lines. In vitro expression studies of several of these mutants have shown that they exhibit abnormalities that may lead to disease. Many of the mutants reduce or modify intercellular communication due to channel alterations (including loss of function or altered gating or due to impaired cellular trafficking which reduces the number of gap junction channels within the plasma membrane. However, the abnormalities detected in studies of other mutants suggest that they cause cataracts through other mechanisms including gain of hemichannel function (leading to cell injury and death and formation of cytoplasmic accumulations (that may act as light scattering particles. These observations and the anticipated results of ongoing studies should elucidate the mechanisms of cataract development due to mutations of lens connexins and abnormalities of other lens proteins. They may also contribute to our understanding of the mechanisms of disease due to connexin mutations in other tissues.

  19. Phacoemulsification in subluxated cataract.

    Directory of Open Access Journals (Sweden)

    Praveen M

    2003-01-01

    Full Text Available Purpose: To evaluate the outcome of phacoemulsification in eyes with subluxated cataract. Materials and Methods: This retrospective study comprised 22 eyes of 20 consecutive patients with subluxated cataracts of varying aetiology operated between March 1998 and March 2001. Detailed preoperative assessment included visual acuity (VA, slitlamp examination, presence of vitreous in anterior chamber, extent of subluxation, intraocular pressure (IOP and detailed fundus examination. Phacoemulsification was done to retain the natural bag support and all patients had acrylic foldable Acrysof IOL implantation either in-the-bag or by scleral fixation. Postoperative observations included best-corrected visual acuity (BCVA, IOP, pupillary reaction and the IOL position. Results: The aetiology of the subluxation was traumatic in 11 patients and non-traumatic in 9 patients. Fifteen were males and 5 were females. Mean follow-up was 11.7 ± 9.71 months (range 4-39. The average age was 39.15 ± 16.33 (range 5 - 74. A 2-port anterior chamber vitrectomy was performed in 6 eyes (27.2%. Capsule tension ring (CTR was implanted in 15 eyes (68.18%. Twelve eyes (54.5% had in-the-bag implants, while 5 (22.72% had scleral fixation. The remaining 5 eyes (22.72% had one haptic in-the-bag and another sutured to sclera. No major intraoperative complications were noted. Twelve eyes (54.5% had clinically and geometrically well centered IOLs while 9 eyes (40.9% had geometrically decentered IOLs. One patient was lost to follow-up. Fifteen eyes (55.55% had postoperative BCVA of 6/12 - 6/6 while 2 eyes (7.40% had BCVA of 6/18. The remaining 4 eyes (14.81% had less than 6/24 BCVA due to pre-existing posterior segment pathology. Postoperative complications included rise in IOP in 1 eye (4.54%, pupillary capture of the IOL optic in 2 eyes (9.09%; the same 2 eyes (9.09% required redialing of IOL. One eye (4.54% had to undergo refixation (one haptic was fixed to sclera year after cataract

  20. Cataract surgery output and cost of hospitalization for cataract ...

    African Journals Online (AJOL)

    Si nous devons réussir à éliminer les arrièrs problèmes des cataracts de plus de ½ million cas, nos efforts sur la chirurgie de cataracte devraient porter principalement sur des programmes visant sur des measures preventives contre les incidences de la cécité. 106 cas des chirurgies cataracts avaient été opérées Durant la ...

  1. Congenital cataracts in two siblings with Wolfram syndrome.

    Science.gov (United States)

    Mets, Rebecca B; Emery, Sarah B; Lesperance, Marci M; Mets, Marilyn B

    2010-12-01

    Wolfram syndrome is characterized by optic atrophy, insulin dependent diabetes mellitus, diabetes insipidus and deafness. There are several other associated conditions reported in the literature, but congenital or early childhood cataracts are not among them. Observational case series with confirmatory genetic analysis. A pair of siblings, followed over 17 years, who manifest congenital or early childhood cataracts, diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. They are both compound heterozygotes for mutations (V415 deletion and A684V substitution) in the WFS1 gene. Their father has congenital sensorineural hearing loss and developed optic atrophy. He is heterozygous for A684V in WFS1. Wolfram syndrome should be in the differential diagnosis of genetic syndromes associated with congenital and early childhood cataracts. Here, we report on a mother who is a phenotypically normal carrier of an autosomal recessive Wolfram syndrome gene, and a father who has some of the findings of the syndrome and carries a single mutation that appears to be responsible for his hearing loss and optic atrophy. Their 2 children are compound heterozygotes and manifest the full Wolfram syndrome, in addition to cataracts.

  2. Three cases of extracapsular cataract extraction for radiation cataract

    International Nuclear Information System (INIS)

    Hirokane, Kenji; Kosaka, Toshiya; Nii, Hiroki; Kiuchi, Yoshiaki; Nakano, Kensuke; Choshi, Kanji

    1996-01-01

    Extracapsular cataract extraction and intraocular lens implantation was performed on 4 eyes of 3 patients with radiation cataract. Case 1 was a 60-year-old man who was exposed to the ionizing radiation of the atomic bomb in Hiroshima 730 meters from the center of the explosion. He developed atomic bomb radiation senile cataracts in both eyes. Despite cataract surgery, a central plaque remained on the posterior capsule in the region corresponding to the central dense opacity in both eyes. Case 2 was an 81-year-old man who was in a streetcar 1,000 meters from the center of the explosion at the time of the atomic bombing. Senile and radiation-induced cataract decreased the visual acuity in both eyes. After extracapsular cataract extraction in his right eye, central opacification and a fibrous white membrane remained on the posterior capsule. These were removed by Nd-YAG laser capsulotomy six days after surgery. Case 3 was a 56-year-old man who developed radiation cataract after radiation therapy to a malignant lymphoma in the right orbit. Phacoemulsification and aspiration could not remove the fibrous white membrane from the posterior capsule in this case. Central opacities and fibrous white membranes on the posterior capsule after cataract surgery appears to be a characteristic of radiation cataract. (author)

  3. Missense Mutations in CRYAB Are Liable for Recessive Congenital Cataracts.

    Directory of Open Access Journals (Sweden)

    Xiaodong Jiao

    Full Text Available This study was initiated to identify causal mutations responsible for autosomal recessive congenital cataracts in consanguineous familial cases.Affected individuals underwent a detailed ophthalmological and clinical examination, and slit-lamp photographs were ascertained for affected individuals who have not yet been operated for the removal of the cataractous lens. Blood samples were obtained, and genomic DNA was extracted from white blood cells. A genome-wide scan was completed with short tandem repeat (STR markers, and the logarithm of odds (LOD scores were calculated. Protein coding exons of CRYAB were sequenced, bi-directionally. Evolutionary conservation was investigated by aligning CRYAB orthologues, and the expression of Cryab in embryonic and postnatal mice lens was investigated with TaqMan probe.The clinical and ophthalmological examinations suggested that all affected individuals had nuclear cataracts. Genome-wide linkage analysis suggested a potential region on chromosome 11q23 harboring CRYAB. DNA sequencing identified a missense variation: c.34C>T (p.R12C in CRYAB that segregated with the disease phenotype in the family. Subsequent interrogation of our entire cohort of familial cases identified a second familial case localized to chromosome 11q23 harboring a c.31C>T (p.R11C mutation. In silico analyses suggested that the mutations identified in familial cases, p.R11C and p.R12C will not be tolerated by the three-dimensional structure of CRYAB. Real-time PCR analysis identified the expression of Cryab in mouse lens as early as embryonic day 15 (E15 that increased significantly until postnatal day 6 (P6 with steady level of expression thereafter.Here, we report two novel missense mutations, p.R11C and p.R12C, in CRYAB associated with autosomal recessive congenital nuclear cataracts.

  4. Radiation-induced cataract

    International Nuclear Information System (INIS)

    Martignoni, K.

    1986-01-01

    Dose assessments for cataract threshold doses are available based on epidemiological studies of radiotherapy patients, survivors of the nuclear bombing of Hiroshima and Nagasaki, and of persons with occupational exposure to radiation. According to these, short-term application of low-level LET radiation of a dose ranging between 0.5 and 2.0 Gy may suffice to cause a cataract in the course of a few months or years which results in inpairment of vision (UNSCEAR, 1982). In fractionated irradiation, cataractogenic threshold dose increases to 4 Sv at treatment times between 3 weeks and 3 months, and to more than 5 Sv at more than 3 months (ICRP 41). Densely ionizing radiation must be assumed to have threshold doses between 2 and 20 Sv. An ICRP assessment (ICRP Publ. No. 41, 1984) gives a threshold dose of more than 8 Sv for a vision-impairing cataract if these was protracted irradiation at a low-level dose rate. Concerning radiation protection, a maximum lens dose of 150 mSv per annum was recommended which should not be exceeded. This indicates a maximum of 7.5 Sv of exposure throughout a period of 50 years of working life. (orig./HP) [de

  5. IOL Implants: Lens Replacement and Cataract Surgery (Intraocular Lenses)

    Science.gov (United States)

    ... Oncology Oculoplastics/Orbit Refractive Management/Intervention Retina/Vitreous Uveitis Focus On Pediatric Ophthalmology ... Are Cataracts? Pediatric Cataracts Cataract Diagnosis and Treatment Cataract Surgery IOL Implants: Lens Replacement After Cataracts ...

  6. Paediatric cataract: challenges and complications

    Directory of Open Access Journals (Sweden)

    Dr P Vijayalakshmi

    2016-10-01

    Full Text Available Amblyopia should always be anticipated in children with unilateral cataract, asymmetrical bilateral cataracts (or where there is a delay between the first and second eye operation, or a delay of more than a year between diagnosis/ detection and surgery, cataracts with anisometropia or traumatic cataracts with corneal scars. When amblyopia is detected, occlusion therapy (eye patching must be instituted at the earliest opportunity. The patching regimen is the same with any strabismic amblyopia and sometimes needs to be aggressive at the start. It is crucial to explain the need for patching to the parents, since compliance is the greatest obstacle to the success of amblyopia treatment.

  7. "Ant-egg" cataract revisited

    DEFF Research Database (Denmark)

    Clemmensen, Kåre; Enghild, Jan J; Ivarsen, Anders

    2017-01-01

    -ray scans and electron microscopy. The purpose of this study was to further characterize "ant-egg" cataract using modern technology and display the history of the "ant-eggs" after cataract extraction. METHODS: "Ant-eggs" were examined using Heidelberg SPECTRALIS Optical Coherence Tomography (OCT...

  8. Autosomal recessive retinitis pigmentosa with RP1 mutations is associated with myopia

    NARCIS (Netherlands)

    Chassine, T.; Bocquet, B.; Daien, V.; Avila-Fernandez, A.; Ayuso, C.; Collin, R.W.J.; Corton, M.; Hejtmancik, J.F.; Born, L.I. van den; Klevering, B.J.; Riazuddin, S.A.; Sendon, N.; Lacroux, A.; Meunier, I.; Hamel, C.P.

    2015-01-01

    OBJECTIVE: To determine the refractive error in patients with autosomal recessive retinitis pigmentosa (arRP) caused by RP1 mutations and to compare it with that of other genetic subtypes of RP. METHODS: Twenty-six individuals had arRP with RP1 mutations, 25 had autosomal dominant RP (adRP) with RP1

  9. Progeria (Hutchison - Gilford syndrome in siblings: In an autosomal recessive pattern of inheritance

    Directory of Open Access Journals (Sweden)

    Raghu Tanjore

    2001-09-01

    Full Text Available Progeria is an autosomal dominant, premature aging syndrome. Six and three year old female siblings had sclcrodermatous changes over the extremities, alopecia, beaked nose, prominent veins and bird-like facies. Radiological features were consistent with features of progeria. The present case highlights rarity of progeria in siblings with a possible autosomal recessive pattern.

  10. Cataract surgery audit at an Australian urban teaching hospital.

    Science.gov (United States)

    Kahawita, Shyalle K; Goggin, Michael

    2015-08-01

    To provide local data on visual acuity and surgical outcomes for cataract surgery performed in an Australian teaching hospital. Continuous audit over 7 years in a public teaching hospital. A total of 3740 eyes had cataract surgery performed at The Queen Elizabeth Hospital, South Australia, from May 2006 to September 2013. Visual acuity and complication rates were recorded for cataract surgery cases operated on between May 2006 and September 2013 on a digital database with data entry contemporaneous with final follow-up. Visual acuity and surgical complications. Of the patients, 91.4% achieved postoperative best-measured vision better than preoperative best-measured vision. The rate of posterior capsular tear was 2.59%, endophthalmitis was 0.11% and the overall complication rate was 11.7%. This audit is the first to document modern cataract surgery, overwhelmingly dominated by phacoemulsification in an Australian population and can be used to benchmark cataract surgery outcome in an urban Australian population. © 2015 Royal Australian and New Zealand College of Ophthalmologists.

  11. Congenital cataract screening

    Directory of Open Access Journals (Sweden)

    Zhale Rajavi

    2016-01-01

    Full Text Available Congenital cataract is a leading cause of visual deprivation which can damage the developing visual system of a child; therefore early diagnosis, management and long-term follow-up are essential. It is recommended that all neonates be screened by red reflex examination at birth and suspected cases be referred to ophthalmic centers. Early surgery (1 year is highly recommended. After surgery, amblyopia treatment and periodic follow-up examinations should be started as soon as possible to achieve a satisfactory visual outcome. Practitioners should consider the possibility of posterior capsular opacity, elevated intraocular pressure and amblyopia during follow-up, especially in eyes with microphthalmia and/or associated congenital anomalies. All strabismic children should undergo slit lamp examination prior to strabismus surgery to rule out congenital lens opacities. From a social point of view, equal and fair medical care should be provided to all children regardless of gender.

  12. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infacts and Leukoencephalopathy (CADASIL)

    Science.gov (United States)

    ... lifestyle with adequate exercise and control of other risk factors for stroke such as high blood pressure, diaetes and high cholesterol are highly recommended. Recently, a randomized trail that tested Donepezil (Aricept), a drug recommended for Alzheimer’s disease, did not find it to be effective ...

  13. Genetics Home Reference: autosomal dominant cerebellar ataxia, deafness, and narcolepsy

    Science.gov (United States)

    ... may help regulate nerve cell (neuron) maturation and specialization (differentiation), the ability of neurons to move (migrate) ... Ataxia Foundation National Sleep Foundation University of Kansas Medical Center Resource List: Deafness and Hard of Hearing ...

  14. Autosomal Dominant Aniridia in A Nigerian Family: A Case Report ...

    African Journals Online (AJOL)

    A 54year old man brought his son to our clinic because of large eyeballs and poor vision from birth. Family history revealed that father and another child had poor vision and used to squeeze their faces especially in bright light. Examination of the boy revealed bilateral aniridia with congenital glaucoma. The father, the other ...

  15. Genetics Home Reference: autosomal dominant hyper-IgE syndrome

    Science.gov (United States)

    ... the brain, which do not affect a person's intelligence. Related Information What does it mean if a ... protein that plays an important role in several body systems. To carry out its roles, the STAT3 ...

  16. Autosomic dominant type II Osteopetrosis (Albers-Schonberg disease)

    International Nuclear Information System (INIS)

    Zambrano, Angela R; Salamanca, Juan C; Ospino, Benjamin

    2003-01-01

    The osteopetrosis type II or albers-schonberg disease is an infrequent disease secondary to the decrease in the bone resorption. The osteoclast is the principal cell involved in the disease. The osteopetrosis is characterized by few symptoms and it also has a benign course, but may further develop medullar insufficiency. We report a case of a young patient that initially shows, thrombocytopenia and bone pain with increase in the bone density, suggestive of osteopetrosis type II. The x ray exam was conclusive of osteopetrosis

  17. Pediatric cataract surgery in Madagascar

    African Journals Online (AJOL)

    2013-03-28

    Mar 28, 2013 ... Results: A total of 60.5 percent of the 86 children operated on during ... cataract, an avoidable cause of blindness and visual disability in children on the island nation. .... counseling services, reimbursement of transportation,.

  18. Combined keratoplasty and cataract extraction.

    Science.gov (United States)

    Demeler, U; Hinzpeter, E N

    1977-04-01

    A short film showing our technique of combined penetrating keratoplasty and intracapsular cataract extraction was shown, and the postoperative results in 72 eyes after an average of 3 years were reported.

  19. Combined Occurrence of Autosomal Dominant Aniridia and Autosomal Recessive Albinism in Several Members of a Family.

    Science.gov (United States)

    Yahalom, Claudia; Sharon, Dror; Dalia, Eli; Simhon, Shiran Ben; Shemesh, Efrat; Blumenfeld, Anat

    2015-06-01

    To characterize clinical and genetic aspects of a family with a unique combination of two hereditary blinding eye diseases. Comprehensive eye examination of proband and family members. Molecular analyses of the TYR and PAX6 genes. A young couple, both legally blind, requested genetic counselling regarding their ocular condition. The female was previously diagnosed with oculocutaneous albinism (OCA1A) and her spouse was diagnosed with Peters anomaly. A comprehensive clinical examination revealed that the female had OCA1A combined with signs of another ocular disease, showing some similarity to aniridia. A complete ocular examination of her family members revealed that her brother also suffered from the same combined phenotype, her father had typical OCA1A signs, and her mother and sister had aniridia-like phenotype, without clinical diagnosis until the time of presentation. Molecular analysis identified two compound heterozygous TYR mutations known to cause OCAIA and cosegregate with oculocutaneous albinism. In addition, we identified a novel heterozygous PAX6 mutation confirming the atypical aniridia phenotype. We report here a unique and rare clinical phenotype that is explained by the segregation of two severe inherited eye diseases. The clinical and genetic analysis in this family allowed them to receive accurate genetic counseling.

  20. The global burden of cataract.

    Science.gov (United States)

    Rao, Gullapalli N; Khanna, Rohit; Payal, Abhishek

    2011-01-01

    To review the previous year's literature related to prevalence of blindness in general, blindness due to cataract, cataract surgical coverage (CSC) and cataract surgical rates (CSRs). Cataracts are the major cause of blindness and visual impairment in developing countries and contributes to more than 90% of the total disability adjusted life years. This review shows that coverage continues to be a problem in many countries, especially for the female population, those residing in rural areas and those who are illiterate. Although CSR is an indicator of the availability and acceptability of services, for measuring the impact of the program, we should look at combining CSR with CSC. This strategy would also enable us achieve our goal of eliminating avoidable blindness due to cataracts by the year 2020. Cataracts still continue- to be a major cause of blindness globally and with the rapidly aging population, it is a challenge to tackle. We need to plan a comprehensive strategy addressing issues related to availability, affordability, accessibility and acceptability of eye-care services.

  1. Autosomal recessive hypophosphataemic rickets with hypercalciuria is not caused by mutations in the type II renal sodium/phosphate cotransporter gene.

    NARCIS (Netherlands)

    Heuvel, L.P.W.J. van den; Koul, K. Op de; Knots, E.; Knoers, N.V.A.M.; Monnens, L.A.H.

    2001-01-01

    BACKGROUND: At present the genetic defect for autosomal recessive and autosomal dominant hypophosphataemic rickets with hypercalciuria (HHRH) is unknown. Type II sodium/phosphate cotransporter (NPT2) gene is a serious candidate for being the causative gene in either or both autosomal recessive and

  2. Aneurisma gigante do segmento intracavernoso da carótida interna associado a doença renal policística autossômica dominante: relato de caso Giant aneurysm of the intracavernous internal carotid artery associated with autosomal dominant polycystic kidney disease: case report

    Directory of Open Access Journals (Sweden)

    Keven F. Ponte

    2006-09-01

    Full Text Available Apresenta-se o caso de mulher de 60 anos com doença renal policística autossômica dominante (DRPAD que desenvolveu quadro de cefaléia e oftalmoplegia completa à direita. A TC levantou a hipótese de um aneurisma gigante do segmento intracavernoso da carótida interna direita, o que foi confirmado pela arteriografia. Realizou-se, então, tratamento endovascular por oclusão do vaso parental com molas destacáveis no segmento supraclinóideo. A paciente evoluiu com a interrupção da cefaléia e com redução parcial da ptose e da oftalmoplegia. Neste artigo, enfatiza-se a relação entre DRPAD e aneurismas intracranianos. Comenta-se a história natural dos aneurismas originados no segmento intracavernoso da artéria carótida interna e comparam-se as opções terapêuticas no manejo destas lesões.We report the case of a 60 years-old woman with autosomal dominant polycystic kidney disease (ADPKD that presented with headache and right complete ophthalmoplegia. The CT scan raised the possibility of a giant aneurysm of the right intracavernous internal carotid artery, confirmed by angiography. The patient underwent endovascular occlusion of parent vessel with detachable coils, then she presented interruption of headache and partial recovery of ptosis and ophthalmoplegia. We emphasize the relationship between ADPKD and intracranial aneurysms. We also discuss the natural history and compare the therapeutic options for the management of giant aneurysms of the cavernous portion of the carotid artery.

  3. Genetics Home Reference: hypomyelination and congenital cataract

    Science.gov (United States)

    ... Eye Institute: Facts About Cataract National Institute of Neurological Disorders and Stroke: Peripheral Neuropathy Fact Sheet Educational Resources (5 links) Boston Children's Hospital: Cataracts in Children Boston Children's Hospital: Nervous ...

  4. Advances in hard nucleus cataract surgery

    Directory of Open Access Journals (Sweden)

    Wei Cui

    2013-11-01

    Full Text Available Security and perfect vision and fewer complications are our goals in cataract surgery, and hard-nucleus cataract surgery is always a difficulty one. Many new studies indicate that micro-incision phacoemulsification in treating hard nucleus cataract is obviously effective. This article reviews the evolution process of hard nuclear cataract surgery, the new progress in the research of artificial intraocular lens for microincision, and analyse advantages and disadvantages of various surgical methods.

  5. The population genetics of X-autosome synthetic lethals and steriles.

    Science.gov (United States)

    Lachance, Joseph; Johnson, Norman A; True, John R

    2011-11-01

    Epistatic interactions are widespread, and many of these interactions involve combinations of alleles at different loci that are deleterious when present in the same individual. The average genetic environment of sex-linked genes differs from that of autosomal genes, suggesting that the population genetics of interacting X-linked and autosomal alleles may be complex. Using both analytical theory and computer simulations, we analyzed the evolutionary trajectories and mutation-selection balance conditions for X-autosome synthetic lethals and steriles. Allele frequencies follow a set of fundamental trajectories, and incompatible alleles are able to segregate at much higher frequencies than single-locus expectations. Equilibria exist, and they can involve fixation of either autosomal or X-linked alleles. The exact equilibrium depends on whether synthetic alleles are dominant or recessive and whether fitness effects are seen in males, females, or both sexes. When single-locus fitness effects and synthetic incompatibilities are both present, population dynamics depend on the dominance of alleles and historical contingency (i.e., whether X-linked or autosomal mutations occur first). Recessive synthetic lethality can result in high-frequency X-linked alleles, and dominant synthetic lethality can result in high-frequency autosomal alleles. Many X-autosome incompatibilities in natural populations may be cryptic, appearing to be single-locus effects because one locus is fixed. We also discuss the implications of these findings with respect to standing genetic variation and the origins of Haldane's rule.

  6. Cerebral gigantism (Sotos' syndrome) and cataracts.

    Science.gov (United States)

    Yeh, H; Price, R L; Lonsdale, D

    1978-01-01

    A five-year-old girl with cerebral gigantism (Sotos' syndrome) and cataracts is described. Sotos' syndrome, characterized by generalized gigantism with normal endocrine studies has rarely been reported with ocular abnormalities and never with cataracts. It is important to study any child with cataracts for systemic disease.

  7. Immediate Sequential Bilateral Cataract Surgery

    DEFF Research Database (Denmark)

    Kessel, Line; Andresen, Jens; Erngaard, Ditte

    2015-01-01

    The aim of the present systematic review was to examine the benefits and harms associated with immediate sequential bilateral cataract surgery (ISBCS) with specific emphasis on the rate of complications, postoperative anisometropia, and subjective visual function in order to formulate evidence......-based national Danish guidelines for cataract surgery. A systematic literature review in PubMed, Embase, and Cochrane central databases identified three randomized controlled trials that compared outcome in patients randomized to ISBCS or bilateral cataract surgery on two different dates. Meta-analyses were...... performed using the Cochrane Review Manager software. The quality of the evidence was assessed using the GRADE method (Grading of Recommendation, Assessment, Development, and Evaluation). We did not find any difference in the risk of complications or visual outcome in patients randomized to ISBCS or surgery...

  8. Factors associated with strabismus after cataract extraction and primary intraocular lens implantation in congenital cataracts

    Directory of Open Access Journals (Sweden)

    Soo Jung Lee

    2014-06-01

    Full Text Available AIM: To evaluate factors associated with the development of strabismus after cataract extraction and primary intraocular lens implantation.METHODS: The medical records of 122 patients, aged 1.5mo to 9y, who had undergone cataract extraction with primary intraocular lens implantation between January 1993 and August 2011 were reviewed. Fourteen patients (17 eyes with strabismus before cataract surgery were excluded. Patients were divided into those with congenital bilateral cataracts (64 patients, 128 eyes and those with unilateral cataracts (44 patients, 44 eyes. The associations between the development of strabismus and age at cataract surgery, pre- and post-cataract extraction corrected distance visual acuity (CDVA, interocular CDVA difference, nystagmus, surgical method, and secondary cataract were evaluated.RESULTS: Factors significantly associated with the development of strabismus included age at cataract surgery (≤1y, preoperative mean CDVA ≤20/100, presence of nystagmus in the bilateral cataract group and postoperative interocular CDVA difference >20/70 in the unilateral group. Postoperative CDVA ≤20/100 and preservation of posterior capsule, and presence of secondary cataract were significant factors in both groups.CONCLUSION: Children with congenital cataracts should be monitored carefully after cataract surgery for the development of strabismus, especially when they underwent surgery at age ≤1y, and they have nystagmus, large postoperative interocular CDVA difference, poor preoperative and postoperative CDVA, preservation of the posterior capsule, or secondary cataract.

  9. Experimental research on preimplantation genetic diagnosis for autosomal dominant polycys-tic kidney disease%常染色体显性多囊肾疾病行胚胎植入前遗传学诊断的实验研究

    Institute of Scientific and Technical Information of China (English)

    朱琴; 徐炳森; 黄学锋; 周颖

    2009-01-01

    目的:建立由PKD1突变所致常染色体显性多囊肾疾病(autosomal dominant polycystic kidney disease,ADPKD)的胚胎植入前遗传学诊断(preimplantation genetic diagnosis,PGD)方法.方法:①通过微卫星连锁分析确定2个多囊肾家系的ADPKD致病基因.检测的微卫星包括为与PKD1连锁的KG8、 SM6、CW4和CW2以及与PKD2连锁的D4S1534、D4S1563、D4S414和D4S423.②对18个淋巴细胞和1个PKD1 突变所致ADPKD成员行常规体外受精胚胎移植后的5个废弃胚胎15个卵裂球行多重巢式PCR和毛细管电泳检测与PKD1连锁的微卫星分型.结果:①KG8、CW4和CW2 可作为连锁微卫星分析外周血和单个细胞的PKD1突变;②2个家系的致病基因均为PKD1;③单个卵裂球扩增成功率为86.67%(13/15),单个淋巴细胞扩增成功率为88.89%(16/18),CW4等位基因脱扣率为25%(4/16),CW2未发现等位基因脱扣,均未发现污染,2个胚胎携带致病基因.结论:PKD1连锁的微卫星分型可作为PKD1突变所致ADPKD的PGD诊断方法.

  10. The Pediatric Cataract Register (PECARE)

    DEFF Research Database (Denmark)

    Haargaard, Birgitte; Nyström, Alf; Rosensvärd, Annika

    2015-01-01

    examination with a pencil light at age 5 weeks, whereas newborn red reflex examination using a handheld ophthalmoscope is routine protocol in Swedish maternity wards. Data regarding age of referral were derived from the Pediatric Cataract Register (PECARE). All children operated on before 1 year of age...

  11. Distintas formas de presentación clínica de un raquitismo hipofosfatémico autosómico dominante por mutación del factor de crecimiento fibroblástico 23 en una familia Different forms of clinical presentation of an autosomal dominant hypophosphatemic rickets caused by a FGF 23 mutation in one family

    Directory of Open Access Journals (Sweden)

    Armando Luis Negri

    2004-04-01

    Full Text Available Describimos distintas formas de presentación clínica de un raquitismo hipofosfatémico autosómico dominante en 4 miembros de una misma familia y su respuesta al tratamiento. Paciente N° 1: de sexo femenino de 60 años que consultó por dolores costales y pélvicos, con osteoporosis densitométrica, hipofosfatemia con bajo umbral renal de fósforo, PTH intacta normal y calcemia normal. Tratada con fósforo neutro y calcitriol logró la normalización bioquímica y una notable mejoría de la densitometría en menos de un año. Paciente N° 2: su nieta, consultó al año y ocho meses de edad por presentar talla en percentil 3 y genu varum. En el laboratorio mostró hipofosfatemia y fosfatasa alcalina total muy elevada y en la Rx de mano, ensanchamiento y deflecamiento epifisario compatible con raquitismo. Tratada con fósforo neutro y calcitriol, normalizó los parámetros bioquímicos y logró un ascenso en el percentil de talla de 3 a 50 a los 20 meses de tratamiento. Paciente N° 3: la madre de la paciente N° 2, quien sin ninguna manifestación clínica y con densitometría ósea normal presentó hipofosfatemia que se normalizó con tratamiento con fosfato neutro. Paciente N° 4: el tío de la paciente N° 2, tuvo raquitismo hipofosfatémico de niño, y luego de los 5 años normalizó el fósforo sin tratamiento. Estudiado a los 29 años presentó fósforo normal y densitometría ósea normal. El análisis del ADN genómico de la paciente N° 3 mostró una mutación con sentido erróneo en el gen del factor de crecimiento fifroblástico 23 (sustitución de arginina por una glutamina en posición 179. Por lo tanto se llegó al diagnóstico de raquitismo/osteomalacia hipofosfatémico autosómico dominante.In this report we describe different forms of clinical presentation of an autosomal dominant hypophosphatemic rickets (ADHR in 4 members of the same family as well as the treatment used in these patients and their response to it. Patient N

  12. Constitutional and acquired autosomal aneuploidy.

    Science.gov (United States)

    Jackson-Cook, Colleen

    2011-12-01

    Chromosomal imbalances can result from numerical or structural anomalies. Numerical chromosomal abnormalities are often referred to as aneuploid conditions. This article focuses on the occurrence of constitutional and acquired autosomal aneuploidy in humans. Topics covered include frequency, mosaicism, phenotypic findings, and etiology. The article concludes with a consideration of anticipated advances that might allow for the development of screening tests and/or lead to improvements in our understanding and management of the role that aneuploidy plays in the aging process and acquisition of age-related and constitutional conditions.

  13. A novel approach identifying hybrid sterility QTL on the autosomes of Drosophila simulans and D. mauritiana.

    Science.gov (United States)

    Dickman, Christopher T D; Moehring, Amanda J

    2013-01-01

    When species interbreed, the hybrid offspring that are produced are often sterile. If only one hybrid sex is sterile, it is almost always the heterogametic (XY or ZW) sex. Taking this trend into account, the predominant model used to explain the genetic basis of F1 sterility involves a deleterious interaction between recessive sex-linked loci from one species and dominant autosomal loci from the other species. This model is difficult to evaluate, however, as only a handful of loci influencing interspecies hybrid sterility have been identified, and their autosomal genetic interactors have remained elusive. One hindrance to their identification has been the overwhelming effect of the sex chromosome in mapping studies, which could 'mask' the ability to accurately map autosomal factors. Here, we use a novel approach employing attached-X chromosomes to create reciprocal backcross interspecies hybrid males that have a non-recombinant sex chromosome and recombinant autosomes. The heritable variation in phenotype is thus solely caused by differences in the autosomes, thereby allowing us to accurately identify the number and location of autosomal sterility loci. In one direction of backcross, all males were sterile, indicating that sterility could be entirely induced by the sex chromosome complement in these males. In the other direction, we identified nine quantitative trait loci that account for a surprisingly large amount (56%) of the autosome-induced phenotypic variance in sterility, with a large contribution of autosome-autosome epistatic interactions. These loci are capable of acting dominantly, and thus could contribute to F1 hybrid sterility.

  14. A novel approach identifying hybrid sterility QTL on the autosomes of Drosophila simulans and D. mauritiana.

    Directory of Open Access Journals (Sweden)

    Christopher T D Dickman

    Full Text Available When species interbreed, the hybrid offspring that are produced are often sterile. If only one hybrid sex is sterile, it is almost always the heterogametic (XY or ZW sex. Taking this trend into account, the predominant model used to explain the genetic basis of F1 sterility involves a deleterious interaction between recessive sex-linked loci from one species and dominant autosomal loci from the other species. This model is difficult to evaluate, however, as only a handful of loci influencing interspecies hybrid sterility have been identified, and their autosomal genetic interactors have remained elusive. One hindrance to their identification has been the overwhelming effect of the sex chromosome in mapping studies, which could 'mask' the ability to accurately map autosomal factors. Here, we use a novel approach employing attached-X chromosomes to create reciprocal backcross interspecies hybrid males that have a non-recombinant sex chromosome and recombinant autosomes. The heritable variation in phenotype is thus solely caused by differences in the autosomes, thereby allowing us to accurately identify the number and location of autosomal sterility loci. In one direction of backcross, all males were sterile, indicating that sterility could be entirely induced by the sex chromosome complement in these males. In the other direction, we identified nine quantitative trait loci that account for a surprisingly large amount (56% of the autosome-induced phenotypic variance in sterility, with a large contribution of autosome-autosome epistatic interactions. These loci are capable of acting dominantly, and thus could contribute to F1 hybrid sterility.

  15. Mutation analysis of GLDC, AMT and GCSH in cataract captive-bred vervet monkeys (Chlorocebus aethiops).

    Science.gov (United States)

    Chauke, Chesa G; Magwebu, Zandisiwe E; Sharma, Jyoti R; Arieff, Zainunisha; Seier, Jürgen V

    2016-08-01

    Non-ketotic hyperglycinaemia (NKH) is an autosomal recessive inborn error of glycine metabolism characterized by accumulation of glycine in body fluids and various neurological symptoms. This study describes the first screening of NKH in cataract captive-bred vervet monkeys (Chlorocebus aethiops). Glycine dehydrogenase (GLDC), aminomethyltransferase (AMT) and glycine cleavage system H protein (GCSH) were prioritized. Mutation analysis of the complete coding sequence of GLDC and AMT revealed six novel single-base substitutions, of which three were non-synonymous missense and three were silent nucleotide changes. Although deleterious effects of the three amino acid substitutions were not evaluated, one substitution of GLDC gene (S44R) could be disease-causing because of its drastic amino acid change, affecting amino acids conserved in different primate species. This study confirms the diagnosis of NKH for the first time in vervet monkeys with cataracts. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Adrenomyeloneuropathy associated with congenital cataract

    International Nuclear Information System (INIS)

    Komori, Tetsuo; Nagashima, Toshiko; Hirose, Kazuhiko; Tanabe, Hitoshi; Tsubaki, Tadao

    1988-01-01

    Two cases of adrenomyeloneuropathy (AMN) in a family and the results of their MRI study are reported. Case 1, a 24-year-old male proband, was admitted to our hospital because of gait disturbance for three years. Bilateral cataracts were pointed out at birth, which required left side lenticotomy at age four. Neurological examinations on admission revealed a marked spastic paraparesis with pathological reflexes and a mild hypesthesia in the distal part of the left leg. No abnormal findings were detected in X-ray studies on the spine and spinal cord, electromyography and nerve conduction test. Serum very long chain fatty acids (VLCFAs) levels were apparently elevated, and the serum cortisol response to ACTH was low. Case 2, a 53-year-old woman, is the mother of Case 1 having a complaint of gait disturbance since age 51. She presented a mild spastic paraparesis with localized hypesthesia in the distal part of the both legs. She also had bilateral congenital cataracts. Her serum VLCFAs analysis indicated the intermediate levels between that of AMN and the normal control. Adrenal functions were normal. Cranial MRI (TR 2,000 msec/TE 80 msec) study disclosed high signal intensity areas in bilateral internal capsules in Case 1. These findings, suggesting the pathological change of dysmyelination, seemed to be well compatible with the clinical pictures. With these clinical findings and the laboratory data, these two cases were diagnosed as AMN. In addition, association of congenital cataract with AMN in both cases was characteristic in this family, which hasn't been reported in the literature. On regarding the genetic background of these two disorders, AMN and congenital cataract, it was speculated that each gene could be closely located on the same or very adjacent locus, possibly on Xq. (author)

  17. Patient satisfaction with cataract surgery

    Directory of Open Access Journals (Sweden)

    Wasfi Ehab I

    2008-10-01

    Full Text Available Abstract Introduction Measuring the patient satisfaction is a very important issue that will help very much in improving the service provided to patients and improve the level of satisfaction. Aim To evaluate patient satisfaction with the cataract surgery service and identify any areas for improvement, determination of patient satisfaction with referral, out-patient consultation, pre-assessment clinic, surgery and post-operative care, also to report patients' comments relating to improvement in service provision. Methodology A retrospective study was undertaken for 150 patients underwent cataract surgery at Barrow General Hospital, UK, the survey sample was by postal questionnaires. We collected our data from the theatre lists for a period of 4 month. Results This study included 150 patients; the response rate was (72% 108 patients, Most patients were referred from their general practitioner 86.1%, 93 (86.1% patients were happy with the time interval from seeing their GP to eye clinic. In the eye out patient department many factors significantly affected the level of patient satisfaction, in general the more information provided for the patient the more the satisfaction. Conclusion Patient satisfaction is on important health outcome old understanding both the domains of satisfaction as well as their relative importance to patients is necessary to improve the overall quality of patient care. Meeting the doctor, presenting all relevant information and giving printed information are very important factors in improving the patient's satisfaction with cataract surgery.

  18. The global state of cataract blindness.

    Science.gov (United States)

    Lee, Cameron M; Afshari, Natalie A

    2017-01-01

    Cataracts are a significant cause of blindness and visual impairment worldwide. The present article reviews the literature and describes the current extent of cataracts globally, barriers to treatment, and recommendations for improving the treatment of cataracts. Prevalence and absolute number of blind because of cataracts remain high, although rates are declining in many areas globally. The age-standardized prevalence of blindness in adults older than 50 remains highest in western sub-Saharan Africa, with a rate of 6.0%. The greatest declines in age-standardized blindness because of cataracts in adults older than 50 between 1990 and 2010 were in East Asia, tropical Latin America, and western Europe. Recent studies have largely found higher rates of cataracts in women than in men. A new simulator for training ophthalmologists in manual small-incision cataract surgery holds promise for the future. The rates of cataract surgery are increasing and postoperative outcomes are improving worldwide, yet challenges to reducing the cataract burden further remain. Cost, an insufficient number of ophthalmologists, and low government funding remain significant barriers but investment in further eye care infrastructure and training of additional ophthalmologists would improve the current situation.

  19. Studies on congenital hereditary cataract and microphthalmia of the miniature schnauzer dog.

    Science.gov (United States)

    Shastry, B S; Reddy, V N

    1994-09-30

    Hereditary cataract in dogs occurs as an autosomal recessive trait. The opacity is primarily in the lens nucleus and posterior cortex. The affected animals also have other ocular abnormalities such as microphthalmia. To understand the genetic basis of this disorder, we have analyzed leukocyte DNA from affected and normal dogs for possible mutations in the homeobox containing gene and myotonic dystrophy locus. The results show that there are no signs of microdeletion, insertion, point mutation and rearrangements in these loci. Although these observations cannot completely rule out the possibility of point mutations, they suggest that the above loci are unlikely to be associated with the disease.

  20. Genetics Home Reference: congenital cataracts, facial dysmorphism, and neuropathy

    Science.gov (United States)

    ... Eye Institute: Facts About Cataracts National Institute of Neurological Disorders and Stroke: Hereditary Neuropathies Educational Resources (5 links) Boston Children's Hospital: Cataracts in Children Centers for Disease Control ...

  1. Visual Outcome of Cataract Surgery | Ukponmwan | Nigerian ...

    African Journals Online (AJOL)

    Purpose: To assess the visu al ou tcome of cataract su rgery in a tertiary hosp ital in Nigeria. Methods: Three hu nd red and seventy eyes (370) that had cataract su rgery in the op hthalmology d ep artment of University of Benin Teaching Hosp ital (UBTH) from July 2007 to December 2008 were includ ed in the stu d y.

  2. Evaluation of Complications of Extracapsular Cataract Extraction ...

    African Journals Online (AJOL)

    hanumantp

    Department of Ophthalmology, University of Nigeria Teaching Hospital, Enugu, 1Department of Ophthalmology, Guinness. Eye Centre, Onitsha, Nigeria. Abstract .... Br J Ophthalmol 2007;91:1315‑7. 6. Hennig A. Sutureless non‑phaco cataract surgery: A solution to reduce worldwide cataract blindness? Community Eye.

  3. Pediatric cataract surgery in Madagascar | Randrianotahina ...

    African Journals Online (AJOL)

    Conclusions: In Madagascar, presentation for congenital and developmental cataract is very late, visual outcome poor and follow‑up inadequate. There is an urgent need for a childhood blindness program to effectively deal with pediatric cataract, an avoidable cause of blindness and visual disability in children on the island ...

  4. Retrobulbar versus subconjunctival anesthesia for cataract surgery ...

    African Journals Online (AJOL)

    Objectives: To compare the effectiveness, in terms of pain relief and akinesia of retrobulbar and subconjunctival an aesthesia during cataract surgery and also to compare the degree of postoperative ptosis associated with each technique. Materials and Methods: Consecutive adult patients undergoing cataract surgery ...

  5. Prevalence of Cataract Blindness in Rural Ethiopia

    African Journals Online (AJOL)

    Bernt Lindtjørn

    Background: Over three-quarter of all blindness worldwide are preventable and usually caused by cataract and trachoma. Objective: To assess the ... Ophthalmologists from other areas conduct cataract operations once or twice each ... Some patients may have two eyes disorder causing visual impairment. The accepted ...

  6. Visual function of cataract with high myopia

    Directory of Open Access Journals (Sweden)

    Jian-Tao Ren

    2013-09-01

    Full Text Available Cataract with high myopia is research priority associated with the large amount of high myopia patients. The unaided visual acuity and the best-corrected visual acuity are partial for the visual acuity of the patients with cataract. The mechanism and clinical significance of modern visual function measurements associated with cataract and high myopia, including accommodation and convergence, stereoscopic vision, contrast sensitivity, have been introduced. These measurements could be of great value in early diagnosis of cataract, assessment of surgical indication, customized intraocular lens(IOLselection and evaluation of visual performance after IOL implantation. They could also be helpful to the analysis of postoperative impaired visual function and its management. Having an adequate understanding of the contents and significance of visual function was helpful to the improvement of cataract surgery techniques and postoperative visual acuity.

  7. Enamelin/ameloblastin gene polymorphisms in autosomal amelogenesis imperfecta among Syrian families.

    Science.gov (United States)

    Dashash, Mayssoon; Bazrafshani, Mohamed Riza; Poulton, Kay; Jaber, Saaed; Naeem, Emad; Blinkhorn, Anthony Stevenson

    2011-02-01

      This study was undertaken to investigate whether a single G deletion within a series of seven G residues (codon 196) at the exon 9-intron 9 boundary of the enamelin gene ENAM and a tri-nucleotide deletion at codon 180 in exon 7 (GGA vs deletion) of ameloblastin gene AMBN could have a role in autosomal amelogenesis imperfecta among affected Syrian families.   A new technique - size-dependent, deletion screening - was developed to detect nucleotide deletion in ENAM and AMBN genes. Twelve Syrian families with autosomal-dominant or -recessive amelogenesis imperfecta were included.   A homozygous/heterozygous mutation in the ENAM gene (152/152, 152/153) was identified in affected members of three families with autosomal-dominant amelogenesis imperfecta and one family with autosomal-recessive amelogenesis imperfecta. A heterozygous mutation (222/225) in the AMBN gene was identified. However, no disease causing mutations was found. The present findings provide useful information for the implication of ENAM gene polymorphism in autosomal-dominant/-recessive amelogenesis imperfecta.   Further investigations are required to identify other genes responsible for the various clinical phenotypes. © 2010 Blackwell Publishing Asia Pty Ltd.

  8. A case report of spontaneous mutation (C33>U) in the iron-responsive element of L-ferritin causing hyperferritinemia-cataract syndrome.

    LENUS (Irish Health Repository)

    Cao, Wei

    2010-01-15

    The hereditary hyperferritinemia cataract syndrome (HHCS) is an autosomal dominant disorder characterized by juvenile-onset cataracts and elevated serum ferritin levels. It is caused by mutation in the iron response element (IRE) within the 5\\'UTR of L-ferritin gene. The mutation results in a loss of post-transcriptional negative feedback exerted by the interaction between iron regulatory proteins 1, 2 (IRP1 and IRP2) and IRE, which leads to uncontrolled expression of L-ferritin. In this paper, we describe the molecular pathogenesis of non-hereditary hyperferritinemia cataract syndrome (non-H-HCS) in a patient with typical HHCS ocular lens morphology and high ferritin levels without obvious family history. Initial sequencing of the full-length L-ferritin cloned from genomic DNA demonstrated a mutation (C33>T) in the IRE of the affected patient but not in her unaffected family members. The mutation (C\\/T heterozygote) was also detected in cDNA derived from her blood mononuclear cells. Structure-prediction-modeling indicates that this mutation would significantly alter the secondary structure of the IRE, resulting in a loss of the interaction between IRP and IRE. By using IRP1\\/IRP2-human IgG1 Fc fusion proteins, we established a novel in vitro report system (modified ELISA) to verify impaired IRE\\/IRP binding. Both the C33>U and A40G mutations (the first identified mutation for HHCS) showed a dramatically decreased binding to IRP1\\/IRP2 protein, compared to the normal IRE RNA. Surprisingly, a decrease in L-ferritin mRNA levels was observed in the affected patient compared to controls suggesting a mechanism of transcriptional negative feedback by high intracellular L-ferritin protein levels not described heretofore. Taken together, spontaneous mutation in the IRE of L-ferritin may cause non-H-HCS by the same mechanism as HHCS. In addition, under abnormal circumstances, the protein level of L-ferritin may be principally controlled by post

  9. Femtosecond laser-assisted compared with standard cataract surgery for removal of advanced cataracts.

    Science.gov (United States)

    Hatch, Kathryn M; Schultz, Tim; Talamo, Jonathan H; Dick, H Burkhard

    2015-09-01

    To compare effective phacoemulsification time (EPT) for the removal of brunescent cataracts treated with femtosecond laser-assisted cataract surgery with standard cataract phacoemulsification techniques. Ruhr University Eye Hospital, Bochum, Germany. Comparative prospective case study. The Lens Opacities Classification System III (LOCS III) grading system was used to measure eyes divided into 4 groups having cataract surgery. Groups 1 and 2 contained eyes with LOCS III grade nuclear opalescence (NO) 3 cataracts treated with standard cataract surgery and femtosecond laser-assisted cataract surgery, respectively. Groups 3 and 4 contained brunescent cataracts, LOCS III grades NO5, treated with standard cataract surgery and femtosecond laser-assisted cataract surgery, respectively. There were 240 eyes, with 60 eyes in each group. The EPT in Group 1 ranged from 0.46 to 3.10 (mean 1.38); the EPT in all eyes in Group 2 was 0 (P Talamo, and Dick are consultants to Abbott Medical Optics, Inc. Dr. Schultz has no financial or proprietary interest in any material or method mentioned. Copyright © 2015 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

  10. Identification of cataract and post-cataract surgery optical images using artificial intelligence techniques.

    Science.gov (United States)

    Acharya, Rajendra Udyavara; Yu, Wenwei; Zhu, Kuanyi; Nayak, Jagadish; Lim, Teik-Cheng; Chan, Joey Yiptong

    2010-08-01

    Human eyes are most sophisticated organ, with perfect and interrelated subsystems such as retina, pupil, iris, cornea, lens and optic nerve. The eye disorder such as cataract is a major health problem in the old age. Cataract is formed by clouding of lens, which is painless and developed slowly over a long period. Cataract will slowly diminish the vision leading to the blindness. At an average age of 65, it is most common and one third of the people of this age in world have cataract in one or both the eyes. A system for detection of the cataract and to test for the efficacy of the post-cataract surgery using optical images is proposed using artificial intelligence techniques. Images processing and Fuzzy K-means clustering algorithm is applied on the raw optical images to detect the features specific to three classes to be classified. Then the backpropagation algorithm (BPA) was used for the classification. In this work, we have used 140 optical image belonging to the three classes. The ANN classifier showed an average rate of 93.3% in detecting normal, cataract and post cataract optical images. The system proposed exhibited 98% sensitivity and 100% specificity, which indicates that the results are clinically significant. This system can also be used to test the efficacy of the cataract operation by testing the post-cataract surgery optical images.

  11. Childhood Cataract: Magnitude, Management, Economics and Impact

    Directory of Open Access Journals (Sweden)

    BR Shamanna

    2004-01-01

    Full Text Available The prevalence of blindness among children in different regions varies from 0.2/1000 children to over 1.5/1000 children with a global figure estimated at 0.7/1000. This means that there are an estimated 1.4 million blind children worldwide.1 The proportion of blindness in children due to cataract varies considerably between regions from 10%-30% with a global average estimated at 14%, giving 190,000 children blind from cataract. 2 While the magnitude of childhood cataracts varies from place to place, it is a priority within all blindness control programmes for children. Children who are blind have to overcome a lifetime of emotional, social and economic difficulties which affect the child, the family and society.3 Loss of vision in children influences their education, employment and social life. The numbers blind with cataract do not reflect the years of disability and lost quality of life. Childhood blindness is second only to adult cataract as a cause of blind-person years. Approximately 70 million blind-person years are caused by childhood blindness of which about 10 million blind-person years (14% is due to childhood cataract. Timely recognition and intervention can eliminate blind-years due to childhood cataract, as the condition is treatable.

  12. Andhidrotic ectodermal dysplasia-autosomal recessive form

    Directory of Open Access Journals (Sweden)

    Inamadar Arun

    1994-01-01

    Full Text Available Anhidrotic ectodermal dysplasia with classical features in 2 sisters is reported. The mode of inheritance in these seems to be autosomal recessive; which is a very rare occurrence.

  13. [Rehabilitation methods for children with complicated cataract].

    Science.gov (United States)

    Ivanov, G; Cuşnir, V; Septichina, Natalia; Cuşnir, Vitalie

    2010-01-01

    The work deals with the results of surgical treatment of 155 patients, who had uveal cataract, by method of facoemulsification with artificial crystalline lens transplanting. The age of the sick varied from 3 to 15 as a result of a complex treatment, involving determination of ethnic factor in the development of uveal cataract, before- and after-operation conservative medical treatment, surgical treatment of abscuration ambliopia 78.1% children and the keenness of sight 0.4 and 68.7% got binocularious sight. The study lot of posttraumatic cataract affected children included 189 patients, from them 68 with stationary cataract, 87 with intumescent cataract and 34 with postoperatorial aphakia. Age from 2 to 15 years. 76.3% cases of evolution without postoperatorial complications, in 13.7% intraoperatorial were observed different complications. The work presents the results of surgical treatment 196 of children, who had innate cataract, by the method of facoasoriation with soft intra-eyepiece lens transplanting from 133 patients who had two-sided cataract, 63 had monolateral cataract. All children underwent laser simulation and videocomputer auto-training in post-operation period. As a result of the treatment, 66.8% patients got the amelioration of sight with 0.4, and 58% got binocular sight. The children's age varied between 6 months and 15 years. This article presents a review of the treatment results of 213 children with posttraumatic, congenital and complicated cataracts. The rehabilitation of the patients with the lens pathology includes a complex of measures of early diagnosis, surgery, optimal correction, medical treatment before and after surgery, the prophilaxis and treatment of complications. This approach permits to increase the visual acuity in 83.8% and to restore the binocular vision in 71.4% patients.

  14. Sutureless Cataract Surgery: Principles and Steps

    Directory of Open Access Journals (Sweden)

    John Sandford-Smith

    2003-01-01

    Full Text Available Introduction. Cataracts cause about 50% of world blindness. There is little likelihood of effective prevention becoming available in the next few years and so the only treatment will remain surgical. For many of the other major causes of world blindness, like trachoma, xerophthalmia and onchocerciasis, the remedy is community-based, not hospital-based, and requires prevention rather than treatment. The prevalence of blinding cataract will only increase as people live longer, so cataract will continue to be, by far, the most important treatable cause of blindness.

  15. A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts.

    Directory of Open Access Journals (Sweden)

    Xiaodong Jiao

    Full Text Available This study was performed to investigate the genetic determinants of autosomal recessive congenital cataracts in large consanguineous families.Affected individuals underwent a detailed ophthalmological examination and slit-lamp photographs of the cataractous lenses were obtained. An aliquot of blood was collected from all participating family members and genomic DNA was extracted from white blood cells. Initially, a genome-wide scan was performed with genomic DNAs of family PKCC025 followed by exclusion analysis of our familial cohort of congenital cataracts. Protein-coding exons of CRYBB1, CRYBB2, CRYBB3, and CRYBA4 were sequenced bidirectionally. A haplotype was constructed with SNPs flanking the causal mutation for affected individuals in all four families, while the probability that the four familial cases have a common founder was estimated using EM and CHM-based algorithms. The expression of Crybb3 in the developing murine lens was investigated using TaqMan assays.The clinical and ophthalmological examinations suggested that all affected individuals had nuclear cataracts. Genome-wide linkage analysis localized the causal phenotype in family PKCC025 to chromosome 22q with statistically significant two-point logarithm of odds (LOD scores. Subsequently, we localized three additional families, PKCC063, PKCC131, and PKCC168 to chromosome 22q. Bidirectional Sanger sequencing identified a missense variation: c.493G>C (p.Gly165Arg in CRYBB3 that segregated with the disease phenotype in all four familial cases. This variation was not found in ethnically matched control chromosomes, the NHLBI exome variant server, or the 1000 Genomes or dbSNP databases. Interestingly, all four families harbor a unique disease haplotype that strongly suggests a common founder of the causal mutation (p<1.64E-10. We observed expression of Crybb3 in the mouse lens as early as embryonic day 15 (E15, and expression remained relatively steady throughout development.Here, we

  16. Cataracts

    Science.gov (United States)

    ... NEI Intranet (Employees Only) *PDF files require the free Adobe® Reader® software for viewing. This website is maintained by the NEI Office of Science Communications, Public Liaison, and Education. Technical questions about this website can be addressed ...

  17. Behavioral Retardation in a Macaque with Autosomal Trisomy and Aging Mother.

    Science.gov (United States)

    Waal, Frans B. M. de; And Others

    1996-01-01

    The social development of a female rhesus monkey was followed from birth until death, age 32 months. The monkey had an extra autosome and was hydrocephalic. The monkey showed serious motor deficiencies, delayed social development, poorly established dominance relationships, and heavy dependence on mother and kin. The monkey was, however, well…

  18. Malignant glaucoma after cataract surgery.

    Science.gov (United States)

    Varma, Devesh K; Belovay, Graham W; Tam, Diamond Y; Ahmed, Iqbal Ike K

    2014-11-01

    To report a series of eyes that developed malignant glaucoma after cataract surgery. Private academic practice, Toronto, Ontario, Canada. Retrospective case series. Eyes that developed malignant glaucoma after cataract surgery were treated with medical therapy. This was followed by laser iridozonulohyaloidotomy, anterior chamber reformation and intraocular lens (IOL) pushback, and finally with surgical iridozonulohyaloidovitrectomy if all other measures were unsuccessful. Refraction, intraocular pressure (IOP), gonioscopy, and anterior chamber depth (ACD) by anterior segment optical coherence tomography were analyzed before treatment and after treatment. The study evaluated 20 eyes of 18 female patients aged 44 to 86 years. Preoperatively, the mean refraction was +3.11 diopters (D) ± 2.89 (SD), the mean axial length was 21.30 ± 1.40 mm, and all eyes had narrow or closed angles. Malignant glaucoma was diagnosed a mean of 5.8 ± 7.1 weeks postoperatively. At diagnosis, the mean refraction was -2.15 ± 2.95 D; the mean ACD, 2.49 ± 0.72 mm; and the mean IOP, 28.3 ± 10.8 mm Hg on a mean of 1.3 ± 1.6 medications. Two eyes responded to cycloplegia, 7 to laser iridozonulohyaloidotomy, and 6 to anterior chamber reformation-IOL pushback; 5 eyes required vitrectomy. Posttreatment, the mean refraction was -0.56 ± 1.07 D; the mean ACD, 3.30 ± 0.50 mm; and the mean IOP, 14.4 ± 4.60 mm Hg on a mean of 1.2 ± 1.4 medications. Cycloplegia was discontinued in 17 eyes. Malignant glaucoma can occur after phacoemulsification and presents with myopic surprise, anterior chamber shallowing and, possibly, elevated IOP. No author has a financial or proprietary interest in any material or method mentioned. Copyright © 2014 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

  19. Dexmedetomidine premedication in cataract surgery under topical ...

    African Journals Online (AJOL)

    0.0001). Noticably, the incidence of dry mouth was higher in group D. Hemodynamic parameters were well maintained in both groups with no adverse events in either group. Conclusions: Dexmedetomidine can be used safely for cataract ...

  20. clinical characteristics of cataract patients with pseudoexfoliation

    African Journals Online (AJOL)

    User

    the clinical characteristics of pseudoexfoliation syndrome among cataract patients examined at ... CONCLUSION: A significant number of patients with PEX had poor zonular integrity and high IOP ... Poor zonular integrity may give rise to.

  1. Economic Constraints in Managing Complicated Cataracts

    African Journals Online (AJOL)

    role in the access to Healthcare Service and Resources ... Patients face financial ... environment presents unusual challenges with the management of even the simplest conditions ... in association with a cataract has been described in.

  2. Cataract Surgery in Anterior Megalophthalmos: A Review

    Science.gov (United States)

    GALVIS, Virgilio; TELLO, Alejandro; M. RANGEL, Carlos

    2015-01-01

    Anterior megalophthalmos is characterized by megalocornea associated with a very broad anterior chamber and ciliary ring elongation. It is also called X-linked megalocornea. It is accompanied by early development of cataracts, zonular anomalies, and, rarely, vitreoretinal disorders. Subluxation of a cataract can occur in cataract surgery because of zonular weakness. In addition, in most patients, standard intraocular lens (IOL) decentration is a risk because of the enlarged sulcus and capsular bag. These unique circumstances make cataract surgery challenging. To date, several approaches have been developed. Implantation of a retropupillary iris-claw aphakic intraocular lens may be a good option because it is easier than suturing the IOL and can have better and more stable anatomic and visual outcomes, compared to other techniques. PMID:27350950

  3. Fluorometholone-induced cataract after photorefractive keratectomy.

    Science.gov (United States)

    Bilgihan, K; Gürelik, G; Akata, F; Hasanreisoglu, B

    1997-01-01

    The use of topical corticosteroids following photorefractive keratectomy (PRK) is widespread. The major complications of potent corticosteroids are glaucoma and cataract formation; in order to decrease these complications, 0.1% fluorometholone administration is usually preferred after PRK. We report here a case of lens opacification which was induced by 0.1% fluorometholone administration after PRK in a period of 4 months. To our knowledge, this is the first reported case of 0.1% fluorometholone-induced cataract after PRK.

  4. A novel NR2E3 gene mutation in autosomal recessive retinitis pigmentosa with cystic maculopathy

    OpenAIRE

    Mahajan, D.; Votruba, Marcela

    2017-01-01

    NR2E3 is a gene that encodes for photoreceptor cell specific nuclear receptor, which is involved in cone proliferation. The splice site mutation 119-2A>C in NR2E3 (15q23) has been previously reported to underlie recessive enhanced cone S sensitivity syndrome, clumped pigmentary retinal degeneration, Goldman-Favre syndrome and also autosomal dominant and autosomal recessive retinitis pigmentosa (RP). However, the mutation c 571 + 2 T > C in NR2E3 has not been previously reported with retinal d...

  5. Dominant inheritance of cerebral gigantism.

    Science.gov (United States)

    Zonana, J; Sotos, J F; Romshe, C A; Fisher, D A; Elders, M J; Rimoin, D L

    1977-08-01

    Cerebral gigantism is a syndrome consisting of characteristic dysmorphic features, accelerated growth in early childhood, and variable degrees of mental retardation. Its etiology and pathogenesis have not been defined. Three families are presented with multiple affected members. The vertical transmission of the trait and equal expression in both sexes in these families indicates a genetic etiology with a dominant pattern of inheritance, probably autosomal. As in previously reported cases, extensive endocrine evaluation failed to define the pathogenesis of the accelerated growth present in this disorder.

  6. Cataract incidence after total-body irradiation

    International Nuclear Information System (INIS)

    Zierhut, D.; Lohr, F.; Schraube, P.; Huber, P.; Haas, R.; Hunstein, W.; Wannenmacher, M.

    1997-01-01

    Purpose: Aim of this retrospective study was to evaluate cataract incidence in a homogeneous group of patients after total-body irradiation followed by autologous bone marrow transplantation or peripheral blood stem cell transplantation. Method and Materials: Between 11/1982 and 6/1994 in total 260 patients received in our hospital total-body irradiation for treatment of haematological malignancy. In 1996-96 patients out of these 260 patients were still alive. 85 from these still living patients (52 men, 33 women) answered evaluable on a questionnaire and could be examined ophthalmologically. Median age of these patients was 38,5 years (15 - 59 years) at time of total-body irradiation. Radiotherapy was applied as hyperfractionated total-body irradiation with a median dose of 14,4 Gy in 12 fractions over 4 days. Minimum time between fractions was 4 hours, photons with a energy of 23 MeV were used, and the dose rate was 7 - 18 cGy/min. Results: Median follow-up is now 5,8 years (1,7 - 13 years). Cataract occurred in (28(85)) patients after a median time of 47 months (1 - 104 months). In 6 out of these 28 patients who developed a cataract, surgery of the cataract was performed. Whole-brain irradiation prior to total-body irradiation was more often in the group of patients developing a cataract (14,3%) vs. 10,7% in the group of patients without cataract. Conclusion: Cataract is a common side effect of total-body irradiation. Cataract incidence found in our patients is comparable to results of other centres using a fractionated regimen for total-body irradiation. The hyperfractionated regimen used in our hospital does obviously not result in a even lower cataract incidence. In contrast to acute and late toxicity in other organ/organsystems, hyperfractionation of total-body irradiation does not further reduce toxicity for the eye-lens. Dose rate may have more influence on cataract incidence

  7. Genetic localization and phenotypic expression of X-linked cataract (Xcat) in Mus musculus.

    Science.gov (United States)

    Favor, J; Pretsch, W

    1990-01-01

    Linkage data relative to the markers tabby and glucose-6-phosphate dehydrogenase are presented to locate X-linked cataract (Xcat) in the distal portion of the mouse X-chromosome between jimpy and hypophosphatemia. The human X-linked cataract-dental syndrome, Nance-Horan Syndrome, also maps closely to human hypophosphatemia and would suggest homology between mouse Xcat and human Nance-Horan Syndrome genes. In hemizygous males and homozygous females penetrance is complete with only slight variation in the degree of expression. Phenotypic expression in Xcat heterozygous females ranges from totally clear to totally opaque lenses. The phenotypic expression between the two lenses of a heterozygous individual could also vary between totally clear and totally opaque lenses. However, a correlation in the degree of expression between the eyes of an individual was observed. A variegated pattern of lens opacity was evident in female heterozygotes. Based on these observations, the site of gene action for the Xcat locus is suggested to be endogenous to the lens cells and the precursor cell population of the lens is concluded to be small. The identification of an X-linked cataract locus is an important contribution to the estimate of the number of mutable loci resulting in cataract, an estimate required so that dominant cataract mutagenesis results may be expressed on a per locus basis. The Xcat mutation may be a useful marker for a distal region of the mouse X-chromosome which is relatively sparsely marked and the X-linked cataract mutation may be employed in gene expression and lens development studies.

  8. Gyrate atrophy of choroid and retina with myopia, cataract and systemic proximal myopathy: A rare case report from rural India

    Directory of Open Access Journals (Sweden)

    Surekha Bangal

    2012-12-01

    Full Text Available AbstractGyrate atrophy is a rare metabolic disease with autosomal recessive inheritance pattern characterised by hyperornithinemia and typical ocular findings. This report presents a 17-year-old intellectually challenged girl consulting for a progressive fall of visual acuity with night blindness. Fundus examination showed patches of chorioretinal atrophy with typical scalloped borders and peri vascular pigmentation in the equatorial region. Fundus fluroscein angiography revealed characteristic staining pattern. Other ocular associations included myopia and posterior sub capsular cataract. Progressive systemic proximal myopathy was one of the associated features. Dietary supplementation of vitamin B6 was advised.

  9. Unilateral Congenital Cataract: Clinical Profile and Presentation.

    Science.gov (United States)

    Khokhar, Sudarshan; Jose, Cijin P; Sihota, Ramanjit; Midha, Neha

    2018-03-01

    To study the clinical profile and presentation of children with unilateral cataract. In this hospital-based, observational, cross-sectional study, patients 15 years of age or younger who presented with unilateral cataract were recruited. Cases of cataract secondary to causes such as trauma or uveitis were excluded. Age at detection and presentation, distance from the treatment center, presenting complaints, cataract morphology, and biometry were noted for each case. A total of 76 patients were recruited. Most patients presented with complaints of leukocoria. Persistent fetal vasculature accounted for 27.6% of cases and was the most common identifiable cause of cataract in this study. Subsequently, patients were divided into two groups: no persistent fetal vasculature (control) and persistent fetal vasculature. A male predominance was noted in both groups. The mean age at detection was 27.58 ± 37.02 and 6.17 ± 8.42 months and the mean age at presentation was 55.613 ± 45.21 and 14.83 ± 17.75 months in the control and persistent fetal vasculature groups, respectively. In the persistent fetal vasculature group, a significant difference was noted in the axial length, keratometry, and corneal diameter between the affected and normal eyes (P = .027, .00176, and .0114, respectively). In the control group, this difference was observed only in keratometry readings (P = .0464). The mean distance traveled by patients to reach the treatment center was 211 km. Persistent fetal vasculature is an important and less identified cause of unilateral cataract. A significant delay is noted in the detection and presentation of unilateral cataract. [J Pediatr Ophthalmol Strabismus. 2018;55(2):107-112.]. Copyright 2017, SLACK Incorporated.

  10. The carbon footprint of cataract surgery.

    Science.gov (United States)

    Morris, D S; Wright, T; Somner, J E A; Connor, A

    2013-04-01

    Climate change is predicted to be one of the largest global health threats of the 21st century. Health care itself is a large contributor to carbon emissions. Determining the carbon footprint of specific health care activities such as cataract surgery allows the assessment of associated emissions and identifies opportunities for reduction. To assess the carbon footprint of a cataract pathway in a British teaching hospital. This was a component analysis study for one patient having first eye cataract surgery in the University Hospital of Wales, Cardiff. Activity data was collected from three sectors, building and energy use, travel and procurement. Published emissions factors were applied to this data to provide figures in carbon dioxide equivalents (CO2eq). The carbon footprint for one cataract operation was 181.8 kg CO2eq. On the basis that 2230 patients were treated for cataracts during 2011 in Cardiff, this has an associated carbon footprint of 405.4 tonnes CO2eq. Building and energy use was estimated to account for 36.1% of overall emissions, travel 10.1% and procurement 53.8%, with medical equipment accounting for the most emissions at 32.6%. This is the first published carbon footprint of cataract surgery and acts as a benchmark for other studies as well as identifying areas for emissions reduction. Within the procurement sector, dialogue with industry is important to reduce the overall carbon footprint. Sustainability should be considered when cataract pathways are designed as there is potential for reduction in all sectors with the possible side effects of saving costs and improving patient care.

  11. Genetic Counselors' Experiences Regarding Communication of Reproductive Risks with Autosomal Recessive Conditions found on Cancer Panels.

    Science.gov (United States)

    Mets, Sarah; Tryon, Rebecca; Veach, Patricia McCarthy; Zierhut, Heather A

    2016-04-01

    The development of hereditary cancer genetic testing panels has altered genetic counseling practice. Mutations within certain genes on cancer panels pose not only a cancer risk, but also a reproductive risk for autosomal recessive conditions such as Fanconi anemia, constitutional mismatch repair deficiency syndrome, and ataxia telangiectasia. This study aimed to determine if genetic counselors discuss reproductive risks for autosomal recessive conditions associated with genes included on cancer panels, and if so, under what circumstances these risks are discussed. An on-line survey was emailed through the NSGC list-serv. The survey assessed 189 cancer genetic counselors' experiences discussing reproductive risks with patients at risk to carry a mutation or variant of uncertain significance (VUS) in a gene associated with both an autosomal dominant cancer risk and an autosomal recessive syndrome. Over half (n = 82, 55 %) reported having discussed reproductive risks; the remainder (n = 66, 45 %) had not. Genetic counselors who reported discussing reproductive risks primarily did so when patients had a positive result and were of reproductive age. Reasons for not discussing these risks included when a patient had completed childbearing or when a VUS was identified. Most counselors discussed reproductive risk after obtaining results and not during the informed consent process. There is inconsistency as to if and when the discussion of reproductive risks is taking place. The wide variation in responses suggests a need to develop professional guidelines for when and how discussions of reproductive risk for autosomal recessive conditions identified through cancer panels should occur with patients.

  12. Evaluation of the Community Cataract Surgical Services of a ...

    African Journals Online (AJOL)

    Evaluation of the Community Cataract Surgical Services of a University Teaching Hospital Using Cataract Surgical Coverage in Nigeria. ... Ethiopian Journal of Health Sciences. Journal Home · ABOUT THIS JOURNAL · Advanced Search ...

  13. Trainee ophthalmologists' opinions on ways to improve cataract ...

    African Journals Online (AJOL)

    2010-02-08

    Feb 8, 2010 ... D'autres incluent local production de la cataracte consommables 22 (81.5%), franchise importation d'ophtalmique ... potential decision makers and implementers of eye ... in rural areas; social welfare package making cataract.

  14. Uptake of cataract surgery in Sava Region, Madagascar: role of cataract case finders in acceptance of cataract surgery.

    Science.gov (United States)

    Razafinimpanana, Narivony; Nkumbe, Henry; Courtright, Paul; Lewallen, Susan

    2012-04-01

    The number of people coming for cataract surgery in Madagascar remains low and most ophthalmologists could do many more surgeries than currently done. Knowing why people identified with cataract do not accept surgery will help to design programs that use existing resources more effectively. The study was carried out in Sava Region of Madagascar. People with blinding (acceptance were proximity to hospital (people from Sambava district were twice as likely to present as people from more distant districts) and perceived price of transport and food (being higher for people not accepting). The actual price of surgery was not the main barrier to acceptance of surgery; instead it appears that distance to the hospital and the willingness to pay are important predictors. Strategies to improve uptake need to be revised in order to ensure that people have access to and use cataract surgical services.

  15. Autosomal recessive Noonan syndrome associated with biallelic LZTR1 variants.

    Science.gov (United States)

    Johnston, Jennifer J; van der Smagt, Jasper J; Rosenfeld, Jill A; Pagnamenta, Alistair T; Alswaid, Abdulrahman; Baker, Eva H; Blair, Edward; Borck, Guntram; Brinkmann, Julia; Craigen, William; Dung, Vu Chi; Emrick, Lisa; Everman, David B; van Gassen, Koen L; Gulsuner, Suleyman; Harr, Margaret H; Jain, Mahim; Kuechler, Alma; Leppig, Kathleen A; McDonald-McGinn, Donna M; Can, Ngoc Thi Bich; Peleg, Amir; Roeder, Elizabeth R; Rogers, R Curtis; Sagi-Dain, Lena; Sapp, Julie C; Schäffer, Alejandro A; Schanze, Denny; Stewart, Helen; Taylor, Jenny C; Verbeek, Nienke E; Walkiewicz, Magdalena A; Zackai, Elaine H; Zweier, Christiane; Zenker, Martin; Lee, Brendan; Biesecker, Leslie G

    2018-02-22

    PurposeTo characterize the molecular genetics of autosomal recessive Noonan syndrome.MethodsFamilies underwent phenotyping for features of Noonan syndrome in children and their parents. Two multiplex families underwent linkage analysis. Exome, genome, or multigene panel sequencing was used to identify variants. The molecular consequences of observed splice variants were evaluated by reverse-transcription polymerase chain reaction.ResultsTwelve families with a total of 23 affected children with features of Noonan syndrome were evaluated. The phenotypic range included mildly affected patients, but it was lethal in some, with cardiac disease and leukemia. All of the parents were unaffected. Linkage analysis using a recessive model supported a candidate region in chromosome 22q11, which includes LZTR1, previously shown to harbor mutations in patients with Noonan syndrome inherited in a dominant pattern. Sequencing analyses of 21 live-born patients and a stillbirth identified biallelic pathogenic variants in LZTR1, including putative loss-of-function, missense, and canonical and noncanonical splicing variants in the affected children, with heterozygous, clinically unaffected parents and heterozygous or normal genotypes in unaffected siblings.ConclusionThese clinical and genetic data confirm the existence of a form of Noonan syndrome that is inherited in an autosomal recessive pattern and identify biallelic mutations in LZTR1.Genet Med advance online publication, 22 February 2018; doi:10.1038/gim.2017.249.

  16. Relationship between cataract severity and socioeconomic status.

    Science.gov (United States)

    Wesolosky, Jason D; Rudnisky, Christopher J

    2013-12-01

    To determine the relationship between cataract severity and socioeconomic status (SES). Retrospective, observational case series. A total of 1350 eyes underwent phacoemulsification cataract extraction by a single surgeon using an Alcon Infiniti system. Cataract severity was measured using phaco time in seconds. SES was measured using area-level aggregate census data: median income, education, proportion of common-law couples, and employment rate. Preoperative best corrected visual acuity was obtained and converted to logarithm of the minimum angle of resolution values. For patients undergoing bilateral surgery, the generalized estimating equation was used to account for the correlation between eyes. Univariate analyses were performed using simple regression, and multivariate analyses were performed to account for variables with significant relationships (p < 0.05) on univariate testing. Sensitivity analyses were performed to assess the effect of including patient age in the controlled analyses. Multivariate analyses demonstrated that cataracts were more severe when the median income was lower (p = 0.001) and the proportion of common-law couples living in a patient's community (p = 0.012) and the unemployment rate (p = 0.002) were higher. These associations persisted even when controlling for patient age. Patients of lower SES have more severe cataracts. Copyright © 2013 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.

  17. Simultaneous versus Sequential Bilateral Cataract Surgery for Infants with Congenital Cataracts: Visual Outcomes and Economic Costs

    Science.gov (United States)

    Dave, Hreem; Phoenix, Vidya; Becker, Edmund R.; Lambert, Scott R.

    2015-01-01

    OBJECTIVES To compare the incidence of adverse events, visual outcomes and economic costs of sequential versus simultaneous bilateral cataract surgery for infants with congenital cataracts. METHODS We retrospectively reviewed the incidence of adverse events, visual outcomes and medical payments associated with simultaneous versus sequential bilateral cataract surgery for infants with congenital cataracts who underwent cataract surgery when 6 months of age or younger at our institution. RESULTS Records were available for 10 children who underwent sequential surgery at a mean age of 49 days for the first eye and 17 children who underwent simultaneous surgery at a mean age of 68 days (p=.25). We found a similar incidence of adverse events between the two treatment groups. Intraoperative or postoperative complications occurred in 14 eyes. The most common postoperative complication was glaucoma. No eyes developed endophthalmitis. The mean absolute interocular difference in logMAR visual acuities between the two treatment groups was 0.47±0.76 for the sequential group and 0.44±0.40 for the simultaneous group (p=.92). Hospital, drugs, supplies and professional payments were on average 21.9% lower per patient in the simultaneous group. CONCLUSIONS Simultaneous bilateral cataract surgery for infants with congenital cataracts was associated with a 21.9% reduction in medical payments and no discernible difference in the incidence of adverse events or visual outcome. PMID:20697007

  18. Acid phosphatase and lipid peroxidation in human cataractous lens epithelium

    Directory of Open Access Journals (Sweden)

    Vasavada Abhay

    1993-01-01

    Full Text Available The anterior lens epithelial cells undergo a variety of degenerative and proliferative changes during cataract formation. Acid phosphatase is primarily responsible for tissue regeneration and tissue repair. The lipid hydroperoxides that are obtained by lipid peroxidation of polysaturated or unsaturated fatty acids bring about deterioration of biological membranes at cellular and tissue levels. Acid phosphatase and lipid peroxidation activities were studied on the lens epithelial cells of nuclear cataract, posterior subcapsular cataract, mature cataract, and mixed cataract. Of these, mature cataractous lens epithelium showed maximum activity for acid phosphatase (516.83 moles of p-nitrophenol released/g lens epithelium and maximum levels of lipid peroxidation (86.29 O.D./min/g lens epithelium. In contrast, mixed cataractous lens epithelium showed minimum activity of acid phosphatase (222.61 moles of p-nitrophenol released/g lens epithelium and minimum levels of lipid peroxidation (54.23 O.D./min/g lens epithelium. From our study, we correlated the maximum activity of acid phosphatase in mature cataractous lens epithelium with the increased areas of superimposed cells associated with the formation of mature cataract. Likewise, the maximum levels of lipid peroxidation in mature cataractous lens epithelium was correlated with increased permeability of the plasma membrane. Conversely, the minimum levels of lipid peroxidation in mixed cataractous lens epithelium makes us presume that factors other than lipid peroxidation may also account for the formation of mixed type of cataract.

  19. Monitoring Cataract Surgical Outcome in a Public Hospital in Orlu ...

    African Journals Online (AJOL)

    Objective: To determine the proportion and causes of poor visual outcome of cataract operations done in a public hospital in southeast Nigeria and propose actions to improve the cataract surgical outcome. Method: A prospective observational analysis of the initial hundred cases of cataract operations done in Imo State ...

  20. Cataract Surgical Outreach in a Tertiary Hospital in Nigeria: An ...

    African Journals Online (AJOL)

    Odarosa M Uhumwangho

    the University of Benin Teaching Hospital (UBTH), Benin City. ... There is a great need to improve access to eye care services in general and cataract surgical ... world.[1] In Nigeria, 42.9% of blindness is caused by cataract. [2] A large number of the cataract blind have not had surgery ..... Change the definition of blindness.

  1. Deprivation amblyopia and congenital hereditary cataract.

    Science.gov (United States)

    Mansouri, Behzad; Stacy, Rebecca C; Kruger, Joshua; Cestari, Dean M

    2013-01-01

    Amblyopia is a neurodevelopmental disorder of vision associated with decreased visual acuity, poor or absent stereopsis, and suppression of information from one eye.(1,2) Amblyopia may be caused by strabismus (strabismic amblyopia), refractive error (anisometropic amblyopia), or deprivation from obstructed vision (deprivation amblyopia). 1 In the developed world, amblyopia is the most common cause of childhood visual impairment, 3 which reduces quality of life 4 and also almost doubles the lifetime risk of legal blindness.(5, 6) Successful treatment of amblyopia greatly depends on early detection and treatment of predisposing disorders such as congenital cataract, which is the most common cause of deprivational amblyopia. Understanding the genetic causes of congenital cataract leads to more effective screening tests, early detection and treatment of infants and children who are at high risk for hereditary congenital cataract.

  2. Cataracts induced by microwave and ionizing radiation

    International Nuclear Information System (INIS)

    Lipman, R.M.; Tripathi, B.J.; Tripathi, R.C.

    1988-01-01

    Microwaves most commonly cause anterior and/or posterior subcapsular lenticular opacities in experimental animals and, as shown in epidemiologic studies and case reports, in human subjects. The formation of cataracts seems to be related directly to the power of the microwave and the duration of exposure. The mechanism of cataractogenesis includes deformation of heat-labile enzymes, such as glutathione peroxide, that ordinarily protect lens cell proteins and membrane lipids from oxidative damage. Oxidation of protein sulfhydryl groups and the formation of high-molecular-weight aggregates cause local variations in the orderly structure of the lens cells. An alternative mechanism is thermoelastic expansion through which pressure waves in the aqueous humor cause direct physical damage to the lens cells. Cataracts induced by ionizing radiation (e.g., X-rays and gamma rays) usually are observed in the posterior region of the lens, often in the form of a posterior subcapsular cataract. Increasing the dose of ionizing radiation causes increasing opacification of the lens, which appears after a decreasing latency period. Like cataract formation by microwaves, cataractogenesis induced by ionizing radiation is associated with damage to the lens cell membrane. Another possible mechanism is damage to lens cell DNA, with decreases in the production of protective enzymes and in sulfur-sulfur bond formation, and with altered protein concentrations. Until further definitive conclusions about the mechanisms of microwaves and ionizing radiation induced cataracts are reached, and alternative protective measures are found, one can only recommend mechanical shielding from these radiations to minimize the possibility of development of radiation-induced cataracts. 74 references

  3. Inadvertent filtering bleb following sutureless cataract surgery

    Directory of Open Access Journals (Sweden)

    Jain Sunil

    2005-01-01

    Full Text Available The case history of a sixty-two-year-old lady, who presented with a bleb in the upper part of her left eye following cataract surgery was studied. The patient had no prior history of any glaucoma surgery. Gonioscopy revealed fishmouthing of the internal aspect of the scleral tunnel incision. The diagnosis of post-cataract filtering bleb was made which was managed by resuturing the wound. This case highlights the use of gonioscopy to visualise and evaluate the internal wound and discusses intraoperative recognition of internal leak and its management with horizontal sutures.

  4. Cataract surgical rate in Yemen: 2012

    Directory of Open Access Journals (Sweden)

    Saleh A. Al-Akily

    2017-01-01

    Conclusion: CSR has increased in Yemen in the recent years but is still below the target suggested by WHO. There is need to increase the cataract surgical rate in Yemen mainly in rural areas. Inadequate number of eye surgeons, limited accessibility of cataract surgical services in rural areas and the affordability of surgery to large sections of society are major constraints that have to be addressed. The information from this study will help and enable Ministry of Health and other eye care providers to more equitably disperse trained ophthalmic personnel and eye units in Yemeni governorates.

  5. Cost-effectiveness analysis of cataract surgery with intraocular lens implantation: extracapsular cataract extraction versus phacoemulsification

    Directory of Open Access Journals (Sweden)

    Mohd R.A. Manaf

    2007-03-01

    Full Text Available A randomized single blinded clinical trial to compare the cost-effectiveness of cataract surgery between extracapsular cataract extraction (ECCE and phacoemulsification (PEA was conducted at Hospital Universiti Kebangsaan Malaysia (HUKM from March 2000 until August 2001. The cost of a cataract surgery incurred by hospital, patients and households were calculated preoperatively, one week, two months (for both techniques and six months (for ECCE only. Effectiveness of cataract surgery was assessed using Visual Function 14 (VF-14, quality of life measurement specifically for vision. The cost analysis results from each 50 subjects of ECCE and PEA group showed that average cost for one ECCE after six months post-operation is USD 458 (± USD 72 and for PEA is USD 528 (± USD 125. VF-14 score showed a significant increased after a week, two months and six months post-operation compared to the score before operation for both techniques (p<0.001. However, there was no significant difference between them (p = 0.225. This study indicated that ECCE is more cost effective compared to PEA with cost per one unit increment of VF-14 score of USD 14 compared to USD 20 for PEA. (Med J Indones 2007; 16:25-31 Keywords: cataract, cost-effectiveness, extracapsular cataract extraction, phacoemulsification, visual function 14

  6. Cataract-free interval and severity of cataract after total body irradiation and bone marrow transplantation: influence of treatment parameters

    International Nuclear Information System (INIS)

    Kempen-Harteveld, M. Loes van; Struikmans, Henk; Kal, Henk B.; Tweel, Ingeborg van der; Mourits, Maarten; Verdonck, Leo F.; Schipper, Jan; Battermann, Jan J.

    2000-01-01

    Purpose: To determine prospectively the cataract-free interval (latency time) after total body irradiation (TBI) and bone marrow transplantation (BMT) and to assess accurately the final severity of the cataract. Methods and Materials: Ninety-three of the patients who received TBI as a part of their conditioning regimen for BMT between 1982 and 1995 were followed with respect to cataract formation. Included were only patients who had a follow-up period of at least 23 months. TBI was applied in one fraction of 8 Gy or two fractions of 5 or 6 Gy. Cataract-free period was assessed and in 56 patients, who could be followed until stabilization of the cataract had occurred, final severity of the cataract was determined using a classification system. With respect to final severity, two groups were analyzed: subclinical low-grade cataract and high-grade cataract. Cataract-free period and final severity were determined with respect to type of transplantation, TBI dose, and posttransplant variables such as graft versus host disease (GVHD) and steroid treatment. Results: Cataract incidence of the analyzed patients was 89%. Median time to develop a cataract was 58 months for autologous transplanted patients. For allogeneic transplanted patients treated or not treated with steroids, median times were 33 and 46 months, respectively. Final severity was not significantly different for autologous or allogeneic patients. In allogeneic patients, however, final severity was significantly different for patients who had or had not been treated with steroids for GVHD: 93% versus 35% high-grade cataract, respectively. Final severity was also different for patients receiving 1 x 8 or 2 x 5 Gy TBI, from patients receiving 2 x 6 Gy as conditioning therapy: 33% versus 79% high-grade cataract, respectively. The group of patients receiving 2 x 6 Gy comprised, however, more patients with steroid treatment for GVHD. So the high percentage of high-grade cataract in the 2 x 6 Gy group might also

  7. Simulation-based certification for cataract surgery

    DEFF Research Database (Denmark)

    Thomsen, Ann Sofia Skou; Kiilgaard, Jens Folke; Kjaerbo, Hadi

    2015-01-01

    PURPOSE: To evaluate the EyeSi(™) simulator in regard to assessing competence in cataract surgery. The primary objective was to explore all simulator metrics to establish a proficiency-based test with solid evidence. The secondary objective was to evaluate whether the skill assessment was specific...

  8. Cataract surgery practices in the United States Veterans Health Administration.

    Science.gov (United States)

    Havnaer, Annika G; Greenberg, Paul B; Cockerham, Glenn C; Clark, Melissa A; Chomsky, Amy

    2017-04-01

    To describe current cataract surgery practices within the United States Veterans Health Administration (VHA). Veterans Health Administration hospitals in the U.S. Retrospective data analysis. An initial e-mail containing a link to an anonymous 32-question survey of cataract surgery practices was sent to participants in May 2016. Two reminder e-mails were sent to nonresponders 1 week and 2 weeks after the initial survey was sent; the remaining nonresponders were called twice over a 2-week period. The data were analyzed using descriptive statistics. The response rate was 75% (67/89). Cataract surgeons routinely ordered preoperative testing in 29 (45%) of 65 sections and preoperative consultations in 26 (39%) of 66 sections. In 22 (33%) of 66 sections, cataract surgeons administered intracameral antibiotics. In 61 (92%) of 66 sections, cataract surgeons used toric intraocular lenses (IOLs). In 20 (30%) of 66 sections, cataract surgeons used multifocal IOLs. Cataract surgeons in 6 (9%) of 66 sections performed femtosecond laser-assisted cataract surgery. In 6 (9%) of 66 sections, cataract surgeons performed immediate sequential bilateral cataract surgery. Forty-nine (74%) ophthalmology chiefs reported a high level of satisfaction with Veterans Affairs ophthalmology. The survey results indicate that in cataract surgery in the VHA, routine preoperative testing is commonly performed and emerging practices, such as femtosecond laser-assisted cataract surgery and immediate sequential bilateral cataract surgery, have limited roles. The results of this survey could benchmark future trends in U.S. cataract surgery practices, especially in teaching hospital settings. Copyright © 2017 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

  9. Cataract surgery in patients with ocular pseudoexpholiation.

    Science.gov (United States)

    Petrovic, Mirjana Janicijevic; Vulovic, Tatjana Sarenac; Vulovic, Dejan; Janicijevic, Katarina; Petrovic, Marko; Vujic, Dragan

    2013-01-01

    Retrospective 5-year study based on general and ophthalmic history records, and including 268 eyes (174 patients), aged 50 years and over. Ophthalmological examination involved visual acuity, measuring of intraocular pressure, slit lamp examination and indirect ophthalmoscopy. Type of surgical treatment was tailored for each patient (extra capsular cataract extraction, phaco-emulsiphication). Preoperative slit lamp examination showed phacodonesis in 17.91% (47), iridodonesis in 2.98% (8), pigment dispersion in 6.72% (18), lens subluxation in 4.85% (13) on the total. Extra capsular cataract extraction was performed in 36.94% (99) and phaco-emulsiphication in the others. Analysis of intra operative complications showed: posterior capsular rupture 17.91% (48), zonular dialysis or break 5.97% (16), lens subluxation 1.86% (5), intraocular bleeding 2.98% (8), vitreous loss 13.80% (37). Postoperative complications include: anterior chamber reaction 45.90% (123), intraocular lens tilt 15.67% (42), endothelial decompensation 21.64% (58), subluxation/luxation IOL 3.73% (10), secondary cataract 21.46% (58), pigment dispersion 37.68% (101), increased IOP 13.80% (37), residual lens matter 13.80% (37), hyphema 3.73% (10), posterior synechiae 6.72% (18), iris prolapsus 2.73% (8). Cataract surgery in PES will frequently encounter small pupils, shallow anterior chambers, posterior adhesions, weak zonular support, partial subluxation or complete dislocation of lens. Authors presented the best possible approach on PES and surgical methods for patients with cataract with special accent of possible surgical complications.

  10. Cx43, ZO-1, alpha-catenin and beta-catenin in cataractous lens

    Indian Academy of Sciences (India)

    Specimens of the anterior lens capsule with an attached monolayer of lens epithelial cells (LECs) were obtained from patients (=52) undergoing cataract surgery. Specimens were divided into three groups based on the type of cataract: nuclear cataract, cortical cataract and posterior subcapsular cataract (PSC).

  11. [Incremental cost effectiveness of multifocal cataract surgery].

    Science.gov (United States)

    Pagel, N; Dick, H B; Krummenauer, F

    2007-02-01

    Supplementation of cataract patients with multifocal intraocular lenses involves an additional financial investment when compared to the corresponding monofocal supplementation, which usually is not funded by German health care insurers. In the context of recent resource allocation discussions, however, the cost effectiveness of multifocal cataract surgery could become an important rationale. Therefore an evidence-based estimation of its cost effectiveness was carried out. Three independent meta-analyses were implemented to estimate the gain in uncorrected near visual acuity and best corrected visual acuity (vision lines) as well as the predictability (fraction of patients without need for reading aids) of multifocal supplementation. Study reports published between 1995 and 2004 (English or German language) were screened for appropriate key words. Meta effects in visual gain and predictability were estimated by means and standard deviations of the reported effect measures. Cost data were estimated by German DRG rates and individual lens costs; the cost effectiveness of multifocal cataract surgery was then computed in terms of its marginal cost effectiveness ratio (MCER) for each clinical benefit endpoint; the incremental costs of multifocal versus monofocal cataract surgery were further estimated by means of their respective incremental cost effectiveness ratio (ICER). An independent meta-analysis estimated the complication profiles to be expected after monofocal and multifocal cataract surgery in order to evaluate expectable complication-associated additional costs of both procedures; the marginal and incremental cost effectiveness estimates were adjusted accordingly. A sensitivity analysis comprised cost variations of +/- 10 % and utility variations alongside the meta effect estimate's 95 % confidence intervals. Total direct costs from the health care insurer's perspective were estimated 3363 euro, associated with a visual meta benefit in best corrected visual

  12. Influence factors of visual quality after phacoemulsification for cataract

    Directory of Open Access Journals (Sweden)

    Zhen-Lin Lin

    2017-12-01

    Full Text Available Cataract refers to the degenerative changes in lens quality caused by various causes of reduced transparency or color change. Surgical treatment is the main treatment modality at present. Among them, phacoemulsification has become the main surgical treatment for cataract because of its advantages such as short operation time, small incision and quicker healing. Today, cataract surgery has gradually shift to refractive surgery, and is no longer simply as cataract surgery. But after cataract phacoemulsification, the symptoms and visual quality are different. The main causes include refractive error, postoperative dry eyes and postoperative corneal astigmatism. This article reviews the factors that influence the visual quality of cataract phacoemulsification and its future trends.

  13. Risk of Retinal Detachment After Pediatric Cataract Surgery

    DEFF Research Database (Denmark)

    Haargaard, Birgitte; Andersen, Elisabeth W; Oudin, Anna

    2014-01-01

    PURPOSE: To determine the long-term risk of retinal detachment following pediatric cataract surgery and to identify risk factors for retinal detachment. METHODS: We included all children (aged 0 to 17 years) who during the time period of 1977 to 2005 underwent pediatric cataract surgery in Denmark...... was based on medical chart review. RESULTS: Among 1043 eyes of 656 children undergoing surgery for pediatric cataract, 25 eyes (23 children) developed retinal detachment at a median time of 9.1 years after surgery. The overall 20-year risk of retinal detachment was 7% (95% confidence interval [CI]: 3...... (16% [95% CI: 6%-24%]). CONCLUSIONS: The estimated overall risk of retinal detachment 20 years after pediatric cataract surgery was 7%, but only 3% for isolated cataract. Particularly high risks of retinal detachment after cataract surgery were associated with mental retardation and having other...

  14. The Effect of Cataract Surgery on Circadian Photoentrainment

    DEFF Research Database (Denmark)

    Brøndsted, Adam Elias; Sander, Birgit; Haargaard, Birgitte

    2015-01-01

    of cataract surgery on circadian photoentrainment and to determine any difference between blue-blocking and neutral intraocular lenses (IOLs). DESIGN: The study was a single-center, investigator-driven, double-masked, block-randomized clinical trial. PARTICIPANTS: One eye in 76 patients with bilateral age......PURPOSE: Cataract decreases blue light transmission. Because of the selective blue light sensitivity of the retinal ganglion cells governing circadian photoentrainment, cataract may interfere with normal sleep-wake regulation and cause sleep disturbances. The purpose was to investigate the effect......-related cataract eligible for cataract surgery was included. METHODS: Intervention was cataract surgery by phacoemulsification. Patients were randomized to receive a blue-blocking or neutral IOL. MAIN OUTCOME MEASURES: Primary outcome was activation of intrinsic photosensitive ganglion cells using post...

  15. Surgical simulators in cataract surgery training.

    Science.gov (United States)

    Sikder, Shameema; Tuwairqi, Khaled; Al-Kahtani, Eman; Myers, William G; Banerjee, Pat

    2014-02-01

    Virtual simulators have been widely implemented in medical and surgical training, including ophthalmology. The increasing number of published articles in this field mandates a review of the available results to assess current technology and explore future opportunities. A PubMed search was conducted and a total of 10 articles were reviewed. Virtual simulators have shown construct validity in many modules, successfully differentiating user experience levels during simulated phacoemulsification surgery. Simulators have also shown improvements in wet-lab performance. The implementation of simulators in the residency training has been associated with a decrease in cataract surgery complication rates. Virtual reality simulators are an effective tool in measuring performance and differentiating trainee skill level. Additionally, they may be useful in improving surgical skill and patient outcomes in cataract surgery. Future opportunities rely on taking advantage of technical improvements in simulators for education and research.

  16. Domination versus disjunctive domination in graphs | Henning ...

    African Journals Online (AJOL)

    Domination versus disjunctive domination in graphs. Michael A Henning, Sinclair A Marcon. Abstract. A dominating set in a graph G is a set S of vertices of G such that every vertex not in S is adjacent to a vertex of S. The domination number of G is the minimum cardinality of a dominating set of G. For a positive integer b, ...

  17. Eliminating the barriers to uptake of cataract surgery in a resource ...

    African Journals Online (AJOL)

    2014-11-03

    Nov 3, 2014 ... Direct surgical fee reduction alone caused only a modest increase in ... for reversing cataract blindness. ... of surgical fee reduction on cataract surgical uptake in a .... deploy the necessary resources and logistics for cataract.

  18. Cataract and its surgery in Fiji.

    Science.gov (United States)

    Brian, Garry; Ramke, Jacqueline; Szetu, John; Qoqonokana, Mundi Qalo

    2011-07-01

    To characterize cataract and its surgery among adults aged ≥40 years in Fiji. Population-based cross-sectional survey using multistage cluster random sampling. 1381 (= 73.0% participation); eight provinces on Viti Levu. Interview-based questionnaire; visual acuity measured; autorefraction; dilated ocular examination. Prevalence; predictors; surgical outcomes. Being Indian (P = 0.001), elderly (P Fiji population aged ≥40 years, prevalence of cataract-induced low vision and blindness were each 1.7% (95% confidence interval [CI] 1.0-2.4%). At least one eye of 4.6% and both of 1.8% participants had surgery (86.4% extracapsular). Gender (P = 0.213), age (P = 0.472) and rural/urban domicile (P = 0.895) were not predictors of surgery among those who required it in at least one eye. After intraocular lens surgery: 50.7% had pupillary posterior capsular opacification; mean spherical equivalent was -1.37 ± 1.95D (range, -6.38 to +2.25D); mean cylindrical error was 2.31 ± 1.75D (range, 0.0 to 8.75D); ≥N8 for 39.5%; ≥6/18 for 56.6%; Fiji population aged ≥40 years, Cataract Surgical Coverage (Person) was 47.5% (95%CI 29.2-65.8%) at Fiji cataract services and outcomes compare favourably with those of neighbouring Papua New Guinea and Timor Leste. © 2011 The Authors. Clinical and Experimental Ophthalmology © 2011 Royal Australian and New Zealand College of Ophthalmologists.

  19. Queen Victoria, her physicians, and her cataracts.

    Science.gov (United States)

    Ravin, J G

    1994-01-01

    Decreasing vision due to cataracts became a significant problem for Queen Victoria toward the end of the 19th century. Her personal physician, Sir James Reid, obtained consultations with two eminent British ophthalmologists, George Lawson and Edward Nettleship. The Queen was not satisfied, and requested an opinion from the German professor Hermann Pagenstecher. All the doctors agreed on the diagnosis, but the Queen never underwent surgery.

  20. Cataract influence on iris recognition performance

    Science.gov (United States)

    Trokielewicz, Mateusz; Czajka, Adam; Maciejewicz, Piotr

    2014-11-01

    This paper presents the experimental study revealing weaker performance of the automatic iris recognition methods for cataract-affected eyes when compared to healthy eyes. There is little research on the topic, mostly incorporating scarce databases that are often deficient in images representing more than one illness. We built our own database, acquiring 1288 eye images of 37 patients of the Medical University of Warsaw. Those images represent several common ocular diseases, such as cataract, along with less ordinary conditions, such as iris pattern alterations derived from illness or eye trauma. Images were captured in near-infrared light (used in biometrics) and for selected cases also in visible light (used in ophthalmological diagnosis). Since cataract is a disorder that is most populated by samples in the database, in this paper we focus solely on this illness. To assess the extent of the performance deterioration we use three iris recognition methodologies (commercial and academic solutions) to calculate genuine match scores for healthy eyes and those influenced by cataract. Results show a significant degradation in iris recognition reliability manifesting by worsening the genuine scores in all three matchers used in this study (12% of genuine score increase for an academic matcher, up to 175% of genuine score increase obtained for an example commercial matcher). This increase in genuine scores affected the final false non-match rate in two matchers. To our best knowledge this is the only study of such kind that employs more than one iris matcher, and analyzes the iris image segmentation as a potential source of decreased reliability