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Sample records for autosomal dominant cataract

  1. A missense mutation S228P in the CRYBB1 gene causes autosomal dominant congenital cataract

    Institute of Scientific and Technical Information of China (English)

    WANG Jun; MA Xu; GU Feng; LIU Ning-pu; HAO Xiao-lin; WANG Kai-jie; WANG Ning-li; ZHU Si-quan

    2007-01-01

    Background Congenital cataract is a highly heterogeneous disorder at both the genetic and phenotypic levels. This study was conducted to identify disease locus for autosomal dominant congenital cataracts in a four generation Chinese family.Methods Family history and clinical data were recorded. All the members were genotyped with microsatellite markers which are close to the known genetic loci for autosomal congenital cataracts. Two-point Lod scores were obtained using the MLINK of the LINKAGE program package (ver 5.1). Candidate genes were amplified by polymerase chain reaction (PCR) and direct cycle sequencing.Results The maximum Lod score of Zmax=2.11 was obtained with three microsatellite markers D22S258, D22S315,and D22S1163 at recombination fraction θ= 0. Haplotype analysis showed that the disease gene was localized to a 18.5 Mbp region on chromosome 22 flanked by markers D22S1174 and D22S270, spanning the β-crystallin gene cluster. A c.752T-->C mutation in exon 6 of CRYBB1 gene, which resulted in a heterozygous S228P mutation in predicted protein,was found to cosegregate with cataract in the family.Conclusions This study identified a novel mutation in CRYBB1 gene in a Chinese family with autosomal dominant congenital cataract. These results provide strong evidence that CRYBB1 is a pathogenic gene for congenital cataract.

  2. A Novel CRYBB2 Stopgain Mutation Causing Congenital Autosomal Dominant Cataract in a Chinese Family

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    Zhou, Yu; Zhai, Yaru; Huang, Lulin; Gong, Bo; Li, Jie; Hao, Fang; Wu, Zhengzheng

    2016-01-01

    Congenital cataract is the most common cause of the visual disability and blindness in childhood. This study aimed to identify gene mutations responsible for autosomal dominant congenital cataract (ADCC) in a Chinese family using next-generation sequencing technology. This family included eight unaffected and five affected individuals. After complete ophthalmic examinations, the blood samples of the proband and two available family members were collected. Then the whole exome sequencing was performed on the proband and Sanger sequencing was applied to validate the causal mutation in the two family members and control samples. After the whole exome sequencing data were filtered through a series of existing variation databases, a heterozygous mutation c.499Tcongenital cataract population and illustrated the important role of CRYBB2 in the genetics research of congenital cataract. PMID:28025620

  3. A novel HSF4 mutation in a Chinese family with autosomal dominant congenital cataract.

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    Liu, Ling; Zhang, Qing; Zhou, Lu-xin; Tang, Zhao-hui

    2015-04-01

    This study was aimed to identify the mutation of the whole coding region of shock transcription factor 4 (HSF4) gene in a Chinese family with autosomal dominant congenital cataract (ADCC). All exons of HSF4 were amplified by PCR. Sequence analysis of PCR products was performed. Restriction fragment length polymorphism (RFLP) analysis was conducted to confirm the pathogenic mutation. The results showed that a C to T substitution occurred at nucleotide 331 in patients of this family, leading to the replacement of the amino acid arginine-111 with cysteine in exon 3. RFLP analysis showed that the amino acid change was co-segregated with all affected individuals. It was concluded that the new mutation of c.331C>T in HSF4 DNA may be responsible for the autosomal dominant congenital cataract in this family.

  4. Wolfram gene (WFS1) mutation causes autosomal dominant congenital nuclear cataract in humans.

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    Berry, Vanita; Gregory-Evans, Cheryl; Emmett, Warren; Waseem, Naushin; Raby, Jacob; Prescott, DeQuincy; Moore, Anthony T; Bhattacharya, Shomi S

    2013-12-01

    Congenital cataracts are an important cause of bilateral visual impairment in infants. Through genome-wide linkage analysis in a four-generation family of Irish descent, the disease-associated gene causing autosomal-dominant congenital nuclear cataract was mapped to chromosome 4p16.1. The maximum logarithm of odds (LOD) score was 2.62 at a recombination fraction θ=0, obtained for marker D4S432 physically close to the Wolfram gene (WFS1). By sequencing the coding regions and intron-exon boundaries of WFS1, we identified a DNA substitution (c.1385A-to-G) in exon 8, causing a missense mutation at codon 462 (E462G) of the Wolframin protein. This is the first report of a mutation in this gene causing an isolated nuclear congenital cataract. These findings suggest that the membrane trafficking protein Wolframin may be important for supporting the developing lens.

  5. Autosomal dominant coralliform cataract related to a missense mutation of the γD-crystallin gene

    Institute of Scientific and Technical Information of China (English)

    徐伟珍; 郑树; 徐世杰; 黄薇; 姚克; 张苏展

    2004-01-01

    Background Congenital cataract is a sight-threatening disease that affects about 1-6 cases per 10?@000 live births and causes 10%-30% of all blindness in children. About 25% of all cases are due to genetic defects. We identified autosomal dominant congenital coralliform cataracts-related genetic defect in a four-generation Chinese family.Methods Complete ophthalmological examinations were performed prior to lens extraction. Lens samples were then studied by electron microscopy. Genomic DNA from family members were examined using whole-genomic linkage analysis, with two-point logarithm of odds (LOD) scores calculated using the Linkage program package (version 5.1). Mutation analysis of candidate genes was performed by direct sequencing. Finally, a three-dimensional protein model was predicted using Swiss-Model (version 2.0).Results Eleven of the 23 examined individuals had congenital cataracts. Ultrastructure studies revealed crystal deposits in the lens, and granules extensively dispersed in transformed lens fiber cells. The maximum two-point LOD score, 3.5 at θ=0.1, was obtained for the marker D2S325. Mutation analysis of the γ-crystallin (CRYG) gene cluster identified a mutation (P23T) in exon 2 of γD-crystallin (CRYGD). Protein structure modeling demonstrated that the P23T mutation caused a subtle change on the surface of the γD protein.Conclusions The results suggest that the coralliform cataract phenotype is due to a mutated CRYGD gene, and that this sequence change is identical to one reported by Santhiya to be related to another distinct clinical condition, lamellar cataract. This study provides evidence that this same genetic defect may be associated with a different phenotype. This is the first report identifying the genetic defect associated with an autosomal dominant congenital coralliform cataract.

  6. A Novel CRYBB2 Stopgain Mutation Causing Congenital Autosomal Dominant Cataract in a Chinese Family

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    Yu Zhou

    2016-01-01

    Full Text Available Congenital cataract is the most common cause of the visual disability and blindness in childhood. This study aimed to identify gene mutations responsible for autosomal dominant congenital cataract (ADCC in a Chinese family using next-generation sequencing technology. This family included eight unaffected and five affected individuals. After complete ophthalmic examinations, the blood samples of the proband and two available family members were collected. Then the whole exome sequencing was performed on the proband and Sanger sequencing was applied to validate the causal mutation in the two family members and control samples. After the whole exome sequencing data were filtered through a series of existing variation databases, a heterozygous mutation c.499Tcataract population and illustrated the important role of CRYBB2 in the genetics research of congenital cataract.

  7. 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.

  8. Autosomal-dominant nystagmus, foveal hypoplasia and presenile cataract associated with a novel PAX6 mutation.

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    Thomas, Shery; Thomas, Mervyn G; Andrews, Caroline; Chan, Wai-Man; Proudlock, Frank A; McLean, Rebecca J; Pradeep, Archana; Engle, Elizabeth C; Gottlob, Irene

    2014-03-01

    Autosomal-dominant idiopathic infantile nystagmus has been linked to 6p12 (OMIM 164100), 7p11.2 (OMIM 608345) and 13q31-q33 (OMIM 193003). PAX6 (11p13, OMIM 607108) mutations can also cause autosomal-dominant nystagmus, typically in association with aniridia or iris hypoplasia. We studied a large multigenerational white British family with autosomal-dominant nystagmus, normal irides and presenile cataracts. An SNP-based genome-wide analysis revealed a linkage to a 13.4-MB region on chromosome 11p13 with a maximum lod score of 2.93. A mutation analysis of the entire coding region and splice junctions of the PAX6 gene revealed a novel heterozygous missense mutation (c.227C>G) that segregated with the phenotype and is predicted to result in the amino-acid substitution of proline by arginine at codon 76 p.(P76R). The amino-acid variation p.(P76R) within the paired box domain is likely to destabilise the protein due to steric hindrance as a result of the introduction of a polar and larger amino acid. Eye movement recordings showed a significant intrafamilial variability of horizontal, vertical and torsional nystagmus. High-resolution in vivo imaging of the retina using optical coherence tomography (OCT) revealed features of foveal hypoplasia, including rudimentary foveal pit, incursion of inner retinal layers, short photoreceptor outer segments and optic nerve hypoplasia. Thus, this study presents a family that segregates a PAX6 mutation with nystagmus and foveal hypoplasia in the absence of iris abnormalities. Moreover, it is the first study showing detailed characteristics using eye movement recordings of autosomal-dominant nystagmus in a multigenerational family with a novel PAX6 mutation.

  9. Identification and functional analysis of GJA8 mutation in a Chinese family with autosomal dominant perinuclear cataracts.

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    Dongmei Su

    Full Text Available Congenital cataract is a clinically and genetically heterogeneous group of eye disorders that causes visual impairment and childhood blindness. The purpose of this study was to identify the genetic defect associated with autosomal dominant congenital perinuclear cataract in a Chinese family. A detailed family history and clinical data of the family were recorded, and candidate gene sequencing was performed to screen for mutation-causing disease in our study. Direct sequencing revealed a c.601G>A (p.E201K transversion in exon 2 of GJA8. This mutation co-segregated with all affected individuals in the family and was not found in unaffected family members or 100 unrelated controls. The function and mechanism of novel GJA8 point mutation E201K in Chinese patients were then investigated in this study. We found E201K aberrantly located in cytoplasm and prevented its location in the plasma membrane. Induction of E201K expression led to a decrease in cell growth and viability by MTT (3-(4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide assay. Our study provides important evidence that GJA8 is a disease-causing gene for congenital cataract and that mutation of GJA8 has a potential causative effect.

  10. 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......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......-type embryos resulted in development of a phenotype similar to the steif mutant. The p.Arg805Trp alteration in the mammalian UNC45B gene suggests that developmental cataract may be caused by a defect in non-muscle myosin assembly during maturation of the lens fiber cells.European Journal of Human Genetics...

  11. A novel 3-base pair deletion of the CRYAA gene identified in a large Chinese pedigree featuring autosomal dominant congenital perinuclear cataract.

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    Kong, X D; Liu, N; Shi, H R; Dong, J M; Zhao, Z H; Liu, J; Li-Ling, J; Yang, Y X

    2015-01-23

    Congenital cataract is caused by reduced transparency of the lens resulting from metabolic disorders during the fetal period. The disease shows great heterogeneity both clinically and genetically. We identified a 4-generation ethnic Han Chinese family affected by autosomal dominant congenital perinuclear cataract. The patients underwent full clinical and ophthalmologic examinations to rule out any concomitant disorders. Blood samples were collected and genomic DNA was extracted. Potential mutations in the candidate gene alpha A crystallin (CRYAA) were screened. Prenatal diagnosis was then provided for a fetus of the affected proband by chorionic villus sampling. In all patients, DNA sequencing of the CRYAA gene revealed a novel 3-bp deletion mutation in exon 3 (c.246_248delCGC), which led to deletion of codon 117 encoding arginine (p.117delR) in the peptide chain. The same mutation was not found among unaffected and healthy individuals. Bioinformatic analysis revealed that although the c.246_248delCGC is an 'in-frame' mutation, removal of arginine resulted in a significant change in the protein structure. The fetus did not possess this mutation and was confirmed to be healthy at 1-year follow-up. A novel disease-causing mutation, c.246_248delCGC (p.117delR), of the CRYAA gene has been identified in a Chinese family with autosomal-type perinuclear congenital cataracts. This is also the first report of prenatal diagnosis of this type of congenital cataract.

  12. Autosomal dominant lamellar ichthyosis.

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    Toribio, J; Fernández Redondo, V; Peteiro, C; Zulaica, A; Fabeiro, J M

    1986-08-01

    Five members of two generations of one family were affected with lamellar ichthyosis, suggesting autosomal dominant transmission. The clinical and histopathological characteristics of the cases described here are similar to those reported by Traupe et al. (1984) as autosomal dominant lamellar ichthyosis and thus confirm the existence of this new form of ichthyosis.

  13. Identification of a Novel Mutation in BRD4 that Causes Autosomal Dominant Syndromic Congenital Cataracts Associated with Other Neuro-Skeletal Anomalies

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    Jin, Hyun-Seok; Kim, Jeonhyun; Kwak, Woori; Jeong, Hyeonsoo; Lim, Gyu-Bin

    2017-01-01

    Congenital cataracts can occur as a non-syndromic isolated ocular disease or as a part of genetic syndromes accompanied by a multi-systemic disease. Approximately 50% of all congenital cataract cases have a heterogeneous genetic basis. Here, we describe three generations of a family with an autosomal dominant inheritance pattern and common complex phenotypes, including bilateral congenital cataracts, short stature, macrocephaly, and minor skeletal anomalies. We did not find any chromosomal aberrations or gene copy number abnormalities using conventional genetic tests; accordingly, we conducted whole-exome sequencing (WES) to identify disease-causing genetic alterations in this family. Based on family WES data, we identified a novel BRD4 missense mutation as a candidate causal variant and performed cell-based experiments by ablation of endogenous BRD4 expression in human lens epithelial cells. The protein expression levels of connexin 43, p62, LC3BII, and p53 differed significantly between control cells and cells in which endogenous BRD4 expression was inhibited. We inferred that a BRD4 missense mutation was the likely disease-causing mutation in this family. Our findings may improve the molecular diagnosis of congenital cataracts and support the use of WES to clarify the genetic basis of complex diseases. PMID:28076398

  14. Autosomal dominant osteopetrosis revisited

    DEFF Research Database (Denmark)

    Bollerslev, Jens; Henriksen, Kim; Nielsen, Morten Frost Munk

    2013-01-01

    Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation...

  15. Targeted Genes Sequencing Identified a Novel 15 bp Deletion on GJA8 in a Chinese Family with Autosomal Dominant Congenital Cataracts

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    Han-Yi Min; Peng-Peng Qiao; Asan; Zhi-Hui Yan; Hui-Feng Jiang; Ya-Ping Zhu; Hui-Qian Du

    2016-01-01

    Background:Congenital cataract (CC) is the leading cause of visual impairment or blindness in children worldwide.Because of highly genetic and clinical heterogeneity,a molecular diagnosis of the lens disease remains a challenge.Methods:In this study,we tested a three-generation Chinese family with autosomal dominant CCs by targeted sequencing of 45 CC genes on next generation sequencing and evaluated the pathogenicity of the detected mutation by protein structure,pedigree validation,and molecular dynamics (MD) simulation.Results:A novel 15 bp deletion on GJA8 (c.426_440delGCTGGAGGGGACCCT or p.143_147delLEGTL) was detected in the family.The deletion,concemed with an in-frame deletion of 5 amino acid residues in a highly evolutionarily conserved region within the cytoplasmic loop domain of the gap junction channel protein connexin 50 (Cx50),was in full cosegregation with the cataract phenotypes in the family but not found in 1100 control exomes.MD simulation revealed that the introduction of the deletion destabilized the Cx50 gap junction channel,indicating the deletion as a dominant-negative mutation.Conclusions:The above results support the pathogenic role of the 15 bp deletion on GJA8 in the Chinese family and demonstrate targeted genes sequencing as a resolution to molecular diagnosis of CCs.

  16. Relative genes of autosomal dominant congenital cataracts%常染色体显性遗传先天性白内障相关基因的研究进展

    Institute of Scientific and Technical Information of China (English)

    邱靖森; 张铭志

    2012-01-01

    先天性白内障是由于胚胎期晶状体代谢异常而导致的自身透明度下降的致盲性疾病,遗传因素与疾病的发生、发展有很大的联系.目前研究发现先天性白内障的发生至少与22个基因的变异有关,其中以常染色体显性遗传为主,涉及的基因包括晶状体蛋白基因(CRY)、缝隙连接通道蛋白基因(GJA)、膜蛋白基因(MIP)、细胞骨架蛋白基因(BFSP)和转录调节因子基因等.本文对近几年来关于常染色体显性遗传先天性白内障致病基因方面的研究进行综述.%Congenital cataract is developed due to the metabolic disturbance of lens in embryo,which induces the degression of the transparency of lens.Genetic factors are associated with development of this disease.Autosomal dominant congenital cataract (ADCC) is the major type in reported congenital cataract.So far,twenty-two genes associated with ADCC have been found.These genes invole CRY,GJA,MIP,BFSP,transcription factor,and so on.This paper summarizes the genetic researches on ADCC in recent years.

  17. 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.

  18. 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.

  19. 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 X......-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....

  20. 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...

  1. Autosomal dominant rolandic epilepsy with speech dyspraxia.

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    Scheffer, I E

    2000-01-01

    Autosomal Dominant Rolandic Epilepsy with Speech Dyspraxia (ADRESD) is a rare disorder which highlights the relationship between Benign Rolandic Epilepsy (BRE) and speech and language disorders. Subtle speech and language disorders have recently been well characterised in BRE. ADRESD is associated with long term, more severe speech and language difficulties. The time course of rolandic epilepsy in ADRESD is typical of that of BRE. ADRESD is inherited in an autosomal dominant manner with anticipation. It is postulated that the anticipation may be due to an, as yet unidentified, triplet repeat expansion in a gene for rolandic epilepsy. BRE follows complex inheritance but it is possible that ADRESD may hold some valuable clues to the pathogenesis of BRE.

  2. 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.

  3. Autosomal dominant craniosynostosis of the sutura metopica.

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    Hennekam, R C; Van den Boogaard, M J

    1990-11-01

    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 without significant head deformity. A paternal sister was possibly also affected. None of the affected persons showed significant other anomalies. Craniosynostosis of the metopic suture may be an autosomal dominantly inherited disorder, not associated with functional brain or other abnormalities.

  4. Enamelin and autosomal-dominant amelogenesis imperfecta.

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    Hu, J C-C; Yamakoshi, Y

    2003-01-01

    Dental enamel forms as a progressively thickening extracellular layer by the action of proteins secreted by ameloblasts. The most abundant enamel protein is amelogenin, which is expressed primarily from a gene on the X-chromosome (AMELX). The two most abundant non-amelogenin enamel proteins are ameloblastin and enamelin, which are expressed from the AMBN and ENAM genes, respectively. The human AMBN and ENAM genes are located on chromosome 4q13.2. The major secretory products of the human AMELX, AMBN, and ENAM genes have 175, 421, and 1103 amino acids, respectively, and are all post-translationally modified, secreted, and processed by proteases. Mutations in AMELX have been shown to cause X-linked amelogenesis imperfecta (AI), which accounts for 5% of AI cases. Mutations in ENAM cause a severe form of autosomal-dominant smooth hypoplastic AI that represents 1.5%, and a mild form of autosomal-dominant local hypoplastic AI that accounts for 27% of AI cases in Sweden. The discovery of mutations in the ENAM gene in AI kindreds proved that enamelin is critical for proper dental enamel formation and that it plays a role in human disease. Here we review how enamelin was discovered, what is known about enamelin protein structure, post-translational modifications, processing by proteases, and its potentially important functional properties such as its affinity for hydroxyapatite and influence on crystal growth in vitro. The primary structures of human, porcine, mouse, and rat enamelin are compared, and the human enamelin gene, its structure, chromosomal localization, temporal and spatial patterns of expression, and its role in the etiology of amelogenesis imperfecta are discussed.

  5. 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.

  6. 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.

  7. Boy with autosomal recessive polycystic kidney and autosomal dominant polycystic liver disease.

    NARCIS (Netherlands)

    Zingg-Schenk, A.; Caduff, J.; Azzarello-Burri, S.; Bergmann, C.; Drenth, J.P.H.; Neuhaus, T.J.

    2012-01-01

    BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) shows a great phenotypic variability between patients, ranging from perinatal demise to mildly affected adults. Autosomal dominant polycystic liver disease (PCLD) does not manifest in childhood. CASE-DIAGNOSIS/TREATMENT: A boy was rep

  8. Autosomal dominant inheritance of left ventricular outflow tract obstruction

    NARCIS (Netherlands)

    Wessels, Marjolein; Berger, Rudolphus; Frohn-Mulder, Ingrid M E; Roos-Hesselink, Jolien W; Hoogeboom, Jeanette J M; Mancini, Grazia S; Bartelings, Margot M; Krijger, Ronald de; Wladimiroff, Jury W; Niermeijer, Martinus F; Grossfeld, Paul; Willems, Patrick J

    2005-01-01

    Most nonsyndromic congenital heart malformations (CHMs) in humans are multifactorial in origin, although an increasing number of monogenic cases have been reported recently. We describe here four new families with presumed autosomal dominant inheritance of left ventricular outflow tract obstruction

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

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    ... Facebook Share on Twitter Your Guide to Understanding Genetic Conditions Search MENU Toggle navigation Home Page Search ... Conditions Genes Chromosomes & mtDNA Resources Help Me Understand Genetics Home Health Conditions ADPEAF autosomal dominant partial epilepsy ...

  10. 先天性膜性白内障一家系致病基因的遗传分析%Mutation of 22q11.2-q12.1 gene in a family with autosomal dominant congenital membranous cataract

    Institute of Scientific and Technical Information of China (English)

    袁芳; 李飞峰; 刘伟; 刘华; 季健; 马旭

    2009-01-01

    目的 分析一个先天性白内障家系的遗传规律,对其突变基因进行初步研究.方法 选取一先天性膜性白内障家系,对家系成员进行临床检查并采集静脉血.标准饱和酚/氯仿抽提法提取DNA,选取多态性微卫星遗传标记,合成引物,聚合酶链反应,聚丙烯酰胺凝胶电泳,基因分型,等位基因共享分析法对已知候选基因进行排除性定位.结果 该家系为常染色体显性遗传性先天性白内障家系.其致病基因与D22S315联系紧密,重组发生在以D22S303和D22S1167为上下边界的范围内.对该范围内已知的先天性白内障致病基因CRYBB1、CRYBB2、CRYBB3、CRYBA4进行DNA直接测序,未发现突变.结论 该家系致病基因定位于22q11.2~q12.1的2.4 Mbp范围内,其致病基因与已知基因座不同.该范围内可能存在导致先天性膜性白内障的新的致病基因.%Objective Autosomal dominant congenital cataract (ADCC) is a common heredit disease.Some known genes and mutated loci related to ADCC have been found.The present study provides other disease-causing genes in the ADCC family.This study was to identify the genetic defect in four generations of a Chinese family with autosomal dominant congenital membranous cataracts and demonstrate the functional analysis of a candidate gene in the family.MethodsThe family with hereditary cataract was recruited from the Tianjin Medical University Eye Center.The family history was collected and recorded.Clinical and ophthalmologic examinations were performed on 6 affected and 14 unaffected family members and periphery blood samples were collected from all of the subjects for genomic DNA preparation.The members were genotyped with microsatellite markers at loci associated with cataracts.Multiplex polymerase chain reaction (PCR) was carried out with microsatellite markers near to candidated loci related to congenital cataracts.PCR products from each DNA sample were separated on a polyarcylamide gel and

  11. [Autosomal dominant cerebellar ataxias in the Netherlands: a national inventory

    NARCIS (Netherlands)

    Warrenburg, B.P.C. van de

    2001-01-01

    OBJECTIVE: To provide a comprehensive estimate of the number of Dutch autosomal dominant cerebellar ataxias (ADCA) families and patients and thus estimate the minimal prevalence of ADCA in the Netherlands. Furthermore, to observe the relative frequency of SCA mutations and to study genotype-phenotyp

  12. Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease

    NARCIS (Netherlands)

    Torres, Vicente E.; Chapman, Arlene B.; Devuyst, Olivier; Gansevoort, Ron T.; Grantham, Jared J.; Higashihara, Eiji; Perrone, Ronald D.; Krasa, Holly B.; Ouyang, John; Czerwiec, Frank S.

    2012-01-01

    BACKGROUND The course of autosomal dominant polycystic kidney disease (ADPKD) is often associated with pain, hypertension, and kidney failure. Preclinical studies indicated that vasopressin V-2-receptor antagonists inhibit cyst growth and slow the decline of kidney function. METHODS In this phase 3,

  13. Autosomal recessive congenital cataract, intellectual disability phenotype linked to STX3 in a consanguineous Tunisian family.

    Science.gov (United States)

    Chograni, M; Alkuraya, F S; Ourteni, I; Maazoul, F; Lariani, I; Chaabouni, H B

    2015-09-01

    The aim of this study is to investigate the genetic basis of autosomal recessive congenital cataract and intellectual disability phenotype in a consanguineous Tunisian family. The whole genome scan of the studied family was performed with single nucleotide polymorphisms (SNPs). The resulted runs of homozygosity (ROH) were analyzed through the integrated Systems Tool for Eye gene discovery (iSyTE) in order to prioritize candidate genes associated with congenital cataract. Selected genes were amplified and sequenced. Bioinformatic analysis was conducted to predict the function of the mutant gene. We identified a new specific lens gene named syntaxin 3 linked to the studied phenotype. The direct sequencing of this gene revealed a novel missense mutation c.122A>G which results in p.E41G. Bioinformatic analysis suggested a deleterious effect of this mutation on protein structure and function. Here, we report for the first time a missense mutation of a novel lens specific gene STX3 in a phenotype associating autosomal recessive congenital cataract and intellectual disability.

  14. [Polycystic liver disease without autosomal dominant polycystic kidney disease].

    Science.gov (United States)

    Peces, R; González, P; Venegas, J L

    2003-01-01

    Polycystic liver disease is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. The natural history and clinical manifestations of polycystic liver disease are based on the disease as it manifests in patients with autosomal dominant polycystic kidney disease (ADPKD). The occurrence of polycystic liver disease independently from polycystic kidney disease has been known for a long time. More recently, a gene for autosomal dominant polycystic liver disease has been identified on chromosome 19p 13.2-13.1. Isolated polycystic liver disease is underdiagnosed and genetically distinct from polycystic liver disease associated with ADPKD but with similar pathogenesis and clinical manifestations. We report here two men with polycystic liver disease no associated with ADPKD. Ultrasound and computed tomography imaging were effective in documenting the underlying lesions non-invasively.

  15. Sacral radicular cysts in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Peces, Ramón; Peces, Carlos; Pérez-Dueñas, Virginia; Vega-Cabrera, Cristina; Campos, Isabel

    2009-10-01

    This is the first report of a case of sacral radicular cysts in a patient with autosomal dominant polycystic kidney disease (ADPKD). A 46-year-old woman with ADPKD was found to have bilateral sacral radicular cysts discovered incidentally by magnetic resonance imaging (MRI). Cysts arising from arachnoid or spinal meningeal sac should be considered one of the manifestations of a more widespread connective tissue disorder associated with ADPKD.

  16. Hypertension in children with autosomal dominant polycystic kidney disease (ADPKD).

    Science.gov (United States)

    Cadnapaphornchai, Melissa A

    2013-02-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease, affecting 1 in 1000 individuals. Previously termed "adult polycystic kidney disease", ADPKD is now known to have important clinical manifestations beginning early in life and even in utero. Hypertension is an important risk factor for progressive renal and cardiovascular disease in children with ADPKD and may signify irremediable organ injury. The purpose of this article is to review current knowledge and treatment strategies in hypertension associated with pediatric ADPKD.

  17. CRYAA gene mutation study in a family with autosomal dominant congenital cataract combined with microcornea%常染色体显性遗传核性白内障合并小角膜的CRYAA基因突变研究

    Institute of Scientific and Technical Information of China (English)

    梁小芳; 肖伟; 石磊; 华芮; 张学

    2011-01-01

    Objective To identify the gene mutation in a four-generation Chinese family with autosomal dominant congenital cataract associated with microcornea. Methods Experimental research.Twelve members in this family (including six affected and six unaffected individuals) were enrolled into this study. They underwent full ophthalmological and clinical examinations to rule out any concomitant disorders.Blood samples were collected and genomic DNA was extracted. Microsatellite markers near the reported loci,which are associated with congenital cataract and microcornea were selected and amplified from DNA samples using polymerase chain reaction. Linkage analysis was performed. The exons and exon/intron junction of candidate gene in the related chromosome were sequenced. The product of the first exon was digested by ApaL Ⅰ restriction enzyme to certify the mutation. Results The phenotype studied in this family was nuclear cataract accompanied with microcornea. At markers D21S1885 and D21S1890 near the locus 21q22. 3, the affected members had the same allele, but the unaffected did not. The Lod scores were 2. 11in both markers, indicating that this locus were linked to the congenital cataract in this family. DNA sequencing of candidate gene CRYAA showed a heterozygous mutation c. 34C > T in exon 1, which led to condon 12 in peptide chain encoding arginine substituted by cysteine. ApaL Ⅰ enzyme digestion certified that all of the affected members had the same mutation c. 34C >T, but the unaffected and normal individuals did not. Conclusion Mutation (p. R12C) of CRYAA is the genetic change that causes the occurrence of congenital cataract with microcornea in this family.%目的 研究一个4代常染色体显性遗传先天性核性白内障伴小角膜家系的致病基因.方法 实验研究.对12例家系成员(6例患者,6例非患者)进行眼部检查并采集静脉血,提取基因组DNA.在已知的与先天性白内障伴小角膜相关致病基因附近选择微

  18. Autosomal-dominant Alzheimer's disease: a review and proposal for the prevention of Alzheimer's disease

    OpenAIRE

    Bateman, R. J.; Aisen, P.S.; De Strooper, B.; Fox, N C.; Lemere, C. A.; Ringman, J.M.; Salloway, S.; Sperling, R. A.; Windisch, M.; Xiong, C.

    2011-01-01

    Autosomal-dominant Alzheimer's disease has provided significant understanding of the pathophysiology of Alzheimer's disease. The present review summarizes clinical, pathological, imaging, biochemical, and molecular studies of autosomal-dominant Alzheimer's disease, highlighting the similarities and differences between the dominantly inherited form of Alzheimer's disease and the more common sporadic form of Alzheimer's disease. Current developments in autosomal-dominant Alzheimer's disease are...

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

    Science.gov (United States)

    Irum, Bushra; Khan, Shahid Y.; Ali, Muhammad; Kaul, Haiba; Kabir, Firoz; Rauf, Bushra; Fatima, Fareeha; Nadeem, Raheela; 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

    Purpose To identify the molecular basis of non-syndromic autosomal recessive congenital cataracts (arCC) in a consanguineous family. Methods 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. Results 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

  20. Guadalajara camptodactyly type III: a new probably autosomal dominant syndrome.

    Science.gov (United States)

    Figuera, L E; Ramírez-Dueñas, M L; Dávalos, I P; Cantú, J M

    2002-10-01

    A Mexican family is presented with the main clinical features of camptodactyly, a distinctive facial appearance because of ocular hypertelorism, telecanthus, symblepharon and spinal defects. Other clinical manifestations included: multiple nevi, simplified ears, retrognathia, congenital shortness of the sternocleidomastoid muscle, thin hands and feet, a small penis and mild mental retardation. Radiographic studies revealed spina bifida occulta at cervical and dorso-lumbar levels, increased bone trabeculae, cortical thickening and delayed bone age. The presence of five affected members through four generations suggests autosomal dominant inheritance although no male-to-male transmission was documented. The authors propose this as a new entity, and have designated it Guadalajara camptodactyly type III.

  1. PENCALC: a program for penetrance estimation in autosomal dominant diseases

    Directory of Open Access Journals (Sweden)

    Andréa R.V. Russo Horimoto

    2010-01-01

    Full Text Available We present a computer program developed for estimating penetrance rates in autosomal dominant diseases by means of family kinship and phenotype information contained within the pedigrees. The program also determines the exact 95% credibility interval for the penetrance estimate. Both executable (PenCalc for Windows and web versions (PenCalcWeb of the software are available. The web version enables further calculations, such as heterozygosity probabilities and assessment of offspring risks for all individuals in the pedigrees. Both programs can be accessed and down-loaded freely at the home-page address http://www.ib.usp.br/~otto/software.htm.

  2. Regional variability of imaging biomarkers in autosomal dominant Alzheimer's disease.

    Science.gov (United States)

    Benzinger, Tammie L S; Blazey, Tyler; Jack, Clifford R; Koeppe, Robert A; Su, Yi; Xiong, Chengjie; Raichle, Marcus E; Snyder, Abraham Z; Ances, Beau M; Bateman, Randall J; Cairns, Nigel J; Fagan, Anne M; Goate, Alison; Marcus, Daniel S; Aisen, Paul S; Christensen, Jon J; Ercole, Lindsay; Hornbeck, Russ C; Farrar, Angela M; Aldea, Patricia; Jasielec, Mateusz S; Owen, Christopher J; Xie, Xianyun; Mayeux, Richard; Brickman, Adam; McDade, Eric; Klunk, William; Mathis, Chester A; Ringman, John; Thompson, Paul M; Ghetti, Bernardino; Saykin, Andrew J; Sperling, Reisa A; Johnson, Keith A; Salloway, Stephen; Correia, Stephen; Schofield, Peter R; Masters, Colin L; Rowe, Christopher; Villemagne, Victor L; Martins, Ralph; Ourselin, Sebastien; Rossor, Martin N; Fox, Nick C; Cash, David M; Weiner, Michael W; Holtzman, David M; Buckles, Virginia D; Moulder, Krista; Morris, John C

    2013-11-19

    Major imaging biomarkers of Alzheimer's disease include amyloid deposition [imaged with [(11)C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [(18)F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer's disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer's disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease.

  3. 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

    Purpose The aim of this study is to identify the molecular basis of autosomal recessive congenital cataracts (arCC) in a large consanguineous pedigree. Methods 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. Results 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. Conclusion Here, we report a novel insertion/deletion mutation at the GCNT2 locus that is responsible for congenital cataracts in a large consanguineous family. PMID:27936067

  4. LAMB3 mutations causing autosomal-dominant amelogenesis imperfecta.

    Science.gov (United States)

    Kim, J W; Seymen, F; Lee, K E; Ko, J; Yildirim, M; Tuna, E B; Gencay, K; Shin, T J; Kyun, H K; Simmer, J P; Hu, J C-C

    2013-10-01

    Amelogenesis imperfecta (AI) can be either isolated or part of a larger syndrome. Junctional epidermolysis bullosa (JEB) is a collection of autosomal-recessive disorders featuring AI associated with skin fragility and other symptoms. JEB is a recessive syndrome usually caused by mutations in both alleles of COL17A1, LAMA3, LAMB3, or LAMC2. In rare cases, heterozygous carriers in JEB kindreds display enamel malformations in the absence of skin fragility (isolated AI). We recruited two kindreds with autosomal-dominant amelogenesis imperfecta (ADAI) characterized by generalized severe enamel hypoplasia with deep linear grooves and pits. Whole-exome sequencing of both probands identified novel heterozygous mutations in the last exon of LAMB3 that likely truncated the protein. The mutations perfectly segregated with the enamel defects in both families. In Family 1, an 8-bp deletion (c.3446_3453del GACTGGAG) shifted the reading frame (p.Gly 1149Glufs*8). In Family 2, a single nucleotide substitution (c.C3431A) generated an in-frame translation termination codon (p.Ser1144*). We conclude that enamel formation is particularly sensitive to defects in hemidesmosome/basement-membrane complexes and that syndromic and non-syndromic forms of AI can be etiologically related.

  5. Frontonasal dysplasia: a family presenting autosomal dominant inheritance pattern.

    Science.gov (United States)

    Koçak, H; Ceylaner, G

    2009-01-01

    Frontonasal dysplasia (FND, also called frontonasal dysostosis or median cleft face syndrome) includes a spectrum of abnormalities affecting the eyes, forehead and nose, and resulting from midfacial dysraphia. The clinical picture is highly variable, but major findings in FND include ocular hypertelorism, a broad nasal root, median cleft affecting nose or both the nose and upper lip, and widow's peak. It is usually a sporadic disorder, although a few familial cases have been reported. We report here a three-generation family with multiple affected members with frontonasal dysplasia. This observation suggests autosomal dominant inheritance. Furthermore, some of the features e.g. over-riding toes, nail changes, vertical crease on plantar region of the feet in the index patient were not reported up to now.

  6. [Urinary electrolyte excretion in autosomal dominant polycystic kidney].

    Science.gov (United States)

    Todorov, V; Iordanova, P; Penkova, S

    1991-01-01

    In 33 patients with autosomal dominant renal polycystosis the urine excretion of the electrolytes sodium and potassium was examined and analyzed in relation to the renal function and the arterial pressure. The clearances, the urine ratio and the excreted fractions of both electrolytes were calculated. It was established that by normal renal function and without arterial hypertension there were no significant differences in the parameters studied between the patients and the healthy controls. In the patients with arterial hypertension and preserved renal function the sodium clearance and urine excretion were lower, but the differences with the normotensive patients were not statistically significant. In the patients with chronic renal failure (when diuretic was applied) higher mean values of the excreted fractions of sodium and potassium were established. The results support the thesis that hypertension in renal polycystosis is of volumetric character.

  7. Renal and extrarenal manifestations of autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    E.A. Romão

    2006-04-01

    Full Text Available The objective of the present study was to determine the frequency of the most common clinical features in patients with autosomal dominant polycystic kidney disease in a sample of the Brazilian population. The medical records of 92 patients with autosomal dominant polycystic kidney disease attended during the period from 1985 to 2003 were reviewed. The following data were recorded: age at diagnosis, gender, associated clinical manifestations, occurrence of stroke, age at loss of renal function (beginning of dialysis, and presence of a family history. The involvement of abdominal viscera was investigated by ultrasonography. Intracranial alterations were prospectively investigated by magnetic resonance angiography in 42 asymptomatic patients, and complemented with digital subtraction arteriography when indicated. Mean age at diagnosis was 35.1 ± 14.9 years, and mean serum creatinine at referral was 2.4 ± 2.8 mg/dL. The most frequent clinical manifestations during the disease were arterial hypertension (63.3%, lumbar pain (55.4%, an abdominal mass (47.8%, and urinary infection (35.8%. Loss of renal function occurred in 27 patients (mean age: 45.4 ± 9.5 years. The liver was the second organ most frequently affected (39.1%. Stroke occurred in 7.6% of the patients. Asymptomatic intracranial aneurysm was detected in 3 patients and arachnoid cysts in 3 other patients. In conclusion, the most common clinical features were lumbar pain, arterial hypertension, abdominal mass, and urinary infection, and the most serious complications were chronic renal failure and stroke. Both intracranial aneurysms and arachnoid cysts occurred in asymptomatic patients at a frequency of 7.14%.

  8. Research on autosomal dominant polycystic kidney disease in China

    Institute of Scientific and Technical Information of China (English)

    DAI Bing; MEI Chang-lin

    2006-01-01

    Objective To review the history and recent development of research on autosomal dominant polycystic kidney disease (ADPKD) in China.Data sources Both Chinese and English literatures were searched in MEDLINE/CD ROM (1979 - 2006) and the Chinese Biomedical Literature Disk (1979 - 2006).Study selection Published articles about ADPKD from mainland of China were selected. Data were mainly extracted from 58 articles which are listed in the reference section of this review.Results Some preliminary reports on cyst decompression surgeries and mutation analysis represent the contribution to the ADPKD research from China in the history. A serial of basic research and clinical studies on ADPKD in recent years also have been summarized. A technique platform for ADPKD research was firstly established. The genomics/proteomics/bioinformatics approach was introduced, which provide a lot of valuable information for understanding the pathogenesis. By denature high performance liquid chromatography (DHPLC)technique the entire PKD1 and PKD2 gene sequence screening system for Chinese Han population has been successfully established. Based on the characteristic data of Chinese patients, an integrated therapy protocol was put forward and won an advantage over the traditional therapy. Some novel experimental studies on therapy also were encouraging. Conclusions Remarkable progress of ADPKD research in China have been made recently. Still many works, including the government support, international collaboration and active participation of more Chinese nephrologists, should be enhanced to advance this process in the near future.

  9. Why kidneys fail in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Grantham, Jared J; Mulamalla, Sumanth; Swenson-Fields, Katherine I

    2011-08-23

    The weight of evidence gathered from studies in humans with hereditary polycystic kidney disease (PKD)1 and PKD2 disorders, as well as from experimental animal models, indicates that cysts are primarily responsible for the decline in glomerular filtration rate that occurs fairly late in the course of the disease. The processes underlying this decline include anatomic disruption of glomerular filtration and urinary concentration mechanisms on a massive scale, coupled with compression and obstruction by cysts of adjacent nephrons in the cortex, medulla and papilla. Cysts prevent the drainage of urine from upstream tributaries, which leads to tubule atrophy and loss of functioning kidney parenchyma by mechanisms similar to those found in ureteral obstruction. Cyst-derived chemokines, cytokines and growth factors result in a progression to fibrosis that is comparable with the development of other progressive end-stage renal diseases. Treatment of renal cystic disorders early enough to prevent or reduce cyst formation or slow cyst growth, before the secondary changes become widespread, is a reasonable strategy to prolong the useful function of kidneys in patients with autosomal dominant polycystic kidney disease.

  10. PARK1 gene mutation of autosomal dominant Parkinson's disease family

    Institute of Scientific and Technical Information of China (English)

    Ligang Jiang; Guohua Hu; Qiuhui Chen; Ying Zhang; Xinyu Hu; Jia Fan; Lifeng Liu; Rui Guo; Yajuan Sun; Yixhi Zhang

    2011-01-01

    Studies have shown that PARK1 gene is associated with the autosomal dominant inheritance of Parkinson's disease.PARK1 gene contains two mutation sites, namely Ala30Pro and AIa53Thr, which are located on exons 3 and 4, respectively.However, the genetic loci of the pathogenic genes remain unclear.In this study, blood samples were collected from 11 members of a family with high prevalence of Parkinson's disease, including four affected cases, five suspected cases,and two non-affected cases.Point mutation screening of common mutation sites on PARK1 gene exon 4 was conducted using PCR, to determine the genetic loci of the causative gene for Parkinson's disease.Gene identification and sequencing results showed that a T base deletion mutation was observed in the PARK1 gene exon 4 of all 11 collected samples.It was confirmed that the PARKf gene exon 4 gene mutation is an important pathogenic mutation for Parkinson's disease.

  11. 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.

  12. 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.

  13. [Related reproductive issues on male autosomal dominant polycystic kidney disease].

    Science.gov (United States)

    Cai, Hong-cai; Shang, Xue-jun; Huang, Yu-feng

    2015-11-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a most common inherited renal disease, about 50% with a family history, although the exact etiology not yet clear. To date, ADPKD, a multisystem disorder without effective preventive and therapeutic means, has been shown to be detrimental to human health. Recent studies show that severe oligoasthenozoospermia, necrospermia, immotile sperm, azoospermia, epididymal cyst, seminal vesicle cyst, and ejaculatory duct cyst found in male ADPKD patients may lead to male infertility, though the specific mechanisms remain unknown. Structural anomaly of spermatozoa, defect of polycystin, mutation of PKD genes, and micro-deletion of the AZF gene could be the reasons for the higher incidence of abnormal semen quality in male ADPKD patients. Assisted reproductive techniques can increase the chances of pregnancy, whereas the health of the offspring should be taken into consideration. This article presents an overview of reproductive issues concerning infertile male ADPKD patients from the perspective of the morbidity, pathophysiological mechanism, diagnosis, and management of the disease.

  14. Patterns of autosomal dominant polycystic kidney diseases in black Africans

    Directory of Open Access Journals (Sweden)

    Fary Ka Elhadj

    2010-01-01

    Full Text Available Autosomal dominant polycystic kidney disease (ADPKD is not well described in black Africans while some data suggesting the disease is exceptional in this race. A retrospective study of patients with ADPKD followed in nephrology department of a teaching hospital in Dakar (January 1, 1995 to December 31, 2005 was therefore undertaken. Prevalence of ADPKD was one in 250. Mean age was 47 ± 5 years with a predominance of male (57%. High blood pressure (HBP was present in 68% of patients. Other renal manifestations were flank pain, hematuria and proteinuria. Majority of patients had impaired renal function at time of diagnosis. Extra-renal cysts were essentially found in liver (45.5%, pancreas and seminal vesicles. Main complications: ESRD (51% occurred within a 6 year mean period, urinary tract infection (13% and cerebral haemorrhage (2%. HBP control, in general needed 2 or more antihypertensive drugs. Fourteen patients died, ten patients had been on haemodialysis and four others died from uremic compli-cations. In conclusion, ADPKD in black African adults is not rare and probably underdiagnosed. Early HBP and ESRD are likely more frequent than in other races. Earlier ultrasound detection and strategies to preserve renal function should be offered to at-risk individuals to improve outcomes.

  15. Impaired default network functional connectivity in autosomal dominant Alzheimer disease

    Science.gov (United States)

    Chhatwal, Jasmeer P.; Schultz, Aaron P.; Johnson, Keith; Benzinger, Tammie L.S.; Jack, Clifford; Ances, Beau M.; Sullivan, Caroline A.; Salloway, Stephen P.; Ringman, John M.; Koeppe, Robert A.; Marcus, Daniel S.; Thompson, Paul; Saykin, Andrew J.; Correia, Stephen; Schofield, Peter R.; Rowe, Christopher C.; Fox, Nick C.; Brickman, Adam M.; Mayeux, Richard; McDade, Eric; Bateman, Randall; Fagan, Anne M.; Goate, Allison M.; Xiong, Chengjie; Buckles, Virginia D.; Morris, John C.

    2013-01-01

    Objective: To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network. Methods: Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO). Results: We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO. Conclusion: Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease. PMID:23884042

  16. 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.

  17. AUTOSOMAL DOMINANT HYPOCALCEMIA (HYPOPARATHYROIDISM TYPES 1 AND 2

    Directory of Open Access Journals (Sweden)

    Kelly Lauter Roszko

    2016-10-01

    Full Text Available Extracellular calcium is essential for life and its concentration in the blood is maintained within a narrow range. This is achieved by a feedback loop that receives input from the calcium-sensing receptor (CASR, expressed on the surface of parathyroid cells. In response to low ionized calcium, the parathyroids increase secretion of parathyroid hormone (PTH which increases serum calcium. The CASR is also highly expressed in the kidneys, where it regulates the reabsorption of calcium from the primary filtrate. Autosomal dominant hypocalcemia (ADH type 1 is caused by heterozygous activating mutations in the CASR which increase the sensitivity of the CASR to extracellular ionized calcium. Consequently, PTH synthesis and secretion is suppressed at normal ionized calcium concentrations. Patients present with hypocalcemia, hyperphosphatemia, low magnesium levels, and low or low-normal levels of PTH. Urinary calcium excretion is typically increased due to the decrease in circulating PTH concentrations and by the activation of the renal tubular CASR. Therapeutic attempts using CASR antagonists (calcilytics to treat ADH are currently under investigation. Recently, heterozygous mutations in the alpha subunit of the G protein G11 (GNA11 have been identified in patients with ADH, and this has been classified as ADH type 2. ADH2 mutations lead to a gain-of-function of Gα11, a key mediator of CASR signaling. Therefore, the mechanism of hypocalcemia appears similar to that of activating mutations in the CASR, namely an increase in the sensitivity of parathyroid cells to extracellular ionized calcium. Studies of activating mutations in the CASR and gain-of-function mutations in GNA11 can help define new drug targets and improve medical management of patients with ADH types 1 and 2.

  18. A novel mutation of p.F32I in GJA8 in human dominant congenital cataracts

    Science.gov (United States)

    Dang, Feng-Tao; Yang, Fa-Yu; Yang, Ye-Qin; Ge, Xiang-Lian; Chen, Ding; Zhang, Liu; Yu, Xin-Ping; Gu, Feng; Zhu, Yi-Hua

    2016-01-01

    AIM To identify a causative mutation in a three-generation family with autosomal dominant congenital total cataract and dissect the molecular consequence of the identified mutation. METHODS Clinical and ophthalmological examinations were performed on the affected and unaffected family members. Mutation were screened in recruited family members by polymerase chain reaction (PCR) of the two reported genes (CRYAA and GJA8) which were linked to human total cataracts and direct sequencing of the PCR product. The molecular consequences of the identified mutation was dissected. The plasmids carrying wild-type and mutant mouse ORF of Gja8, coding for connexin 50 (Cx50), were generated and ectopic expressed in 293 cells. Recombinant protein expression and cellular localization of recombinated Cx50 were assessed by confocal microscopy. RESULTS Clinical and ophthalmological examinations were performed on the affected and unaffected family members. Mutation were screened in recruited family members by PCR of the two reported genes (CRYAA and GJA8) which were linked to human total cataracts and direct sequencing of the PCR product. The molecular consequences of the identified mutation was dissected. The plasmids carrying wild-type and mutant mouse ORF of Gja8, coding for Cx50, were generated and ectopic expressed in 293 cells. Recombinant protein expression and cellular localization of recombinated Cx50 were assessed by confocal microscopy. CONCLUSION This study has identified a novel cataract mutation in GJA8, which adds a novel mutation to the existing spectrum of Cx50 mutations with cataract. The molecular consequences of p.F32I mutation in GJA8 exclude instability and the mislocalization of mutant Cx50 protein. PMID:27990357

  19. 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 mental

  20. Dominant cataract mutations and specific-locus mutations in mice induced by radiation or ethylnitrosourea

    Energy Technology Data Exchange (ETDEWEB)

    Ehling, U.H.; Favor, J.; Kratochvilova, J.; Neuhaeuser-Klaus, A. (Gesellschaft fuer Strahlen- und Umweltforschung m.b.H. Muenchen, Neuherberg (Germany, F.R.). Inst. fuer Genetik)

    1982-01-01

    In a combined experiment, dominant cataract mutations and specific-locus mutations were scored in the same offspring. In radiation experiments, a total of 15 dominant cataract and 38 specific-locus mutations was scored in 29396 offspring. In experiments with ethylnitrosourea (ENU), a total of 12 dominant cataracts and 54 specific-locus mutations was observed in 12712 offspring. The control frequency for dominant cataracts was 0 in 9954 offspring and for specific-locus mutations 11 in 169955 offspring. The two characteristic features of radiation-induced specific-locus mutations - the augmenting effect of dose fractionation and the quantitative differences in the mutation rates between spermatogonial and post-spermatogonial stages - can also be demonstrated for the induction of dominant cataracts. The dominant cataract mutations recovered can be categorized into 7 phenotypic classes. The only noteworthy difference observed between the radiation- and ENU-induced mutations recovered was that, of the 2 radiation-induced total lens opacities, both were associated with an iris anomaly and microphthalmia whereas the ENU-induced total opacities were not.

  1. Renal relevant radiology: radiologic imaging in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Rahbari-Oskoui, Frederic; Mittal, Ankush; Mittal, Pardeep; Chapman, Arlene

    2014-02-01

    Autosomal-dominant polycystic kidney disease is a systemic disorder and the most common hereditary renal disease, which is characterized by cyst growth, progressive renal enlargement, and development of renal failure. The cystic nature of autosomal dominant polycystic kidney disease and its renal and extrarenal complications (kidney stones, cyst hemorrhage, intracerebral aneurysm, liver cysts, cardiac valve abnormalities, etc.) give radiologic imaging studies a central role in the management of these patients. This article reviews the indications, comparative use, and limitation of various imaging modalities (ultrasonography, magnetic resonance imaging, computerized tomography scan, Positron emission tomography scan, and renal scintigraphy) for the diagnosis and management of complications in autosomal dominant polycystic kidney disease. Finally, this work provides evidence for the value of total kidney volume to predict disease progression in autosomal dominant polycystic kidney disease.

  2. 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.

  3. 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)....

  4. 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.

  5. A Missense Mutation in the LIM2 Gene Is Associated with Autosomal Recessive Presenile Cataract in an Inbred Iraqi Jewish Family

    Science.gov (United States)

    Pras, Eran; Levy-Nissenbaum, Etgar; Bakhan, Tangiz; Lahat, Hadas; Assia, Ehud; Geffen-Carmi, Noa; Frydman, Moshe; Goldman, Boleslaw; Pras, Elon

    2002-01-01

    In an inbred Iraqi Jewish family, we have studied three siblings with presenile cataract first noticed between the ages of 20 and 51 years and segregating in an autosomal recessive mode. Using microsatellite repeat markers in close proximity to 25 genes and loci previously associated with congenital cataracts in humans and mice, we identified five markers on chromosome 19q that cosegregated with the disease. Sequencing of LIM2, one of two candidate genes in this region, revealed a homozygous T→G change resulting in a phenylalanine-to-valine substitution at position 105 of the protein. To our knowledge, this constitutes the first report, in humans, of cataract formation associated with a mutation in LIM2. Studies of late-onset single-gene cataracts may provide insight into the pathogenesis of the more common age-related cataracts. PMID:11917274

  6. A gene for autosomal dominant congenital nystagmus localizes to 6p12

    Energy Technology Data Exchange (ETDEWEB)

    Kerrison, J.B.; Arnould, V.J.; Koenekoop, R.K. [Johns Hopkins Hospital, Baltimore, MD (United States)] [and others

    1996-05-01

    Congenital nystagmus is an idiopathic disorder characterized by bilateral ocular oscillations usually manifest during infancy. Vision is typically decreased due to slippage of images across the fovea. As such, visual acuity correlates with nystagmus intensity, which is the amplitude and frequency of eye movements at a given position of gaze. X-linked, autosomal dominant, and autosomal recessive pedigrees have been described, but no mapping studies have been published. We recently described a large pedigree with autosomal dominant congenital nystagmus. A genome-wide search resulted in six markers on 6p linked by two-point analysis at {theta} = 0 (D6S459, D6S452, D6S465, FTHP1, D6S257, D6S430). Haplotype analysis localizes the gene for autosomal dominant congenital motor mystagmus to an 18-cM region between D6S271 and D6S455. 16 refs., 1 fig., 1 tab.

  7. High serum soluble α-Klotho levels in patients with autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Sari, Funda; Inci, Ayca; Dolu, Suleyman; Ellidag, Hamit Yasar; Cetinkaya, Ramazan; Ersoy, Fettah Fevzi

    2017-02-01

    This study aims to determine fibroblast growth factor-23 and soluble α-Klotho levels in patients with autosomal dominant polycystic kidney disease. A total of 76 patients with autosomal dominant polycystic kidney disease and 32 healthy volunteers were included in the study. Serum fibroblast growth factor-23 and soluble α-Klotho levels were measured with ELISA kits. Parathyroid hormone, phosphate, calcium, creatinine, 25-hydroxyvitamin D3 levels, urinary protein to creatinine ratio and estimated glomerular filtration rate were also measured or calculated. Patients with autosomal dominant polycystic kidney disease had significantly higher serum parathyroid hormone (pserum 25-hydroxyvitamin D3 levels (pSerum fibroblast growth factor-23, soluble α-Klotho and 25-hydroxyvitamin D3 levels were similar in all five chronic kidney disease stages of autosomal dominant polycystic kidney disease (p>0.05). Fibroblast growth factor-23 (r=-0.251, p=0.034) and soluble α-Klotho levels (r=-0.251, p=0.034) were found to be negatively correlated with estimated glomerular filtration rate. This study shows increased fibroblast growth factor-23 levels in patients with autosomal dominant polycystic kidney disease which is in harmony with the general trend in patients with chronic kidney disease of other aetiologies, but, unlike them, also a significant increase in serum soluble α-Klotho levels in patients with autosomal dominant polycystic kidney disease suggesting an aberrant production or a decreased clearance of α-Klotho molecule. Considering the unique increases in erythropoietin levels due to erythropoietin production in renal cysts, we assume, patients with autosomal dominant polycystic kidney disease may potentially have different soluble α-Klotho production/clearance characteristics than the patients with other parenchymal renal diseases.

  8. 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 ......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...

  9. Autosomal dominant familial spastic paraplegia: Tight linkage to chromosome 15q

    Energy Technology Data Exchange (ETDEWEB)

    Fink, J.K.; Wu, C.B.; Jones, S.M.; Lesicki, A.; Reinglass, T. [Univ. of Michigan, Ann Arbor, MI (United States); Sharp, G.B.; Lange, B.M. [Arkansas Children`s Hospital, Little Rock, AR (United States); Varvil, T.; Otterud, B.; Leppert, M. [Univ. of Utah, Salt Lake City, UT (United States)

    1995-01-01

    Autosomal dominant, uncomplicated familial spastic paraplegia (FSP) is a genetically heterogeneous disorder characterized by insidiously progressive lower-extremity spasticity. Recently, a locus on chromosome 14q was shown to be tightly linked with the disorder in one of three families. We performed linkage analysis in a kindred with autosomal dominant uncomplicated FSP. After excluding the chromosome 14q locus, we observed tight linkage of the disorder to a group of markers on chromosome 15q (maximum two-point lod score 9.70; {theta} = .05). Our results clearly establish the existence of a locus for autosomal dominant FSP in the centromeric region of chromosome 15q. Comparing clinical and genetic features in FSP families linked to chromosome 14q with those linked to chromosome 15q may provide insight into the pathophysiology of this disorder. 34 refs., 1 fig., 1 tab.

  10. Altered fibrinolysis in autosomal dominant thrombomodulin-associated coagulopathy

    Science.gov (United States)

    Burley, Kate; Whyte, Claire S.; Westbury, Sarah K.; Walker, Mary; Stirrups, Kathleen E.; Turro, Ernest; Chapman, Oliver G.; Reilly-Stitt, Christopher; Mutch, Nicola J.

    2016-01-01

    Thrombomodulin-associated coagulopathy (TM-AC) is a newly recognized dominant bleeding disorder in which a p.Cys537Stop variant in the thrombomodulin (TM) gene THBD, results in high plasma TM levels and protein C-mediated suppression of thrombin generation. Thrombin in complex with TM also activates thrombin-activatable fibrinolysis inhibitor (TAFI). However, the effect of the high plasma TM on fibrinolysis in TM-AC is unknown. Plasma from TM-AC cases and high-TM model control samples spiked with recombinant soluble TM showed reduced tissue factor–induced thrombin generation. Lysis of plasma clots from TM-AC cases was significantly delayed compared with controls but was completely restored when TM/thrombin-mediated TAFI activation was inhibited. Clots formed in blood from TM-AC cases had the same viscoelastic strength as controls but also showed a TAFI-dependent delay in fibrinolysis. Delayed fibrinolysis was reproduced in high-TM model plasma and blood samples. Partial restoration of thrombin generation with recombinant activated factor VII or activated prothrombin complex concentrate did not alter the delayed fibrinolysis in high-TM model blood. Our finding of a previously unrecognized fibrinolytic phenotype indicates that bleeding in TM-AC has a complex pathogenesis and highlights the pivotal role of TM as a regulator of hemostasis. PMID:27436851

  11. 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...

  12. 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......3-methylglutaconic aciduria (3-MGA-uria) is a nonspecific finding associated with mitochondrial dysfunction, including defects of oxidative phosphorylation. 3-MGA-uria is classified into five groups, of which one, type IV, is genetically heterogeneous. Here we report five children with a form...

  13. Multiple thoracic paraspinal meningeal cysts in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Coche, Emmanuel; Persu, Alexandre; Cosnard, Guy; Quoidbach, Albert; Pirson, Yves

    2003-02-01

    Spinal meningeal cysts have been reported in 3 patients as an extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). The authors report on a fourth patient with ADPKD who was found to harbor 7 thoracic meningeal cysts, appearing as paraspinal masses on plain films. The authors provide a comprehensive radiologic description of this abnormality.

  14. 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 examine...

  15. Improved prognosis in patients with autosomal dominant polycystic kidney disease in Denmark

    DEFF Research Database (Denmark)

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

    2010-01-01

    The introduction of new therapies, including agents that block the renin-angiotensin system, may have affected progression of autosomal dominant polycystic kidney disease (ADPKD). We investigated whether the age when reaching ESRD and survival during renal replacement therapy in Danish patients w...

  16. Management of renal cyst infection in patients with autosomal dominant polycystic kidney disease : a systematic review

    NARCIS (Netherlands)

    Lantinga, Marten A; Casteleijn, Niek F; Geudens, Alix; de Sévaux, Ruud G L; van Assen, Sander; Leliveld, Anna; Gansevoort, Ron T; Drenth, Joost P H

    2017-01-01

    BACKGROUND: Renal cyst infection is one of the complications faced by patients with autosomal dominant polycystic kidney disease (ADPKD). Cyst infection is often difficult to treat and potentially leads to sepsis and death. No evidence-based treatment strategy exists. We therefore performed a system

  17. 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...

  18. MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease

    NARCIS (Netherlands)

    Stoffels, Monique; Szperl, Agata; Simon, Anna; Netea, Mihai G.; Plantinga, Theo S.; van Deuren, Marcel; Kamphuis, Sylvia; Lachmann, Helen J.; Cuppen, Edwin; Kloosterman, Wigard P.; Frenkel, Joost; van Diemen, Cleo C.; Wijmenga, Cisca; van Gijn, Marielle; van der Meer, Jos W. M.

    2014-01-01

    Objectives Autoinflammatory disorders are disorders of the innate immune system. Standard genetic testing provided no correct diagnosis in a female patient from a non-consanguineous family of British descent with a colchicine-responsive autosomal dominant periodic fever syndrome. We aimed to unravel

  19. Autosomal dominant optic neuropathy and sensorineual hearing loss associated with a novel mutation of WFS1

    NARCIS (Netherlands)

    Hogewind, B.F.T.; Pennings, R.J.E.; Hol, F.A.; Kunst, H.P.M.; Hoefsloot, E.H.; Cruysberg, J.R.M.; Cremers, C.W.R.J.

    2010-01-01

    PURPOSE: To describe the phenotype of a novel Wolframin (WFS1) mutation in a family with autosomal dominant optic neuropathy and deafness. The study is designed as a retrospective observational case series. METHODS: Seven members of a Dutch family underwent ophthalmological, otological, and genetica

  20. Mutations in KIF11 cause autosomal-dominant microcephaly variably associated with congenital lymphedema and chorioretinopathy

    NARCIS (Netherlands)

    Ostergaard, P.; Simpson, M.A.; Mendola, A.; Vasudevan, P.; Connell, F.C.; Impel, A. van; Moore, A.T.; Loeys, B.L.; Ghalamkarpour, A.; Onoufriadis, A.; Martinez-Corral, I.; Devery, S.; Leroy, J.G.; Laer, L. van; Singer, A.; Bialer, M.G.; McEntagart, M.; Quarrell, O.; Brice, G.; Trembath, R.C.; Schulte-Merker, S.; Makinen, T.; Vikkula, M.; Mortimer, P.S.; Mansour, S.; Jeffery, S.

    2012-01-01

    We have identified KIF11 mutations in individuals with syndromic autosomal-dominant microcephaly associated with lymphedema and/or chorioretinopathy. Initial whole-exome sequencing revealed heterozygous KIF11 mutations in three individuals with a combination of microcephaly and lymphedema from a mic

  1. 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...

  2. Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe

    DEFF Research Database (Denmark)

    Spithoven, Edwin M; Kramer, Anneke; Meijer, Esther;

    2014-01-01

    BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common renal disease requiring renal replacement therapy (RRT). Still, there are few epidemiological data on the prevalence of, and survival on RRT for ADPKD. METHODS: This study used data from the ERA-EDTA Registry...

  3. 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...

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

    NARCIS (Netherlands)

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

    2014-01-01

    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,

  5. Localization of a gene for autosomal dominant amelogenesis imperfecta (ADAI) to chromosome 4q

    Energy Technology Data Exchange (ETDEWEB)

    Forsman, K.; Lind. L.; Westermark, E. [Univ. of Umea (Sweden)] [and others

    1994-09-01

    Amelogenesis imperfecta (AI), a disorder affecting the formation of enamel, is significantly more common in Northern Sweden than in other parts of the world. The disease is genetically and clinically heterogenous, and autosomal dominant, autosomal recessive and X-linked inheritance patterns have been recognized. Linkage analysis has identified two different loci for X-linked AI, one of which is identical to the gene encoding the enamel protein amelogenin. However, in families with an autosomal inheritance pattern for AI, the genetic basis of the disease still remains unknown. We report a linkage analysis study performed on three Swedish families where the affected members had an autosomal dominant variant of AI (ADAI) clinically characterized as local hypoplastic. Significant linkage to microsatellite markers on chromosome 4q were obtained, with a maximum lod score of 5.55 for the marker D4S428. Recombinations in the family localized the ADAI locus to the interval between D4S392 and D4S395. This chromosome region contains both a locus for the dental disorder dentinogenesis imperfecta and the albumin gene. Serum albumin has been suggested to play a role in enamel formation, and the albumin gene is therefore a candidate gene for this genetic disease.

  6. Molecular genetics of congenital nuclear cataract.

    Science.gov (United States)

    Deng, Hao; Yuan, Lamei

    2014-02-01

    A cataract is defined as opacification of the normally transparent crystalline lens. Congenital cataract (CC) is a type of cataract that presents at birth or during early childhood. CC is one of the most common causes of visual impairment or blindness in children worldwide. Approximately 50% of all CC cases may have a genetic cause which is quite heterogeneous. CC occurs in a variety of morphologic configurations, including polar/subcapsular, nuclear, lamellar, sutural, cortical, membranous/capsular and complete. Nuclear cataract refers to the opacification limited to the embryonic and/or fetal nuclei of the lens. Although congenital nuclear cataract can be caused by multiple factors, genetic mutation remains to be the most common cause. It can be inherited in one of the three patterns: autosomal dominant, autosomal recessive, or X-linked transmission. Autosomal dominant inheritance is the most frequent mode with high penetrance. There may be no obvious correlation between the genotype and phenotype of congenital nuclear cataract. Animal models have been established to study the pathogenesis of congenital nuclear cataract and to identify candidate genes. In this review, we highlight identified genetic mutations that account for congenital nuclear cataract. Our review may be helpful for genetic counseling and prenatal diagnosis.

  7. Imaging characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL)

    Science.gov (United States)

    Stojanov, Dragan; Aracki-Trenkic, Aleksandra; Vojinovic, Slobodan; Ljubisavljevic, Srdjan; Benedeto-Stojanov, Daniela; Tasic, Aleksandar; Vujnovic, Sasa

    2015-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) is an autosomal dominant vascular disorder. Diagnosis and follow-up in patients with CADASIL are based mainly on magnetic resonance imaging (MRI). MRI shows white matter hyperintensities (WMHs), lacunar infarcts and cerebral microbleeds (CMBs). WMHs lesions tend to be symmetrical and bilateral, distributed in the periventricular and deep white matter. The anterior temporal lobe and external capsules are predilection sites for WMHs, with higher specificity and sensitivity of anterior temporal lobe involvement compared to an external capsule involvement. Lacunar infarcts are presented by an imaging signal that has intensity of cerebrospinal fluid in all MRI sequences. They are localized within the semioval center, thalamus, basal ganglia and pons. CMBs are depicted as focal areas of signal loss on T2 images which increases in size on the T2*-weighted gradient echo planar images (“blooming effect”). PMID:25725137

  8. Locus heterogeneity in autosomal dominant spinocerebellar ataxia: Evidence for the existence of a fifth locus

    Energy Technology Data Exchange (ETDEWEB)

    Sarrazin, J.; Rouleau, G.A. [Montreal General Hospital, Quebec (Canada); Andermann, E. [Montreal Neurological Institute and Hospital, Quebec (Canada)] [and others

    1994-09-01

    The autosomal dominantly inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative disorders. To date, four loci have been identified: the SCA-1 locus (on chromosome (chr) 6p), the SCA-2 locus (on chr 12q), the SCA-3/MJD locus (on chr 14q), and more recently an SCA-4 locus was described (chr 16q) in a Utah kindred. We have studied one large French Canadian kindred with four generations of living affected individuals segregating an autosomal dominant form of SCA. Linkage analysis using anonymous DNA markers which flank the four previously described loci significantly excludes the French Canadian kindred from the SCA-1, SCA-2, SCA-3/MJD and SCA-4 loci. Therefore a fifth, still unmapped, SCA locus remains to be identified.

  9. [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.

  10. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in a Chinese pedigree

    Institute of Scientific and Technical Information of China (English)

    Erhe Xu; Huiqing Dong; Milan Zhang; Min Xu

    2012-01-01

    The present study enrolled a Chinese family that comprised 34 members and spanned three generations. Eight members were diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, and disease diagnoses corresponded with autosomal incomplete dominance inheritance. The primary clinical manifestations included paralysis, dysarthria, and mild cognitive deficits. Magnetic resonance imaging revealed diffuse leukoencephalopathy with involvement of bilateral anterior temporal lobes, in particular the pons. In addition, multiple cerebral infarction was identified in the proband. Sural nerve biopsy findings of the proband revealed granular osmophilic material deposits in the extracellular matrix, which were adjacent to smooth muscle cells of dermal arterioles. Screening exons 2-4 for NOTCH 3 mutations by direct sequencing did not reveal any abnormalities.

  11. Functional characterization of an AQP0 missense mutation, R33C, that causes dominant congenital lens cataract, reveals impaired cell-to-cell adhesion.

    Science.gov (United States)

    Kumari, Sindhu S; Gandhi, Jason; Mustehsan, Mohammed H; Eren, Semih; Varadaraj, Kulandaiappan

    2013-11-01

    Aquaporin 0 (AQP0) performs dual functions in the lens fiber cells, as a water pore and as a cell-to-cell adhesion molecule. Mutations in AQP0 cause severe lens cataract in both humans and mice. An arginine to cysteine missense mutation at amino acid 33 (R33C) produced congenital autosomal dominant cataract in a Chinese family for five generations. We re-created this mutation in wild type human AQP0 (WT-AQP0) cDNA by site-directed mutagenesis, and cloned and expressed the mutant AQP0 (AQP0-R33C) in heterologous expression systems. Mutant AQP0-R33C showed proper trafficking and membrane localization like WT-AQP0. Functional studies conducted in Xenopus oocytes showed no significant difference (P > 0.05) in water permeability between AQP0-R33C and WT-AQP0. However, the cell-to-cell adhesion property of AQP0-R33C was significantly reduced (P cataract suggest that the conserved positive charge of Extracellular Loop A may play an important role in bringing fiber cells closer. The proposed schematic models illustrate that cell-to-cell adhesion elicited by AQP0 is vital for lens transparency and homeostasis.

  12. 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.

  13. Genetics of Congenital Cataract.

    Science.gov (United States)

    Pichi, Francesco; Lembo, Andrea; Serafino, Massimiliano; Nucci, Paolo

    2016-01-01

    Congenital cataract is a type of cataract that presents at birth or during early childhood, and it is one of the most easily treatable causes of visual impairment and blindness during infancy, with an estimated prevalence of 1-6 cases per 10,000 live births. Approximately 50% of all congenital cataract cases may have a genetic cause, and such cases are quite heterogeneous. Although congenital nuclear cataract can be caused by multiple factors, genetic mutation remains the most common cause. All three types of Mendelian inheritance have been reported for cataract; however, autosomal dominant transmission seems to be the most frequent. The transparency and high refractive index of the lens are achieved by the precise architecture of fiber cells and homeostasis of the lens proteins in terms of their concentrations, stabilities, and supramolecular organization. Research on hereditary congenital cataract has led to the identification of several classes of candidate genes that encode proteins such crystallins, lens-specific connexins, aquaporin, cytoskeletal structural proteins, and developmental regulators. In this review, we highlight the identified genetic mutations that account for congenital nuclear cataract.

  14. 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

  15. 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

  16. Genetic linkage studies in autosomal dominant ataxia families with an MJD phenotype

    Energy Technology Data Exchange (ETDEWEB)

    Silveira, I.; Lopes-Cendes, I.; Paciel, P. [McGill Univ., Montreal (Canada)] [and others

    1994-09-01

    Machado-Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration which was originally described in patients originating from the Portuguese islands of the Azores. The first non-Portuguese kindred was described in 1979 and was an American black family originating from North Carolina. Since then the number of pedigrees of non-Azorean, non-Portuguese origin has increased with families being reported from other European countries, as well as Brazil, Japan, India, The United States and Australia. The autosomal dominant ataxias are a clinically and genetically heterogeneous group of disorders. To date, genetic analysis of families with autosomal dominant ataxias has permitted the identification of four loci, the SCA1 (spinocerebellar ataxia type 1) locus on chromosome 6p, the SCA2 locus on chromosome 12q, a third locus on chromosome 14q, the MJD/SCA3 and, more recently, the DRPLA (Dentatorubral-pallidoluysian atrophy) locus on chromosome 12p. We ascertained a total of 181 individuals with 60 affected from eight Indian, two Brazilian and one Sicilian-American family; all of them have received the clinical diagnosis of MJD. Recently, we have begun molecular genetic studies in these families in order to test these four candidate regions. The SCA1 mutation and the DRPLA mutation has been found to be an expansion of a CAG repeat. Direct analysis of the SCA1 and DRPLA expansion has been performed in all families and no expansion was found in the affected individuals. We are now running flanking markers for the SCA2 and MJD/SCA3 loci. These results will also be presented.

  17. Autosomal Dominant Inheritance of a Predisposition to Thoracic Aortic Aneurysms and Dissections and Intracranial Saccular Aneurysms

    Science.gov (United States)

    Regalado, Ellen; Medrek, Sarah; Tran-Fadulu, Van; Guo, Dong-Chuan; Pannu, Hariyadarshi; Golabbakhsh, Hossein; Smart, Suzanne; Chen, Julia H.; Shete, Sanjay; Kim, Dong H.; Stern, Ralph; Braverman, Alan C.; Milewicz, Dianna M.

    2013-01-01

    A genetic predisposition for thoracic aortic aneurysms and dissections (TAAD) can be inherited in an autosomal dominant manner with decreased penetrance and variable expression. Four genes identified to date for familial TAAD account for approximately 20% of the heritable predisposition. In a cohort of 514 families with two or more members with presumed autosomal dominant TAAD, 48 (9.3%) families have one or more members who were at 50% risk to inherit the presumptive gene causing TAAD had an intracranial vascular event. In these families, gender is significantly associated with disease presentation (p <0.001), with intracranial events being more common in women (65.4%) while TAAD events occurred more in men (64.2%,). Twenty-nine of these families had intracranial aneurysms (ICA) that could not be designated as saccular or fusiform due to incomplete data. TGFBR1, TGFBR2, and ACTA2 mutations were found in 4 families with TAAD and predominantly fusiform ICAs. In 15 families, of which 14 tested negative for 3 known TAAD genes, 17 family members who were at risk for inheriting TAAD had saccular ICAs. In 2 families, women who harbored the genetic mutation causing TAAD had ICAs. In 2 additional families, intracranial, thoracic and abdominal aortic aneurysms were observed. This study documents the autosomal dominant inheritance of TAADs with saccular ICAs, a previously recognized association that has not been adequately characterized as heritable.I these families, routine cerebral and aortic imaging for at risk members could prove beneficial for timely medical and surgical management to prevent a cerebral hemorrhage or aortic dissection. PMID:21815248

  18. Clinical and genetic analysis of a four-generation family with a distinct autosomal dominant cerebellar ataxia

    NARCIS (Netherlands)

    Schelhaas, H J; Ippel, P F; Hageman, G; Sinke, R J; van der Laan, E N; Beemer, F A

    2001-01-01

    The autosomal dominant cerebellar ataxias (ADCAs) are a heterogeneous group of neurodegenerative disorders characterised by progressive cerebellar dysfunction in combination with a variety of other associative features. Since 1993 ADCAs have been increasingly characterised in terms of their genetic

  19. Autosomal-Dominant Multiple Pterygium Syndrome Is Caused by Mutations in MYH3.

    Science.gov (United States)

    Chong, Jessica X; Burrage, Lindsay C; Beck, Anita E; Marvin, Colby T; McMillin, Margaret J; Shively, Kathryn M; Harrell, Tanya M; Buckingham, Kati J; Bacino, Carlos A; Jain, Mahim; Alanay, Yasemin; Berry, Susan A; Carey, John C; Gibbs, Richard A; Lee, Brendan H; Krakow, Deborah; Shendure, Jay; Nickerson, Deborah A; Bamshad, Michael J

    2015-05-01

    Multiple pterygium syndrome (MPS) is a phenotypically and genetically heterogeneous group of rare Mendelian conditions characterized by multiple pterygia, scoliosis, and congenital contractures of the limbs. MPS typically segregates as an autosomal-recessive disorder, but rare instances of autosomal-dominant transmission have been reported. Whereas several mutations causing recessive MPS have been identified, the genetic basis of dominant MPS remains unknown. We identified four families affected by dominantly transmitted MPS characterized by pterygia, camptodactyly of the hands, vertebral fusions, and scoliosis. Exome sequencing identified predicted protein-altering mutations in embryonic myosin heavy chain (MYH3) in three families. MYH3 mutations underlie distal arthrogryposis types 1, 2A, and 2B, but all mutations reported to date occur in the head and neck domains. In contrast, two of the mutations found to cause MPS in this study occurred in the tail domain. The phenotypic overlap among persons with MPS, coupled with physical findings distinct from other conditions caused by mutations in MYH3, suggests that the developmental mechanism underlying MPS differs from that of other conditions and/or that certain functions of embryonic myosin might be perturbed by disruption of specific residues and/or domains. Moreover, the vertebral fusions in persons with MPS, coupled with evidence of MYH3 expression in bone, suggest that embryonic myosin plays a role in skeletal development.

  20. Activation of AMP-activated kinase as a strategy for managing autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    McCarty, Mark F; Barroso-Aranda, Jorge; Contreras, Francisco

    2009-12-01

    There is evidence that overactivity of both mammalian target of rapamycin (mTOR) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes importantly to the progressive expansion of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). Recent research has established that AMP-activated kinase (AMPK) can suppress the activity of each of these proteins. Clinical AMPK activators such as metformin and berberine may thus have potential in the clinical management of ADPKD. The traditional use of berberine in diarrhea associated with bacterial infections may reflect, in part, the inhibitory impact of AMPK on chloride extrusion by small intestinal enterocytes.

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

    DEFF Research Database (Denmark)

    Winkelmann, Juliane; Lin, Ling; Schormair, Barbara

    2012-01-01

    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.......GLY605Ala mutation was subsequently identified. Narcolepsy and deafness were the first symptoms to appear in all pedigrees, followed by ataxia. DNMT1 is a widely expressed DNA methyltransferase maintaining methylation patterns in development, and mediating transcriptional repression by direct binding...

  2. [Massive inferior vena cava thrombosis in a patient with autosomal dominant polycystic hepatorenal disease].

    Science.gov (United States)

    Peces, R; Gil, F; Costero, O; Pobes, A

    2002-01-01

    We report a 68-year-old man with autosomal dominant polycystic kidney disease, who developed multiple venous thromboses (inferior vena cava, left renal vein and iliofemoral veins) caused by local compression of the intrahepatic inferior vena cava by hepatic cysts. To our knowledge this is the first reported case of inferior vena cava thrombosis caused by hepatic cysts compression. Doppler ultrasound, computed tomography, and magnetic resonance imaging were effective in documenting the venous thromboses and the underlying lesions non-invasively. Long-term anticoagulation was an efficient and safe treatment.

  3. Octreotide reduces hepatic, renal and breast cystic volume in autosomal-dominant polycystic kidney disease.

    Science.gov (United States)

    Peces, Ramón; Cuesta-López, Emilio; Peces, Carlos; Pérez-Dueñas, Virginia; Vega-Cabrera, Cristina; Selgas, Rafael

    2011-06-01

    A 43-year-old woman with autosomal-dominant polycystic kidney disease (ADPKD) received octreotide for 12 months, and this was associated with a 6.3% reduction in liver volume, an 8% reduction in total kidney volume and stabilization of renal function. There was also a reduction of cyst size in fibrocystic disease of breast. These data suggest that the cyst fluid accumulation in different organs from patients with ADPKD is a dynamic process which can be reversed by octreotide. This is the first report of a case of simultaneous reduction in hepatic, renal and breast cystic volume with preservation of renal function in a patient with ADPKD receiving octreotide.

  4. [Mapping of pathogenic genes in two families with autosomal dominant ichthyosis vulgaris].

    Science.gov (United States)

    Gong, Hui-Yong; Zhang, Jing; Hu, Zheng-Mao; Wu, Ling-Qian; Liang, De-Sheng; Xie, Zhi-Guo; Pan, Qian; Bu, Feng-Xiao; Peng, Yu; Xia, Kun; Xia, Jia-Hui

    2008-07-01

    To localize the pathogenic genes of autosomal dominant ichthyosis vulgaris, we ascertained two ichthyosis vulgaris families from Hunan Province. Venous blood samples were collected from affected and unaffected family members and genomic DNA was extracted. We then performed genome scan and linkage analysis using microsatellite markers around known ichthyosis vulgaris loci in chromosomes 1 and 10. In family 1, the locus linked to ichthyosis vulgaris was located near D1S498 (1q21), which overlapped with known ichthyosis vulgaris loci. In family 2, however, all known loci for ichthyosis vulgaris were excluded and the new locus remains to be identified.

  5. Multifocal renal cell carcinoma of different histological subtypes in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Na, Ki Yong; Kim, Hyun-Soo; Park, Yong-Koo; Chang, Sung-Goo; Kim, Youn Wha

    2012-08-01

    Renal cell carcinoma (RCC) in autosomal dominant polycystic kidney (ADPKD) is rare. To date, 54 cases of RCC in ADPKD have been reported. Among these, only 2 cases have different histologic types of RCC. Here we describe a 45-year-old man who received radical nephrectomy for multifocal RCC with synchronous papillary and clear cell histology in ADPKD and chronic renal failure under regular hemodialysis. The case reported herein is another example of the rare pathological finding of RCC arising in a patient with ADPKD.

  6. Mechanisms and management of hypertension in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Rahbari-Oskoui, Frederic; Williams, Olubunmi; Chapman, Arlene

    2014-12-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease, characterized by progressive cyst growth and renal enlargement, resulting in renal failure. Hypertension is common and occurs early, prior to loss of kidney function. Whether hypertension in ADPKD is a primary vasculopathy secondary to mutations in the polycystin genes or secondary to activation of the renin-angiotensin-aldosterone system by cyst expansion and intrarenal ischemia is unclear. Dysregulation of the primary cilium causing endothelial and vascular smooth muscle cell dysfunction is a component of ADPKD. In this article, we review the epidemiology, pathophysiology and clinical characteristics of hypertension in ADPKD and give specific recommendations for its treatment.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Directory of Open Access Journals (Sweden)

    Larsen Michael

    2011-04-01

    Full Text Available Abstract Background 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 in ADOA, the frequency of OPA1 genomic rearrangements in Denmark, where ADOA has a high prevalence, is unknown. The aim of the study was to identify copy number variations in OPA1 in Danish ADOA patients. Methods Forty unrelated ADOA patients, selected from a group of 100 ADOA patients as being negative for OPA1 point mutations, were tested for genomic rearrangements in OPA1 by multiplex ligation probe amplification (MLPA. When only one probe was abnormal results were confirmed by additional manually added probes. Segregation analysis was performed in families with detected mutations when possible. Results Ten families had OPA1 deletions, including two with deletions of the entire coding region and eight with intragenic deletions. Segregation analysis was possible in five families, and showed that the deletions segregated with the disease. Conclusion Deletions in the OPA1 gene were found in 10 patients presenting with phenotypic autosomal dominant optic neuropathy. Genetic testing for deletions in OPA1 should be offered for patients with clinically diagnosed ADOA and no OPA1 mutations detected by DNA sequencing analysis.

  9. Autosomal dominant tubulointerstitial kidney disease: diagnosis, classification, and management--A KDIGO consensus report.

    Science.gov (United States)

    Eckardt, Kai-Uwe; Alper, Seth L; Antignac, Corinne; Bleyer, Anthony J; Chauveau, Dominique; Dahan, Karin; Deltas, Constantinos; Hosking, Andrew; Kmoch, Stanislav; Rampoldi, Luca; Wiesener, Michael; Wolf, Matthias T; Devuyst, Olivier

    2015-10-01

    Rare autosomal dominant tubulointerstitial kidney disease is caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor-1β (HNF1B), renin (REN), and mucin-1 (MUC1). Multiple names have been proposed for these disorders, including 'Medullary Cystic Kidney Disease (MCKD) type 2', 'Familial Juvenile Hyperuricemic Nephropathy (FJHN)', or 'Uromodulin-Associated Kidney Disease (UAKD)' for UMOD-related diseases and 'MCKD type 1' for the disease caused by MUC1 mutations. The multiplicity of these terms, and the fact that cysts are not pathognomonic, creates confusion. Kidney Disease: Improving Global Outcomes (KDIGO) proposes adoption of a new terminology for this group of diseases using the term 'Autosomal Dominant Tubulointerstitial Kidney Disease' (ADTKD) appended by a gene-based subclassification, and suggests diagnostic criteria. Implementation of these recommendations is anticipated to facilitate recognition and characterization of these monogenic diseases. A better understanding of these rare disorders may be relevant for the tubulointerstitial fibrosis component in many forms of chronic kidney disease.

  10. Gene mapping of autosomal dominant retinitis pigmentosa in a Chinese family

    Institute of Scientific and Technical Information of China (English)

    DAI Li-li; SUN Da-wei; WANG Zheng; FU Song-bin; HUANG Shang-zhi; ZHANG Zhong-yu; ZENG Guang; PENG Shao-min

    2009-01-01

    Background The autosomal dominant form of retinitis pigmentosa (ADRP) can be caused by mutations in 14 genes and further loci remains to be identified. This study was intended to identify mutations in a Chinese pedigree with ADRP. Methods A large Chinese family with retinitis pigmentosa was collected. The genetic analysis of the family suggested an autosomal dominant pattern. Microsatellite (STR) markers tightly linked to genes known to be responsible for ADRP were selected for linkage analysis. Exons along with adjacent splice junctions of PRPF31 were amplified by polymerase chain reaction (PCR) and screened by direct sequencing.Results The caused gene of ADRP was mapped to 19q13.4 between markers D19S572 and D19S877, with a maximum LOD score of 3.01 at marker D19S418 (recombination fraction=0).Conclusion The affected gene linked to the 19q13.4 in a Chinese family with ADRP, which is different from other mutations at the same loci in other Chinese families.

  11. Familial clustering of medullary sponge kidney is autosomal dominant with reduced penetrance and variable expressivity.

    Science.gov (United States)

    Fabris, Antonia; Lupo, Antonio; Ferraro, Pietro M; Anglani, Franca; Pei, York; Danza, Francesco M; Gambaro, Giovanni

    2013-02-01

    Medullary sponge kidney (MSK) is a renal malformation typically associated with nephrocalcinosis and recurrent calcium nephrolithiasis. Approximately 12% of recurrent stone formers have MSK, which is generally considered a sporadic disorder. Since its discovery, three pedigrees have been described in which an apparently autosomal dominant inheritance was suggested. Here, family members of 50 patients with MSK were systematically investigated by means of interviews, renal imaging, and biochemical studies in an effort to establish whether MSK is an inheritable disorder. Twenty-seven MSK probands had 59 first- and second-degree relatives of both genders with MSK in all generations. There were progressively lower mean levels of serum calcium, urinary sodium, pH, and volume, combined with higher serum phosphate and potassium from probands to relatives with bilateral, to those with unilateral, and to those unaffected by MSK. This suggests that most affected relatives have a milder form of MSK than the probands, which would explain why they had not been so diagnosed. Thus, our study provides strong evidence that familial clustering of MSK is common, and has an autosomal dominant inheritance, a reduced penetrance, and variable expressivity.

  12. Linkage of the late onset autosomal dominant familial spastic paraplegia (DFSPII) to chromosome 2p markers

    Energy Technology Data Exchange (ETDEWEB)

    Hentati, A.; Wasserman, B.; Siddique, T. [Northwestern Univ. Medical School, Chicago, IL (United States)] [and others

    1994-09-01

    Pure familial spastic paraplegias (FSP) is a neurodegenerative disease characterized by spasticity of lower limbs. FSP in inherited as an autosomal dominant (DFSP) or an autosomal recessive (RFSP) trait. DFSP has been classified into early onset (DFSPI) and late onset (DFSPII) based on the mean age of onset in families. A locus for RFSP has been mapped to chromosome 8, while a locus for DFSPI has been mapped to chromosome 14q. Genetic locus heterogeneity was observed in both of these forms. The location of DFSPII locus (or loci) is unknown. We collected DNA samples from 81 individuals including 26 affecteds from three DFSPII families (9998, 840, 581). The mean age of onset of systems was 26.5, 42.5, and 35.2 years, respectively. We first tested 156 DNA markers distributed throughout the human 22 autosomes with family 9998 and positive lod scores were obtained with chromosome 2p markers D2S174 (Z({theta})=2.93 at {theta}=0.00), D2S146 (Z({theta})=1.03 at {theta}=0.00) and D2S177 (Z({theta})=1.04 at {theta}=0.00). Analysis of the 2 additional families confirmed the linkage with a peak lod score of Z({theta})=4.62 at {theta}=0.105 with D2S174. The multipoint linkage analysis using the map D2S175-10cM-D2S174-14cM-D2DS177 suggested that the DFSPII locus most likely maps between D2S174 and D2S177 with Z({theta})=6.11. There was no evidence in our data supporting genetic locus heterogeneity for the DFSPII.

  13. 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.

  14. 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

  15. SIPA1L3 identified by linkage analysis and whole-exome sequencing as a novel gene for autosomal recessive congenital cataract.

    Science.gov (United States)

    Evers, Christina; Paramasivam, Nagarajan; Hinderhofer, Katrin; Fischer, Christine; Granzow, Martin; Schmidt-Bacher, Annette; Eils, Roland; Steinbeisser, Herbert; Schlesner, Matthias; Moog, Ute

    2015-12-01

    Congenital cataract (CC) is one of the most important causes for blindness or visual impairment in infancy. A substantial proportion of isolated CCs has monogenic causes. The disease is genetically heterogeneous, and all Mendelian modes of inheritance have been reported. We mapped a locus for isolated CC on 19p13.1-q13.2 in a distantly consanguineous German family with two sisters affected by dense white cataracts. Whole-exome sequencing identified a homozygous nonsense variant c.4489C>T (p.(R1497*)) in SIPA1L3 (signal-induced proliferation-associated 1 like 3) in both affected children. SIPA1L3 encodes a GTPase-activating protein (GAP), which interacts with small GTPases of the Rap family via its Rap-GAP-domain. The suggested role of Rap GTPases in cell growth, differentiation and organization of the cytoskeleton in the human lens, and lens-enriched expression of the murine ortholog gene Sipa1l3 in embryonic mice indicates that this gene is crucial for early lens development. Our results provide evidence that sequence variants in human SIPA1L3 cause autosomal recessive isolated CC and give new insight into the molecular pathogenesis underlying human cataracts.

  16. Fine localization of the locus for autosomal dominant retinitis pigmentosa on chromosome 17p

    Energy Technology Data Exchange (ETDEWEB)

    Goliath, R.; Janssens, P.; Beighton, P. [Univ. of Cape Town (South Africa)] [and others

    1995-10-01

    The term {open_quotes}retintis pigmentosa{close_quotes} (RP) refers to a group of inherited retinal degenerative disorders. Clinical manifestations include night-blindness, with variable age of onset, followed by constriction of the visual field that may progress to total loss of sight in later life. Previous studies have shown that RP is caused by mutations within different genes and may be inherited as an X-linked recessive (XLRRP), autosomal recessive (ARRP), or autosomal dominant (ADRP) trait. The AD form of this group of conditions has been found to be caused by mutations within the rhodopsin gene in some families and the peripherin/RDS gene in others. In addition, some ADRP families have been found to be linked to anonymous markers on 8cen, 7p, 7q,19q, and, more recently, 17p. The ADRP gene locus on the short arm of chromosome 17 was identified in a large South African family (ADRP-SA) of British origin. The phenotypic expression of the disorder, which has been described elsewhere is consistent in the pedigree with an early onset of disease symptoms. In all affected subjects in the family, onset of symptoms commenced before the age of 10 years. 16 refs., 3 figs., 1 tab.

  17. Autosomal dominant familial spastic paraplegia; Linkage analysis and evidence for linkage to chromosome 2p

    Energy Technology Data Exchange (ETDEWEB)

    Figlewicz, D.A. [Univ. of Rochester, NY (United States); Dube, M.P.; Rouleau, G.A. [McGill Univ., Montreal (Canada)] [and others

    1994-09-01

    Familial spastic paraplegia (FSP) is a degenerative disorder of the motor system characterized by progressive weakness and spasticity of the lower limbs. Little is known about the pathophysiology of this disorder. FSP can be inherited as an autosomal dominant (AD), autosomal recessive, or X-linked trait. We have undertaken linkage analysis for a group of 36 AD FSP families from which we have collected blood samples from 427 individuals, including 148 affected individuals. Typing of polymorphic markers has allowed us to exclude more than 50% of the genome. Recently, linkage for AD FSP to a locus on chromosome 14q was reported. Our AD FSP kindreds were tested for linkage to markers spanning the 20 cM region between D14S69 and D14S66; however, we were not able to establish linkage for any of our families to chromosome 14. Lod scores suggestive of linkage for some AD FSP kindreds have been obtained for markers on chromosome 2p. We have tested seven polymorphic markers spanning the region between D2S405 and D2S177. Our highest aggregate lod score, including all families tested, was obtained at the locus D2S352: 2.4 at 20 cM. Results from HOMOG analysis for linkage heterogeneity will be reported.

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

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    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.

  19. [Seminal vesicle cysts and infertility in autosomal dominant polycystic kidney disease].

    Science.gov (United States)

    Peces, R; Venegas, J L

    2005-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a systemic hereditary disorder characterized by bilateral diffuse renal cysts. Extrarenal involvement is a well known manifestation of ADPKD. Cysts in the liver, pancreas, lung, spleen, oesophagus, ovary, testis, epididymis, prostate, thyroid, bladder, uterus, brain, paraespinal, and seminal vesicle have also been described. The occurrence of seminal vesicle cysts is often unrecognised. We report here a man with seminal vesicle cysts and azoospermia associated with ADPKD. Seminal vesicle cysts are not uncommon in ADPKD and in some cases it is associated with infertility. Ultrasound and computed tomography imaging were effective in documenting the underlying lesions non-invasively. Studies evaluating fertility in patients with seminal vesicle cysts and ADPKD are needed.

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

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    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.

  1. AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD IN A LARGE IRANIAN FAMILY

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    D.D. Farhud

    1999-08-01

    Full Text Available Study of a family with autosomal dominant polycystic kidney diseases (ADPKD in five generations, including 96 healthy and 47 affected individuals, has been carried out in Tehran. Investigation on individuals, including final diagnoses by clinical findings, sonography, radiography and laboratory results, have Lead to the completion of genealogical chart of the family. The affected individuals have reached a stage of the disease with confirmed occurrence of renal damages. Uncertain diagnoses, unconfirmed statements of the family members about probable presence of the disease in some other members, and also the death of some members by other reasons were not possible to be registered in the chart. Up to now the chart has been the largest and the most complete in Iran, compared with the ones reported in the available literature.

  2. Disseminated kidney tuberculosis complicating autosomal dominant polycystic kidney disease: a case report.

    Science.gov (United States)

    Takeshita, Hideki; Amemiya, Morimasa; Chiba, Koji; Urushibara, Masayasu; Satoh, Jun-Ichi; Noro, Akira

    2012-03-01

    Mycobacterium tuberculosis infection in patients with autosomal dominant polycystic kidney disease (ADPKD) is rare, and its diagnosis and treatment are difficult because numerous cysts are exposed to infection and antibiotics do not easily penetrate infected cysts. Here, we report the case of a 43-year-old Japanese man with disseminated urogenital tuberculosis (TB) and ADPKD without human immunodeficiency virus (HIV) infection. Delayed diagnosis and ineffective anti-TB chemotherapy worsened his condition. Finally, he underwent bilateral nephrectomy but experienced postoperative complications. In conclusion, kidney TB should be recognized as a cause of renal infection in ADPKD, and surgical treatment should be instituted without delay. The importance of early diagnosis and treatment cannot be overemphasized to prevent kidney TB deterioration.

  3. Autosomal dominant rolandic epilepsy and speech dyspraxia: a new syndrome with anticipation.

    Science.gov (United States)

    Scheffer, I E; Jones, L; Pozzebon, M; Howell, R A; Saling, M M; Berkovic, S F

    1995-10-01

    We describe a family of 9 affected individuals in three generations with nocturnal oro-facio-brachial partial seizures, secondarily generalized partial seizures, and centro-temporal epileptiform discharges, associated with oral and speech dyspraxia and cognitive impairment. The speech disorder was prominent, but differed from that of Landau-Kleffner syndrome and of epilepsy with continuous spike and wave during slow-wave sleep. The electroclinical features of this new syndrome of autosomal dominant rolandic epilepsy resemble those of benign rolandic epilepsy, a common inherited epilepsy of childhood. This family shows clinical anticipation of the seizure disorder, the oral and speech dyspraxia, and cognitive dysfunction, suggesting that the genetic mechanism could be expansion of an unstable triplet repeat. Molecular studies on this syndrome, where the inheritance pattern is clear, could also be relevant to identifying a gene for benign rolandic epilepsy where anticipation does not occur and the mode of inheritance is uncertain.

  4. Primary shunt hyperbilirubinaemia in a large four-generation family confirming autosomal dominant genetic disorder

    Institute of Scientific and Technical Information of China (English)

    Chun-Lian Wang; Xiao-Wei Liu; Fang-Gen Lu; Xiao-Ping Wu; Chun-Hui Ouyang; Dong-Ye Yang

    2006-01-01

    AIM: To describe the pattern of inheritance and confirm the diagnosdc criteria of primary shunt hyperbilirubinaemia (PSH).METHODS: Forty members of a family pedigree across four generations were included in this study. All family members were interviewed and investigated by physical examination, hematology and liver function test and the pattern of inheritance was analyzed.RESULTS: Nine of the forty family members suffered primary shunt hyperbilirubinaemia. The mature erythrocytes of the propositus were irregular in shape and size.The pedigree showed transmission of the trait through four generations with equal distribution in male and female. No individual with a primary shunt hyperbilirubinaemia was born to unaffected parents. The penetrance was complete in adult.CONCLUSION: The pattern of inheritance is autosomal dominant. The abnormality of erythrocytes and decrease in white blood cell could be supplemented in the diagnosis of PSH. The PSH is a genetic disorder and could by renamed as hereditary shunt hyperbilirubinaemia.

  5. Mutational screening of 320 Brazilian patients with autosomal dominant spinocerebellar ataxia.

    Science.gov (United States)

    Cintra, Vívian Pedigone; Lourenço, Charles Marques; Marques, Sandra Elisabete; de Oliveira, Luana Michelli; Tumas, Vitor; Marques, Wilson

    2014-12-15

    Autosomal dominant spinocerebellar ataxias (SCAs) are a clinical and genetically heterogeneous group of debilitating neurodegenerative diseases that are related to at least 36 different genetic loci; they are clinically characterized by progressive cerebellar ataxia and are frequently accompanied by other neurological and non-neurological manifestations. The relative frequency of SCA varies greatly among different regions, presumably because of a founder effect or local ethnicities. Between July 1998 and May 2012, we investigated 320 Brazilian patients with an SCA phenotype who belonged to 150 unrelated families with an autosomal dominant inheritance pattern and 23 sporadic patients from 13 Brazilian states. A total of 265 patients (82.8%) belonging to 131 unrelated families (87.3%) were found to have a definite mutation, and SCA3 accounted for most of the familial cases (70.7%), followed by SCA7 (6%), SCA1 (5.3%), SCA2 (2.7%), SCA6 (1.3%), SCA8 (0.7%) and SCA10 (0.7%). In the Ribeirão Preto mesoregion, which is located in the northeast part of São Paulo State, the prevalence of SCA3 was approximately 5 per 100,000 inhabitants, which is the highest prevalence found in Brazil. No mutation was found in the SCA12, SCA17 and DRPLA genes, and all the sporadic cases remained without a molecular diagnosis. This study further characterizes the spectrum of SCA mutations found in Brazilian patients, which suggests the existence of regional differences and demonstrates the expansion of the SCA8 locus in Brazilian families.

  6. Clinical features and linkage analysis for a Chinese family with autosomal dominant central areolar choroidal dystrophy

    Institute of Scientific and Technical Information of China (English)

    MA Kai; LIU Ning-pu; YANG Xiu-fen; HAN Cui; ZHANG Ning; XU Jun; LIU Shou-bin; LU Hal; Torkel Snellingen; WANG Ning-li

    2009-01-01

    Background A Chinese family with autosomal dominant central areolar choroidal dystrophy (CACD) was identified.The purpose of this study was to collect the clinical findings from the family and to identify the genetic entity by linkage nalysis.Methods Forty-three individuals from 3 generations of the family underwent ophthalmologic examinations, including best-corrected visual acuity, examination of the anterior segments, and inspection of the ocular fundus after pharmacologic mydriasis. Affected family members further underwent color vision test, color fundus photography,fluorescein angiography, automated perimetry, and electroretinography. The family was followed up for 30 months.Peripheral venous blood or buccal swabs were collected from each family member and genomic DNA was extracted.Linkage analysis was performed for candidate genes or loci using microsatellite markers.Results Seven family members in 3 continuous generations were diagnosed as having autosomal dominant CACD.The family showed progressive development of the disease, affecting both male and female. Age of onset of visual disturbances varied between 11 and 50 years. Phenotypic variability among affected individuals was apparent and ranged from relatively normal-appearing fundus with mild parafoveal pigment mottling to geographic atrophy of the macula. Fluorescein angiography showed hyperfluorescent parafoveal changes in early stage or well-demarcated area of chorioretinal atrophy with enhanced visibility of the residual underlying choroidal vessels in the late stage. Peripheral retina and visual fields were normal in affected individuals. Electroretinogram showed normal or mild reduction in the photopic amplitude. Eight candidate genes (STGD4, RCD1, peripherin/RDS, GUCA1A, RIMS1, UNC119, GUC Y2D, and AIPL1) and two genetic loci (4p15.2-16.3, and 17p13) were excluded to be responsible for the disease by linkage analysis.Conclusions The clinical findings of this Chinese family with CACD shared

  7. 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.

  8. Autosomal dominant familial spastic paraplegia: Tight linkage to chromosome 15q

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    Fink, J.K.; Wu, C.T.B.; Jones, S.M.

    1994-09-01

    Familial spastic paraplegia (FSP) (MIM No.18260) constitutes a clinically and genetically diverse group of disorders that share the primary feature of progressive, severe, lower extremity spasticity. FSP is classified according to the mode of inheritance and whether progressive spasticity occurs in isolation ({open_quotes}uncomplicated FSP{close_quotes}) or with other neurologic abnormalities ({open_quotes}complicated FSP{close_quotes}), including optic neuropathy, retinopathy, extrapyramidal disturbance, dementia, ataxia, ichthyosis, mental retardation, or deafness. Recently, autosomal dominant, uncomplicated FSP was shown to be genetically heterogeneous and tightly linked to a group of microsatellite markers on chromosome 14q in one large kindred. We examined 126 members of a non-consanguineous North American kindred of Irish descent. FSP was diagnosed in 31 living subjects who developed insidiously progressive gait disturbance between ages 12 and 35 years. Using genetic linkage analysis to microsatellite DNA polymorphisms, we showed that the FSP locus on chromosome 14q was exluded from linkage with the disorder in our family. Subsequently, we searched for genetic linkage between the disorder and microsatellite DNA polymorphisms spanning approximately 50% of the genome. We observed significantly positive, two-point maximum lod scores (Z) for markers on chromosome 15q: D15S128 (Z=9.70, {theta}=0.05), D15S165 (Z=3.30, {theta}=0.10), and UT511 (Z=3.86, {theta}=0.10). Our data clearly establishes that one locus for autosomal dominant, uncomplicated FSP is mapped to the pericentric region of chromosome 15q. Identifying genes responsible for chromosome 15q-linked and chromosome 14q-linked FSP will greatly advance our understanding of this condition and hopefully other inherited and degenerative brain and spinal cord disorders that are also characterized by axonal degeneration.

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

    Institute of Scientific and Technical Information of China (English)

    Ting Chen; Xiang-Hui Lu; Hui-Fang Wang; Rui Ban; Hua-Xu Liu; Qiang Shi; Qian Wang

    2016-01-01

    Background:Myopathies with rimmed vacuoles are a heterogeneous group of muscle disorders with progressive muscle weakness and varied clinical manifestations but similar features in muscle biopsies.Here,we describe a novel autosomal dominant myopathy with rimmed vacuoles in a large family with 11 patients of three generations affected.Methods:A clinical study including family history,obstetric,pediatric,and development history was recorded.Clinical examinations including physical examination,electromyography (EMG),serum creatine kinase (CK),bone X-rays,and brain magnetic resonance imaging (MRI) were performed in this family.Open muscle biopsies were performed on the proband and his mother.To find the causative gene,the whole-exome sequencing was carried out.Results:Disease onset was from adolescence to adulthood,but the affected patients of the third generation presented an earlier onset and more severe clinical manifestations than the older generations.Clinical features were characterized as dysarthria,dysphagia,external ophthalmoplegia,limb weakness,hypophrenia,deafness,and impaired vision.However,not every patient manifested all symptoms.Serum CK was mildly elevated and EMG indicated a myopathic pattern.Brain MRI showed cerebellum and brain stem mildly atrophy.Rimmed vacuoles and inclusion bodies were observed in muscle biopsy.The whole-exome sequencing was performed,but the causative gene has not been found.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.

  10. Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease

    Science.gov (United States)

    Benzinger, Tammie L. S.; Blazey, Tyler; Jack, Clifford R.; Koeppe, Robert A.; Su, Yi; Xiong, Chengjie; Raichle, Marcus E.; Snyder, Abraham Z.; Ances, Beau M.; Bateman, Randall J.; Cairns, Nigel J.; Fagan, Anne M.; Goate, Alison; Marcus, Daniel S.; Aisen, Paul S.; Christensen, Jon J.; Ercole, Lindsay; Hornbeck, Russ C.; Farrar, Angela M.; Aldea, Patricia; Jasielec, Mateusz S.; Owen, Christopher J.; Xie, Xianyun; Mayeux, Richard; Brickman, Adam; McDade, Eric; Klunk, William; Mathis, Chester A.; Ringman, John; Thompson, Paul M.; Ghetti, Bernardino; Saykin, Andrew J.; Sperling, Reisa A.; Johnson, Keith A.; Salloway, Stephen; Correia, Stephen; Schofield, Peter R.; Masters, Colin L.; Rowe, Christopher; Villemagne, Victor L.; Martins, Ralph; Ourselin, Sebastien; Rossor, Martin N.; Fox, Nick C.; Cash, David M.; Weiner, Michael W.; Holtzman, David M.; Buckles, Virginia D.; Moulder, Krista; Morris, John C.

    2013-01-01

    Major imaging biomarkers of Alzheimer’s disease include amyloid deposition [imaged with [11C]Pittsburgh compound B (PiB) PET], altered glucose metabolism (imaged with [18F]fluro-deoxyglucose PET), and structural atrophy (imaged by MRI). Recently we published the initial subset of imaging findings for specific regions in a cohort of individuals with autosomal dominant Alzheimer’s disease. We now extend this work to include a larger cohort, whole-brain analyses integrating all three imaging modalities, and longitudinal data to examine regional differences in imaging biomarker dynamics. The anatomical distribution of imaging biomarkers is described in relation to estimated years from symptom onset. Autosomal dominant Alzheimer’s disease mutation carrier individuals have elevated PiB levels in nearly every cortical region 15 y before the estimated age of onset. Reduced cortical glucose metabolism and cortical thinning in the medial and lateral parietal lobe appeared 10 and 5 y, respectively, before estimated age of onset. Importantly, however, a divergent pattern was observed subcortically. All subcortical gray-matter regions exhibited elevated PiB uptake, but despite this, only the hippocampus showed reduced glucose metabolism. Similarly, atrophy was not observed in the caudate and pallidum despite marked amyloid accumulation. Finally, before hypometabolism, a hypermetabolic phase was identified for some cortical regions, including the precuneus and posterior cingulate. Additional analyses of individuals in which longitudinal data were available suggested that an accelerated appearance of volumetric declines approximately coincides with the onset of the symptomatic phase of the disease. PMID:24194552

  11. A Three-Generation Family with Idiopathic Facial Palsy Suggesting an Autosomal Dominant Inheritance with High Penetrance

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    Christian Grønhøj Larsen

    2015-01-01

    Full Text Available 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 with low or variable penetrance, but the present family indicates an autosomal dominant trait with high or complete penetrance. Chromosome microarray studies did not reveal a pathogenic copy number variation, which could enable identification of a candidate gene.

  12. Autosomal dominant polycystic kidney disease with diffuse proliferative glomerulonephritis - an unusual association: a case report and review of the literature

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    Kapoor Vinay

    2010-04-01

    Full Text Available Abstract Introduction Autosomal dominant polycystic kidney disease is an inherited disorder that is characterized by the development and growth of cysts in the kidneys and other organs. Urinary protein excretion is usually less than 1 g/24 hours in autosomal dominant polycystic kidney disease, and an association of nephrotic syndrome with this condition is considered rare. There are only anecdotal case reports of autosomal dominant polycystic kidney disease associated with nephrotic syndrome, with focal segmental glomerulosclerosis being the most commonly reported histopathological diagnosis. Nephrotic-range proteinuria in the presence of autosomal dominant polycystic kidney disease, with or without an accompanying decline in renal function, should be investigated by open renal biopsy to exclude coexisting glomerular disease. To the best of our knowledge, this is the first case of autosomal dominant polycystic kidney disease with histologically proven diffuse proliferative glomerulonephritis presenting with nephrotic-range proteinuria. No other reports of this could be found in a global electronic search of the literature. Case presentation We report the case of a 35-year-old Indo-Aryan man with autosomal dominant polycystic kidney disease associated with nephrotic syndrome and a concomitant decline in his glomerular filtration rate. Open renal biopsy revealed diffuse proliferative glomerulonephritis. An accurate diagnosis enabled us to manage him conservatively with a successful outcome, without the use of corticosteroid which is the standard treatment and the drug most commonly used to treat nephrotic syndrome empirically. Conclusion Despite the reluctance of physicians to carry out a renal biopsy on patients with autosomal dominant polycystic kidney disease, our case supports the idea that renal biopsy is needed in patients with polycystic kidney disease with nephrotic-range proteinuria to make an accurate diagnosis. It also illustrates the

  13. 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.

  14. Cyclic mood disorder heralding adult-onset autosomal dominant leucodystrophy: a clinical masquerader.

    Science.gov (United States)

    Jain, Rajendra S; Prakash, Swayam; Raghavendra, B S; Nagpal, Kadam; Handa, Rahul

    2014-06-01

    Leucodystrophies are a heterogeneous group of progressive white matter diseases which may be inherited in dominant, recessive or X-linked fashion depending on the type. Adrenoleucodystrophy (ALD) and metachromatic leucodystrophy (MLD) are rather commoner forms of leucodystrophies whereas krabbes disease, alexander disease, cannavans disease etc. are of less common type. Adult-onset autosomal dominant leucodystrophy (ADLD) is a lately described rarer form of leucodystrophy with perhaps no case report from India. Various leucodystrophies may have different clinical presentations, ranging from subtle cognitive and psychiatric manifestations to gross motor disabilities, visual impairment and seizure. Psychiatric manifestations in the form of psychoses and frank schizophrenia are commonly described in MLD. Depression though uncommonly reported in MLD, cyclic mood disorders have been rarely described in any form of leucodystrophies. We are reporting an eye opener, a case of ADLD which masqueraded as a rapid cyclic mood disorder for initial four years, later to be followed by progressive neurological signs and symptoms. To the best of our knowledge, this is perhaps the first case report of ADLD presenting as rapid cyclic mood disorder in the world literature.

  15. Novel LDB3 Mutation in a Patient With Autosomal Dominant Myofibrillar Myopathy

    Directory of Open Access Journals (Sweden)

    Talebi

    2016-01-01

    Full Text Available Introduction Myofibrillar myopathy (MFM is a rare human disease, characterized by a distinct histopathological pattern of myofibrillar degeneration and protein aggregates. LDB3 protein encoded by this gene is a key Z-disk protein that interacts with α-actinin and protein kinase C. Case Presentation In this paper, we identified the novel heterozygous, and hence, dominant mutation in the LIM domain-binding protein 3 gene (LDB3 in a patient affected by myofibrillar myopathy (MFM. We performed direct sequencing in an Iranian patient with autosomal-dominant inheritance of MFM characterized by clinical features, and we identified a heterozygous missense mutation in exon 10, c.1687A > G (p.Ile563Val in the LDB3 gene on chromosome 10:88476524. Conclusions Bioinformatics analyses using SIFT, Mutation Taster and Polyphen-2 indicated that p.Ile563Val was predicted to be damaging, disease causing, and probably damaging to and causing LDB3 dysfunction. As such, this mutation produces novel protein coding transcripts, which might explain the MFM phenotype in the patient.

  16. 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

  17. BDNF Val66Met moderates memory impairment, hippocampal function and tau in preclinical autosomal dominant Alzheimer's disease.

    Science.gov (United States)

    Lim, Yen Ying; Hassenstab, Jason; Cruchaga, Carlos; Goate, Alison; Fagan, Anne M; Benzinger, Tammie L S; Maruff, Paul; Snyder, Peter J; Masters, Colin L; Allegri, Ricardo; Chhatwal, Jasmeer; Farlow, Martin R; Graff-Radford, Neill R; Laske, Christoph; Levin, Johannes; McDade, Eric; Ringman, John M; Rossor, Martin; Salloway, Stephen; Schofield, Peter R; Holtzman, David M; Morris, John C; Bateman, Randall J

    2016-10-01

    SEE ROGAEVA AND SCHMITT-ULMS DOI101093/AWW201 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is implicated in synaptic excitation and neuronal integrity, and has previously been shown to moderate amyloid-β-related memory decline and hippocampal atrophy in preclinical sporadic Alzheimer's disease. However, the effect of BDNF in autosomal dominant Alzheimer's disease is unknown. We aimed to determine the effect of BDNF Val66Met on cognitive function, hippocampal function, tau and amyloid-β in preclinical autosomal dominant Alzheimer's disease. We explored effects of apolipoprotein E (APOE) ε4 on these relationships. The Dominantly Inherited Alzheimer Network conducted clinical, neuropsychological, genetic, biomarker and neuroimaging measures at baseline in 131 mutation non-carriers and 143 preclinical autosomal dominant Alzheimer's disease mutation carriers on average 12 years before clinical symptom onset. BDNF genotype data were obtained for mutation carriers (95 Val66 homozygotes, 48 Met66 carriers). Among preclinical mutation carriers, Met66 carriers had worse memory performance, lower hippocampal glucose metabolism and increased levels of cerebrospinal fluid tau and phosphorylated tau (p-tau) than Val66 homozygotes. Cortical amyloid-β and cerebrospinal fluid amyloid-β42 levels were significantly different from non-carriers but did not differ between preclinical mutation carrier Val66 homozygotes and Met66 carriers. There was an effect of APOE on amyloid-β levels, but not cognitive function, glucose metabolism or tau. As in sporadic Alzheimer's disease, the deleterious effects of amyloid-β on memory, hippocampal function, and tau in preclinical autosomal dominant Alzheimer's disease mutation carriers are greater in Met66 carriers. To date, this is the only genetic factor found to moderate downstream effects of amyloid-β in autosomal dominant Alzheimer's disease.

  18. Autosomal dominant inheritance of cardiac valves anomalies in two families: extended spectrum of left-ventricular outflow tract obstruction.

    NARCIS (Netherlands)

    Wessels, M.W.; Laar, I.M. van de; Roos-Hesselink, J.W.; Strikwerda, S.; Majoor-Krakauer, D.F.; Vries, L.B.A. de; Kerstjens-Frederikse, W.S.; Vos, Y.J.; Graaf, B.M. de; Bertoli-Avella, A.M.; Willems, P.J.

    2009-01-01

    Only a limited number of families with clear monogenic inheritance of nonsyndromic forms of congenital valve defects have been described. We describe two multiplex pedigrees with a similar nonsyndromic form of heart valve anomalies that segregate as an autosomal dominant condition. The first family

  19. Autosomal Dominant Inheritance of Cardiac Valves Anomalies in Two Families : Extended Spectrum of Left-Ventricular Outflow Tract Obstruction

    NARCIS (Netherlands)

    Wessels, Maria W.; van de Laar, Ingrid M. B. H.; Roos-Hesselink, Jolien; Strikwerda, Sipke; Majoor-Krakauer, Danielle F.; de Vries, Bert B. A.; Kerstjens-Frederikse, Wilhelmina S.; Vos, Yvonne J.; de Graaf, Bianca M.; Bertoli-Avella, Aida M.; Willems, Patrick J.

    2009-01-01

    Only a limited number of families with clear monogenic inheritance of nonsyndromic forms of congenital valve defects have been described. We describe two multiplex pedigrees with a similar nonsyndromic form of heart valve anomalies that segregate as an autosomal dominant condition. The first family

  20. Autosomal dominant rhegmatogenous retinal detachment associated with an Arg453Ter mutation in the COL2A1 gene.

    NARCIS (Netherlands)

    Go, S.L.; Maugeri, A.; Mulder, J.J.S.; Driel, M.A. van; Cremers, F.P.M.; Hoyng, C.B.

    2003-01-01

    PURPOSE: To investigate the clinical features and molecular causes of autosomal dominant rhegmatogenous retinal detachment (RRD) in two large families. METHODS: Clinical examination and linkage analysis of both families using markers flanking the COL2A1 gene associated with Stickler syndrome type 1,

  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; 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.

    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 activ

  2. Urodynamic evaluation of patients with autosomal dominant pure spastic paraplegia linked to chromosome 2p21-p24

    DEFF Research Database (Denmark)

    Jensen, L N; Gerstenberg, T; Kallestrup, E B

    1998-01-01

    OBJECTIVES: There are at least three clinically indistinguishable but genetically different types of autosomal dominant pure spastic paraplegia (ADPSP). Lower urinary tract symptoms are often present but have not been described in a homogeneous patient population. In this study lower urinary tract...

  3. A Mutation in VEGFC, a Ligand for VEGFR3, is Associated with Autosomal Dominant Milroy-like Primary Lymphedema

    NARCIS (Netherlands)

    Gordon, K.; Schulte, D.; Brice, G.; Simpson, M.A.; Roukens, M.G.; Impel, Van A.; Connell, F.; Kalidas, K.; Jeffery, S.; Mortimer, P.S.; Mansour, S.; Schulte-Merker, S.; Ostergaard, P.

    2013-01-01

    Rationale: Mutations in vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic het

  4. Urinary EGF Receptor Ligand Excretion in Patients with Autosomal Dominant Polycystic Kidney Disease and Response to Tolvaptan

    NARCIS (Netherlands)

    Harskamp, Laura R.; Gansevoort, Ron T.; Boertien, Wendy E.; van Oeveren, Wim; Engels, Gerwin E.; van Goor, Harry; Meijer, Esther

    2015-01-01

    Background and objectives Recent animal experiments suggest that dysregulation of the EGF receptor pathway plays a role in the pathophysiology of autosomal dominant polycystic kidney disease (ADPKD). Research on EGF receptor ligands in humans with ADPKD is lacking. EGF receptor figands were measured

  5. DFNA8/12 caused by TECTA mutations is the most identified subtype of nonsyndromic autosomal dominant hearing loss

    NARCIS (Netherlands)

    Hildebrand, M.S.; Morin, M.; Meyer, N.C.; Mayo, F.; Modamio-Hoybjor, S.; Mencia, A.; Olavarrieta, L.; Morales-Angulo, C.; Nishimura, C.J.; Workman, H.; DeLuca, A.P.; Castillo, I. del; Taylor, K.R.; Tompkins, B.; Goodman, C.W.; Schrauwen, I.; Wesemael, M.V.; Lachlan, K.; Shearer, A.E.; Braun, T.A.; Huygen, P.L.M.; Kremer, J.M.J.; Camp, G. van; Moreno, F.; Casavant, T.L.; Smith, R.J.; Moreno-Pelayo, M.A.

    2011-01-01

    The prevalence of DFNA8/DFNA12 (DFNA8/12), a type of autosomal dominant nonsyndromic hearing loss (ADNSHL), is unknown as comprehensive population-based genetic screening has not been conducted. We therefore completed unbiased screening for TECTA mutations in a Spanish cohort of 372 probands from AD

  6. Relative Contribution of Mutations in Genes for Autosomal Dominant Distal Hereditary Motor Neuropathies: A Genotype-Phenotype Correlation Study

    Science.gov (United States)

    Dierick, Ines; Baets, Jonathan; Irobi, Joy; Jacobs, An; De Vriendt, Els; Deconinck, Tine; Merlini, Luciano; Van den Bergh, Peter; Rasic, Vedrana Milic; Robberecht, Wim; Fischer, Dirk; Morales, Raul Juntas; Mitrovic, Zoran; Seeman, Pavel; Mazanec, Radim; Kochanski, Andrzej; Jordanova, Albena; Auer-Grumbach, Michaela; Helderman-van den Enden, A. T. J. M.; Wokke, John H. J.; Nelis, Eva; De Jonghe, Peter; Timmerman, Vincent

    2008-01-01

    Distal hereditary motor neuropathy (HMN) is a clinically and genetically heterogeneous group of disorders affecting spinal alpha-motor neurons. Since 2001, mutations in six different genes have been identified for autosomal dominant distal HMN; "glycyl-tRNA synthetase (GARS)," "dynactin 1 (DCTN1)," "small heat shock 27 kDa protein 1 (HSPB1),"…

  7. Autosomal Dominant Pseudohypoaldosteronism Type 1 in an Infant with Salt Wasting Crisis Associated with Urinary Tract Infection and Obstructive Uropathy

    Directory of Open Access Journals (Sweden)

    Sasigarn A. Bowden

    2013-01-01

    Full Text Available Type 1 pseudohypoaldosteronism (PHA1 is a salt wasting syndrome caused by renal resistance to aldosterone. Primary renal PHA1 or autosomal dominant PHA1 is caused by mutations in mineralocorticoids receptor gene (NR3C2, while secondary PHA1 is frequently associated with urinary tract infection (UTI and/or urinary tract malformations (UTM. We report a 14-day-old male infant presenting with severe hyperkalemia, hyponatremic dehydration, metabolic acidosis, and markedly elevated serum aldosterone level, initially thought to have secondary PHA1 due to the associated UTI and posterior urethral valves. His serum aldosterone remained elevated at 5 months of age, despite resolution of salt wasting symptoms. Chromosomal microarray analysis revealed a deletion of exons 3–5 in NR3C2 in the patient and his asymptomatic mother who also had elevated serum aldosterone level, confirming that he had primary or autosomal dominant PHA1. Our case raises the possibility that some patients with secondary PHA1 attributed to UTI and/or UTM may instead have primary autosomal dominant PHA1, for which genetic testing should be considered to identify the cause, determine future recurrence risk, and possibly prevent the life-threatening salt wasting in a subsequent family member. Future clinical research is needed to investigate the potential overlapping between secondary PHA1 and primary autosomal dominant PHA1.

  8. 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...

  9. Is There any Effect of Urogenital Cysts on Semen Parameters in Autosomal Dominant Polycystic Kidney Disease?

    Directory of Open Access Journals (Sweden)

    Sami UZUN

    2015-09-01

    Full Text Available OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD is a systemic disease with cysts in many organs including the urogenital tract. The aim of the study was to evaluate the relationship between urogenital cysts, semen pathologies and infertility in ADPKD. MATERIAL and METHODS: Male ADPKD patients aged 18-60 with creatinine clearance years higher than 60 ml/min were included. All patients had magnetic resonance imaging of the urinary system and pelvis, scrotal Doppler ultrasonography and sperm analysis. The results were compared with those of a healthy control group. RESULTS: 27 patients and 17 volunteers were included. Seminal vesicle and prostate cysts were detected in four (15% and six (22% patients, respectively. Five of the 23 married patients (21% had infertility and this rate was higher than in the control group (p=0.044. The ratio of sperms with normal morphology and progressive motility was lower, and the rate of hypospermia, oligozoospermia, azospermia, asthenozoospermia and teratozoospermia were higher in the patient group. There was no significant difference between patients with/without urogenital cysts regarding seminal pathologies. CONCLUSION: Seminal abnormalities and infertility are more frequent in patients with ADPKD. Defects in spermatogenesis and sperm motility may be related to urogenital cysts as well as ciliary pathologies. There is a need for further studies evaluating the role of urogenital cysts in semen pathologies.

  10. A gene for autosomal dominant hearing loss on the short arm of chromosome 1

    Energy Technology Data Exchange (ETDEWEB)

    Van Camp, G.; Coucke, P.; Willems, P.J. [and others

    1994-09-01

    Hearing loss is the most common form of sensory impairment and many cases are attributable to genetic causes. The genetic defects underlying several syndromic forms of deafness have been identified, but little is known about the causes of non-syndromic hereditary deafness which accounts for the majority of inherited hearing loss. We report here a large Indonesian family with non-syndromal postlingual hearing loss starting in the high frequencies and showing autosomal dominant inheritance. To locate the gene responsible for the hearing loss in this family, we performed a genome search by genetic linkage analysis with microsatellite markers distributed over the whole genome. We have mapped the gene causing deafness in an extended Indonesian family to chromosome 1p with a multipoint lod score higher than 7. Two other smaller families, showing a similar hereditary hearing loss, were also tested for linkage with chromosome 1p. One family originating from the U.S. was linked to this new locus with a multipoint lod score exceeding 5. In another family from the Netherlands this locus was excluded. The flanking markers D1S255 and D1S211 define a region of 6 cM on chromosome 1p which is likely to contain the deafness gene present in the Indonesian and American family.

  11. Neuropathology of Autosomal Dominant Alzheimer Disease in the National Alzheimer Coordinating Center Database.

    Science.gov (United States)

    Ringman, John M; Monsell, Sarah; Ng, Denise W; Zhou, Yan; Nguyen, Andy; Coppola, Giovanni; Van Berlo, Victoria; Mendez, Mario F; Tung, Spencer; Weintraub, Sandra; Mesulam, Marek-Marsel; Bigio, Eileen H; Gitelman, Darren R; Fisher-Hubbard, Amanda O; Albin, Roger L; Vinters, Harry V

    2016-03-01

    Alzheimer disease (AD) represents a genetically heterogeneous entity. To elucidate neuropathologic features of autosomal dominant AD ([ADAD] due to PSEN1, APP, or PSEN2 mutations), we compared hallmark AD pathologic findings in 60 cases of ADAD and 120 cases of sporadic AD matched for sex, race, ethnicity, and disease duration. Greater degrees of neuritic plaque and neurofibrillary tangle formation and cerebral amyloid angiopathy (CAA) were found in ADAD (p values < 0.01). Moderate to severe CAA was more prevalent in ADAD (63.3% vs. 39.2%, p = 0.003), and persons with PSEN1 mutations beyond codon 200 had higher average Braak scores and severity and prevalence of CAA than those with mutations before codon 200. Lewy body pathology was less extensive in ADAD but was present in 27.1% of cases. We also describe a novel pathogenic PSEN1 mutation (P267A). The finding of more severe neurofibrillary pathology and CAA in ADAD, particularly in carriers of PSEN1 mutations beyond codon 200, warrants consideration when designing trials to treat or prevent ADAD. The finding of Lewy body pathology in a substantial minority of ADAD cases supports the assertion that development of Lewy bodies may be in part driven by abnormal β-amyloid protein precursor processing.

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

    Science.gov (United States)

    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.

  13. A novel autosomal dominant inclusion body myopathy linked to 7q22.1-31.1.

    Directory of Open Access Journals (Sweden)

    Yan Lu

    Full Text Available We describe a novel autosomal dominant hereditary inclusion body myopathy (HIBM that clinically mimics limb girdle muscular dystrophy in a Chinese family. We performed a detailed clinical assessment of 36 individuals spanning four generations. The age of onset ranged from the 30s to the 50s. Hip girdle, neck flexion and axial muscle weakness were involved at an early stage. This disease progressed slowly, and a shoulder girdle weakness appeared later in the disease course. Muscle biopsies showed necrotic, regenerating, and rimmed vacuolated fibers as well as congophilic inclusions in some of the fibers. Electron micrograph revealed cytoplasmic inclusions of 15-21 nm filaments. A genomewide scan and haplotype analyses were performed using an Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM, which traced the disease to a new locus on chromosome 7q22.1-31.1 with a maximum multi-point LOD score of 3.65. The critical locus for this unique disorder, which is currently referred to as hereditary inclusion body myopathy 4 (HIBM4, spans 8.78 Mb and contains 65 genes. This localization raises the possibility that one of the genes clustered within this region may be involved in this disorder.

  14. A new locus for autosomal dominant amelogenesis imperfecta on chromosome 8q24.3.

    Science.gov (United States)

    Mendoza, Gustavo; Pemberton, Trevor J; Lee, Kwanghyuk; Scarel-Caminaga, Raquel; Mehrian-Shai, Ruty; Gonzalez-Quevedo, Catalina; Ninis, Vasiliki; Hartiala, Jaana; Allayee, Hooman; Snead, Malcolm L; Leal, Suzanne M; Line, Sergio R P; Patel, Pragna I

    2007-01-01

    Amelogenesis imperfecta (AI) is a collective term used to describe phenotypically diverse forms of defective tooth enamel development. AI has been reported to exhibit a variety of inheritance patterns, and several loci have been identified that are associated with AI. We have performed a genome-wide scan in a large Brazilian family segregating an autosomal dominant form of AI and mapped a novel locus to 8q24.3. A maximum multipoint LOD score of 7.5 was obtained at marker D8S2334 (146,101,309 bp). The disease locus lies in a 1.9 cM (2.1 Mb) region according to the Rutgers Combined Linkage-Physical map, between a VNTR marker (at 143,988,705 bp) and the telomere (146,274,826 bp). Ten candidate genes were identified based on gene ontology and microarray-facilitated gene selection using the expression of murine orthologues in dental tissue, and examined for the presence of a mutation. However, no causative mutation was identified.

  15. 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.

  16. Anomalous superficial radial nerve: a patient with probable autosomal dominant inheritance of the anomaly.

    Science.gov (United States)

    Kuruvilla, Abraham; Laaksonen, Satu; Falck, Björn

    2002-11-01

    The sensory symptoms due to lesions of the superficial branch of the radial nerve are usually limited to the dorsolateral area of the hand. We describe a 40-year-old woman who presented with numbness of the dorsomedial aspect of the right hand following arthroplasty of the wrist. Clinically, the sensory loss suggested a lesion of the dorsal branch of the ulnar nerve. However, nerve conduction studies showed that the sensory loss was due to a lesion of a branch of the superficial branch of the radial nerve. The patient had bilateral, anomalous innervation of the dorsum of the hand-the dorsal branch of the ulnar nerve could not be demonstrated with nerve conduction techniques and the superficial branch of the radial nerve innervated most of the dorsum of the hand. Antidromic stimulation of the dorsal branch of the ulnar nerve and superficial branch of the radial nerve with paired surface recording of sensory nerve action potentials from the dorsolateral (radial side) and dorsomedial (ulnar side) hand is useful for evaluating this anomaly. Our patient had two children, one of them with a similar anomaly. This suggests an autosomal dominant inheritance of the anomaly.

  17. Multiple liver cyst infection caused by Salmonella ajiobo in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Himeno, Akihiro; Suzuki, Hiromichi; Suzuki, Yumiko; Kawaguchi, Hiroshi; Isozaki, Taisuke

    2013-06-01

    Most Salmonella infections are usually self-limited; however, some cases of enteritis result in bacteremia, and there have been reports of extra-intestinal manifestations. Cyst infections are rare, and few cases have been reported. We report a 77-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) complicated with a multiple liver cyst infection caused by Salmonella ajiobo. The patient was hospitalized for fever, abdominal pain, and diarrhea. The blood culture identified Salmonella sp., but the source of infection was not detected by computed tomography or echography. The patient was initially treated with meropenem followed by fluoroquinolones for 3 weeks; however, her C-reactive protein level was high (10-20 mg/dL) even after the antimicrobial therapy. The patient had a fever again on day 51, and Salmonella sp. was detected again from 2 sets of blood cultures. Despite the antimicrobial treatment, her general condition gradually deteriorated, and she died on day 66. The autopsy revealed that most of the liver had been replaced by cysts. Several cysts filled with pus were detected and Salmonella ajiobo was identified in the pus of the infected cysts.

  18. A new autosomal dominant eye and lung syndrome linked to mutations in TIMP3 gene

    Science.gov (United States)

    Meunier, Isabelle; Bocquet, Béatrice; Labesse, Gilles; Zeitz, Christina; Defoort-Dhellemmes, Sabine; Lacroux, Annie; Mauget-Faysse, Martine; Drumare, Isabelle; Gamez, Anne-Sophie; Mathieu, Cyril; Marquette, Virginie; Sagot, Lola; Dhaenens, Claire-Marie; Arndt, Carl; Carroll, Patrick; Remy-Jardin, Martine; Cohen, Salomon Yves; Sahel, José-Alain; Puech, Bernard; Audo, Isabelle; Mrejen, Sarah; Hamel, Christian P.

    2016-01-01

    To revisit the autosomal dominant Sorsby fundus dystrophy (SFD) as a syndromic condition including late-onset pulmonary disease. We report clinical and imaging data of ten affected individuals from 2 unrelated families with SFD and carrying heterozygous TIMP3 mutations (c.572A > G, p.Y191C, exon 5, in family 1 and c.113C > G, p.S38C, exon 1, in family 2). In family 1, all SFD patients older than 50 (two generations) had also a severe emphysema, despite no history of smoking or asthma. In the preceding generation, the mother died of pulmonary emphysema and she was blind after the age of 50. Her two great-grandsons (<20 years), had abnormal Bruch Membrane thickness, a sign of eye disease. In family 2, eye and lung diseases were also associated in two generations, both occurred later, and lung disease was moderate (bronchiectasis). This is the first report of a syndromic SFD in line with the mouse model uncovering the role of TIMP3 in human lung morphogenesis and functions. The TIMP3 gene should be screened in familial pulmonary diseases with bronchiectasis, associated with a medical history of visual loss. In addition, SFD patients should be advised to avoid tobacco consumption, to practice sports, and to undergo regular pulmonary examinations. PMID:27601084

  19. Erythropoietin Slows Photoreceptor Cell Death in a Mouse Model of Autosomal Dominant Retinitis Pigmentosa.

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    Tonia S Rex

    Full Text Available To test the efficacy of systemic gene delivery of a mutant form of erythropoietin (EPO-R76E that has attenuated erythropoietic activity, in a mouse model of autosomal dominant retinitis pigmentosa.Ten-day old mice carrying one copy of human rhodopsin with the P23H mutation and both copies of wild-type mouse rhodopsin (hP23H RHO+/-,mRHO+/+ were injected into the quadriceps with recombinant adeno-associated virus (rAAV carrying either enhanced green fluorescent protein (eGFP or EpoR76E. Visual function (electroretinogram and retina structure (optical coherence tomography, histology, and immunohistochemistry were assessed at 7 and 12 months of age.The outer nuclear layer thickness decreased over time at a slower rate in rAAV.EpoR76E treated as compared to the rAAV.eGFP injected mice. There was a statistically significant preservation of the electroretinogram at 7, but not 12 months of age.Systemic EPO-R76E slows death of the photoreceptors and vision loss in hP23H RHO+/-,mRHO+/+ mice. Treatment with EPO-R76E may widen the therapeutic window for retinal degeneration patients by increasing the number of viable cells. Future studies might investigate if co-treatment with EPO-R76E and gene replacement therapy is more effective than gene replacement therapy alone.

  20. 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

    2017-03-21

    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.

  1. A Missense Mutation in KCTD17 Causes Autosomal Dominant Myoclonus-Dystonia

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    Mencacci, Niccolo E.; Rubio-Agusti, Ignacio; Zdebik, Anselm; Asmus, Friedrich; Ludtmann, Marthe H.R.; Ryten, Mina; Plagnol, Vincent; Hauser, Ann-Kathrin; Bandres-Ciga, Sara; Bettencourt, Conceição; Forabosco, Paola; Hughes, Deborah; Soutar, Marc M.P.; Peall, Kathryn; Morris, Huw R.; Trabzuni, Daniah; Tekman, Mehmet; Stanescu, Horia C.; Kleta, Robert; Carecchio, Miryam; Zorzi, Giovanna; Nardocci, Nardo; Garavaglia, Barbara; Lohmann, Ebba; Weissbach, Anne; Klein, Christine; Hardy, John; Pittman, Alan M.; Foltynie, Thomas; Abramov, Andrey Y.; Gasser, Thomas; Bhatia, Kailash P.; Wood, Nicholas W.

    2015-01-01

    Myoclonus-dystonia (M-D) is a rare movement disorder characterized by a combination of non-epileptic myoclonic jerks and dystonia. SGCE mutations represent a major cause for familial M-D being responsible for 30%–50% of cases. After excluding SGCE mutations, we identified through a combination of linkage analysis and whole-exome sequencing KCTD17 c.434 G>A p.(Arg145His) as the only segregating variant in a dominant British pedigree with seven subjects affected by M-D. A subsequent screening in a cohort of M-D cases without mutations in SGCE revealed the same KCTD17 variant in a German family. The clinical presentation of the KCTD17-mutated cases was distinct from the phenotype usually observed in M-D due to SGCE mutations. All cases initially presented with mild myoclonus affecting the upper limbs. Dystonia showed a progressive course, with increasing severity of symptoms and spreading from the cranio-cervical region to other sites. KCTD17 is abundantly expressed in all brain regions with the highest expression in the putamen. Weighted gene co-expression network analysis, based on mRNA expression profile of brain samples from neuropathologically healthy individuals, showed that KCTD17 is part of a putamen gene network, which is significantly enriched for dystonia genes. Functional annotation of the network showed an over-representation of genes involved in post-synaptic dopaminergic transmission. Functional studies in mutation bearing fibroblasts demonstrated abnormalities in endoplasmic reticulum-dependent calcium signaling. In conclusion, we demonstrate that the KCTD17 c.434 G>A p.(Arg145His) mutation causes autosomal dominant M-D. Further functional studies are warranted to further characterize the nature of KCTD17 contribution to the molecular pathogenesis of M-D. PMID:25983243

  2. 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.

  3. 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.

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

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    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.

  5. 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.

  6. 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

    2011-05-05

    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.

  7. Differences in allele frequencies of autosomal dominant hypercholesterolemia SNPs in the Malaysian population.

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    Alex, Livy; Chahil, Jagdish Kaur; Lye, Say Hean; Bagali, Pramod; Ler, Lian Wee

    2012-06-01

    Hypercholesterolemia is caused by different interactions of lifestyle and genetic determinants. At the genetic level, it can be attributed to the interactions of multiple polymorphisms, or as in the example of familial hypercholesterolemia (FH), it can be the result of a single mutation. A large number of genetic markers, mostly single nucleotide polymorphisms (SNP) or mutations in three genes, implicated in autosomal dominant hypercholesterolemia (ADH), viz APOB (apolipoprotein B), LDLR (low density lipoprotein receptor) and PCSK9 (proprotein convertase subtilisin/kexin type-9), have been identified and characterized. However, such studies have been insufficiently undertaken specifically in Malaysia and Southeast Asia in general. The main objective of this study was to identify ADH variants, specifically ADH-causing mutations and hypercholesterolemia-associated polymorphisms in multiethnic Malaysian population. We aimed to evaluate published SNPs in ADH causing genes, in this population and to report any unusual trends. We examined a large number of selected SNPs from previous studies of APOB, LDLR, PCSK9 and other genes, in clinically diagnosed ADH patients (n=141) and healthy control subjects (n=111). Selection of SNPs was initiated by searching within genes reported to be associated with ADH from known databases. The important finding was 137 mono-allelic markers (44.1%) and 173 polymorphic markers (55.8%) in both subject groups. By comparing to publicly available data, out of the 137 mono-allelic markers, 23 markers showed significant differences in allele frequency among Malaysians, European Whites, Han Chinese, Yoruba and Gujarati Indians. Our data can serve as reference for others in related fields of study during the planning of their experiments.

  8. Spinal cord magnetic resonance imaging in autosomal dominant hereditary spastic paraplegia

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    Hedera, P. [University of Michigan, Department of Neurology, Ann Arbor, MI (United States); Vanderbilt University, Department of Neurology, Nashville, TN (United States); Eldevik, O.P.; Maly, P. [University of Michigan, Department of Radiology, Ann Arbor, MI (United States); Rainier, S. [University of Michigan, Department of Neurology, Ann Arbor, MI (United States); Fink, J.K. [University of Michigan, Department of Neurology, Ann Arbor, MI (United States); Ann Arbor Veterans Affairs Medical Center, Geriatric Research Education and Clinical Center, Ann Arbor, MI (United States)

    2005-10-01

    Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders characterized by progressive lower extremity weakness and spasticity. HSP pathology involves axonal degeneration that is most pronounced in the terminal segments of the longest descending (pyramidal) and ascending (dorsal columns) tracts. In this study, we compared spinal cord magnetic resonance imaging (MRI) in 13 HSP patients with four different types of autosomal dominant hereditary spastic paraplegia (SPG3A, SPG4, SPG6, and SPG8) with age-matched control subjects. The cross-section area of HSP subjects at cervical level C2 was 59.42{+-}12.57 mm{sup 2} and at thoracic level T9 was 28.58{+-}5.25 mm{sup 2}. Both of these values were less than in the healthy controls (p<0.001). The degree of cord atrophy was more prominent in patients with SPG6 and SPG8 who had signs of severe cord atrophy (47.60{+-}6.58 mm{sup 2} at C2, 21.40{+-}2.4 mm{sup 2} at T9) than in subjects with SPG3 and SPG4 (66.0{+-}8.94 mm{sup 2} at C2, p<0.02; 31.75{+-}2.76 mm{sup 2} at T9, p<0.001). These observations indicate that spinal cord atrophy is a common finding in the four genetic types of HSP. Spinal cord atrophy was more severe in SPG6 and SPG8 HSP subjects than in other types of HSP we studied. This may suggest a different disease mechanism with more prominent axonal degeneration in these two types of HSP when compared with HSP due to spastin and atlastin mutations. (orig.)

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

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    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.

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

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    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.

  11. PKD1 and PKD2 mutations in Slovenian families with autosomal dominant polycystic kidney disease

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    Vouk, Katja; Strmecki, Lana; Stekrova, Jitka; Reiterova, Jana; Bidovec, Matjaz; Hudler, Petra; Kenig, Anton; Jereb, Simona; Zupanic-Pajnic, Irena; Balazic, Joze; Haarpaintner, Guido; Leskovar, Bostjan; Adamlje, Anton; Skoflic, Antun; Dovc, Reina; Hojs, Radovan; Komel, Radovan

    2006-01-01

    Background Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder caused by mutations in at least two different loci. Prior to performing mutation screening, if DNA samples of sufficient number of family members are available, it is worthwhile to assign the gene involved in disease progression by the genetic linkage analysis. Methods We collected samples from 36 Slovene ADPKD families and performed linkage analysis in 16 of them. Linkage was assessed by the use of microsatellite polymorphic markers, four in the case of PKD1 (KG8, AC2.5, CW3 and CW2) and five for PKD2 (D4S1534, D4S2929, D4S1542, D4S1563 and D4S423). Partial PKD1 mutation screening was undertaken by analysing exons 23 and 31–46 and PKD2 . Results Lod scores indicated linkage to PKD1 in six families and to PKD2 in two families. One family was linked to none and in seven families linkage to both genes was possible. Partial PKD1 mutation screening was performed in 33 patients (including 20 patients from the families where linkage analysis could not be performed). We analysed PKD2 in 2 patients where lod scores indicated linkage to PKD2 and in 7 families where linkage to both genes was possible. We detected six mutations and eight polymorphisms in PKD1 and one mutation and three polymorphisms in PKD2. Conclusion In our study group of ADPKD patients we detected seven mutations: three frameshift, one missense, two nonsense and one putative splicing mutation. Three have been described previously and 4 are novel. Three newly described framesfift mutations in PKD1 seem to be associated with more severe clinical course of ADPKD. Previously described nonsense mutation in PKD2 seems to be associated with cysts in liver and milder clinical course. PMID:16430766

  12. PKD1 and PKD2 mutations in Slovenian families with autosomal dominant polycystic kidney disease

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    Adamlje Anton

    2006-01-01

    Full Text Available Abstract Background Autosomal dominant polycystic kidney disease (ADPKD is a genetically heterogeneous disorder caused by mutations in at least two different loci. Prior to performing mutation screening, if DNA samples of sufficient number of family members are available, it is worthwhile to assign the gene involved in disease progression by the genetic linkage analysis. Methods We collected samples from 36 Slovene ADPKD families and performed linkage analysis in 16 of them. Linkage was assessed by the use of microsatellite polymorphic markers, four in the case of PKD1 (KG8, AC2.5, CW3 and CW2 and five for PKD2 (D4S1534, D4S2929, D4S1542, D4S1563 and D4S423. Partial PKD1 mutation screening was undertaken by analysing exons 23 and 31–46 and PKD2 . Results Lod scores indicated linkage to PKD1 in six families and to PKD2 in two families. One family was linked to none and in seven families linkage to both genes was possible. Partial PKD1 mutation screening was performed in 33 patients (including 20 patients from the families where linkage analysis could not be performed. We analysed PKD2 in 2 patients where lod scores indicated linkage to PKD2 and in 7 families where linkage to both genes was possible. We detected six mutations and eight polymorphisms in PKD1 and one mutation and three polymorphisms in PKD2. Conclusion In our study group of ADPKD patients we detected seven mutations: three frameshift, one missense, two nonsense and one putative splicing mutation. Three have been described previously and 4 are novel. Three newly described framesfift mutations in PKD1 seem to be associated with more severe clinical course of ADPKD. Previously described nonsense mutation in PKD2 seems to be associated with cysts in liver and milder clinical course.

  13. Mutational analysis of the LDL receptor and APOB genes in Mexican individuals with autosomal dominant hypercholesterolemia.

    Science.gov (United States)

    Vaca, Gerardo; Vàzquez, Alejandra; Magaña, Marìa Teresa; Ramìrez, Marìa Lourdes; Dàvalos, Ingrid P; Martìnez, Esperanza; Marìn, Bertha; Carrillo, Gabriela

    2011-10-01

    The goal of this project was to identify families with autosomal dominant hypercholesterolemia (ADH) to facilitate early detection and treatment and to provide genetic counselling as well as to approximate the mutational diversity of ADH in Mexico. Mutational analysis of the LDLR and APOB genes in 62 index cases with a clinical and/or biochemical diagnosis of ADH was performed. Twenty-five mutations (24 LDLR, 1 APOB) were identified in 38 index cases. A total of 162 individuals with ADH were identified using familial segregation analysis performed in 269 relatives of the index cases. In addition, a novel PCSK9 mutation, c.1850 C>A (p.Ala617Asp), was detected. The LDLR mutations showed the following characteristics: (1) four mutations are novel: c.695 -1G>T, c.1034_1035insA, c.1586 G>A, c.2264_2273del; (2) the most common mutations were c.682 G>A (FH-Mexico), c.1055 G>A (FH-Mexico 2), and c.1090 T>C (FH-Mexico 3); (3) five mutations were identified in 3 or more apparently unrelated probands; (4) three mutations were observed in a true homozygous state; and (5) four index cases were compound heterozygous, and one was a carrier of two mutations in the same allele. These results suggest that, in Mexico, ADH exhibits allelic heterogeneity with 5 relatively common LDLR mutations and that mutations in the APOB gene are not a common cause of ADH. This knowledge is important for the genotype-phenotype correlation and for optimising both cholesterol lowering therapies and mutational analysis protocols. In addition, these data contribute to the understanding of the molecular basis of ADH in Mexico.

  14. Contribution of renal innervation to hypertension in rat autosomal dominant polycystic kidney disease.

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    Gattone, Vincent H; Siqueira, Tibério M; Powell, Charles R; Trambaugh, Chad M; Lingeman, James E; Shalhav, Arieh L

    2008-08-01

    The kidney has both afferent (sensory) and efferent (sympathetic) nerves that can influence renal function. Renal innervation has been shown to play a role in the pathogenesis of many forms of hypertension. Hypertension and flank pain are common clinical manifestations of autosomal dominant (AD) polycystic kidney disease (PKD). We hypothesize that renal innervation contributes to the hypertension and progression of cystic change in rodent PKD. In the present study, the contribution of renal innervation to hypertension and progression of renal histopathology and dysfunction was assessed in male Han:SPRD-Cy/+ rats with ADPKD. At 4 weeks of age, male offspring from crosses of heterozygotes (Cy/+) were randomized into either 1) bilateral surgical renal denervation, 2) surgical sham denervation control, or 3) nonoperated control groups. A midline laparotomy was performed to allow the renal denervation (i.e., physical stripping of the nerves and painting the artery with phenol/alcohol). Blood pressure (tail cuff method), renal function (BUN) and histology were assessed at 8 weeks of age. Bilateral renal denervation reduced the cystic kidney size, cyst volume density, systolic blood pressure, and improved renal function (BUN) as compared with nonoperated controls. Operated control cystic rats had kidney weights, cyst volume densities, systolic blood pressures, and plasma BUN levels that were intermediate between those in the denervated animals and the nonoperated controls. The denervated group had a reduced systolic blood pressure compared with the operated control animals, indicating that the renal innervations was a major contributor to the hypertension in this model of ADPKD. Renal denervation was efficacious in reducing some pathology, including hypertension, renal enlargement, and cystic pathology. However, sham operation also affected the cystic disease but to a lesser extent. We hypothesize that the amelioration of hypertension in Cy/+ rats was due to the effects

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

    Directory of Open Access Journals (Sweden)

    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.

  16. Autosomal dominant polycystic liver disease in a family without polycystic kidney disease associated with a novel missense protein kinase C substrate 80K-H mutation.

    NARCIS (Netherlands)

    Peces, R.; Drenth, J.P.H.; Morsche, R.H.M. te; Gonzalez, P.; Peces, C.

    2005-01-01

    Polycystic liver disease (PLD) is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. PLD can manifest itself in patients with severe autosomal dominant polycystic kidney disease (ADPKD). Isolated autosomal dominant polycystic liver disease

  17. Clinical aspects of an autosomal dominantly inherited hearing impairment linked to the DFNA60 locus on chromosome 2q23.1-2q23.3

    NARCIS (Netherlands)

    Beelen, E. van; Schraders, M.; Huygen, P.L.M.; Oostrik, J.; Plantinga, R.F.; Drunen, W.J. van; Collin, R.W.J.; Kooper, D.P.; Pennings, R.J.E.; Cremers, C.W.R.J.; Kremer, H.; Kunst, H.P.M.

    2013-01-01

    A total of 64 loci for autosomal dominant non-syndromic hearing impairment have been described, and the causative genes have been identified for 24 of these. The present study reports on the clinical characteristics of an autosomal dominantly inherited hearing impairment that is linked to a region w

  18. Anesthetic considerations in a patient of autosomal dominant polycystic kidney disease on hemodialysis for emergency cesarean section

    Directory of Open Access Journals (Sweden)

    Sarita D Fernandes

    2011-01-01

    Full Text Available Renal disease, either preexisting or occurring during gestation may impair maternal and fetal health. A 35-year-old primigravida with autosomal dominant polycystic kidney disease on hemodialysis was scheduled for emergency cesarean section. She was managed successfully with low-dose intrathecal bupivacaine and fentanyl. In the case of pregnancy in such a patient, early involvement of the nephrologists along with the obstetrician can improve maternal and fetal outcome.

  19. JAK2-STAT3 pathway regulates the expression of complement factor B in autosomal dominant polycystic kidney disease

    Institute of Scientific and Technical Information of China (English)

    周晨晨

    2014-01-01

    Objective To investigate the role of JAK2-STAT3pathway in the expression of complement factor B(CFB)in autosomal dominant polycystic kidney disease(ADP KD).Methods Renal tissue samples of patients with ADPKD after nephrectomy were collected.Normal rena tissue samples as control were taken from patients afte radical nephrectomy.Renal tissue samples of Han:SPRD Cy/+rats(ADPKD model)and wild-type Han:

  20. Retinal vessel diameters decrease with macular ganglion cell layer thickness in autosomal dominant optic atrophy and in healthy subjects

    DEFF Research Database (Denmark)

    Rönnbäck, Cecilia; Grønskov, Karen; Larsen, Michael

    2014-01-01

    PURPOSE: To investigate retinal trunk vessel diameters in subjects with autosomal dominant optic atrophy (ADOA) and mutation-free healthy relatives. METHODS: This cross-sectional study included 52 ADOA patients with the optic atrophy 1 (OPA1) exon 28 (c.2826_2836delinsGGATGCTCCA) mutation (age 8....... are a consequence rather than the cause of inner retinal hypoplasia or atrophy, although longitudinal studies are needed to confirm this hypothesis....

  1. Identification of a Locus for Autosomal Dominant Polycystic Liver Disease, on Chromosome 19p13.2-13.1

    OpenAIRE

    Reynolds, David M.; Falk, Cathy T.; Li, Airong; King, Bernard F.; Kamath, Patrick S.; Huston III, John; Shub, Clarence; Iglesias, Diana M.; Martin, Rodolfo S.; Pirson, Yves; Torres, Vicente E.; Somlo, Stefan

    2000-01-01

    Polycystic liver disease (PCLD) is characterized by the growth of fluid-filled cysts of biliary epithelial origin in the liver. Although the disease is often asymptomatic, it can, when severe, lead to complications requiring surgical therapy. PCLD is most often associated with autosomal dominant polycystic kidney disease (ADPKD); however, families with an isolated polycystic liver phenotype without kidney involvement have been described. The clinical presentation and histological features of ...

  2. Tinea imbricata: autosomal dominant pattern of susceptibility in a polygamous indigenous family of the Nahuatl zone in Mexico.

    Science.gov (United States)

    Bonifaz, A; Araiza, J; Koffman-Alfaro, Susana; Paredes-Solis, Vanessa; Cuevas-Covarrubias, S; Rivera, M R

    2004-08-01

    We report on 9 confirmed cases of tinea imbricata (Tokelau, infection due to Trichophyton concentricum) out of 16 family members. They had a common mother with three different fathers. The genetic analysis of the family suggests an autosomal dominant pattern of susceptibility. Most cases (8/9) were presented as concentric and lamellar forms. One patient also had onychomycosis due to T. concentricum. Only two out of nine cases had a positive response to trichophytin.

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

    OpenAIRE

    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.

    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 ge...

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

    OpenAIRE

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

    2016-01-01

    Background 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. Design ADPKD patients presenting with abdominal pain and/or fever between 01/2005 and 06/2015 were retrospectively identified in a systematic com...

  5. 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

  6. 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

  7. Hyperaldosteronism and cardiovascular risk in patients with autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Lai, Silvia; Petramala, Luigi; Mastroluca, Daniela; Petraglia, Emanuela; Di Gaeta, Alessandro; Indino, Elena; Panebianco, Valeria; Ciccariello, Mauro; Shahabadi, Hossein H; Galani, Alessandro; Letizia, Claudio; D'Angelo, Anna Rita

    2016-07-01

    Hypertension is commonly associated with autosomal dominant polycystic kidney disease (ADPKD), often discovered before the onset of renal failure, albeit the pathogenetic mechanisms are not well elucidated. Hyperaldosteronism in ADPKD may contribute to the development of insulin resistance and endothelial dysfunction, and progression of cardiorenal disease. The aim of study was to evaluate the prevalence of primary aldosteronism (PA) in ADPKD patients and identify some surrogate biomarkers of cardiovascular risk.We have enrolled 27 hypertensive ADPKD patients with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, evaluating the renin-angiotensin-aldosterone system (RAAS), inflammatory indexes, nutritional status, homocysteine (Hcy), homeostasis model assessment-insulin resistance (HOMA-IR), mineral metabolism, microalbuminuria, and surrogate markers of atherosclerosis [carotid intima media thickness (cIMT), ankle/brachial index (ABI), flow mediated dilation (FMD), renal resistive index (RRI) and left ventricular mass index (LVMI)]. Furthermore, we have carried out the morpho-functional magnetic resonance imaging (MRI) with high-field 3 T Magnetom Avanto.We have divided patients into group A, with normal plasma aldosterone concentration (PAC) and group B with PA, present in 9 (33%) of overall ADPKD patients. Respect to group A, group B showed a significant higher mean value of LVMI, HOMA-IR and Hcy (P = 0.001, P = 0.004, P = 0.018; respectively), and a lower value of FMD and 25-hydroxyvitamin D (25-OH-VitD) (P = 0.037, P = 0.019; respectively) with a higher prevalence of non-dipper pattern at Ambulatory Blood Pressure Monitoring (ABPM) (65% vs 40%, P < 0.05) at an early stage of the disease.In this study, we showed a high prevalence of PA in ADPKD patients, associated to higher LVMI, HOMA-IR, Hcy, lower FMD, and 25-OH-VitD, considered as surrogate markers of atherosclerosis, compared to ADPKD patients with normal PAC values. Our

  8. Simultaneous Native Nephrectomy and Kidney Transplantation in Patients With Autosomal Dominant Polycystic Kidney Disease.

    Directory of Open Access Journals (Sweden)

    Massimiliano Veroux

    Full Text Available To evaluate the feasibility of simultaneous unilateral nephrectomy with kidney transplantation and to determine the effect of this procedure on perioperative morbidity and mortality and graft and patient survival.Between January 2000 and May 2015, 145 patients with autosomal dominant polycystic kidney disease (ADPKD underwent kidney transplantation. Of those, 40 (27.5% underwent concurrent ipsilateral native nephrectomy (group NT. Patients in group NT were compared with patients with ADPKD not undergoing concurrent nephrectomy (group NT- and asymptomatic patients undergoing pretransplant nephrectomy (group PNT.The average follow-up was 66 months. The graft survival rate at 1 and 5 years was 95% and 87.5% versus 93% and 76.2% in the NT and NT- groups, respectively (P = .903 and P = .544, respectively; 1-year patient survival was 100% for NT and 97% for NT- patients (P = .288, whereas 5-year patient survival was 100% and 92% for NT and NT- groups, respectively (P = .128. After propensity score matching (34 patients per group no significant differences were observed in 1-year (97.1% in NT and 94.1%; P = 1 and 5-year (88.2% in NT and 91.2% in NT-; P = 1 graft survival, and in 1-year (100% for both groups; P = 1 and 5-year (100% in NT and 94.1% in NT-; P = 1 patient survival. Perioperative mortality was 0% among NT and 1.2% among NT- patients, whereas perioperative surgical complications were similar in both groups. One- and 5-year graft and patient survival were similar between the NT and PNT groups, but patients in the PNT group had significantly lower levels of hemoglobin and residual diuresis volumes at the time of transplant. Moreover, PNT patients had a longer pretransplant dialysis and a longer time on the waiting list.Simultaneous unilateral nephrectomy does not have a negative effect on patient and graft survival in patients with ADPKD and is associated with low morbidity. Pretransplant nephrectomy should be restricted only to highly

  9. An autosomal recessive syndrome of severe mental retardation, cataract, coloboma and kyphosis maps to the pericentromeric region of chromosome 4.

    Science.gov (United States)

    Kahrizi, Kimia; Najmabadi, Hossein; Kariminejad, Roxana; Jamali, Payman; Malekpour, Mahdi; Garshasbi, Masoud; Ropers, Hans Hilger; Kuss, Andreas Walter; Tzschach, Andreas

    2009-01-01

    We report on three siblings with a novel mental retardation (MR) syndrome who were born to distantly related Iranian parents. The clinical problems comprised severe MR, cataracts with onset in late adolescence, kyphosis, contractures of large joints, bulbous nose with broad nasal bridge, and thick lips. Two patients also had uni- or bilateral iris coloboma. Linkage analysis revealed a single 10.4 Mb interval of homozygosity with significant LOD score in the pericentromeric region of chromosome 4 flanked by SNPs rs728293 (4p12) and rs1105434 (4q12). This interval contains more than 40 genes, none of which has been implicated in MR so far. The identification of the causative gene defect for this syndrome will provide new insights into the development of the brain and the eye.

  10. A novel frameshift mutation of POU4F3 gene associated with autosomal dominant non-syndromic hearing loss

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hee Keun [Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu (Korea, Republic of); Park, Hong-Joon [Soree Ear Clinic, Seoul (Korea, Republic of); Lee, Kyu-Yup [Vestibulocochlear Research Center, College of Medicine, Wonkwang University, Iksan (Korea, Republic of); Park, Rekil, E-mail: rkpark@wku.ac.kr [Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Kyungpook National University, Daegu (Korea, Republic of); Kim, Un-Kyung, E-mail: kimuk@knu.ac.kr [Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu (Korea, Republic of)

    2010-06-04

    Autosomal dominant mutations in the transcription factor POU4F3 gene are associated with non-syndromic hearing loss in humans; however, there have been few reports of mutations in this gene worldwide. We performed a mutation analysis of the POU4F3 gene in 42 unrelated Koreans with autosomal dominant non-syndromic hearing loss, identifying a novel 14-bp deletion mutation in exon 2 (c.662del14) in one patient. Audiometric examination revealed severe bilateral sensorineural hearing loss in this patient. The novel mutation led to a truncated protein that lacked both functional POU domains. We further investigated the functional distinction between wild-type and mutant POU4F3 proteins using in vitro assays. The wild-type protein was completely localized in the nucleus, while the truncation of protein seriously affected its nuclear localization. In addition, the mutant failed to activate reporter gene expression. This is the first report of a POU4F3 mutation in Asia, and moreover our data suggest that further investigation will need to delineate ethnicity-specific genetic background for autosomal dominant non-syndromic hearing loss within Asian populations.

  11. Identification of a Novel GJA8 (Cx50) Point Mutation Causes Human Dominant Congenital Cataracts

    Science.gov (United States)

    Ge, Xiang-Lian; Zhang, Yilan; Wu, Yaming; Lv, Jineng; Zhang, Wei; Jin, Zi-Bing; Qu, Jia; Gu, Feng

    2014-02-01

    Hereditary cataracts are clinically and genetically heterogeneous lens diseases that cause a significant proportion of visual impairment and blindness in children. Human cataracts have been linked with mutations in two genes, GJA3 and GJA8, respectively. To identify the causative mutation in a family with hereditary cataracts, family members were screened for mutations by PCR for both genes. Sequencing the coding regions of GJA8, coding for connexin 50, revealed a C > A transversion at nucleotide 264, which caused p.P88T mutation. To dissect the molecular consequences of this mutation, plasmids carrying wild-type and mutant mouse ORFs of Gja8 were generated and ectopically expressed in HEK293 cells and human lens epithelial cells, respectively. The recombinant proteins were assessed by confocal microscopy and Western blotting. The results demonstrate that the molecular consequences of the p.P88T mutation in GJA8 include changes in connexin 50 protein localization patterns, accumulation of mutant protein, and increased cell growth.

  12. Renal failure in a patient with autosomal dominant polycystic kidney disease and coexisting dermato-polymyositis: first report in the literature.

    Science.gov (United States)

    Bahceci, Funda; Sari, Ramazan; Sarikaya, Metin; Atik, Esin; Karincaoglu, Yelda; Sevinc, Alper

    2004-06-01

    Autosomal dominant polycystic kidney disease is a multisystem disorder characterized by multiple, bilateral renal cysts and is also associated with cysts in other organs, such as the liver, pancreas, and arachnoid membranes. Dermatomyositis is a disease which mainly involves the skin and muscles, although occasionally other organs are affected. In this report, a 56-year-old male patient with a four-year history of autosomal dominant polycystic kidney disease was presented. Renal failure was exacerbated by a coexisting dermato-polymyositis. Prednisone treatment with hemodialysis improved the situation. This is the first report renal failure in a patient with autosomal dominant polycystic kidney disease and dermato-polymyositis.

  13. The genetic and molecular basis of congenital cataract

    Directory of Open Access Journals (Sweden)

    Alessandro Santana

    2011-04-01

    Full Text Available Congenital cataracts are one of the most treatable causes of visual impairment and blindness during infancy, with an estimated prevalence of 1 to 6 cases per 10,000 live births. Approximately fifty percent of all congenital cataract cases may have a genetic cause. All three types of Mendelian inheritance have been reported for cataract; however, autosomal dominant transmission seems to be the most frequent. The transparency and high refractive index of the lens are achieved by the precise architecture of the fiber cells and the homeostasis of the lens proteins in terms of their concentration, stability, and supramolecular organization. Research on hereditary congenital cataract led to the identification of several classes of candidate genes that encode proteins such crystallins, lens specific connexins, aquaporine, cytoskeletal structural proteins, and developmental regulators. The purpose of this study was to review the literature on the recent advances made in understanding the molecular genetic basis of congenital cataracts.

  14. 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. Novel A CTG1 mutation causing autosomal dominant non-syndromic hearing impairment in a Chinese family

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Theγ-actin(ACTG1)gene is a cytoplasmic nonmuscle actin gene,which encodes a major cytoskeletal protein in the sensory hair cells of the cochlea.Mutations in ACTG1 were found to cause autosomal dominant,progressive,sensorineural hearing loss linked to the DFNA 20/26 locus on chromosome 17q25.3 in European and American families,respectively.In this study,a novel missense mutation (c.364A>G;p.I122V)co-segregated with the affected individuals in the family and did not exist in the unaffected family members and 150 unrelated normal controls.The alteration of residue I1e122 was predicted to damage its interaction with actin-binding proteins,which may cause disruption of hair cell organization and function.These findings strongly suggested that the I122V mutation in ACTG1 caused autosomal dominant non-syndromic hearing impairment in a Chinese family and expanded the spectrum of ACTG1 mutations causing hearing loss.

  2. An unusual case of cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy with occipital lobe involvement

    Directory of Open Access Journals (Sweden)

    Bhavesh Trikamji

    2016-01-01

    Full Text Available Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL is an autosomal dominant angiopathy caused by a mutation in the notch 3 gene on chromosome 19. Clinically, patients may be asymptomatic or can present with recurrent ischemic episodes and strokes leading to dementia, depression, pseudobulbar palsy, and hemi- or quadraplegia. Additional manifestations that have been described include migraine (mostly with aura, psychiatric disturbances, and epileptic seizures. Neuroimaging is essential to the diagnosis of CADASIL. On imaging CADASIL is characterized by symmetric involvement by confluent lesions located subcortically in the frontal and temporal lobes as well as in the insula, periventricularly, in the centrum semiovale, in the internal and external capsule, basal ganglia, and brain stem; with relative sparing of the fronto-orbital and the occipital subcortical regions. We describe a 49 year old male with CADASIL with absence of temporal lobe findings on MRI but predominant lesions within the periventricular white matter, occipital lobes with extension into the subcortical frontal lobes, corpus callosum and cerebellar white matter. Although CADASIL characteristically presents with anterior temporal lobe involvement, these findings may be absent and our case addresses the atypical imaging findings in CADASIL.

  3. Congenital and infantile cataract: aetiology and management.

    Science.gov (United States)

    Chan, Wai H; Biswas, Susmito; Ashworth, Jane L; Lloyd, I Christopher

    2012-04-01

    Congenital cataract is the commonest worldwide cause of lifelong visual loss in children. Although congenital cataracts have a diverse aetiology, in many children, a cause is not identified; however, autosomal dominant inheritance is commonly seen. Early diagnosis either on the post-natal ward or in the community is important because appropriate intervention can result in good levels of visual function. However, visual outcome is largely dependent on the timing of surgery when dense cataracts are present. Good outcomes have been reported in children undergoing surgery before 6 weeks of age in children with unilateral cataract and before 10 weeks of age in bilateral cases. Placement of an artificial intraocular lens implant after removal of the cataract has become established practice in children over 2 years of age. There remains debate over the safety and predictability of intraocular lens implantation in infants. Despite early surgery and aggressive optical rehabilitation, children may still develop deprivation amblyopia, nystagmus, strabismus, and glaucoma. The diagnosis and management of congenital cataracts has improved substantially over the past 30 years with a concurrent improvement in outcomes for affected children. Many aspects of the pre-, intra-, and postoperative management of these patients continue to be refined, highlighting the need for good quality data and prospective collaborative studies in this field.

  4. A novel mutation in the TECTA gene in a Chinese family with autosomal dominant nonsyndromic hearing loss.

    Directory of Open Access Journals (Sweden)

    Yu Su

    Full Text Available TECTA-related deafness can be inherited as autosomal-dominant nonsyndromic deafness (designated DFNA or as the autosomal-recessive version. The α-tectorin protein, which is encoded by the TECTA gene, is one of the major components of the tectorial membrane in the inner ear. Using targeted DNA capture and massively parallel sequencing (MPS, we screened 42 genes known to be responsible for human deafness in a Chinese family (Family 3187 in which common deafness mutations had been ruled out as the cause, and identified a novel mutation, c.257-262CCTTTC>GCT (p. Ser86Cys; p. Pro88del in exon 3 of the TECTA gene in the proband and his extended family. All affected individuals in this family had moderate down-sloping hearing loss across all frequencies. To our knowledge, this is the second TECTA mutation identified in Chinese population. This study demonstrates that targeted genomic capture, MPS, and barcode technology might broaden the availability of genetic testing for individuals with undiagnosed DFNA.

  5. Genetic forms of nephrogenic diabetes insipidus (NDI): Vasopressin receptor defect (X-linked) and aquaporin defect (autosomal recessive and dominant).

    Science.gov (United States)

    Bichet, Daniel G; Bockenhauer, Detlef

    2016-03-01

    Nephrogenic diabetes insipidus (NDI), which can be inherited or acquired, is characterized by an inability to concentrate urine despite normal or elevated plasma concentrations of the antidiuretic hormone, arginine vasopressin (AVP). Polyuria with hyposthenuria and polydipsia are the cardinal clinical manifestations of the disease. About 90% of patients with congenital NDI are males with X-linked NDI who have mutations in the vasopressin V2 receptor (AVPR2) gene encoding the vasopressin V2 receptor. In less than 10% of the families studied, congenital NDI has an autosomal recessive or autosomal dominant mode of inheritance with mutations in the aquaporin-2 (AQP2) gene. When studied in vitro, most AVPR2 and AQP2 mutations lead to proteins trapped in the endoplasmic reticulum and are unable to reach the plasma membrane. Prior knowledge of AVPR2 or AQP2 mutations in NDI families and perinatal mutation testing is of direct clinical value and can avert the physical and mental retardation associated with repeated episodes of dehydration.

  6. 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.

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

    Science.gov (United States)

    Gutiérrez, Sandra; Torres, Diana; Briceño, Ignacio; Gómez, Ana Maria; Baquero, Eliana

    2012-07-01

    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.

  8. The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway.

    Science.gov (United States)

    Barr, M M; DeModena, J; Braun, D; Nguyen, C Q; Hall, D H; Sternberg, P W

    2001-09-04

    Autosomal dominant polycystic kidney disease (ADPKD) strikes 1 in 1000 individuals and often results in end-stage renal failure. Mutations in either PKD1 or PKD2 account for 95% of all cases [1-3]. It has recently been demonstrated that polycystin-1 and polycystin-2 (encoded by PKD1 and PKD2, respectively) assemble to form a cation channel in vitro [4]. Here we determine that the Caenorhabditis elegans PKD1 and PKD2 homologs, lov-1 [5] and pkd-2, act in the same pathway in vivo. Mutations in either lov-1 or pkd-2 result in identical male sensory behavioral defects. Also, pkd-2;lov-1 double mutants are no more severe than either of the single mutants, indicating that lov-1 and pkd-2 act together. LOV-1::GFP and PKD-2::GFP are expressed in the same male-specific sensory neurons and are concentrated in cilia and cell bodies. Cytoplasmic, nonnuclear staining in cell bodies is punctate, suggesting that one pool of PKD-2 is localized to intracellular membranes while another is found in sensory cilia. In contrast to defects in the C. elegans autosomal recessive PKD gene osm-5 [6-8], the cilia of lov-1 and pkd-2 single mutants and of lov-1;pkd-2 double mutants are normal as judged by electron microscopy, demonstrating that lov-1 and pkd-2 are not required for ultrastructural development of male-specific sensory cilia.

  9. The aquaporin-2 water channel in autosomal dominant primary nocturnal enuresis.

    NARCIS (Netherlands)

    Deen, P.M.T.; Dahl, N.; Caplan, M.J.

    2002-01-01

    PURPOSE: Nocturnal enuresis is one of the most common diagnoses in a pediatric clinic. Recently, linkage analysis revealed a 2-point lod score of 4.2 in 6 families with dominant primary nocturnal enuresis around the aquaporin-2 (AQP2) water channel locus. Since primary nocturnal enuresis is ameliora

  10. The R1947X mutation of NF1 causing autosomal dominant neurofibromatosis type 1 in a Chinese family

    Institute of Scientific and Technical Information of China (English)

    Qinbo Yang; Changzheng Huang; Xiaoying Yang; Yinfu Feng; Qing Wang; Mugen Liu

    2008-01-01

    Neurofibromatosis type 1 is a common autosomal dominant disorder with a high rate of penetrance. It is caused by the mutation of the tumor suppressor gene NF1, which encodes neurofibromin. The main function of neurofibromin is down-regulating the biological activity of the proto-oncoprotein Ras by acting as a Ras-specific GTPase activating protein. In this study, we identified a Chinese family affected with neurofibromatosis type 1. The known gene NF1 associated with NF1 was studied by linkage analysis and by direct sequencing of the entire coding region and exon-intron boundaries of the NF1 gene. The R1947X mutation of NF1 was identified, which was co-segregated with affected individuals in the Chinese family, but not present in unaffected family members. This is the first report, which states that the R1947X mutation of NF1 may be one of reasons for neurofibromatosis type 1 in Chinese population.

  11. Extra-renal manifestations of autosomal dominant polycystic kidney disease (ADPKD): considerations for routine screening and management.

    Science.gov (United States)

    Luciano, Randy L; Dahl, Neera K

    2014-02-01

    Autosomal-dominant polycystic kidney disease (ADPKD) is a systemic disease, marked by progressive increase of bilateral renal cysts, resulting in chronic kidney disease (CKD) and often leading to end-stage renal disease (ESRD). Apart from renal cysts, patients often have extra-renal disease, involving the liver, heart and vasculature. Other less common but equally important extra-renal manifestations of ADPKD include diverticular disease, hernias, male infertility and pain. Extra-renal disease burden is often asymptomatic, but may result in increased morbidity and mortality. If the disease burden is significant, screening may prove beneficial. We review the rationale for current screening recommendations and propose some guidelines for screening and management of ADPKD patients.

  12. Novel LDB3 Mutation in a Patient With Autosomal Dominant Myofibrillar Myopathy

    OpenAIRE

    2016-01-01

    Introduction Myofibrillar myopathy (MFM) is a rare human disease, characterized by a distinct histopathological pattern of myofibrillar degeneration and protein aggregates. LDB3 protein encoded by this gene is a key Z-disk protein that interacts with α-actinin and protein kinase C. Case Presentation In this paper, we identified the novel heterozygous, and hence, dominant mutation in the LIM domain-binding protein 3 gene (LDB3) in ...

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

    Science.gov (United States)

    Koutlas, Ioannis G; Forsman, Cynthia L; Kyrkanides, Stephanos; Oetting, William S; Petryk, Anna

    2012-01-01

    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 (BMP) 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 (TWSG1) 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.

  14. 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.

  15. 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.

  16. 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

    2012-04-01

    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.

  17. Two pedigrees of autosomal dominant atrioventricular canal defect (AVCD): Exclusion from the critical region on 8p

    Energy Technology Data Exchange (ETDEWEB)

    Amati, F.; Mari, A.; Mingarelli, R. [Universita Tor Vergata, Rome (Italy)] [and others

    1995-07-03

    Atrioventricular canal defects (AVCD) constitute the predominant congenital heart defect in Down`s syndrome. For this reason, a candidate gene involved in atrioventricular canal development was previously searched and excluded in dominant pedigrees of AVCD, using linkage analysis of polymorphisms from chromosome 21. Because of the striking association between 8p deletion and AVCD, a search for an AVCD gene was carried out in two pedigrees of individuals with autosomal dominant AVCD using a set of DNA markers of the 8pter{r_arrow}q12 region. These two families include affected individuals and subjects who have transmitted the defect but are not clinically affected. Two-point lod scores were significantly negative for all markers at penetrance levels of 90% and 50%. Multipoint analysis excluded the region covered by the markers LPL-D8S262 and 30 cM to either side of this area. This result corroborates heterogeneity of this heart defect and indicates that the genetic basis of familial AVCD is different from AVCD associated to either trisomy 21 or 8p deletion. 25 refs., 3 figs., 2 tabs.

  18. A comparison of seminal vesicle size on CT between autosomal dominant polycystic kidney disease (ADPKD) patients and normal subjects

    Energy Technology Data Exchange (ETDEWEB)

    Joo, Ijin; Kim, Seung Hyup; Cho, Jeong Yeon (Dept. of Radiology, Seoul National Univ. College of Medicine, Inst. of Radiation Medicine, Seoul National Univ., Seoul (Korea)), e-mail: kimsh@radcom.snu.ac.kr

    2010-06-15

    Background: Extrarenal manifestations are common in autosomal dominant polycystic kidney disease (ADPKD). Although seminal vesicles can also be involved in patients with ADPKD, little is known about the size differences of the seminal vesicles between ADPKD patients and normal subjects. Purpose: To determine whether the size of seminal vesicles in ADPKD patients is larger than that in normal subjects with the use of three-dimensional (3D) CT. Material and Methods: Using a retrospective case-control study design, we reviewed the findings of 696 male patients with an age range of 20-69 years who underwent contrast enhanced multi-detector computed tomography (MDCT) imaging of the kidney in our institution from August 2007 to July 2008. A total of 68 male patients with ADPKD comprised the study group. Another 68 age-matched non-ADPKD male patients comprised the control group. The size of bilateral seminal vesicles was assessed by measurement of the short dimension on axial, coronal, and sagittal images by the use of a picture archiving and communication system (PACS). Results: The mean width of seminal vesicles in ADPKD patients was 1.70+-0.40 cm (axial images), 1.86+-0.45 cm (coronal), and 1.59+-0.39 cm (sagittal). For control group subjects, the mean width was 1.53+-0.29 cm (axial), 1.68+-0.43 cm (coronal), and 1.48+-0.31 cm (sagittal). The mean size differences between the ADPKD and control groups for the measured widths on axial and coronal images were statistically significant (P=0.01 and P=0.02, respectively). The width as measured on axial images showed a decrease with age in the control group subjects (linear trend, P=0.005), but no significant decrease was noted in ADPKD patients. Conclusion: The seminal vesicles were demonstrated to be larger in ADPKD patients as compared with normal subjects as determined with the use of 3D CT . Keywords: Autosomal dominant polycystic kidney disease (ADPKD), seminal vesicle, computed tomography, CT

  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. Identification of a novel missense mutation of MIP in a Chinese family with congenital cataracts by target region capture sequencing

    OpenAIRE

    Jiang,Bo; chen, Yanhua; Baisheng XU; Hong, Nan; Liu, Rongrong; Qi, Ming; Shen, Liping

    2017-01-01

    Congenital cataract is both clinically diverse and genetically heterogeneous. To investigate the underlying genetic defect in three-generations of a Chinese family with autosomal dominant congenital cataracts, we recruited family members who underwent comprehensive ophthalmic examinations. A heterozygous missense mutation c.634G > C (p.G212R) substitution was identified in the MIP gene through target region capture sequencing. The prediction results of PolyPhen-2 and SIFT indicated that this ...

  1. 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.

    2014-01-01

    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 wo

  2. Neonatal onset autosomal dominant polycystic kidney disease (ADPKD) in a patient homozygous for a PKD2 missense mutation due to uniparental disomy.

    NARCIS (Netherlands)

    Losekoot, M.; Ruivenkamp, C.A.; Tholens, A.P.; Grimbergen, J.E.; Vijfhuizen, L.; Vermeer, S.; Dijkman, H.B.P.M.; Cornelissen, E.A.M.; Bongers, M.H.F.; Peters, D.J.

    2012-01-01

    Autosomal dominant polycystic kidney disease (ADPKD), due to a heterozygous mutation in PKD1 or PKD2, is usually an adult onset disease. Renal cystic disease is generally milder in PKD2 patients than in PKD1 patients. Recently, several PKD1 patients with a severe renal cystic phenotype due to a seco

  3. Mapping of the SCA23 locus involved in autosomal dominant cerebellar ataxia to chromosome region 20p13-12.3

    NARCIS (Netherlands)

    Verbeek, D S; van de Warrenburg, B P; Wesseling, P; Pearson, P L; Kremer, H P; Sinke, R J

    2004-01-01

    We report upon a Dutch autosomal dominant cerebellar ataxia (ADCA) family, clinically characterized by a late-onset (>40 years), slowly progressive, isolated spinocerebellar ataxia (SCA). Neuropathological examination in one affected subject showed neuronal loss in the Purkinje cell layer, dentate n

  4. Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe: prevalence and survival-an analysis of data from the ERA-EDTA Registry.

    NARCIS (Netherlands)

    Spithoven, E.M.; Kramer, A.; Meijer, E.; Orskov, B.; Wanner, C.; Abad, J.M.; Areste, N.; Torre, R.A. de la; Caskey, F.; Couchoud, C.; Finne, P.; Heaf, J.; Hoitsma, A.J.; Meester, J. de; Pascual, J.; Postorino, M.; Ravani, P.; Zurriaga, O.; Jager, K.J.; Gansevoort, R.T.

    2014-01-01

    BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common renal disease requiring renal replacement therapy (RRT). Still, there are few epidemiological data on the prevalence of, and survival on RRT for ADPKD. METHODS: This study used data from the ERA-EDTA Registry

  5. Renal replacement therapy for autosomal dominant polycystic kidney disease (ADPKD) in Europe : prevalence and survival-an analysis of data from the ERA-EDTA Registry

    NARCIS (Netherlands)

    Spithoven, Edwin M.; Kramer, Anneke; Meijer, Esther; Orskov, Bjarne; Wanner, Christoph; Abad, Jose M.; Areste, Nuria; Alonso de la Torre, Ramon; Caskey, Fergus; Couchoud, Cecile; Finne, Patrik; Heaf, James; Hoitsma, Andries; de Meester, Johan; Pascual, Julio; Postorino, Maurizio; Ravani, Pietro; Zurriaga, Oscar; Jager, Kitty J.; Gansevoort, Ron T.

    2014-01-01

    Background. Autosomal dominant polycystic kidney disease (ADPKD) is the fourth most common renal disease requiring renal replacement therapy (RRT). Still, there are few epidemiological data on the prevalence of, and survival on RRT for ADPKD. Methods. This study used data from the ERA-EDTA Registry

  6. Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia

    NARCIS (Netherlands)

    Bolar, N.A.; Golzio, C.; Zivna, M.; Hayot, G.; Hemelrijk, C. van; Schepers, D.; Vandeweyer, G.; Hoischen, A.; Huyghe, J.R.; Raes, A.; Matthys, E.; Sys, E.; Azou, M.; Gubler, M.C.; Praet, M.; Van Camp, G.; McFadden, K.; Pediaditakis, I.; Pristoupilova, A.; Hodanova, K.; Vyletal, P.; Hartmannova, H.; Stranecky, V.; Hulkova, H.; Baresova, V.; Jedlickova, I.; Sovova, J.; Hnizda, A.; Kidd, K.; Bleyer, A.J.; Spong, R.S.; Vande Walle, J.; Mortier, G.; Brunner, H.; Van Laer, L.; Kmoch, S.; Katsanis, N.; Loeys, B.L.

    2016-01-01

    Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are respon

  7. Total Kidney Volume in Autosomal Dominant Polycystic Kidney Disease: A Biomarker of Disease Progression and Therapeutic Efficacy.

    Science.gov (United States)

    Alam, Ahsan; Dahl, Neera K; Lipschutz, Joshua H; Rossetti, Sandro; Smith, Patricia; Sapir, Daniel; Weinstein, Jordan; McFarlane, Philip; Bichet, Daniel G

    2015-10-01

    Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially life-threatening monogenic disorder in humans, characterized by progressive development and expansion of fluid-filled cysts in the kidneys and other organs. Ongoing cyst growth leads to progressive kidney enlargement, whereas kidney function remains stable for decades as a result of hyperfiltration and compensation by unaffected nephrons. Kidney function irreversibly declines only in the late stages of the disease, when most of the parenchyma is lost to cystic and fibrotic tissue and the remaining compensatory capacity is overwhelmed. Hence, conventional kidney function measures, such as glomerular filtration rate, do not adequately assess disease progression in ADPKD, especially in its early stages. Given the recent development of potential targeted therapies in ADPKD, it has become critically important to identify relevant biomarkers that can be used to determine the degree of disease progression and evaluate the effects of therapeutic interventions on the course of the disease. We review the current evidence to provide an informed perspective on whether total kidney volume (TKV) is a suitable biomarker for disease progression and whether TKV can be used as an efficacy end point in clinical trials. We conclude that because cystogenesis is the central factor leading to kidney enlargement, TKV appears to be an appropriate biomarker and is gaining wider acceptance. Several studies have identified TKV as a relevant imaging biomarker for monitoring and predicting disease progression and support its use as a prognostic end point in clinical trials.

  8. 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.

  9. Urine-sample-derived human induced pluripotent stem cells as a model to study PCSK9-mediated autosomal dominant hypercholesterolemia.

    Science.gov (United States)

    Si-Tayeb, Karim; Idriss, Salam; Champon, Benoite; Caillaud, Amandine; Pichelin, Matthieu; Arnaud, Lucie; Lemarchand, Patricia; Le May, Cédric; Zibara, Kazem; Cariou, Bertrand

    2016-01-01

    Proprotein convertase subtilisin kexin type 9 (PCSK9) is a critical modulator of cholesterol homeostasis. Whereas PCSK9 gain-of-function (GOF) mutations are associated with autosomal dominant hypercholesterolemia (ADH) and premature atherosclerosis, PCSK9 loss-of-function (LOF) mutations have a cardio-protective effect and in some cases can lead to familial hypobetalipoproteinemia (FHBL). However, limitations of the currently available cellular models preclude deciphering the consequences of PCSK9 mutation further. We aimed to validate urine-sample-derived human induced pluripotent stem cells (UhiPSCs) as an appropriate tool to model PCSK9-mediated ADH and FHBL. To achieve our goal, urine-sample-derived somatic cells were reprogrammed into hiPSCs by using episomal vectors. UhiPSC were efficiently differentiated into hepatocyte-like cells (HLCs). Compared to control cells, cells originally derived from an individual with ADH (HLC-S127R) secreted less PCSK9 in the media (-38.5%; P=0.038) and had a 71% decrease (Pcells originally derived from an individual with FHBL (HLC-R104C/V114A) displayed a strong decrease in PCSK9 secretion (-89.7%; Pcells for reprogramming and hepatocyte differentiation, but also a powerful tool to further decipher PCSK9 mutations and function.

  10. 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.)

  11. Heterozygous Pathogenic Variant in DACT1 Causes an Autosomal-Dominant Syndrome with Features Overlapping Townes–Brocks Syndrome

    Science.gov (United States)

    Webb, Bryn D.; Metikala, Sanjeeva; Wheeler, Patricia G.; Sherpa, Mingma D.; Houten, Sander M.; Horb, Marko E.; Schadt, Eric E.

    2017-01-01

    A heterozygous nonsense variant was identified in dapper, antagonist of beta-catenin, 1 (DACT1) via whole-exome sequencing in family members with imperforate anus, structural renal abnormalities, genitourinary anomalies, and/or ear anomalies. The DACT1 c.1256G>A;p.Trp419* variant segregated appropriately in the family consistent with an autosomal dominant mode of inheritance. DACT1 is a member of the Wnt-signaling pathway, and mice homozygous for null alleles display multiple congenital anomalies including absent anus with blind-ending colon and genitourinary malformations. To investigate the DACT1 c.1256G>A variant, HEK293 cells were transfected with mutant DACT1 cDNA plasmid, and immunoblotting revealed stability of the DACT1 p.Trp419* protein. Overexpression of DACT1 c.1256G>A mRNA in Xenopus embryos revealed a specific gastrointestinal phenotype of enlargement of the proctodeum. Together, these findings suggest that the DACT1 c.1256G>A nonsense variant is causative of a specific genetic syndrome with features overlapping Townes–Brocks syndrome. PMID:28054444

  12. Mitochondrial oxidative phosphorylation compensation may preserve vision in patients with OPA1-linked autosomal dominant optic atrophy.

    Science.gov (United States)

    Van Bergen, Nicole J; Crowston, Jonathan G; Kearns, Lisa S; Staffieri, Sandra E; Hewitt, Alex W; Cohn, Amy C; Mackey, David A; Trounce, Ian A

    2011-01-01

    Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies.

  13. Automated segmentation of liver and liver cysts from bounded abdominal MR images in patients with autosomal dominant polycystic kidney disease

    Science.gov (United States)

    Kim, Youngwoo; Bae, Sonu K.; Cheng, Tianming; Tao, Cheng; Ge, Yinghui; Chapman, Arlene B.; Torres, Vincente E.; Yu, Alan S. L.; Mrug, Michal; Bennett, William M.; Flessner, Michael F.; Landsittel, Doug P.; Bae, Kyongtae T.

    2016-11-01

    Liver and liver cyst volume measurements are important quantitative imaging biomarkers for assessment of disease progression in autosomal dominant polycystic kidney disease (ADPKD) and polycystic liver disease (PLD). To date, no study has presented automated segmentation and volumetric computation of liver and liver cysts in these populations. In this paper, we proposed an automated segmentation framework for liver and liver cysts from bounded abdominal MR images in patients with ADPKD. To model the shape and variations in ADPKD livers, the spatial prior probability map (SPPM) of liver location and the tissue prior probability maps (TPPMs) of liver parenchymal tissue intensity and cyst morphology were generated. Formulated within a three-dimensional level set framework, the TPPMs successfully captured liver parenchymal tissues and cysts, while the SPPM globally constrained the initial surfaces of the liver into the desired boundary. Liver cysts were extracted by combined operations of the TPPMs, thresholding, and false positive reduction based on spatial prior knowledge of kidney cysts and distance map. With cross-validation for the liver segmentation, the agreement between the radiology expert and the proposed method was 84% for shape congruence and 91% for volume measurement assessed by the intra-class correlation coefficient (ICC). For the liver cyst segmentation, the agreement between the reference method and the proposed method was ICC  =  0.91 for cyst volumes and ICC  =  0.94 for % cyst-to-liver volume.

  14. A ninth locus (RP18) for autosomal dominant retinitis pigmentosa maps in the pericentromeric region of chromosome 1.

    Science.gov (United States)

    Xu, S Y; Schwartz, M; Rosenberg, T; Gal, A

    1996-08-01

    We studied a large Danish family of seven generations in which autosomal dominant retinitis pigmentosa (adRP), a heterogeneous genetic form of retinal dystrophy, was segregating. After linkage had been excluded to all known adRP loci on chromosomes 3q, 6p, 7p, 7q, 8q, 17p, 17q and 19q, a genome screening was performed. Positive lod scores suggestive of linkage with values ranging between Z = 1.58-5.36 at theta = 0.04-0.20 were obtained for eight loci on proximal 1p and 1q. Close linkage without recombination and a maximum lod score of 7.22 at theta = 0.00 was found between the adRP locus (RP18) in this family and D1S498 which is on 1q very near the centromere. Analysis of multiply informative meioses suggests that in this family D1S534 and D1S305 flank RP18 in interval 1p13-q23. No linkage has been found to loci from this chromosomal region in six other medium sized adRP families in which the disease locus has been excluded from all known chromosomal regions harbouring an adRP gene or locus suggesting that there is (at least) one further adRP locus to be mapped in the future.

  15. SDOCT Thickness Measurements of Various Retinal Layers in Patients with Autosomal Dominant Optic Atrophy due to OPA1 Mutations

    Directory of Open Access Journals (Sweden)

    Andrea M. Schild

    2013-01-01

    Full Text Available Purpose. To specify thickness values of various retinal layers on macular spectral domain Optical Coherence Tomography (SDOCT scans in patients with autosomal dominant optic atrophy (ADOA compared to healthy controls. Methods. SDOCT volume scans of 7 patients with ADOA (OPA-1 mutation and 14 healthy controls were quantitatively analyzed using manual grading software. Mean thickness values for the ETDRS grid subfields 5–8 were calculated for the spaces neurosensory retina, retinal nerve fiber layer (RNFL, ganglion cell layer (GCL, a combined space of inner plexiform layer/outer plexiform layer/inner nuclear layer (IPL+INL+OPL, and a combined space of outer nuclear layer/photoreceptor layers (ONL+PL. Results. ADOA patients showed statistically significant lower retinal thickness values than controls (. RNFL ( and GCL thicknesses ( were significantly lower in ADOA patients. There was no difference in IPL+INL+OPL and in ONL+PL thickness. Conclusion. Manual subanalysis of macular SDOCT volume scans allowed detailed subanalysis of various retinal layers. Not only RNFL but also GCL thicknesses are reduced in the macular area of ADOA patients whereas subjacent layers are not involved. Together with clinical findings, macular SDOCT helps to identify patients with suspicion for hereditary optic neuropathy before genetic analysis confirms the diagnosis.

  16. Autosomal dominant polycystic kidney disease: Localization of the second gene to chromosome 4q13-q23

    Energy Technology Data Exchange (ETDEWEB)

    Kimberling, W.J.; Kumar, S.; Kenyon, J.B.; Connolly, C.J. (Creighton Univ. Medical School, Omaha, NE (United States)); Gabow, P.A. (Colorado Univ. Health Sciences Center, Denver, CO (United States)); Somlo, S. (Albert Einstein School of Medicine, Bronx, NY (United States))

    1993-12-01

    At least two loci are known to exist for autosomal dominant polycystic kidney disease (ADPKD). One was localized to 16p, but the second less common locus has remained unlinked. Over 100 microsatellite markers, distributed across all chromosomes, have been typed on informative family members from the large Sicilian kindred in which the genetic heterogeneity was first discovered. Both the affected and the unaffected status of every family member used in the study were consulted in the successful localization of a second ADPKD gene to chromosome 4q. It was found to be flanked by the markers D4S231 and D4S414, defining a segment that spans about 9 cM. The new locus has been designated PKD4. This second localization will allow researchers to target another ADPKD gene for isolation in an effort to understand the pathogenesis of this common disorder. Furthermore, when flanking markers for the second ADPKD gene are used in conjunction with flanking markers for PKD1, the accuracy of the diagnosis of the subtype of ADPKD present in any particular family will be enhanced. This will improve the accuracy of linkage-based presymptomatic diagnoses by reducing the error due to genetic heterogeneity. 42 refs., 3 figs., 1 tab.

  17. A secreted WNT-ligand-binding domain of FZD5 generated by a frameshift mutation causes autosomal dominant coloboma.

    Science.gov (United States)

    Liu, Chunqiao; Widen, Sonya A; Williamson, Kathleen A; Ratnapriya, Rinki; Gerth-Kahlert, Christina; Rainger, Joe; Alur, Ramakrishna P; Strachan, Erin; Manjunath, Souparnika H; Balakrishnan, Archana; Floyd, James A; Li, Tiansen; Waskiewicz, Andrew; Brooks, Brian P; Lehmann, Ordan J; FitzPatrick, David R; Swaroop, Anand

    2016-04-01

    Ocular coloboma is a common eye malformation resulting from incomplete fusion of the optic fissure during development. Coloboma is often associated with microphthalmia and/or contralateral anophthalmia. Coloboma shows extensive locus heterogeneity associated with causative mutations identified in genes encoding developmental transcription factors or components of signaling pathways. We report an ultra-rare, heterozygous frameshift mutation in FZD5 (p.Ala219Glufs*49) that was identified independently in two branches of a large family with autosomal dominant non-syndromic coloboma. FZD5 has a single-coding exon and consequently a transcript with this frameshift variant is not a canonical substrate for nonsense-mediated decay. FZD5 encodes a transmembrane receptor with a conserved extracellular cysteine rich domain for ligand binding. The frameshift mutation results in the production of a truncated protein, which retains the Wingless-type MMTV integration site family member-ligand-binding domain, but lacks the transmembrane domain. The truncated protein was secreted from cells, and behaved as a dominant-negative FZD5 receptor, antagonizing both canonical and non-canonical WNT signaling. Expression of the resultant mutant protein caused coloboma and microphthalmia in zebrafish, and disruption of the apical junction of the retinal neural epithelium in mouse, mimicking the phenotype of Fz5/Fz8 compound conditional knockout mutants. Our studies have revealed a conserved role of Wnt-Frizzled (FZD) signaling in ocular development and directly implicate WNT-FZD signaling both in normal closure of the human optic fissure and pathogenesis of coloboma.

  18. 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.

  19. De novo post-transplant thrombotic microangiopathy localized only to the graft in autosomal dominant polycystic kidney disease with thrombophilia

    Science.gov (United States)

    Rolla, Davide; Fontana, Iris; Ravetti, Jean Louis; Marsano, Luigina; Bellino, Diego; Panaro, Laura; Ansaldo, Francesca; Mathiasen, Lisa; Storace, Giulia; Trezzi, Matteo

    2015-01-01

    Introduction: Thrombotic microangiopathy (TMA) is a serious complication of renal transplantation and is mostly related to the prothrombotic effect of calcineurin inhibitors (CNIs). A subset of TMA (29%-38%) is localized only to the graft. Case 1: A young woman suffering from autosomal dominant polycystic kidney disease (ADPKD) underwent kidney transplant. After 2 months, she showed slow renal deterioration (serum creatinine from 1.9 to 3.1 mg/dl), without hematological signs of hemolytic-uremic syndrome (HUS); only LDH enzyme transient increase was detected. Renal biopsy showed TMA: temporary withdraw of tacrolimus and plasmapheresis was performed. The renal function recovered (serum creatinine 1.9 mg/dl). From screening for thrombophilia, we found a mutation of the Leiden factor V gene. Case 2: A man affected by ADPKD underwent kidney transplantation, with delay graft function; first biopsy showed acute tubular necrosis, but a second biopsy revealed TMA, while no altered hematological parameters of HUS was detected. We observed only a slight increase of lactate dehydrogenase (LDH) levels. The tacrolimus was halved and plasmapheresis was performed: LDH levels normalized within 10 days and renal function improved (serum creatinine from 9 to 2.9 mg/dl). We found a mutation of the prothrombin gene. Only a renal biopsy clarifies the diagnosis of TMA, but it is necessary to pay attention to light increasing level of LDH. Conclusion: Prothrombotic effect of CNIs and mTOR inhibitor, mutation of genes encoding factor H or I, anticardiolipin antibodies, vascular rejection, cytomegalovirus infection are proposed to trigger TMA; we detected mutations of factor II and Leiden factor V, as facilitating conditions for TMA in patients affected by ADPKD. PMID:26693501

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

    Directory of Open Access Journals (Sweden)

    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.

  1. Nephroangiosclerosis in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: is NOTCH3 mutation the common culprit?

    Science.gov (United States)

    Guerrot, Dominique; François, Arnaud; Boffa, Jean-Jacques; Boulos, Nada; Hanoy, Melanie; Legallicier, Bruno; Triquenot-Bagan, Aude; Guyant-Marechal, Lucie; Laquerriere, Annie; Freguin-Bouilland, Caroline; Ronco, Pierre; Godin, Michel

    2008-08-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a systemic arterial disease characterized by impairment of vascular smooth muscle cell structure and function related to NOTCH3 mutations. Pathological findings include pathognomonic granular osmiophilic material (GOM) deposition with nonspecific hyalinization within the artery wall in a variety of tissues. The main clinical presentation is iterative strokes in young adults despite the lack of cardiovascular risk factors, leading to early dementia. Although arteriosclerosis and GOM have been found in kidneys from patients with CADASIL, kidney disease has been described only once up to now, in association with immunoglobulin A nephropathy. We report the case of a 61-year-old patient with a medical history of CADASIL and recent mild hypertension. His mother also showed neuropsychiatric symptoms and end-stage renal disease of unknown cause. The patient had a chronic kidney disease defined by means of estimated glomerular filtration rate using the 4-variable Modification of Diet in Renal Disease Study equation of 58 mL/min/1.73 m(2) associated with mild proteinuria and intermittent microscopic hematuria. Renal histological analysis showed severe arteriosclerosis and mild interstitial fibrosis. Glomeruli did not show mesangial immunoglobulin A deposition or focal segmental proliferation. Electron microscopic analysis showed typical GOM deposition in the vicinity of altered vascular smooth muscle cells in interlobular and juxtaglomerular arteries. The nephroangiosclerosis-like lesions were unusually severe in contrast to the recent mild hypertension. The presence of GOM strongly suggests that renal lesions were related to the NOTCH3 mutation. Here, we describe the first case of familial occurrence of kidney disease with decreased kidney function in the absence of coexisting nephropathy in patients with CADASIL. We discuss the role of NOTCH3 mutation in the pathogenesis

  2. Somatotroph Pituitary Adenoma with Acromegaly and Autosomal Dominant Polycystic Kidney Disease – SSTR5 polymorphism and PKD1 mutation

    Science.gov (United States)

    Syro, Luis V.; Sundsbak, Jamie L.; Scheithauer, Bernd W.; Toledo, Rodrigo A.; Camargo, Mauricio; Heyer, Christina M.; Sekiya, Tomoko; Uribe, Humberto; Escobar, Jorge I.; Vasquez, Martin; Rotondo, Fabio; Toledo, Sergio P. A.; Kovacs, Kalman; Horvath, Eva; Babovic-Vuksanovic, Dusica; Harris, Peter C.

    2014-01-01

    A 39-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) presented with acromegaly and a pituitary macroadenoma. There was a family history of this renal disorder. She had undergone surgery for pituitary adenoma 6 years prior. Physical examination disclosed bitemporal hemianopsia and elevation of both basal growth hormone (GH) 106 ng/mL (normal 0–5) and insulin-like growth factor (IGF-1) 811 ng/mL (normal 48–255) blood levels. A magnetic resonance imaging scan disclosed a 3.0 cm sellar and suprasellar mass with both optic chiasm compression and left cavernous sinus invasion. Histologic, immunohistochemical and ultrastructural studies of the lesion disclosed a sparsely granulated somatotroph adenoma. Standard chromosome analysis on the blood sample showed no abnormality. Sequence analysis of the coding regions of PKD1 and PKD2 employing DNA from both peripheral leukocytes and the tumor revealed the most common PKD1 mutation, 5014_5015delAG. Analysis of the entire SSTR5 gene disclosed the variant c.143C>A (p.L48M, rs4988483) change in the heterozygous state in both blood and tumor, while no pathogenic mutations were noted in the MEN1, AIP, p27Kip1 and SSTR2 genes. To our knowledge, this is the fourth reported case of a GH-producing pituitary adenoma associated with ADPKD, but the first subject to extensive morphological, ultrastructural, cytogenetic and molecular studies. The question arises whether the physical proximity of the PKD1 and SSTR5 genes on chromosome 16 indicates a causal relationship between ADPKD and the somatotroph adenoma. PMID:21744088

  3. Identification of a Novel Gene on 10q22.1 Causing Autosomal Dominant Retinitis Pigmentosa (adRP).

    Science.gov (United States)

    Daiger, Stephen P; Sullivan, Lori S; Bowne, Sara J; Koboldt, Daniel C; Blanton, Susan H; Wheaton, Dianna K; Avery, Cheryl E; Cadena, Elizabeth D; Koenekoop, Robert K; Fulton, Robert S; Wilson, Richard K; Weinstock, George M; Lewis, Richard A; Birch, David G

    2016-01-01

    Whole-genome linkage mapping identified a region on chromosome 10q21.3-q22.1 with a maximum LOD score of 3.0 at 0 % recombination in a six-generation family with autosomal dominant retinitis pigmentosa (adRP). All known adRP genes and X-linked RP genes were excluded in the family by a combination of methods. Whole-exome next-generation sequencing revealed a missense mutation in hexokinase 1, HK1 c.2539G > A, p.Glu847Lys, tracking with disease in all affected family members. One severely-affected male is homozygous for this region by linkage analysis and has two copies of the mutation. No other potential mutations were detected in the linkage region nor were any candidates identified elsewhere in the genome. Subsequent testing detected the same mutation in four additional, unrelated adRP families, for a total of five mutations in 404 probands tested (1.2 %). Of the five families, three are from the Acadian population in Louisiana, one is French Canadian and one is Sicilian. Haplotype analysis of the affected chromosome in each family and the homozygous individual revealed a rare, shared haplotype of 450 kb, suggesting an ancient founder mutation. HK1 is a widely-expressed gene, with multiple, abundant retinal transcripts, coding for hexokinase 1. Hexokinase catalyzes phosphorylation of glucose to glusose-6-phospate, the first step in glycolysis. The Glu847Lys mutation is in a highly-conserved site, outside of the active site or known functional sites.

  4. Genetic diagnosis of autosomal dominant polycystic kidney disease by targeted capture and next-generation sequencing: utility and limitations.

    Science.gov (United States)

    Qi, Xiao-Ping; Du, Zhen-Fang; Ma, Ju-Ming; Chen, Xiao-Ling; Zhang, Qing; Fei, Jun; Wei, Xiao-Ming; Chen, Dong; Ke, Hai-Ping; Liu, Xuan-Zhu; Li, Feng; Chen, Zhen-Guang; Su, Zheng; Jin, Hang-Yang; Liu, Wen-Ting; Zhao, Yan; Jiang, Hu-Ling; Lan, Zhang-Zhang; Li, Peng-Fei; Fang, Ming-Yan; Dong, Wei; Zhang, Xian-Ning

    2013-03-01

    Mutation-based molecular diagnostics of autosomal dominant polycystic kidney disease (ADPKD) is complicated by genetic and allelic heterogeneity, large multi-exon genes, and duplication sequences of PKD1. Recently, targeted resequencing by pooling long-range polymerase chain reaction (LR-PCR) amplicons has been used in the identification of mutations in ADPKD. Despite its high sensitivity, specificity and accuracy, LR-PCR is still complicated. We performed whole-exome sequencing on two unrelated typical Chinese ADPKD probands and evaluated the effectiveness of this approach compared with Sanger sequencing. Meanwhile, we performed targeted gene and next-generation sequencing (targeted DNA-HiSeq) on 8 individuals (1 patient from one family, 5 patients and 2 normal individuals from another family). Both whole-exome sequencing and targeted DNA-HiSeq confirmed c.11364delC (p.H3788QfsX37) within the unduplicated region of PKD1 in one proband; in the other family, targeted DNA-HiSeq identified a small insertion, c.401_402insG (p.V134VfsX79), in PKD2. These methods do not overcome the screening complexity of homology. However, the true positives of variants confirmed by targeted gene and next-generation sequencing were 69.4%, 50% and 100% without a false positive in the whole coding region and the duplicated and unduplicated regions, which indicated that the screening accuracy of PKD1 and PKD2 can be largely improved by using a greater sequencing depth and elaborate design of the capture probe.

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

    Science.gov (United States)

    Perganta, Georgia; Barnard, Alun R; Katti, Christiana; Vachtsevanos, Athanasios; Douglas, Ron H; MacLaren, Robert E; Votruba, Marcela; Sekaran, Sumathi

    2013-01-01

    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.

  6. Novel method for genomic analysis of PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Tan, Ying-Cai; Blumenfeld, Jon D; Anghel, Raluca; Donahue, Stephanie; Belenkaya, Rimma; Balina, Marina; Parker, Thomas; Levine, Daniel; Leonard, Debra G B; Rennert, Hanna

    2009-02-01

    Genetic testing of PKD1 and PKD2 is useful for diagnosis and prognosis of autosomal dominant polycystic kidney disease (ADPKD), particularly in asymptomatic individuals or those without a family history. PKD1 testing is complicated by the large transcript size, complexity of the gene region, and the extent of gene variations. A molecular assay was developed using Transgenomic's SURVEYOR Nuclease and WAVE Nucleic Acid High Sensitivity Fragment Analysis System to screen for PKD1 and PKD2 variants, followed by sequencing of variant gene segments, thereby reducing the sequencing reactions by 80%. This method was compared to complete DNA sequencing performed by a reference laboratory for 25 ADPKD patients from 22 families. The pathogenic potential of gene variations of unknown significance was examined by evolutionary comparison, effects of amino acid substitutions on protein structure, and effects of splice-site alterations. A total of 90 variations were identified, including all 82 reported by the reference laboratory (100% sensitivity). A total of 76 variations (84.4%) were in PKD1 and 14 (15.6%) in PKD2. Definite pathogenic mutations (seven nonsense, four truncation, and three splicing defects) were detected in 64% (14/22) of families. The remaining 76 variants included 26 missense, 33 silent, and 17 intronic changes. Two heterozygous nonsense mutations were incorrectly determined by the reference laboratory as homozygous. "Probably pathogenic" mutations were identified in an additional five families (overall detection rate 86%). In conclusion, the SURVEYOR nuclease method was comparable to direct sequencing for detecting ADPKD mutations, achieving high sensitivity with lower cost, providing an important tool for genetic analysis of complex genes.

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

    Science.gov (United States)

    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. PMID:28050599

  8. Autosomal dominant polycystic liver disease in a family without polycystic kidney disease associated with a novel missense protein kinase C substrate 80K-H mutation.

    Science.gov (United States)

    Peces, Ramón; Drenth, Joost P H; Te Morsche, Rene H M; González, Pedro; Peces, Carlos

    2005-12-28

    Polycystic liver disease (PLD) is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. PLD can manifest itself in patients with severe autosomal dominant polycystic kidney disease (ADPKD). Isolated autosomal dominant polycystic liver disease (ADPLD) is genetically distinct from PLD associated with ADPKD, although it may have similar pathogenesis and clinical manifestations. Recently, mutations in two causative genes for ADPLD, independently from ADPKD, have been identified. We report here a family (a mother and her daughter) with a severe form of ADPLD not associated with ADPKD produced by a novel missense protein kinase C substrate 80K-H (PRKCSH) mutation (R281W). This mutation causes a severe phenotype, since the two affected subjects manifested signs of portal hypertension. Doppler sonography, computed tomography (CT) and magnetic resonance (MR) imaging are effective in documenting the underlying lesions in a non-invasive way.

  9. Autosomal dominant familial spastic paraplegia: Reduction of the FSPI candidate region on chromosome 14q to 7 cM and locus heterogeneity

    Energy Technology Data Exchange (ETDEWEB)

    Gispert, S.; Santos, N.; Auburger, G.; Damen, R.; Voit, T. [University Hospital, Duesseldorf (Germany); Schulz, J.; Klockgether, T. [University Hospital, Tuebingen (Germany); Orozco, G. [Hospital Lenin, Holguin (Cuba); Kreuz, F. [Technical Univ., Dresden (Netherlands); Weissenbach, J. [Unite de Genetique, Paris (France)

    1995-01-01

    Three large pedigrees of Germany descent with autosomal dominant {open_quotes}pure{close_quotes} familial spastic paraplegia (FSP) were characterized clinically and genetically. Haplotype and linkage analyses, with microsatellites covering the FSP region on chromosome 14q (locus FSP1), were performed. In pedigree W, we found a haplotype that cosegregates with the disease and observed three crossing-over events, reducing the FSP1 candidate region to 7 cM; in addition, the observation of apparent anticipation in this family suggests a trinucleotide repeat expansion as the mutation. In pedigree D and S, the gene locus could be excluded from the whole FSP1 region, confirming the locus heterogeneity of autosomal dominant FSP. 11 refs., 2 figs., 2 tabs.

  10. Autosomal dominant polycystic liver disease in a family without polycystic kidney disease associated with a novel missense protein kinase C substrate 80K-H mutation

    Institute of Scientific and Technical Information of China (English)

    Ramón Peces; Joost PH Drenth; Rene HM te Morsche; Pedro González; Carlos Peces

    2005-01-01

    Polycystic liver disease (PLD) is characterized by the presence of multiple bile duct-derived epithelial cysts scattered in the liver parenchyma. PLD can manifest itself in patients with severe autosomal dominant polycystic kidney disease (ADPKD). Isolated autosomal dominant polycystic liver disease (ADPLD) is genetically distinct from PLD associated with ADPKD, although it may have similar pathogenesis and clinical manifestations.Recently, mutations in two causative genes for ADPLD,independently from ADPKD, have been identified. We report here a family (a mother and her daughter) with a severe form of ADPLD not associated with ADPKD produced by a novel missense protein kinase C substrate 80K-H (PRKCSH) mutation (R281W). This mutation causes a severe phenotype, since the two affected subjects manifested signs of portal hypertension. Doppler sonography, computed tomography (CT) and magnetic resonance (MR) imaging are effective in documenting the underlying lesions in a non-invasive way.

  11. Design and baseline characteristics of participants in the study of antihypertensive therapy in children and adolescents with autosomal dominant polycystic kidney disease (ADPKD).

    Science.gov (United States)

    Cadnapaphornchai, Melissa A; Fick-Brosnahan, Godela M; Duley, Irene; Johnson, Ann M; Strain, John D; DeGroff, Curt G; Schrier, Robert W

    2005-04-01

    In this manuscript, we describe our ongoing randomized clinical trial to assess the efficacy of blood pressure control with angiotensin converting enzyme (ACE) inhibition on renal cyst growth over a 5-year study period in children and young adults aged 4-21 years with autosomal dominant polycystic kidney disease (ADPKD). Baseline demographic and laboratory data for the study groups are reported. Results of this study could significantly impact the standard of care for management of ADPKD in this population.

  12. Low birth weight is associated with earlier onset of end-stage renal disease in Danish patients with autosomal dominant polycystic kidney disease

    DEFF Research Database (Denmark)

    Orskov, Bjarne; Christensen, Karl Bang; Feldt-Rasmussen, Bo

    2012-01-01

    Low-birth-weight individuals have a higher risk of hypertension and end-stage renal disease (ESRD). Here we investigated whether low birth weight was associated with earlier onset of ESRD in patients with autosomal dominant polycystic kidney disease (ADPKD). In collaboration with all Danish depar...... birth weight may contribute to considerable phenotypic variability in the progression of renal disease between individuals with ADPKD....

  13. Brief Screening of Vascular Cognitive Impairment in Patients With Cerebral Autosomal-Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy Without Dementia

    OpenAIRE

    2016-01-01

    Background and Purpose - Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic form of cerebral small vessel disease leading to early-onset stroke and dementia, with younger patients frequently showing subclinical deficits in cognition. At present, there are no targeted cognitive screening measures for this population. However, the Brief Memory and Executive Test (BMET) and the Montreal Cognitive Assessment (MoCA) have shown utilit...

  14. 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

  15. 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

  16. Chronic asymptomatic pyuria precedes overt urinary tract infection and deterioration of renal function in autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    Hwang Jin Ho

    2013-01-01

    Full Text Available Abstract Background Urinary tract infection (UTI occurs in 30%-50% of individuals with autosomal dominant polycystic kidney disease (ADPKD. However, the clinical relevance of asymptomatic pyuria in ADPKD patients remains unknown. Methods We retrospectively reviewed medical records of 256 ADPKD patients who registered to the ADPKD clinic at Seoul National University Hospital from Aug 1999 to Aug 2010. We defined the asymptomatic pyuria as more than 5-9 white blood cells in high-power field with no related symptoms or signs of overt UTI. Patients were categorized into 2 groups depending on its duration and frequency: Group A included non-pyuria and transient pyuria patients; Group B included recurrent and persistent pyuria patients. The association between asymptomatic pyuria and both the development of overt UTI and the deterioration of renal function were examined. Results With a mean follow-up duration of 65.3 months, 176 (68.8% out of 256 patients experienced 681 episodes of asymptomatic pyuria and 50 episodes of UTI. The annual incidence of asymptomatic pyuria was 0.492 episodes/patient/year. The patients in group B showed female predominance (58.5% vs. 42.0%, P=0.01 and experienced an upper UTI more frequently (hazard ratio: 4.612, 95% confidence interval: 1.735-12.258; P=0.002, adjusted for gender and hypertension. The annual change in estimated glomerular filtration rate (ΔeGFR was significantly larger in magnitude in group B than in group A (-2.7��4.56 vs. -1.17±5.8, respectively; P=0.01. Age and Group B found to be the independent variables for ΔeGFR and developing end-stage renal disease (16.0% vs. 4.3%, respectively; P=0.001. Conclusions Chronic asymptomatic pyuria may increase the risk of developing overt UTI and may contribute to declining renal function in ADPKD.

  17. Identification of a novel oligomerization disrupting mutation in CRYΑA associated with congenital cataract in a South Australian family.

    Science.gov (United States)

    Laurie, Kate J; Dave, Alpana; Straga, Tania; Souzeau, Emmanuelle; Chataway, Timothy; Sykes, Matthew J; Casey, Theresa; Teo, Theodosia; Pater, John; Craig, Jamie E; Sharma, Shiwani; Burdon, Kathryn P

    2013-03-01

    Congenital cataract is a heterogeneous disorder causing severe visual impairment in affected children. We screened four South Australian families with autosomal dominant congenital cataract for mutations in 10 crystallin genes known to cause congenital cataract. We identified a novel segregating heterozygous mutation, c.62G>A (p.R21Q), in the CRYΑA gene in one family. Western blotting of proteins freshly extracted from cataractous lens material of the proband demonstrated a marked reduction in the amount of the high-molecular-weight oligomers seen in the lens material of an unaffected individual. We conclude that the p.R21Q mutation, which is located in the highly conserved and structurally significant N-terminal region of the protein, is responsible for the cataract phenotype observed in the family as this mutation likely reduces the formation of the functional oligomeric alpha-crystallin.

  18. Cataract Surgery

    Science.gov (United States)

    ... and Videos: What Do Cataracts Look Like? Cataract Surgery Written by: Kierstan Boyd Reviewed by: Elena M ... how they work. What to expect with cataract surgery Before surgery: Your ophthalmologist will measure your eye ...

  19. In Vivo CRISPR/Cas9 Gene Editing Corrects Retinal Dystrophy in the S334ter-3 Rat Model of Autosomal Dominant Retinitis Pigmentosa.

    Science.gov (United States)

    Bakondi, Benjamin; Lv, Wenjian; Lu, Bin; Jones, Melissa K; Tsai, Yuchun; Kim, Kevin J; Levy, Rachelle; Akhtar, Aslam Abbasi; Breunig, Joshua J; Svendsen, Clive N; Wang, Shaomei

    2016-03-01

    Reliable genome editing via Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR)/Cas9 may provide a means to correct inherited diseases in patients. As proof of principle, we show that CRISPR/Cas9 can be used in vivo to selectively ablate the rhodopsin gene carrying the dominant S334ter mutation (Rho(S334)) in rats that model severe autosomal dominant retinitis pigmentosa. A single subretinal injection of guide RNA/Cas9 plasmid in combination with electroporation generated allele-specific disruption of Rho(S334), which prevented retinal degeneration and improved visual function.

  20. Denaturing high-performance liquid chromatography to diagnose cerebral autosomal dominant arteriopathy in Chinese patients with subcortical infarcts and leukoencephalopathy

    Institute of Scientific and Technical Information of China (English)

    Xiaomei Tang; Biao Chen

    2008-01-01

    BACKGROUND: Notch3 mutations are the molecular genetic foundation for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Of all currently available detection methods, direct sequencing or restriction enzymes are frequently used, but the cost is relatively high, because the Notch3 gene is composed of many exons and mutational sites are widely distributed. Denaturing high-performance liquid chromatography (DHPLC) exhibits high efficiency and specificity and has been applied to gene detection. To date, there has no report regarding DHPLC in gene detection of large-scale CADASIL families in China. OBJECTIVE: To explore the application and value of DHPLC in the diagnosis of CADASIL by a mutation screening for Notch3 gene in CADASIL probands and their family members. DESIGN, TIME AND SETTING: A comparative observation was performed at the Genetic Diagnosis Laboratory of Institute of Geriatrics, Xuanwu Hospital of Capital Medical University and the Key Laboratory for Neurodegenerative Disease of the Ministry of Education between August 2003 and May 2004. PARTICIPANTS: Fourteen CADASIL patients and their family members, comprising eight males and six females, aged 38-62 years, were included. Their key features included recurrent sub-cortical ischemic events and vascular dementia. In addition, 100 healthy physical examinees were selected as controls, including 52 males and 48 females, aged 56-72 years, who had no neurodegenerative disease or psychosis, and no history or high risk for cerebrovascular disease. METHODS: DNA was extracted from white blood cells. Ten hotspots of the Notch3 gene for sequence variation were first amplified by PCR, and the products were detected using DHPLC. Exons exhibiting a variant in the DHPLC profile underwent another PCR amplification, followed by DNA sequencing to identify the mutation type. In addition, patients with normal DHPLC peak profiles underwent PCR amplification for the remaining

  1. Brain imaging and blood biomarker abnormalities in children with autosomal-dominant Alzheimer's disease: A cross-sectional Study

    Science.gov (United States)

    Quiroz, Y.T.; Schultz, A.; Chen, K.; Protas, H.; Brickhouse, M.; Fleisher, A.S.; Langbaum, J.B.; Thiyyagura, P.; Fagan, A.M.; Shah, A.R.; Muniz, M.; Arboleda-Velasquez, JF; Munoz, C.; Garcia, G.; Acosta-Baena, N.; Giraldo, M.; Tirado, V.; Ramirez, D.; Tariot, PN; Dickerson, B.C.; Sperling, R.A.; Lopera, F.; Reiman, E.M.

    2015-01-01

    IMPORTANCE Brain imaging and fluid biomarkers are characterized in children at risk for autosomal dominant Alzheimer disease (ADAD). OBJECTIVE To characterize and compare structural magnetic resonance imaging (MRI), resting-state and task-dependent functional MRI, and plasma amyloid-β (Aβ) measurements in presenilin 1 (PSEN1) E280A mutation–carrying and noncarrying children with ADAD. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional measures of structural and functional MRI and plasma Aβ assays were assessed in 18 PSEN1 E280A carriers and 19 noncarriers aged 9 to 17 years from a Colombian kindred with ADAD. Recruitment and data collection for this study were conducted at the University of Antioquia and the Hospital Pablo Tobon Uribe in Medellin, Colombia, between August 2011 and June 2012. MAIN OUTCOMES AND MEASURES All participants had blood sampling, structural MRI, and functional MRI during associative memory encoding and resting-state and cognitive assessments. Outcome measures included plasma Aβ1-42 concentrations and Aβ1-42:Aβ1-40 ratios, memory encoding–dependent activation changes, resting-state connectivity, and regional gray matter volumes. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to AD. RESULTS Similar to findings in adult mutation carriers, in the later preclinical and clinical stages of ADAD, mutation-carrying children were distinguished from control individuals by significantly higher plasma Aβ1-42 levels (mean [SD]: carriers, 18.8 [5.1] pg/mL and noncarriers, 13.1 [3.2] pg/mL; P < .001) and Aβ1-42:Aβ1-40 ratios (mean [SD]: carriers, 0.32 [0.06] and noncarriers, 0.21 [0.03]; P < .001), as well as less memory encoding task–related deactivation in parietal regions (eg, mean [SD] parameter estimates for the right precuneus were −0.590 [0.50] for noncarriers and −0.087 [0.38] for carriers; P < .005 uncorrected). Unlike carriers in the later stages, mutation

  2. 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

  3. A novel candidate locus on chromosome 11p14.1-p11.2 for autosomal dominant hereditary spastic paraplegia

    Institute of Scientific and Technical Information of China (English)

    ZHAO Guo-hua; TANG Bei-sha; HU Zheng-mao; SHEN Lu; JIANG Hong; REN Zhi-jun; LIU Xiao-min; XIA Kun; GUO Peng; PAN Qian

    2008-01-01

    Background Hereditary spastic paraplegia(HSP)is a group of inherited neurodegenerative disorders with the shared characteristics of slowly progressive spasticity and weakness of the lower limbs.Thirteen loci for autosomal dominant HSP have been mapped.Methods A Chinese family with HSP was found in the Shandong province and Inner Mongolia Autonomous Region of China and genomic DNA of all 19 family members was isolated.After exclusion of known autosomal dominant loci,a genome wide scan and linkage analysis were performed.Results The known autosomal dominant loci of SPG3A,SPG4,SPG6,SPG8,SPG9,SPG10,SPGl2,SPG13,SPG17,SPG19,SPG29,SPG31 and SPG33 were excluded by linkage analysis.The results of a genome wide scan demonstrated candidate linkage to a locus on chromosome 11p14.1-p11.2,over an 18.88 cM interval between markers D11S1324 and D11S1933.A maximal,two point LOD score of 2.36 for marker D11S935 at a recombination fraction(Φ)of 0 and a multipoint LOD score of 2.36 for markers D11S1776,D11S1751,D11S1392,D11S4203,D11S935,D11S4083,and D11S4148at Φ=0,suggest linkage to this locus.Conclusion The HSP neuropathy in this family may represent a novel genetic entity,which will facilitate discovery of this causative gene.

  4. 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...... 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...

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

    DEFF Research Database (Denmark)

    Tranebjærg, Lisbeth; Rendtorff, Nanna D; Topsakal, Vedat;

    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...... tested frequencies with statistically significant progression. In family 2 eleven subjects were affected with mild to moderate SNHL starting in the second decade. Most of them showed a flat audiogram, but some had mid-frequency hearing loss. Significant progression of thresholds was present at 4 and 8 k...

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

    Science.gov (United States)

    Sainaresh, Vv; Jain, Sh; Patel, Hv; Shah, Pr; Vanikar, Av; Trivedi, Hl

    2011-04-01

    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).

  7. c.G2114A MYH9 mutation (DFNA17) causes non-syndromic autosomal dominant hearing loss in a Brazilian family

    Science.gov (United States)

    Dantas, Vitor G.L.; Lezirovitz, Karina; Yamamoto, Guilherme L.; Moura de Souza, Carolina Fischinger; Ferreira, Simone Gomes; Mingroni-Netto, Regina C.

    2014-01-01

    We studied a family presenting 10 individuals affected by autosomal dominant deafness in all frequencies and three individuals affected by high frequency hearing loss. Genomic scanning using the 50k Affymetrix microarray technology yielded a Lod Score of 2.1 in chromosome 14 and a Lod Score of 1.9 in chromosome 22. Mapping refinement using microsatellites placed the chromosome 14 candidate region between markers D14S288 and D14S276 (8.85 cM) and the chromosome 22 near marker D22S283. Exome sequencing identified two candidate variants to explain hearing loss in chromosome 14 [PTGDR – c.G894A:p.R298R and PTGER2 – c.T247G:p.C83G], and one in chromosome 22 [MYH9, c.G2114A:p.R705H]. Pedigree segregation analysis allowed exclusion of the PTGDR and PTGER2 variants as the cause of deafness. However, the MYH9 variant segregated with the phenotype in all affected members, except the three individuals with different phenotype. This gene has been previously described as mutated in autosomal dominant hereditary hearing loss and corresponds to DFNA17. The mutation identified in our study is the same described in the prior report. Thus, although linkage studies suggested a candidate gene in chromosome 14, we concluded that the mutation in chromosome 22 better explains the hearing loss phenotype in the Brazilian family. PMID:25505834

  8. Clinical and molecular analysis of a Chinese family with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel missense mutation in the vasopressin-neurophysin II gene.

    Science.gov (United States)

    Luo, Yongfeng; Wang, Binbin; Qiu, Yu; Zhang, Chuan; Jin, Chengluo; Zhao, Yakun; Zhu, Qingguo; Ma, Xu

    2012-08-01

    The objective of this study is to identify the genetic defects in a Chinese family with autosomal dominant familial neurohypophyseal diabetes insipidus. Complete physical examination, fluid deprivation, and DDAVP tests were performed in three affected and three healthy members of the family. Genomic DNA was extracted from leukocytes of venous blood of these individuals for polymerase chain reaction amplification and direct sequencing of all three coding exons of arginine vasopressin-neurophysin II (AVP-NPII) gene. Seven members of this family were suspected to have symptomatic vasopressin-deficient diabetes insipidus. The water deprivation test in all the patients confirmed the diagnosis of vasopressin-deficient diabetes insipidus, with the pedigree demonstrating an autosomal dominant inheritance. Direct sequence analysis revealed a novel mutation (c.193T>A) and a synonymous mutation (c.192C>A) in the AVP-NPII gene. The missense mutation resulted in the substitution of cysteine by serine at a highly conserved codon 65 of exon 2 of the AVP-NPII gene in all affected individuals, but not in unaffected members. We concluded that a novel missense mutation in the AVP-NPII gene caused neurohypophyseal diabetes insipidus in this family, due to impaired neurophysin function as a carrier protein for AVP. The Cys65 is essential for NPII in the formation of a salt bridge with AVP. Presence of this mutation suggests that the portion of the neurophysin peptide encoded by this sequence is important for the normal expression of vasopressin.

  9. Autosomal P[ovoD1] dominant female-sterile insertions in Drosophila and their use in generating germ-line chimeras.

    Science.gov (United States)

    Chou, T B; Noll, E; Perrimon, N

    1993-12-01

    The 'dominant female-sterile' technique used to generate germ-line mosaics in Drosophila is a powerful tool to determine the tissue specificity (germ line versus somatic) of recessive female-sterile mutations as well as to analyze the maternal effect of recessive zygotic lethal mutations. This technique requires the availability of germ-line-dependent, dominant female-sterile (DFS) mutations that block egg laying but do not affect viability. To date only one X-linked mutation, ovoD1 has been isolated that completely fulfills these criteria. Thus the 'DFS technique' has been largely limited to the X-chromosome. To extend this technique to the autosomes, we have cloned the ovoD1 mutation into a P-element vector and recovered fully expressed P[ovoD1] insertions on each autosomal arm. We describe the generation of these P[ovoD1] strains as well as demonstrate their use in generating germ-line chimeras. Specifically, we show that the Gap1 gene, which encodes a Drosophila homologue of mammalian GTPase-activating protein, is required in somatic follicle cells for embryonic dorsoventral polarity determination.

  10. 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.

  11. Genome-wide linkage and copy number variation analysis reveals 710 kb duplication on chromosome 1p31.3 responsible for autosomal dominant omphalocele

    Science.gov (United States)

    Radhakrishna, Uppala; Nath, Swapan K; McElreavey, Ken; Ratnamala, Uppala; Sun, Celi; Maiti, Amit K; Gagnebin, Maryline; Béna, Frédérique; Newkirk, Heather L; Sharp, Andrew J; Everman, David B; Murray, Jeffrey C; Schwartz, Charles E; Antonarakis, Stylianos E; Butler, Merlin G

    2017-01-01

    Background Omphalocele is a congenital birth defect characterised by the presence of internal organs located outside of the ventral abdominal wall. The purpose of this study was to identify the underlying genetic mechanisms of a large autosomal dominant Caucasian family with omphalocele. Methods and findings A genetic linkage study was conducted in a large family with an autosomal dominant transmission of an omphalocele using a genome-wide single nucleotide polymorphism (SNP) array. The analysis revealed significant evidence of linkage (non-parametric NPL = 6.93, p=0.0001; parametric logarithm of odds (LOD) = 2.70 under a fully penetrant dominant model) at chromosome band 1p31.3. Haplotype analysis narrowed the locus to a 2.74 Mb region between markers rs2886770 (63014807 bp) and rs1343981 (65757349 bp). Molecular characterisation of this interval using array comparative genomic hybridisation followed by quantitative microsphere hybridisation analysis revealed a 710 kb duplication located at 63.5–64.2 Mb. All affected individuals who had an omphalocele and shared the haplotype were positive for this duplicated region, while the duplication was absent from all normal individuals of this family. Multipoint linkage analysis using the duplication as a marker yielded a maximum LOD score of 3.2 at 1p31.3 under a dominant model. The 710 kb duplication at 1p31.3 band contains seven known genes including FOXD3, ALG6, ITGB3BP, KIAA1799, DLEU2L, PGM1, and the proximal portion of ROR1. Importantly, this duplication is absent from the database of genomic variants. Conclusions The present study suggests that development of an omphalocele in this family is controlled by overexpression of one or more genes in the duplicated region. To the authors’ knowledge, this is the first reported association of an inherited omphalocele condition with a chromosomal rearrangement. PMID:22499347

  12. C.57 C > T Mutation in MIR 184 is Responsible for Congenital Cataracts and Corneal Abnormalities in a Five-generation Family from Galicia, Spain.

    Science.gov (United States)

    Bykhovskaya, Yelena; Caiado Canedo, Ana L; Wright, Kenneth W; Rabinowitz, Yaron S

    2015-01-01

    A c.57 C > T mutation in the seed region of MIR184 located at the 15q25.1 chromosomal region has been independently associated with autosomal dominant keratoconus with early-onset anterior polar cataract in the Northern Irish family and with autosomal dominant EDICT (Endothelial Dystrophy, Iris hypoplasia, Congenital cataracts, and stromal Thinning) syndrome. In this study we report a five-generation family originating in Galicia, Spain with early onset cataracts and variable corneal abnormalities which include non-ectatic corneal thinning and severe early-onset keratoconus. We identified a heterozygous c.57 C > T mutation in miR-184 in the proband and two additional affected relatives on the maternal side. This finding represents a third independent occurrence of this mutation in familiar ocular disease thus strengthening the link between miR-184 abnormalities and inherited eye defects.

  13. 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.)

  14. Rapamycin reduces kidney volume and delays the loss of renal function in a patient with autosomal-dominant polycystic kidney disease.

    Science.gov (United States)

    Peces, Ramón; Peces, Carlos; Pérez-Dueñas, Virginia; Cuesta-López, Emilio; Azorín, Sebastián; Selgas, Rafael

    2009-04-01

    This is the first report of a case of a reduction in kidney volume and preservation of renal function in a patient with autosomal-dominant polycystic kidney disease (ADPKD) receiving rapamycin. A 42-year-old man with ADPKD and a severe persistent bleeding from his solitary left kidney was successfully treated with tranexamic acid (TXA). He also received low-dose rapamycin for 8 months, and this was associated with a 23.5% reduction in kidney volume, improvement and stabilization of renal function, and normalization of haemoglobin levels. When treatment with rapamycin was interrupted, renal function deteriorated within an 8-month period and haemodialysis (HD) became necessary. Kidney volume increased at once, and life-threatening bleeding prompted a nephrectomy 4 months after the onset of HD. These data suggest that the reduction in kidney volume and preservation of renal function with rapamycin could be the result of the antiangiogenic, antiproliferative effects of rapamycin.

  15. 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...... (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...

  16. Splicing defects caused by exonic mutations in PKD1 as a new mechanism of pathogenesis in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Claverie-Martin, Felix; Gonzalez-Paredes, Francisco J; Ramos-Trujillo, Elena

    2015-01-01

    The correct splicing of precursor-mRNA depends on the actual splice sites plus exonic and intronic regulatory elements recognized by the splicing machinery. Surprisingly, an increasing number of examples reveal that exonic mutations disrupt the binding of splicing factors to these sequences or generate new splice sites or regulatory elements, causing disease. This contradicts the general assumption that missense mutations disrupt protein function and that synonymous mutations are merely polymorphisms. Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder caused mainly by mutations in the PKD1 gene. Recently, we analyzed a substantial number of PKD1 missense or synonymous mutations to further characterize their consequences on pre-mRNA splicing. Our results showed that one missense and 2 synonymous mutations induce significant defects in pre-mRNA splicing. Thus, it appears that aberrant splicing as a result of exonic mutations is a previously unrecognized cause of ADPKD.

  17. Novel heterozygous C243Y A20/TNFAIP3 gene mutation is responsible for chronic inflammation in autosomal-dominant Behçet's disease

    Science.gov (United States)

    Shigemura, Tomonari; Kaneko, Naoe; Kobayashi, Norimoto; Kobayashi, Keiko; Takeuchi, Yusuke; Nakano, Naoko; Masumoto, Junya; Agematsu, Kazunaga

    2016-01-01

    Objective Although Behçet's disease (BD) is a chronic inflammatory disorder of uncertain aetiology, the existence of familial BD with autosomal-dominant traits suggests that a responsibility gene (or genes) exists. We investigated a Japanese family with a history of BD to search for pathogenic mutations underlying the biological mechanisms of BD. Methods 6 patients over 4 generations who had suffered from frequent oral ulcers, genital ulcers and erythaema nodosum-like lesions in the skin were assessed. Whole-exome sequencing was performed on genomic DNA, and cytokine production was determined from stimulated mononuclear cells. Inflammatory cytokine secretion and Nod2-mediated NF-κB activation were analysed using the transfected cells. Results By whole-exome sequencing, we identified a common heterozygous missense mutation in A20/TNFAIP3, a gene known to regulate NF-κB signalling, for which all affected family members carried a heterozygous C243Y mutation in the ovarian tumour domain. Mononuclear cells obtained from the proband and his mother produced large amounts of interleukin 1β, IL-6 and tumour necrosis factor α (TNF-a) on stimulation as compared with those from normal controls. Although inflammatory cytokine secretion was suppressed by wild-type transfected cells, it was suppressed to a much lesser extent by mutated C243Y A20/TNFAIP3-transfected cells. In addition, impaired suppression of Nod2-mediated NF-κB activation by C243Y A20/TNFAIP3 was observed. Conclusions A C243Y mutation in A20/TNFAIP3 was likely responsible for increased production of human inflammatory cytokines by reduced suppression of NF-κB activation, and may have accounted for the autosomal-dominant Mendelian mode of BD transmission in this family. PMID:27175295

  18. 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

  19. Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia.

    Science.gov (United States)

    Bolar, Nikhita Ajit; Golzio, Christelle; Živná, Martina; Hayot, Gaëlle; Van Hemelrijk, Christine; Schepers, Dorien; Vandeweyer, Geert; Hoischen, Alexander; Huyghe, Jeroen R; Raes, Ann; Matthys, Erve; Sys, Emiel; Azou, Myriam; Gubler, Marie-Claire; Praet, Marleen; Van Camp, Guy; McFadden, Kelsey; Pediaditakis, Igor; Přistoupilová, Anna; Hodaňová, Kateřina; Vyleťal, Petr; Hartmannová, Hana; Stránecký, Viktor; Hůlková, Helena; Barešová, Veronika; Jedličková, Ivana; Sovová, Jana; Hnízda, Aleš; Kidd, Kendrah; Bleyer, Anthony J; Spong, Richard S; Vande Walle, Johan; Mortier, Geert; Brunner, Han; Van Laer, Lut; Kmoch, Stanislav; Katsanis, Nicholas; Loeys, Bart L

    2016-07-07

    Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)-both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD.

  20. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, genetic homogeneity, and mapping of the locus within a 2-cM interval

    Energy Technology Data Exchange (ETDEWEB)

    Ducros, A.; Alamowitch, S.; Nagy, T. [INSERM U25, Paris (France)] [and others

    1996-01-01

    Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a recently identified autosomal dominant cerebral arteriopathy characterized by the recurrence of subcortical infarcts leading to dementia. A genetic linkage analysis conducted in two large families recently allowed us to map the affected gene on chromosome 19 in a 12-cM interval bracketed by D19S221 and D19S215. In the present study, these first 2 families and 13 additional ones, including a total of 199 potentially informative meiosis, have been genotyped with eight polymorphic markers located between D19S221 and D19S215. All families were linked to chromosome 19. The highest combined lod score (Z{sub max} = 37.24 at {theta} = .01) was obtained with marker D19S841, a new CA{sub n} microsatellite marker that we isolated from chromosome 19 cosmids. The recombinant events observed within these families were used to refine the genetic mapping of CADASIL within a 2-cM interval that is now bracketed by D19S226 and D19S199 on 19p13.1. These data strongly suggest the genetic homogeneity of this recently identified condition and establish the value of its clinical and neuroimaging diagnostic criteria. Besides their importance for the ongoing positional cloning of the CADASIL gene, these data help to refine the genetic mapping of CADASIL relative to familial hemiplegic migraine and hereditary paroxysmal cerebellar ataxia, conditions that we both mapped within the same chromosome 19 region. 35 refs., 5 figs., 2 tabs.

  1. Clinical aspects of an autosomal dominantly inherited hearing impairment linked to the DFNA60 locus on chromosome 2q23.1-2q23.3.

    Science.gov (United States)

    van Beelen, E; Schraders, M; Huygen, P L M; Oostrik, J; Plantinga, R F; van Drunen, W; Collin, R W J; Kooper, D P; Pennings, R J E; Cremers, C W R J; Kremer, H; Kunst, H P M

    2013-06-01

    A total of 64 loci for autosomal dominant non-syndromic hearing impairment have been described, and the causative genes have been identified for 24 of these. The present study reports on the clinical characteristics of an autosomal dominantly inherited hearing impairment that is linked to a region within the DFNA60 locus located on chromosome 2 in q22.1-24.1. A pedigree spanning four generations was established with 13 affected individuals. Linkage analysis demonstrated that the locus extended over a 2.96 Mb region flanked by markers D2S2335 and D2S2275. The audiograms mainly showed a distinctive U-shaped configuration. Deterioration of hearing started at a wide age range, from 12 to 40 years. Cross-sectional analysis showed rapid progression of hearing impairment from mild to severe, between the ages of 40 and 60 years, a phenomenon that is also observed in DFNA9 patients. The results of the individual longitudinal analyses were generally in line with those obtained by the cross-sectional analysis. Speech recognition scores related to the level of hearing impairment (PTA1,2,4 kHz) appeared to be fairly similar to those of presbyacusis patients. It is speculated that hearing impairment starting in mid-life, as shown by DFNA60 patients, could play a role in the development of presbyacusis. Furthermore, speech recognition did not deteriorate appreciably before the sixth decade of life. We conclude that DFNA60 should be considered in hearing impaired patients who undergo a rapid progression in middle age and are negative for DFNA9. Furthermore, cochlear implantation resulted in good rehabilitation in two DFNA60 patients.

  2. 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.

  3. Repair of rhodopsin mRNA by spliceosome-mediated RNA trans-splicing: a new approach for autosomal dominant retinitis pigmentosa.

    Science.gov (United States)

    Berger, Adeline; Lorain, Stéphanie; Joséphine, Charlène; Desrosiers, Melissa; Peccate, Cécile; Voit, Thomas; Garcia, Luis; Sahel, José-Alain; Bemelmans, Alexis-Pierre

    2015-05-01

    The promising clinical results obtained for ocular gene therapy in recent years have paved the way for gene supplementation to treat recessively inherited forms of retinal degeneration. The situation is more complex for dominant mutations, as the toxic mutant gene product must be removed. We used spliceosome-mediated RNA trans-splicing as a strategy for repairing the transcript of the rhodopsin gene, the gene most frequently mutated in autosomal dominant retinitis pigmentosa. We tested 17 different molecules targeting the pre-mRNA intron 1, by transient transfection of HEK-293T cells, with subsequent trans-splicing quantification at the transcript level. We found that the targeting of some parts of the intron promoted trans-splicing more efficiently than the targeting of other areas, and that trans-splicing rate could be increased by modifying the replacement sequence. We then developed cell lines stably expressing the rhodopsin gene, for the assessment of phenotypic criteria relevant to the pathogenesis of retinitis pigmentosa. Using this model, we showed that trans-splicing restored the correct localization of the protein to the plasma membrane. Finally, we tested our best candidate by AAV gene transfer in a mouse model of retinitis pigmentosa that expresses a mutant allele of the human rhodopsin gene, and demonstrated the feasibility of trans-splicing in vivo. This work paves the way for trans-splicing gene therapy to treat retinitis pigmentosa due to rhodopsin gene mutation and, more generally, for the treatment of genetic diseases with dominant transmission.

  4. DVL3 Alleles Resulting in a −1 Frameshift of the Last Exon Mediate Autosomal-Dominant Robinow Syndrome

    Science.gov (United States)

    White, Janson J.; Mazzeu, Juliana F.; Hoischen, Alexander; Bayram, Yavuz; Withers, Marjorie; Gezdirici, Alper; Kimonis, Virginia; Steehouwer, Marloes; Jhangiani, Shalini N.; Muzny, Donna M.; Gibbs, Richard A.; van Bon, Bregje W.M.; Sutton, V. Reid; Lupski, James R.; Brunner, Han G.; Carvalho, Claudia M.B.

    2016-01-01

    Robinow syndrome is a rare congenital disorder characterized by mesomelic limb shortening, genital hypoplasia, and distinctive facial features. Recent reports have identified, in individuals with dominant Robinow syndrome, a specific type of variant characterized by being uniformly located in the penultimate exon of DVL1 and resulting in a −1 frameshift allele with a premature termination codon that escapes nonsense-mediated decay. Here, we studied a cohort of individuals who had been clinically diagnosed with Robinow syndrome but who had not received a molecular diagnosis from variant studies of DVL1, WNT5A, and ROR2. Because of the uniform location of frameshift variants in DVL1-mediated Robinow syndrome and the functional redundancy of DVL1, DVL2, and DVL3, we elected to pursue direct Sanger sequencing of the penultimate exon of DVL1 and its paralogs DVL2 and DVL3 to search for potential disease-associated variants. Remarkably, targeted sequencing identified five unrelated individuals harboring heterozygous, de novo frameshift variants in DVL3, including two splice acceptor mutations and three 1 bp deletions. Similar to the variants observed in DVL1-mediated Robinow syndrome, all variants in DVL3 result in a −1 frameshift, indicating that these highly specific alterations might be a common cause of dominant Robinow syndrome. Here, we review the current knowledge of these peculiar variant alleles in DVL1- and DVL3-mediated Robinow syndrome and further elucidate the phenotypic features present in subjects with DVL1 and DVL3 frameshift mutations. PMID:26924530

  5. Frequency analysis of autosomal dominant spinocerebellar ataxias in mainland Chinese patients and clinical and molecular characterization of spinocerebellar ataxia type 6

    Institute of Scientific and Technical Information of China (English)

    JIANG Hong; TANG Bei-sha; XU Bo; ZHAO Guo-hua; SHEN Lu; TANG Jian-guang; LI Qing-hua; XIA Kun

    2005-01-01

    Background Dominantly inherited spinocerebellar ataxia (SCA) is a clinically and genetically heterogeneous group of neurodegenerative disorders. This study was to further assess the frequency of SCA1 (spinocerebellar ataxia type 1), SCA2, SCA3/MJD (spinocerebellar ataxia type 3/Machado-Joseph disease), SCA6, SCA7, SCA8, SCA10, SCA12, SCA14, SCA17 and DRPLA (dentatorubro-pallidoluysian atrophy) in mainland Chinese, and to specifically characterize mainland Chinese patients with SCA6 in terms of clinical and molecular features.Methods Using a molecular approach, we investigated SCA in 120 mainland Chinese families with dominantly inherited ataxias and in 60 mainland Chinese patients with sporadic ataxias. Clinical and molecular features of SCA6 were further characterized in 13 patients from 4 families. Results SCA3/MJD was the most common type of autosomal dominant SCA in mainland Chinese, accounting for 83 patients from 59 families (49.2%), followed by SCA2[8(6.7%)], SCA1[7(5.8%)], SCA6[4(3.3%)], SCA7[1(0.8%)], SCA8(0%), SCA10(0%), SCA12(0%), SCA14(0%), SCA17(0%) and DRPLA(0%). The genes responsible for 41 (34.2%) of dominantly inherited SCA families remain to be determined. Among the 60 patients with sporadic ataxias in the present series, 3 (5.0%) was found to harbor SCA3 mutations while none was found to harbor SCA6 mutations. In the 4 families with SCA6, significant anticipation was found in the absence of genetic instability on transmission.Conclusion A geographic cluster of families with SCA6 subtype was initially identified in a mainland Chinese population.

  6. Combined Liver and Kidney Transplant in a Patient with Budd-Chiari Syndrome Secondary to Autosomal Dominant Polycystic Kidney Disease Associated with Polycystic Liver Disease: Report of a Case with a 9-Year Follow-Up

    Science.gov (United States)

    Ramírez de la Piscina, Patricia; Duca, Ileana; Estrada, Silvia; Calderón, Rosario; Ganchegui, Idoia; Campos, Amaia; Spicakova, Katerina; Salvador, Marta; Delgado, Elvira; Bengoa, Raquel; García-Campos, Francisco

    2014-01-01

    Polycystic liver disease (PLD) is a hereditary disease inherited by autosomal dominant trait that occurs as a frequent extrarenal manifestation of autosomal dominant polycystic kidney disease (ADPKD). We report a case of a 59-year-old woman diagnosed with ADPKD associated with PLD. End-stage chronic renal failure with a secondary Budd-Chiari syndrome developed during the patient's clinical course. She underwent combined liver and kidney transplantation, with a successful response over a 9-year follow-up period. PMID:24987537

  7. Autosomal recessive transmission of a rare KRT74 variant causes hair and nail ectodermal dysplasia: allelism with dominant woolly hair/hypotrichosis.

    Directory of Open Access Journals (Sweden)

    Doroteya Raykova

    Full Text Available Pure hair and nail ectodermal dysplasia (PHNED comprises a heterogeneous group of rare heritable disorders characterized by brittle hair, hypotrichosis, onychodystrophy and micronychia. Autosomal recessive (AR PHNED has previously been associated with mutations in either KRT85 or HOXC13 on chromosome 12p11.1-q14.3. We investigated a consanguineous Pakistani family with AR PHNED linked to the keratin gene cluster on 12p11.1 but without detectable mutations in KRT85 and HOXC13. Whole exome sequencing of affected individuals revealed homozygosity for a rare c.821T>C variant (p.Phe274Ser in the KRT74 gene that segregates AR PHNED in the family. The transition alters the highly conserved Phe274 residue in the coil 1B domain required for long-range dimerization of keratins, suggesting that the mutation compromises the stability of intermediate filaments. Immunohistochemical (IHC analyses confirmed a strong keratin-74 expression in the nail matrix, the nail bed and the hyponychium of mouse distal digits, as well as in normal human hair follicles. Furthermore, hair follicles and epidermis of an affected family member stained negative for Keratin-74 suggesting a loss of function mechanism mediated by the Phe274Ser substitution. Our observations show for the first time that homozygosity for a KRT74 missense variant may be associated with AR PHNED. Heterozygous KRT74 mutations have previously been associated with autosomal dominant woolly hair/hypotrichosis simplex (ADWH. Thus, our findings expand the phenotypic spectrum associated with KRT74 mutations and imply that a subtype of AR PHNED is allelic with ADWH.

  8. A novel DFNA36 mutation in TMC1 orthologous to the Beethoven (Bth) mouse associated with autosomal dominant hearing loss in a Chinese family.

    Science.gov (United States)

    Zhao, Yali; Wang, Dayong; Zong, Liang; Zhao, Feifan; Guan, Liping; Zhang, Peng; Shi, Wei; Lan, Lan; Wang, Hongyang; Li, Qian; Han, Bing; Yang, Ling; Jin, Xin; Wang, Jian; Wang, Jun; Wang, Qiuju

    2014-01-01

    Mutations in the transmembrane channel-like gene 1 (TMC1) can cause both DFNA36 and DFNB7/11 hearing loss. More than thirty DFNB7/11 mutations have been reported, but only three DFNA36 mutations were reported previously. In this study, we found a large Chinese family with 222 family members showing post-lingual, progressive sensorineural hearing loss which were consistent with DFNA36 hearing loss. Auditory brainstem response (ABR) test of the youngest patient showed a special result with nearly normal threshold but prolonged latency, decreased amplitude, and the abnormal waveform morphology. Exome sequencing of the proband found four candidate variants in known hearing loss genes. Sanger sequencing in all family members found a novel variant c.1253T>A (p.M418K) in TMC1 at DFNA36 that co-segregated with the phenotype. This mutation in TMC1 is orthologous to the mutation found in the hearing loss mouse model named Bth ten years ago. In another 51 Chinese autosomal dominant hearing loss families, we screened the segments containing the dominant mutations of TMC1 and no functional variants were found. TMC1 is expressed in the hair cells in inner ear. Given the already known roles of TMC1 in the mechanotransduction in the cochlea and its expression in inner ear, our results may provide an interesting perspective into its function in inner ear.

  9. A novel DFNA36 mutation in TMC1 orthologous to the Beethoven (Bth mouse associated with autosomal dominant hearing loss in a Chinese family.

    Directory of Open Access Journals (Sweden)

    Yali Zhao

    Full Text Available Mutations in the transmembrane channel-like gene 1 (TMC1 can cause both DFNA36 and DFNB7/11 hearing loss. More than thirty DFNB7/11 mutations have been reported, but only three DFNA36 mutations were reported previously. In this study, we found a large Chinese family with 222 family members showing post-lingual, progressive sensorineural hearing loss which were consistent with DFNA36 hearing loss. Auditory brainstem response (ABR test of the youngest patient showed a special result with nearly normal threshold but prolonged latency, decreased amplitude, and the abnormal waveform morphology. Exome sequencing of the proband found four candidate variants in known hearing loss genes. Sanger sequencing in all family members found a novel variant c.1253T>A (p.M418K in TMC1 at DFNA36 that co-segregated with the phenotype. This mutation in TMC1 is orthologous to the mutation found in the hearing loss mouse model named Bth ten years ago. In another 51 Chinese autosomal dominant hearing loss families, we screened the segments containing the dominant mutations of TMC1 and no functional variants were found. TMC1 is expressed in the hair cells in inner ear. Given the already known roles of TMC1 in the mechanotransduction in the cochlea and its expression in inner ear, our results may provide an interesting perspective into its function in inner ear.

  10. Clinical and molecular genetic spectrum of autosomal dominant Emery-Dreifuss muscular dystrophy due to mutations of the lamin A/C gene.

    Science.gov (United States)

    Bonne, G; Mercuri, E; Muchir, A; Urtizberea, A; Bécane, H M; Recan, D; Merlini, L; Wehnert, M; Boor, R; Reuner, U; Vorgerd, M; Wicklein, E M; Eymard, B; Duboc, D; Penisson-Besnier, I; Cuisset, J M; Ferrer, X; Desguerre, I; Lacombe, D; Bushby, K; Pollitt, C; Toniolo, D; Fardeau, M; Schwartz, K; Muntoni, F

    2000-08-01

    Emery-Dreifuss muscular dystrophy (EDMD) is characterized by early contractures of the elbows and Achilles tendons, slowly progressive muscle wasting and weakness, and life-threatening cardiomyopathy with conduction blocks. We recently identified LMNA encoding two nuclear envelope proteins, lamins A and C, to be implicated in the autosomal dominant form of EDMD. Here, we report on the variability of the phenotype and spectrum of LMNA mutations in 53 autosomal dominant EDMD patients (36 members of 6 families and 17 sporadic cases). Twelve of the 53 patients showed cardiac involvement exclusively, although the remaining 41 all showed muscle weakness and contractures. We were able to identify a common phenotype among the patients with skeletal muscle involvement, consisting of humeroperoneal wasting and weakness, scapular winging, rigidity of the spine, and elbow and Achilles tendon contractures. The disease course was generally slow, but we observed either a milder phenotype characterized by late onset and a mild degree of weakness and contractures or a more severe phenotype with early presentation and a rapidly progressive course in a few cases. Mutation analysis identified 18 mutations in LMNA (i.e., 1 nonsense mutation, 2 deletions of a codon, and 15 missense mutations). All the mutations were distributed between exons 1 and 9 in the region of LMNA that is common to lamins A and C. LMNA mutations arose de novo in 76% of the cases; 2 of these de novo mutations were typical hot spots, and 2 others were identified in 2 unrelated cases. There was no clear correlation between the phenotype and type or localization of the mutations within the gene. Moreover, a marked inter- and intra-familial variability in the clinical expression of LMNA mutations exists, ranging from patients expressing the full clinical picture of EDMD to those characterized only by cardiac involvement, which points toward a significant role of possible modifier genes in the course of this disease

  11. Solving a 50 year mystery of a missing OPA1 mutation: more insights from the first family diagnosed with autosomal dominant optic atrophy

    Directory of Open Access Journals (Sweden)

    Zrenner Eberhart

    2010-06-01

    Full Text Available Abstract Background Up to the 1950s, there was an ongoing debate about the diversity of hereditary optic neuropathies, in particular as to whether all inherited optic atrophies can be ascribed to Leber's hereditary optic neuropathy (LHON or represent different disease entities. In 1954 W. Jaeger published a detailed clinical and genealogical investigation of a large family with explicit autosomal dominant segregation of optic atrophy thus proving the existence of a discrete disease different from LHON, which is nowadays known as autosomal dominant optic atrophy (ADOA. Since the year 2000 ADOA is associated with genomic mutations in the OPA1 gene, which codes for a protein that is imported into mitochondria where it is required for mitochondrial fusion. Interestingly enough, the underlying mutation in this family has not been identified since then. Results We have reinvestigated this family with the aim to identify the mutation and to further clarify the underlying pathomechanism. Patients showed a classical non-syndromic ADOA. The long term deterioration in vision in the two teenagers examined 50 years later is of particular note 5/20 to 6/120. Multiplex ligation probe amplification revealed a duplication of the OPA1 exons 7-9 which was confirmed by long distance PCR and cDNA analysis, resulting in an in-frame duplication of 102 amino acids. Segregation was verified in 53 available members of the updated pedigree and a penetrance of 88% was calculated. Fibroblast cultures from skin biopsies were established to assess the mitochondrial network integrity and to qualitatively and quantitatively study the consequences of the mutation on transcript and protein level. Fibroblast cultures demonstrated a fragmented mitochondrial network. Processing of the OPA1 protein was altered. There was no correlation of the OPA1 transcript levels and the OPA1 protein levels in the fibroblasts. Intriguingly an overall decrease of mitochondrial proteins was observed

  12. Osteoclasts from patients with autosomal dominant osteopetrosis type I caused by a T253I mutation in low-density lipoprotein receptor-related protein 5 are normal in vitro, but have decreased resorption capacity in vivo

    DEFF Research Database (Denmark)

    Henriksen, Kim; Gram, Jeppe; Høegh-Andersen, Pernille;

    2005-01-01

    Autosomal dominant osteopetrosis type I (ADOI) is presumably caused by gain-of-function mutations in the LRP5 gene. Patients with a T253I mutation in LRP5 have a high bone mass phenotype, characterized by increased mineralizing surface index but abnormally low numbers of small osteoclasts...

  13. Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease.

    NARCIS (Netherlands)

    Spithoven, E.M.; Kramer, A.; Meijer, E.; Orskov, B.; Wanner, C.; Caskey, F.; Collart, F.; Finne, P.; Fogarty, D.G.; Groothoff, J.W.; Hoitsma, A.J.; Nogier, M.B.; Postorino, M.; Ravani, P.; Zurriaga, O.; Jager, K.J.; Gansevoort, R.T.; Bindels, R.J.M.

    2014-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end-stage kidney failure, but is often identified early and therefore amenable to timely treatment. Interventions known to postpone the need for renal replacement therapy (RRT) in non-ADPKD patients have also been tested in ADP

  14. Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease

    NARCIS (Netherlands)

    Spithoven, Edwin M.; Kramer, Anneke; Meijer, Esther; Orskov, Bjarne; Wanner, Christoph; Caskey, Fergus; Collart, Frederic; Finne, Patrik; Fogarty, Damian G.; Groothoff, Jaap W.; Hoitsma, Andries; Nogier, Marie-Beatrice; Postorino, Maurizio; Ravani, Pietro; Zurriaga, Oscar; Jager, Kitty J.; Gansevoort, Ron T.

    2014-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end-stage kidney failure, but is often identified early and therefore amenable to timely treatment. Interventions known to postpone the need for renal replacement therapy (RRT) in non-ADPKD patients have also been tested in ADP

  15. A novel splice site mutation of the arginine vasopressin-neurophysin II gene identified in a kindred with autosomal dominant familial neurohypophyseal diabetes insipidus.

    Science.gov (United States)

    Tae, Hyun-Jung; Baek, Ki-Hyun; Shim, Sun-Mi; Yoo, Soon-Jib; Kang, Moo-Il; Cha, Bong-Yun; Lee, Kwang-Woo; Son, Ho-Young; Kang, Sung-Koo

    2005-01-01

    Autosomal dominant familial neurohypophyseal diabetes insipidus is an inherited deficiency of arginine vasopressin (AVP), and this is caused by mutations in the AVP-neurophysin II (AVP-NP II) gene. Most of these mutations have been located in the signal peptide or in the NP II moiety. In the present study, we have analyzed the AVP-NP II gene in a Korean family. Clinical and genetic studies were performed on three members of the family, and on a normal healthy unrelated individual. The diagnosis of neurohypophyseal diabetes insipidus was done by performing a fluid deprivation test and a vasopressin challenge. For genetic analysis, the genomic DNA was extracted and the AVP-NP II gene was amplified by polymerase chain reaction (PCR). Clinical assessment of the affected individuals confirmed the diagnosis of neurohypophyseal diabetes insipidus. Genetic analysis of the AVP-NP II gene revealed a novel deletion mutation of a single nucleotide (guanine) within the splice acceptor site of intron 2 (IVS2 +1 delG). The affected individuals were heterozygous for this mutation. We also demonstrated through RT-PCR analysis of the mutant gene that this mutation resulted in the retention of intron 2 during pre-mRNA splicing. We concluded that a novel splicing mutation in the AVP-NP II gene causes neurohypophyseal diabetes insipidus in this family.

  16. Mislocalisation of BEST1 in iPSC-derived retinal pigment epithelial cells from a family with autosomal dominant vitreoretinochoroidopathy (ADVIRC)

    Science.gov (United States)

    Carter, David A.; Smart, Matthew J. K.; Letton, William V. G.; Ramsden, Conor M.; Nommiste, Britta; Chen, Li Li; Fynes, Kate; Muthiah, Manickam N.; Goh, Pollyanna; Lane, Amelia; Powner, Michael B.; Webster, Andrew R.; da Cruz, Lyndon; Moore, Anthony T.; Coffey, Peter J.; Carr, Amanda-Jayne F.

    2016-01-01

    Autosomal dominant vitreoretinochoroidopathy (ADVIRC) is a rare, early-onset retinal dystrophy characterised by distinct bands of circumferential pigmentary degeneration in the peripheral retina and developmental eye defects. ADVIRC is caused by mutations in the Bestrophin1 (BEST1) gene, which encodes a transmembrane protein thought to function as an ion channel in the basolateral membrane of retinal pigment epithelial (RPE) cells. Previous studies suggest that the distinct ADVIRC phenotype results from alternative splicing of BEST1 pre-mRNA. Here, we have used induced pluripotent stem cell (iPSC) technology to investigate the effects of an ADVIRC associated BEST1 mutation (c.704T > C, p.V235A) in patient-derived iPSC-RPE. We found no evidence of alternate splicing of the BEST1 transcript in ADVIRC iPSC-RPE, however in patient-derived iPSC-RPE, BEST1 was expressed at the basolateral membrane and the apical membrane. During human eye development we show that BEST1 is expressed more abundantly in peripheral RPE compared to central RPE and is also expressed in cells of the developing retina. These results suggest that higher levels of mislocalised BEST1 expression in the periphery, from an early developmental stage, could provide a mechanism that leads to the distinct clinical phenotype observed in ADVIRC patients. PMID:27653836

  17. The impact of the availability of prevention studies on the desire to undergo predictive testing in persons at risk for autosomal dominant Alzheimer's disease.

    Science.gov (United States)

    Hooper, Megan; Grill, Joshua D; Rodriguez-Agudelo, Yaneth; Medina, Luis D; Fox, Michelle; Alvarez-Retuerto, Ana Isabel; Wharton, David; Brook, Jenny; Ringman, John M

    2013-09-01

    Persons at risk for autosomal dominant neurodegenerative diseases provide the opportunity to efficiently test preventive interventions. Only a minority of such persons, however, choose to undergo revealing genetic testing, presenting a challenge to enrollment. Thirty-four preclinical Latinos (n = 26) and non-Latinos at risk for familial Alzheimer's disease (FAD) unaware of their genetic status were administered a questionnaire exploring their interest in undergoing revealing genetic testing at baseline and in the context of eligibility for four prevention trials of increasing invasiveness. Forty-four percent of subjects expressed a baseline interest in undergoing revealing testing which increased to 85% in order to be eligible for a study of an oral drug "felt to be very safe." If there were a 50% chance of receiving placebo, this number dropped to 62% (p = 0.02). Among those not interested in a study involving a 50% chance of receiving placebo, a range of 5% to 40% chance of receiving placebo was given as acceptable. For more invasive studies, living in the United States (as opposed to Mexico) positively influenced the likelihood of participating. Our data suggest that clinical trial designs in which persons must confront their genetic status prior to enrollment are feasible. Study designs to minimize the likelihood of being placed on placebo or provide the eventual administration of the drug through open-label extensions should be considered.

  18. Exome sequencing identifies a novel frameshift mutation of MYO6 as the cause of autosomal dominant nonsyndromic hearing loss in a Chinese family.

    Science.gov (United States)

    Cheng, Jing; Zhou, Xueya; Lu, Yu; Chen, Jing; Han, Bing; Zhu, Yuhua; Liu, Liyang; Choy, Kwong-Wai; Han, Dongyi; Sham, Pak C; Zhang, Michael Q; Zhang, Xuegong; Yuan, Huijun

    2014-11-01

    Autosomal dominant types of nonsyndromic hearing loss (ADNSHL) are typically postlingual in onset and progressive. High genetic heterogeneity, late onset age, and possible confounding due to nongenetic factors hinder the timely molecular diagnoses for most patients. In this study, exome sequencing was applied to investigate a large Chinese family segregating ADNSHL in which we initially failed to find strong evidence of linkage to any locus by whole-genome linkage analysis. Two affected family members were selected for sequencing. We identified two novel mutations disrupting known ADNSHL genes and shared by the sequenced samples: c.328C>A in COCH (DFNA9) resulting in a p.Q110K substitution and a deletion c. 2814_2815delAA in MYO6 (DFNA22) causing a frameshift alteration p.R939Tfs*2. The pathogenicity of novel coding variants in ADNSHL genes was carefully evaluated by analysis of co-segregation with phenotype in the pedigree and in light of established genotype-phenotype correlations. The frameshift deletion in MYO6 was confirmed as the causative variant for this pedigree, whereas the missense mutation in COCH had no clinical significance. The results allowed us to retrospectively identify the phenocopy in one patient that contributed to the negative finding in the linkage scan. Our clinical data also supported the emerging genotype-phenotype correlation for DFNA22.

  19. Phenotypic variability in a seven-generation Swedish family segregating autosomal dominant hearing impairment due to a novel EYA4 frameshift mutation.

    Science.gov (United States)

    Frykholm, Carina; Klar, Joakim; Arnesson, Hanna; Rehnman, Anna-Carin; Lodahl, Marianne; Wedén, Ulla; Dahl, Niklas; Tranebjærg, Lisbeth; Rendtorff, Nanna D

    2015-05-25

    Linkage to an interval overlapping the DFNA10 locus on chromosome 6q22-23 was found through genome wide linkage analysis in a seven-generation Swedish family segregating postlingual, autosomal dominant nonsyndromic sensorineural hearing impairment. A novel heterozygous frame-shift mutation (c.579_580insTACC, p.(Asp194Tyrfs*52)) in EYA4 was identified that truncates the so-called variable region of the protein. The mutation is predicted to result in haploinsufficiency of the EYA4 product. No evidence for dilated cardiomyopathy was found in the family, contrasting to a previous family with a deletion resulting in a similar truncation in the variable region. A highly variable age of onset was seen in the mutation carriers. For assessment of the aetiology of this variability, clinical and audiometric data analyses were performed. The affected family members all had similar cross-sectional and longitudinal deterioration of pure tone average (PTA) once the process of hearing deterioration had started, and no gender, parent-of-origin or family branch differences on PTA could be found. Age at onset varied between the family branches. In summary, this is the ninth published genetically verified DFNA10 family. The results imply that unidentified factors, genetic or environmental, other than the EYA4 mutation, are of importance for the age at onset of DFNA10, and that mutation early in the variable region of the EYA4 protein can occur in the absence of dilated cardiomyopathy.

  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. A novel locus (CORD12 for autosomal dominant cone-rod dystrophy on chromosome 2q24.2-2q33.1

    Directory of Open Access Journals (Sweden)

    Meunier Isabelle

    2011-04-01

    Full Text Available Abstract Background Rod-cone dystrophy, also known as retinitis pigmentosa (RP, and cone-rod dystrophy (CRD are degenerative retinal dystrophies leading to blindness. To identify new genes responsible for these diseases, we have studied one large non consanguineous French family with autosomal dominant (ad CRD. Methods Family members underwent detailed ophthalmological examination. Linkage analysis using microsatellite markers and a whole-genome SNP analysis with the use of Affymetrix 250 K SNP chips were performed. Five candidate genes within the candidate region were screened for mutations by direct sequencing. Results We first excluded the involvement of known adRP and adCRD genes in the family by genotyping and linkage analysis. Then, we undertook a whole-genome scan on 22 individuals in the family. The analysis revealed a 41.3-Mb locus on position 2q24.2-2q33.1. This locus was confirmed by linkage analysis with specific markers of this region. The maximum LOD score was 2.86 at θ = 0 for this locus. Five candidate genes, CERKL, BBS5, KLHL23, NEUROD1, and SF3B1 within this locus, were not mutated. Conclusion A novel locus for adCRD, named CORD12, has been mapped to chromosome 2q24.2-2q33.1 in a non consanguineous French family.

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

    Directory of Open Access Journals (Sweden)

    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.

  3. Heterogeneidade genética em atrofia óptica autossômica dominante Genetic heterogeneity in autosomal dominant optic atrophy

    Directory of Open Access Journals (Sweden)

    Juliana Maria Ferraz Sallum

    2002-08-01

    locus para esta doença.Purpose: Autosomal dominant optic atrophy is a hereditary optic neuropathy characterized by progressive visual loss in childhood, color vision anomalies, visual field defects and temporal pallor of the optic disc. This disease has been mapped to a 1.4 cM interval in chromosome 3q28-29 between markers D3S3669 and D3S3562. One family was mapped to chromosome 18q12.2-12.3. Linkage analysis in three families with autosomal dominant optic atrophy with polymorphic DNA markers for chromosome 3q28-29 and 18q12.2-12.3. Methods: 57 individuals from three families underwent ophthalmological examination. Genomic DNA was extracted from blood samples. Linkage analysis was performed between the disease and 11 polymorphic markers around 3q28-qter and 18q12.2-12.3. Polymerase chain reaction (PCR fragments sizes were identified in a scanner gel using a 373 DNA sequencer. These numbers were used as alleles for pedigree analysis. The lod scores were calculated using the MLINK program. Results: All three families presented optic atrophy with autosomal dominant pattern of inheritance, variable expression and high penetrance. Two families were linked to 3q28-29 markers. A maximal lod score of 3.56, at a recombination fraction of zero, was obtained using the marker D3S3669 in one family. The linkage area was defined in a 2 cM interval by haplotype analysis between markers D3S2418 and D3S1305, because patients III.4 and III.14 showed crossing-overs. The third family was not linked to 3q28-29 neither to 18q12.2-12.3. Conclusions: There is genetic heterogeneity in autosomal dominant optic atrophy, because the third family did not map to any known locus. And a third locus for this disease may exist.

  4. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. Intermediate volume on computed tomography imaging defines a fibrotic compartment that predicts glomerular filtration rate decline in autosomal dominant polycystic kidney disease patients.

    Science.gov (United States)

    Caroli, Anna; Antiga, Luca; Conti, Sara; Sonzogni, Aurelio; Fasolini, Giorgio; Ondei, Patrizia; Perico, Norberto; Remuzzi, Giuseppe; Remuzzi, Andrea

    2011-08-01

    Total kidney and cyst volumes have been used to quantify disease progression in autosomal dominant polycystic kidney disease (ADPKD), but a causal relationship with progression to renal failure has not been demonstrated. Advanced image processing recently allowed to quantify extracystic tissue, and to identify an additional tissue component named "intermediate," appearing hypoenhanced on contrast-enhanced computed tomography (CT). The aim of this study is to provide a histological characterization of intermediate volume, investigate its relation with renal function, and provide preliminary evidence of its role in long-term prediction of functional loss. Three ADPKD patients underwent contrast-enhanced CT scans before nephrectomy. Histological samples of intermediate volume were drawn from the excised kidneys, and stained with hematoxylin and eosin and with saturated picrosirius solution for histological analysis. Intermediate volume showed major structural changes, characterized by tubular dilation and atrophy, microcysts, inflammatory cell infiltrate, vascular sclerosis, and extended peritubular interstitial fibrosis. A significant correlation (r = -0.69, P < 0.001) between relative intermediate volume and baseline renal function was found in 21 ADPKD patients. Long-term prediction of renal functional loss was investigated in an independent cohort of 13 ADPKD patients, followed for 3 to 8 years. Intermediate volume, but not total kidney or cyst volume, significantly correlated with glomerular filtration rate decline (r = -0.79, P < 0.005). These findings suggest that intermediate volume may represent a suitable surrogate marker of ADPKD progression and a novel therapeutic target.

  7. Mapping one form of autosomal dominant postaxial polydactyly type A to chromosome 7p15-q11.23 by linkage analysis

    Energy Technology Data Exchange (ETDEWEB)

    Radhakrishna, U.; Mehenni, H.; Antonarakis, S.E. [Geneva Medical School (Switzerland)] [and others

    1997-03-01

    Postaxial polydactyly type-A (PAP-A) in humans is an autosomal dominant trait characterized by an extra digit in the ulnar and/or fibular side of the upper and/or lower extremities. The extra digit is well formed and articulates with the fifth, or extra, metacarpal/metatarsal, and thus it is usually functional. In order to map the gene responsible for PAP-A, we studied a five-generation Indian family of 37 individuals (15 of whom were affected). A genomewide search with highly informative polymorphic markers on part of the pedigree showed linkage between the PAP-A phenotype and markers on chromosome 7p15-q11.23 (no crossovers were found with D7S526, D7S795, D7S528, D7S521, D7S691, D7S667, D7S478, D7S1830, D7S803, D7S801, or ELN). The highest LOD score was obtained with marker D7S801 (Z{sub max} = 4.21; {theta} = 0). Haplotype analysis enabled the mapping of the PAP-A phenotype in this family between markers D7S2848 and D7S669. Analysis of additional families with PAP-A will narrow down the critical genomic region, facilitate positional cloning of the PAP-A gene, and/or uncover potential genetic heterogeneity. 42 refs., 4 figs., 1 tab.

  8. SNP linkage analysis and whole exome sequencing identify a novel POU4F3 mutation in autosomal dominant late-onset nonsyndromic hearing loss (DFNA15.

    Directory of Open Access Journals (Sweden)

    Hee-Jin Kim

    Full Text Available Autosomal dominant non-syndromic hearing loss (AD-NSHL is one of the most common genetic diseases in human and is well-known for the considerable genetic heterogeneity. In this study, we utilized whole exome sequencing (WES and linkage analysis for direct genetic diagnosis in AD-NSHL. The Korean family had typical AD-NSHL running over 6 generations. Linkage analysis was performed by using genome-wide single nucleotide polymorphism (SNP chip and pinpointed a genomic region on 5q31 with a significant linkage signal. Sequential filtering of variants obtained from WES, application of the linkage region, bioinformatic analyses, and Sanger sequencing validation identified a novel missense mutation Arg326Lys (c.977G>A in the POU homeodomain of the POU4F3 gene as the candidate disease-causing mutation in the family. POU4F3 is a known disease gene causing AD-HSLH (DFNA15 described in 5 unrelated families until now each with a unique mutation. Arg326Lys was the first missense mutation affecting the 3(rd alpha helix of the POU homeodomain harboring a bipartite nuclear localization signal sequence. The phenotype findings in our family further supported previously noted intrafamilial and interfamilial variability of DFNA15. This study demonstrated that WES in combination with linkage analysis utilizing bi-allelic SNP markers successfully identified the disease locus and causative mutation in AD-NSHL.

  9. Refining the localization of the PKD2 locus on chromosome 4q by linkage analysis in Spanish families with autosomal dominant polycystic kidney disease type 2

    Energy Technology Data Exchange (ETDEWEB)

    San Millan, J.L.; Viribay, M.; Peral, B.; Moreno, F. [Unidad de Genetica Molecular, Madrid (Spain); Martinez, I. [Hospital de Galdacano (Spain); Weissenbach, J. [Genethon, Evry (France)

    1995-01-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a genetically heterogeneous disorder. At least two distinct forms of ADPKD are now well defined. In {approximately}86% of affected European families, a gene defect localized to 16p13.3 was responsible for ADPKD, while a second locus has been recently localized to 4q13-q23 as candidate for the disease in the remaining families. We present confirmation of linkage to microsatellite markers on chromosome 4q in eight Spanish families with ADPKD, in which the disease was not linked to 16p13.3. By linkage analysis with marker D4S423, a maximum lod score of 9.03 at a recombination fraction of .00 was obtained. Multipoint linkage analysis, as well as a study of recombinant haplotypes, placed the PKD2 locus between D4S1542 and D4S1563, thereby defining a genetic interval of {approximately}1 cM. The refined map will serve as a genetic framework for additional genetic and physical mapping of the region and will improve the accuracy of presymptomatic diagnosis of PKD2. 25 refs., 4 figs., 1 tab.

  10. The disruption of a novel limb cis-regulatory element of SHH is associated with autosomal dominant preaxial polydactyly-hypertrichosis.

    Science.gov (United States)

    Petit, Florence; Jourdain, Anne-Sophie; Holder-Espinasse, Muriel; Keren, Boris; Andrieux, Joris; Duterque-Coquillaud, Martine; Porchet, Nicole; Manouvrier-Hanu, Sylvie; Escande, Fabienne

    2016-01-01

    The expression gradient of the morphogen Sonic Hedgehog (SHH) is crucial in establishing the number and the identity of the digits during anteroposterior patterning of the limb. Its anterior ectopic expression is responsible for preaxial polydactyly (PPD). Most of these malformations are due to the gain-of-function of the Zone of Polarizing Activity Regulatory Sequence, the only limb-specific enhancer of SHH known to date. We report a family affected with a novel condition associating PPD and hypertrichosis of the upper back, following an autosomal dominant mode of inheritance. This phenotype is consistent with deregulation of SHH expression during limb and follicle development. In affected members, we identified a 2 kb deletion located ~240 kb upstream from the SHH promoter. The deleted sequence is capable of repressing the transcriptional activity of the SHH promoter in vitro, consistent with a silencer activity. We hypothesize that the deletion of this silencer could be responsible for SHH deregulation during development, leading to a PPD-hypertrichosis phenotype.

  11. 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.

  12. Congenital cataract

    Science.gov (United States)

    ... EA, eds. Duane's Ophthalmology . 16th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013:chap 74. Junk AK, Morris ... EA, eds. Duane's Ophthalmology . 16th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2013:chap 41. Read More Cataract - ...

  13. Congenital cataract facial dysmorphism neuropathy syndrome: a clinically recognizable entity.

    NARCIS (Netherlands)

    Shabo, G.; Scheffer, H.; Cruysberg, J.R.M.; Lammens, M.M.Y.; Pasman, J.W.; Spruit, M.; Willemsen, M.A.A.P.

    2005-01-01

    Congenital cataracts facial dysmorphism neuropathy syndrome is a recently delineated autosomal recessive condition exclusively found in the Gypsy population. Congenital cataracts facial dysmorphism neuropathy syndrome is caused by a homozygous mutation in the CTDP1 gene, leading to disruption of the

  14. Bilateral Severe Ectropion and Mature Cataract in Lamellar Ichthyosis

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    Intiyaz A. Lone, Reyaz A. Untoo, Sheikh S. Ahmad

    2004-07-01

    Full Text Available Lamellar ichthyosis is a rare, autosomal recessive, genetically heterogeneous skin disorder causedby mutations in the transglutaminase-1 gene. Eye abnormalities include bilateral ectropion of lowerlids, chronic blepharitis and rarely cataract. A case of lamellar ichthyosis with bilateral lower lidectropion and bilateral mature cataract is hereby presented for its rarity.

  15. 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

  16. 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.

  17. Localization of a gene (CMT2A) for autosomal dominant Charcot-Marie-Tooth disease type 2 to chromosome 1p and evidence of genetic heterogeneity

    Energy Technology Data Exchange (ETDEWEB)

    Othmane, K.B.; Loprest, L.J.; Wilkinson, K.M. (Duke Univ. Medical Center, Durham, NC (United States)); Middleton, L.T. (Cyprus Institute of Neurology and Genetics, Nicosia (Cyprus)) (and others)

    1993-08-01

    Charcot-Marie-Tooth (CMT) disease type 2 (CMT2) is an inherited peripheral neuropathy characterized by variable age of onset and normal or slightly diminished nerve conduction velocity. CMT2 is pathologically and genetically distinct from CMT type 1 (CMT1). While CMT1 has been shown to be genetically heterogeneous, no chromosomal localization has been established for CMT2. The authors have performed pedigree linkage analysis in six large autosomal dominant CMT2 families and have demonstrated linkage and heterogeneity to a series of microsatellites (D1S160, D1S170, D1S244, D1S228 and D1S199) in the distal region of the short arm of chromosome 1. Significant evidence for heterogeneity was found using admixture analyses and the two-point lod scores. Admixture analyses using the multipoint results for the markers D1S244, D1S228, and D1S199 supported the two-point findings. Three families, DUK662, DUK1241, and 1523 gave posterior probabilities of 1.0, 0.98, and 0.88 of being of the linked type. Multipoint analysis examining the [open quotes]linked[close quotes] families showed that the most favored location for the CMT2A gene is within the interval flanked by D1S244 and D1S228 (odds approximately 70:1 of lying within versus outside that interval). These findings suggest that the CMT2 phenotype is secondary to at least two different genes and demonstrate further heterogeneity in the CMT phenotype.

  18. N-CAM dysfunction and unexpected accumulation of PSA-NCAM in brain of adult-onset autosomal-dominant leukodystrophy.

    Science.gov (United States)

    Piccinini, Marco; Buccinnà, Barbara; De Marco, Giovanni; Lupino, Elisa; Ramondetti, Cristina; Grifoni, Silvia; Votta, Barbara; Giordana, Maria Teresa; Rinaudo, Maria Teresa

    2010-03-01

    Previously, myelin from cerebral white matter (CWM) of two subjects of a family with orthochromatic adult-onset autosomal-dominant leukodystrophy (ADLD) was disclosed to exhibit defective large isoform of myelin-associated glycoprotein (L-MAG) and patchy distribution only in the elder subject. L-MAG and neural cell adhesion molecule (N-CAM) (N-CAM 180, 140, and 120) are structurally related and concur to myelin/axon interaction. In early developmental stages, in neurons and glia N-CAM is converted into polysialylated (PSA)-NCAM by two sialyltransferases sialyltransferase-X (STX) and polysialyltransferase-1 (PST). Notably, PSA-NCAM disrupts N-CAM adhesive properties and is nearly absent in the adult brain. Here, CWM extracts and myelin of the two subjects were searched for the expression pattern of the N-CAM isoforms and PSA-NCAM, and their CWM was evaluated for N-CAM, STX and PST gene copy number and gene expression as mRNA. Biochemically, we disclosed that in CWM extracts and myelin from both subjects, PSA-NCAM accumulates, N-CAM 180 considerably increases, N-CAM 140 is modestly modified and N-CAM 120 remarkably decreases; duplication of genes encoding N-CAM, STX and PST was not revealed, whereas PST mRNA was clearly increased. Immunohistochemically, in CWM of both subjects, we found an unusually diffuse accumulation of PSA-NCAM without inflammation markers. PSA-NCAM persistence, up-regulated PST mRNA and previously uncovered defective L-MAG may be early pathogenetic events in this ADLD form.

  19. Comprehensive genetic screening of KCNQ4 in a large autosomal dominant nonsyndromic hearing loss cohort: genotype-phenotype correlations and a founder mutation.

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    Takehiko Naito

    Full Text Available The present study of KCNQ4 mutations was carried out to 1 determine the prevalence by unbiased population-based genetic screening, 2 clarify the mutation spectrum and genotype/phenotype correlations, and 3 summarize clinical characteristics. In addition, a review of the reported mutations was performed for better understanding of this deafness gene. The screening using 287 probands from unbiased Japanese autosomal dominant nonsyndromic hearing loss (ADNSHL families identified 19 families with 7 different disease causing mutations, indicating that the frequency is 6.62% (19/287. While the majority were private mutations, one particular recurrent mutation, c.211delC, was observed in 13 unrelated families. Haplotype analysis in the vicinity of c.211delC suggests existence of a common ancestor. The majority of the patients showed all frequency, but high-frequency predominant, sensorineural hearing loss. The present study adds a new typical audiogram configuration characterized by mid-frequency predominant hearing loss caused by the p.V230E mutation. A variant at the N-terminal site (c. 211delC showed typical ski-slope type audiogram configuration. Concerning clinical features, onset age was from 3 to 40 years old, and mostly in the teens, and hearing loss was gradually progressive. Progressive nature is a common feature of patients with KCNQ4 mutations regardless of the mutation type. In conclusion, KCNQ4 mutations are frequent among ADNSHL patients, and therefore screening of the gene and molecular confirmation of these mutations have become important in the diagnosis of these conditions.

  20. Modeling of autosomal-dominant retinitis pigmentosa in Caenorhabditis elegans uncovers a nexus between global impaired functioning of certain splicing factors and cell type-specific apoptosis.

    Science.gov (United States)

    Rubio-Peña, Karinna; Fontrodona, Laura; Aristizábal-Corrales, David; Torres, Silvia; Cornes, Eric; García-Rodríguez, Francisco J; Serrat, Xènia; González-Knowles, David; Foissac, Sylvain; Porta-De-La-Riva, Montserrat; Cerón, Julián

    2015-12-01

    Retinitis pigmentosa (RP) is a rare genetic disease that causes gradual blindness through retinal degeneration. Intriguingly, seven of the 24 genes identified as responsible for the autosomal-dominant form (adRP) are ubiquitous spliceosome components whose impairment causes disease only in the retina. The fact that these proteins are essential in all organisms hampers genetic, genomic, and physiological studies, but we addressed these difficulties by using RNAi in Caenorhabditis elegans. Our study of worm phenotypes produced by RNAi of splicing-related adRP (s-adRP) genes functionally distinguishes between components of U4 and U5 snRNP complexes, because knockdown of U5 proteins produces a stronger phenotype. RNA-seq analyses of worms where s-adRP genes were partially inactivated by RNAi, revealed mild intron retention in developing animals but not in adults, suggesting a positive correlation between intron retention and transcriptional activity. Interestingly, RNAi of s-adRP genes produces an increase in the expression of atl-1 (homolog of human ATR), which is normally activated in response to replicative stress and certain DNA-damaging agents. The up-regulation of atl-1 correlates with the ectopic expression of the pro-apoptotic gene egl-1 and apoptosis in hypodermal cells, which produce the cuticle, but not in other cell types. Our model in C. elegans resembles s-adRP in two aspects: The phenotype caused by global knockdown of s-adRP genes is cell type-specific and associated with high transcriptional activity. Finally, along with a reduced production of mature transcripts, we propose a model in which the retina-specific cell death in s-adRP patients can be induced through genomic instability.

  1. Structure-Function Modeling of Optical Coherence Tomography and Standard Automated Perimetry in the Retina of Patients with Autosomal Dominant Retinitis Pigmentosa.

    Directory of Open Access Journals (Sweden)

    Travis B Smith

    Full Text Available To assess relationships between structural and functional biomarkers, including new topographic measures of visual field sensitivity, in patients with autosomal dominant retinitis pigmentosa.Spectral domain optical coherence tomography line scans and hill of vision (HOV sensitivity surfaces from full-field standard automated perimetry were semi-automatically aligned for 60 eyes of 35 patients. Structural biomarkers were extracted from outer retina b-scans along horizontal and vertical midlines. Functional biomarkers were extracted from local sensitivity profiles along the b-scans and from the full visual field. These included topographic measures of functional transition such as the contour of most rapid sensitivity decline around the HOV, herein called HOV slope for convenience. Biomarker relationships were assessed pairwise by coefficients of determination (R2 from mixed-effects analysis with automatic model selection.Structure-function relationships were accurately modeled (conditional R(2>0.8 in most cases. The best-fit relationship models and correlation patterns for horizontally oriented biomarkers were different than vertically oriented ones. The structural biomarker with the largest number of significant functional correlates was the ellipsoid zone (EZ width, followed by the total photoreceptor layer thickness. The strongest correlation observed was between EZ width and HOV slope distance (marginal R(2 = 0.85, p<10(-10. The mean sensitivity defect at the EZ edge was 7.6 dB. Among all functional biomarkers, the HOV slope mean value, HOV slope mean distance, and maximum sensitivity along the b-scan had the largest number of significant structural correlates.Topographic slope metrics show promise as functional biomarkers relevant to the transition zone. EZ width is strongly associated with the location of most rapid HOV decline.

  2. 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.

  3. Network analysis of a Pkd1-mouse model of autosomal dominant polycystic kidney disease identifies HNF4α as a disease modifier.

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    Luis F Menezes

    Full Text Available Autosomal Dominant Polycystic Kidney Disease (ADPKD; MIM ID's 173900, 601313, 613095 leads to end-stage kidney disease, caused by mutations in PKD1 or PKD2. Inactivation of Pkd1 before or after P13 in mice results in distinct early- or late-onset disease. Using a mouse model of ADPKD carrying floxed Pkd1 alleles and an inducible Cre recombinase, we intensively analyzed the relationship between renal maturation and cyst formation by applying transcriptomics and metabolomics to follow disease progression in a large number of animals induced before P10. Weighted gene co-expression network analysis suggests that Pkd1-cystogenesis does not cause developmental arrest and occurs in the context of gene networks similar to those that regulate/maintain normal kidney morphology/function. Knowledge-based Ingenuity Pathway Analysis (IPA software identifies HNF4α as a likely network node. These results are further supported by a meta-analysis of 1,114 published gene expression arrays in Pkd1 wild-type tissues. These analyses also predict that metabolic pathways are key elements in postnatal kidney maturation and early steps of cyst formation. Consistent with these findings, urinary metabolomic studies show that Pkd1 cystic mutants have a distinct profile of excreted metabolites, with pathway analysis suggesting altered activity in several metabolic pathways. To evaluate their role in disease, metabolic networks were perturbed by inactivating Hnf4α and Pkd1. The Pkd1/Hnf4α double mutants have significantly more cystic kidneys, thus indicating that metabolic pathways could play a role in Pkd1-cystogenesis.

  4. Identification of Two Disease-causing Genes TJP2 and GJB2 in a Chinese Family with Unconditional Autosomal Dominant Nonsyndromic Hereditary Hearing Impairment

    Institute of Scientific and Technical Information of China (English)

    Hong-Yang Wang; Ya-Li Zhao; Qiong Liu; Hu Yuan; Yun Gao; Lan Lan; Lan Yu

    2015-01-01

    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.Y136* 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.

  5. FOXE3 plays a significant role in autosomal recessive microphthalmia.

    Science.gov (United States)

    Reis, Linda M; Tyler, Rebecca C; Schneider, Adele; Bardakjian, Tanya; Stoler, Joan M; Melancon, Serge B; Semina, Elena V

    2010-03-01

    FOXE3 forkhead transcription factor is essential to lens development in vertebrates. The eyes of Foxe3/foxe3-deficient mice and zebrafish fail to develop normally. In humans, autosomal dominant and recessive mutations in FOXE3 have been associated with variable phenotypes including anterior segment anomalies, cataract, and microphthalmia. We undertook sequencing of FOXE3 in 116 probands with a spectrum of ocular defects ranging from anterior segment dysgenesis and cataract to anophthalmia/microphthalmia. Recessive mutations in FOXE3 were found in four of 26 probands affected with bilateral microphthalmia (15% of all bilateral microphthalmia and 100% of consanguineous families with this phenotype). FOXE3-positive microphthalmia was accompanied by aphakia and/or corneal defects; no other associated systemic anomalies were observed in FOXE3-positive families. The previously reported c.720C > A (p.C240X) nonsense mutation was identified in two additional families in our sample and therefore appears to be recurrent, now reported in three independent microphthalmia families of varied ethnic backgrounds. Several missense variants were identified at varying frequencies in patient and control groups with some apparently being race-specific, which underscores the importance of utilizing race/ethnicity-matched control populations in evaluating the relevance of genetic screening results. In conclusion, FOXE3 mutations represent an important cause of nonsyndromic autosomal recessive bilateral microphthalmia.

  6. [Mosaic isochromosome Xq and microduplication 17p13.3p13.2 in a patient with Turner syndrome and congenital cataract].

    Science.gov (United States)

    Rojas Martínez, Jorge A; Acosta Guio, Johanna C

    2015-01-01

    The combination of Turner syndrome with other genetic disorders such as congenital cataract has been reported, but its association with a congenital form with autosomal dominant inheritance and incomplete penetrance has not been previously reported in the literature. There are no reports on its presentations with rearrangements on chromosome 17. We report the exceptional case of a 20 months old girl with a constellation of major and minor anomalies, diagnosed with mosaic Turner syndrome by isochromosome Xq associated with a microduplication 17p13.3p13.2, who also had bilateral congenital nuclear cataract autosomal dominant with incomplete penetrance. We reviewed in the literature the origin and cause of these genetic alterations and we provided an approach to the hypothesis of the pathogenesis of the association of two of these genetic disorders in the same patient.

  7. 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.

  8. 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.

  9. Hippo通路在常染色体显性多囊肾病中的作用%Role of Hippo pathway in autosomal dominant polycystic kidney disease

    Institute of Scientific and Technical Information of China (English)

    贺靓靓; 胡文娟; 梅长林; 胡惠民; 付丽丽

    2015-01-01

    目的 探讨Hippo通路分子在常染色体显性多囊肾病(ADPKD)发病机制中的作用,寻找可能的药物治疗靶点.方法 采用免疫荧光染色、Western印迹和实时定量PCR技术检测Han:SPRD大鼠杂合型和ADPKD患者肾组织Hippo通路分子分布、表达量以及磷酸化水平的差异.小干扰RNA特异性抑制囊肿衬里上皮细胞(WT9-12) YAP (Yes kinaseassociated protein)、TAZ(transcriptional coactivator with PDZ binding motif)和LATS1(large tumor suppressor kinase1)的表达后观察对细胞增殖、凋亡和细胞周期的影响.结果 与野生型大鼠相比,Han:SPRD杂合型大鼠囊肿衬里上皮细胞LATS1表达降低;YAP表达量及去磷酸化活化水平增加;TAZ表达与分布无明显改变.ADPKD患者肾组织中,Hippo通路分子MST1/2(macrophage stimulating1/2)、LATS1 mRNA表达显著低于正常对照(P<0.05),而YAP mRNA表达水平显著高于正常对照(P<0.05).抑制WT9-12细胞LATS1表达,能促进细胞增殖和分裂;下调YAP表达阻滞细胞于分裂间期,抑制增殖;下调TAZ表达对细胞增殖和周期无显著影响.结论 ADPKD中Hippo通路效应因子YAP去磷酸化活性增强可能是导致疾病发生、发展的重要原因之一.体外实验证实下调YAP表达可抑制肾囊肿衬里上皮细胞分裂增殖,提示YAP的表达和活性是潜在的多囊肾病治疗靶点.%Objective To explore the role of Hippo pathway in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD),and find potential targets for drug therapy.Methods By means of immunofluorescence staining,Western blotting,Real-time PCR,the differences of sublocalization,expression and phosphorylation level about Hippo pathway molecules in Han:SPRD (cy/+) and ADPKD patients compared with the control were observed.Knockdown Yes kinaseassociated protein (YAP),transcriptional coactivator with PDZ binding motif (TAZ) and large tumor suppressor kinase1 (LATS1) in cystic lining epithelium cell line WT9

  10. 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, Bjoern; 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.; Krueger, 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,

  11. Cataract complications

    Directory of Open Access Journals (Sweden)

    David Yorston

    2008-03-01

    Full Text Available Any eye surgeon, no matter how experienced, will occasionally encounter a serious cataract complication. Although complications may be devastating for the patient and are always distressing for the surgeon, are they really a major issue for VISION 2020? The evidence says that they are.

  12. 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.

  13. 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.

  14. The Hereditary Hyperferritinemia-Cataract Syndrome in 2 Italian Families

    Science.gov (United States)

    Arcioni, Francesco; Cerri, Carla; La Starza, Roberta; Romanelli, Donatella; Capolsini, Ilaria; Caniglia, Maurizio

    2013-01-01

    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. PMID:24368960

  15. 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 ...

  16. 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.

  17. Coexistence of mal de Meleda and congenital cataract in a consanguineous Tunisian family: two case reports

    Directory of Open Access Journals (Sweden)

    Mokni Mourad

    2010-04-01

    Full Text Available Abstract Introduction Mal de Meleda is a rare form of palmoplantar keratoderma, with autosomal recessive transmission. It is characterized by diffuse erythema and hyperkeratosis of the palms and soles. Recently, mutations in the ARS (component B gene (ARS, MIM: 606119 on chromosome 8q24.3 have been identified in families with this disorder. Congenital cataract is a visual disease that may interfere with sharp imaging of the retina. Mutations in the heat-shock transcription factor 4 gene (HSF4; MIM: 602438 may result in both autosomal dominant and autosomal recessive congenital cataracts. Case presentation A Tunisian family with two female siblings aged 45 and 30 years, presented with a clinical association of mal de Meleda and congenital cataract. The two patients exhibited diffuse palmoplantar keratodermas. One of them presented with a total posterior subcapsular cataract and had a best corrected visual acuity at 1/20 in the left eye and with the right eye was only able to count fingers at a distance of one foot. The other woman had a slight posterior subcapsular lenticular opacity and her best corrected visual acuity was 8/10 in the right eye and with her left eye she was only able to count fingers at a distance of one foot. A mutational analysis of their ARS gene revealed the presence of the homozygous missense mutation C99Y and two single nucleotide polymorphisms (-55G>C and -60G>C. The splice mutation (c.1327+4A-G within intron 12 of the HSF4 gene, which has been previously described in Tunisian families with congenital cataract, was not found in the two probands within this family. Conclusion To the best of our knowledge, such original clinical association has not been reported previously. The association of these two autosomal recessive diseases might have occurred in this family due to a high degree of inbreeding. The C99Y mutation may be specific to the Tunisian population as it has been exclusively reported so far in only three

  18. 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 ...

  19. Refinement of the OPA1 gene locus on chromosome 3q28-q29 to a region of 2-8 cM, in one Cuban pedigree with autosomal dominant optic atrophy type Kjer

    Energy Technology Data Exchange (ETDEWEB)

    Lunkes, A.; Hartung, U.; Auburger, G. [Univ. Hospital Duesseldorf (Germany)] [and others

    1995-10-01

    Kjer type autosomal dominant optic atrophy was reported to have a prevalence of 1:50,000 and is therefore the most common form of familial optic atrophy. Age at onset and chronic progressive course were used as subclassification criteria by Kjer, Jaeger, and Smith, stating that almost all cases manifested subacutely before 8 years of age. Typically, tritan color defects and small paracentral scotomas are found together with both variable reduction of visual acuity, of approximately 0.3/0.1, and a temporal pallor on fundoscopy. Pathologically the retinal ganglion cells are affected, resulting in a progressive degeneration of the optic nerve. 12 refs., 1 fig., 1 tab.

  20. Refined genetic mapping of autosomal dominant retinitis pigmentosa locus RP18 reduces the critical region to 2 cM between D1S442 and D1S2858 on chromosome 1q.

    Science.gov (United States)

    Xu, S Y; Rosenberg, T; Gal, A

    1998-04-01

    Linkage analysis was performed on a large Danish family to refine the position of RP18, the locus for autosomal dominant retinitis pigmentosa, mapped previously between D1S534 and D1S305 in chromosome 1p13-q21. We genotyped the family members for five microsatellite-type DNA polymorphisms and mapped RP18 between D1S422 and D1S2858 to a region of less than 2 cM. No obvious candidate gene has yet been assigned to the chromosomal interval defined here.

  1. Autosomal recessive epidermolytic palmoplantar keratoderma.

    Science.gov (United States)

    Alsaleh, Q A; Teebi, A S

    1990-08-01

    Palmoplantar keratoderma (PPK) is a heterogeneous group of disorders. Epidermolytic PPK is a well delineated autosomal dominant entity, but no recessive form is known. Here we report two sons of phenotypically normal, consanguineous, Arab parents with features suggestive of PPK. They presented with patchy eczematous skin lesions followed by PPK and raised serum levels of IgE. Skin biopsy from the keratotic lesions showed the features of epidermolytic hyperkeratosis. Autosomal recessive inheritance is suggested and the differential diagnosis is discussed.

  2. 托伐普坦治疗常染色体显性多囊性肾病患者的研究进展%Progress of tolvaptan in treatment of patients with autosomal dominant polycystic kidney disease

    Institute of Scientific and Technical Information of China (English)

    刘玉法; 陈广新; 刘纳新; 苏立军

    2014-01-01

    通过搜索PubMed,ScienceDirect,万方,CNKI数据库,选择1990~2014年文献,对托伐普坦治疗常染色体显性多囊性肾病(autosomal dominant polycystic kidney disease,ADPKD)研究情况进行综述、总结。常染色体显性多囊肾病是一种慢性进行性疾病,可显著地增加经济负担和致死率。目前尚没有特定药物用于治疗或延缓该病的进程。ADPKD患者早期使用托伐普坦可减慢疾病进程,但可能伴发频繁的、严重的不良事件,需密切监护。%Databases of PubMed,CNKI,ScienceDirect and Wanfang were searched,and the literatures were selected from 1990 to 2014,to review the studies of tolvaptan on autosomal dominant polycystic kidney disease(ADPKD).ADPKD is a chronic progressive disease which significantly enhance the economy burden and death rate.No specific drug can be used to treat or prevent the progress of ADPKD.Tolvaptan applicated in early phase could prolong the progress of ADPKD,but with frequent and serious adverse events.

  3. Congenital posterior pole cataract and adult onset dilating cardiomyopathy: expanding the phenotype of αB-crystallinopathies.

    Science.gov (United States)

    van der Smagt, J J; Vink, A; Kirkels, J H; Nelen, M; ter Heide, H; Molenschot, M M C; Weger, R A; Schellekens, P A W; Hoogendijk, J; Dooijes, D

    2014-04-01

    Mutations in the αB-crystallin gene (CRYAB) have been reported in desmin-related myopathies, with or without cardiac involvement. Mutations in this gene have also been documented in large multi-generation families with autosomal dominant congenital posterior pole cataract (CPPC). In these congenital cataract families no cardiac or muscular phenotype was reported. This report describes a family with an unusual read-through mutation in CRYAB, leading to the elongation of the normal αB-crystallin protein with 19 amino acid residues. Affected family members combine a CPPC with an adult onset dilated cardiomyopathy (DCM), thereby expanding the αB-crystallinopathy phenotype. Repolarisation abnormalities preceded the onset of cardiomyopathy and were already present in childhood. No skeletal myopathy was observed. This report illustrates that congenital cataract can be a prelude to more severe disease even outside the context of inborn errors of metabolism. The identification of a CRYAB mutation in this family supports the notion that mutations in this gene are a rare cause of genetically determined DCM. The combined congenital cataract/cardiomyopathy phenotype adds to our understanding of the complex phenotypic spectrum of αB-crystallinopathies.

  4. A novel splice site mutation of CRYBA3/A1 gene associated with congenital cataract in a Chinese family

    Science.gov (United States)

    Wu, Meng-Han; Yu, Yin-Hui; Hao, Qin-Long; Gong, Xiao-Hua; Yao, Ke

    2017-01-01

    AIM To identify the disease-causing mutation responsible for the presence of congenital cataract in a Chinese family. METHODS The study recruited a four-generation Chinese pedigree affected by autosomal dominant congenital cataract (ADCC). Family history and the history of cataract extraction were recorded. Blood samples were collected from individuals for DNA extraction. Direct sequencing of congenital cataract-associated genes was performed. Single-strand conformational polymorphism and bioinformatic analysis were conducted to further study the mutation. RESULTS Direct sequencing revealed a novel splice site mutation of c.30-2 A>G in the CRYBA3/A1 gene. The mutation co-segregated within all affected individuals in the family and was not found in unaffected members or 100 unrelated normal controls. These results were further confirmed by single-strand conformational polymorphism and bioinformatic analysis using the Human Splicing Finder and MaxEnt online software and Annovar computer software. CONCLUSION c.30-2 A>G mutation of CRYBA3/A1 gene is a novel mutation and broadens the genetic spectrum of ADCC.

  5. Mutations of rhodopsin gene in a family with autosomal dominant retinitis pigmentosa%一个常染色体显性视网膜色素变性家系表型分析和RHO基因突变检测

    Institute of Scientific and Technical Information of China (English)

    章雪敏; 刘铁城; 金鑫; 袁慧军; 张宝全; 王瑛

    2012-01-01

    目的 分析一常染色体显性视网膜色素变性(autosomal dominant retinitis pigmentosa,adRP)家系的临床表型,确定该家系与视紫红质(rhodopsin,RHO)基因的关系.方法 依据RP诊断标准及患者临床表型,确定一连续4代发病的adRP家系遗传的特点;采集家系中13位成员外周血8-10ml,提取基因组DNA;聚合酶链反应(polymerase chain reaction,PCR)扩增RHO基因的第1-5外显子基因片段,产物纯化后直接测序;测序结果与美国国立生物技术信息中心(National Center for Biotechnology Information,NCBI)数据库上公布的核酸标准序列进行比对分析.结果 该家系临床特点为所有患者均于10岁左右出现夜盲,1例22岁出现视野损害,2例40岁左右出现视野损害,并且于50岁左右双眼相继发生急性闭角型青光眼和并发性白内障.该家系5例患者在RHO基因外显子、上下游非编码序列以及内含子及外显子拼接部中均未发现碱基改变.结论 本研究家系患者存在遗传异质性和表型异质性,RHO基因不是该家系的致病基因.%Objective To study the relation between a family with autosomal dominant retinitis pigmentosa(adRP) and rhodopsin (RHO) by analyzing the clinical phenotype of adRP. Methods Genetic characteristics of the family with adRP occurring in 4 consecutive generations were observed according to the RP diagnostic criteria of retinitis pigmentosa(RP) and the clinical phenotype of the adRP family members. Peripheral blood samples(8-10ml) were taken from 13 family members of the family with adRP. Genomic DNA was isolated and the first 5 exons of RHO gene segments were amplified by PCR. The purified PCR products were directly sequenced, which was compared with the standard sequence of nucleic acid from National Center for Biotechnology Information(NCBl). Results Night blindness occurred in all members of the family at the age of about 10 years. Visual field damage was observed in 1 member at the age of

  6. The molecular genetics progress of congenital cataract%先天性白内障的分子遗传学研究进展

    Institute of Scientific and Technical Information of China (English)

    孙倩倩; 杨昭庆; 黄小琴

    2012-01-01

    先天性白内障(congenital cataract)是指在孕期或胎儿期由于各种因素使晶状体发育受到影响,是儿童致盲的首要原因之一.先天性白内障有明显的临床异质性和遗传异质性,一般与晶体蛋白基因、缝隙连接蛋白基因、转录因子基因及其他基因突变有关,常见的遗传方式有常染色体显性遗传、常染色体隐性遗传和性染色体连锁遗传,其中以常染色体显性遗传最为常见.近几年先天性白内障的分子遗传学水平有了新的突破,此文就其研究进展进行综述.%Congenital cataract,defined as abnormal development of crystalline lens,is caused by various factors during pregnancy.It is one of the major causes of blindness in children.Congenital cataract is usually hereditary.The autosomal dominant inheritance with complete penetrance is the most important type.Autosomal recessive and X-linked inheritances are also frequently seen.In the development of congenital cataract,genetic factors are very important,which has obviously phenotypical and genotypical heterogeneities.The objective of this review is to discuss the progress in the molecular genetics of congenital cataracts,including the mutations of structural proteins in the lens,transcription factors,and some other genes.

  7. 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

    Science.gov (United States)

    Eltawansy, Sherif Ali; Thomas, Maria Joana; Daniels, Jeffrey

    2015-01-01

    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. PMID:25861484

  8. 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.

  9. Genetics Home Reference: autosomal dominant hypocalcemia

    Science.gov (United States)

    ... in the hands and feet (carpopedal spasms) and muscle cramping, prickling or tingling sensations (paresthesias), or twitching of ... plays an important role in the control of muscle movement, and a shortage of this molecule can lead to cramping or twitching of the muscles. Impairment of the ...

  10. Linkage analysis of congenital nuclear cataract and DLAD locus%先天性核性白内障家系DLAD基因的连锁分析

    Institute of Scientific and Technical Information of China (English)

    陈琳琳; 唐爱兰; 张学; 张劲松

    2005-01-01

    目的:为进一步确定DLAD基因缺陷与人类白内障发生的关系.方法:对6个先天性白内障家系进行临床遗传学分析,然后进行连锁分析.结果:D1 S551和D1 S3471(GATA65B07)引物两点LOD值均为负值.结论:该6个家系的先天性白内障的发生与DLAD基因缺陷无关.%· AIM: DLAD (DnaseII-like acid Dnase) is an acid DNase that is highly expressed in human and murine lens fibre cells. Recently, the DLAD-/- mice with a deficience in DLAD gene were reported to develop nuclear cataract.To elucidate whether a deficient DLAD gene can cause some human cataract, we studied autosomal dominant nuclear catarat in 6 families and analysed linkage between cataract and DLAD locus.·METHODS: Two-point Lod score values were obtained for markers D1S551 and GATA65B07.· RESULTS: The results show negative Lod scores (z=-∞ at θ =0), so linkage was excluded between the defect and DLAD locus in these families.·CONCLUSION: no evidence for cataracts in these families linkage to chromosome 1p22.3, the DLAD locus.

  11. 先天性白内障的分子遗传学研究进展%Current research on molecular genetics of congenital cataract

    Institute of Scientific and Technical Information of China (English)

    王云

    2013-01-01

    先天性白内障是世界范围内约1/10儿童致盲的主要原因,是中国儿童致盲的第二大眼病.先天性白内障30% ~50%具有遗传性,主要为常染色体显性遗传,还包括常染色体隐性遗传、X连锁遗传等.通过连锁分析等方法已发现近20多种致病基因、数百个突变位点与不同类型的先天性白内障发病有关,目前根据白内障致病基因的功能不同分为晶状体蛋白基因、膜蛋白相关基因、转录因子调节基因及其他基因4类,各种类型的致病基因通过不同的机制引起的先天性白内障表型不同.了解先天性白内障的致病基因及其分子遗传学机制对于该病的基因学诊断和治疗具有重要意义.就近年来先天性白内障的分子遗传学研究进展进行综述.%Congenital cataract accounts for 10% of childhood blindness worldwide and is the second leading cause of childhood blindness in China.30%-50% of congenital cataract patients are caused by heritability,and majority of them is autosomal dominant traits.In addition,autosomal recessive and X-linked fashion also are found to lead to congenital cataract.Up to now,more than 20 disease-causing genes and 100 mutation locus have been mapped to different chromosomal locations in the human genome using genetic linkage methods.The cataract-associated genes were classified as four categories,including crystallin gene,membrane protein gene,transcription factor regulatory gene and others,and they induce different phenotypes of cataract by different molecular mechanisms.To understand the disease-causing genes and their mechanism is helpful for the genetic diagnosis and treatment of congenital cataract.The current researching progress in molecular genetics of cataract is summarized in this review.

  12. Mutation Screening for Candidate Genes in a Chinese Pedigree with Autosomal Dominant Hereditary Auditory Neuropathy Spectrum Disorder (ANSD)%常染色体显性遗传性听神经病基因突变筛查

    Institute of Scientific and Technical Information of China (English)

    赵昱; 石力; 王剑; 梁鹏飞; 王淑娟; 邱建华

    2014-01-01

    目的:针对一个常染色体显性遗传性非综合征性听神经病谱系障碍家系进行已知致病基因筛查分析,了解是否存在可能致病的基因突变。方法选择本课题组收集到的一个家系4代24人作为研究对象,采集受试者外周静脉血提取基因组DNA,应用在线引物设计软件Primers进行引物设计,采用直接测序法对已知听神经病相关基因进行测序,使用DNAMan软件对序列进行比对分析。结果该家系遗传方式符合显性遗传特征,患者听力学特征符合非综合征型听神经病谱系障碍,对家系中全部患者及部分听力正常成员完成DIAPH3、OTOF、PJVK、GJB2基因外显子及线粒体DNA12S rRNA1494、1555位点的测序分析,未发现可疑致病突变。结论该家系未检测到已知相关基因致病突变,高度提示新基因突变致病的可能,有待于进一步研究。%Objective To identify possible pathogenic gene mutations in a Chinese pedigree with autosomal dominant hereditary non-syndromic auditory neuropathy spectrum disorder (ANSD) . Methods A pedigree of 4 generations (24 people ) was studied. Genomic DNA was extracted from peripheral blood. Primers were designed using a free internet primer de-sign software. Known auditory neuropathy related genes were analyzed by direct sequencing and gene sequences were ana-lyzed comparatively using the DNAMan software. Results In this pedigree, the mode of inheritance was consistent with autoso-mal dominant genetic diseases, and the characteristics of patients were in accordance with the diagnosis of auditory neuropa-thy spectrum disorder (ANSD). Direct sequencing of exons of the DIAPH3, OTOF, PJVK, GJB2 and GJB3 genes as well as the mitochondrial 12SrRNA gene in all patients and some other members with normal hearing in this pedigree showed no suspi-cious mutation. Conclusion None of the known pathogenic mutations is detected in this Chinese ANSD family, suggesting the

  13. 一中国人家系常染色体显性遗传垂体性尿崩症基因突变研究%Mutation of autosomal dominant neurohypophyseal diabetes insipidus in a Chinese pedigree

    Institute of Scientific and Technical Information of China (English)

    陈育才; 谢文煌; 王柠; 慕容慎行; 黄妙辉; 黄梅芳

    2001-01-01

    Objective To elucidate the molecular mechanism of autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) in Chinese. Methods A Chinese family with ADNDI was studied. Polymerase chain reaction-single strand conformation polymorphisms (PCR-SSCP) of exon 1 and exon 2 of arginine vasopressin neurophysin Ⅱ (AVP-NPII) gene were performed in 4 patients and 4 normal phenotypic members of the pedigree and 1 patient from other family. Direct DNA sequencing of PCR-amplified geomic DNA in exon 2 are carried out. Results In exon 1, the affected patients and unaffected people in same kindred and a nonfamilial insipidus from other family had the same strand in SSCP analysis. But there were differences in SSCP analysis from exon 2 as follows: besides having the same strand as healthy man in same kindred or a nonfamilial affected patient, SSCP analysis showed that affected patients from ADNDI had two new different strands. The results were confirmed by direct DNA sequencing of PCR-amplified geomic DNA. A 3-base pair deletion (GAG) out of two consecutive GAG sequence (nucleotides 1826-1831) was identified in affected individual with ADNDI. This mutation should yield an abnormal AVP precursor lacking Glu47 in its neurophysin-Ⅱ moeity. Since Glu47 is essential for NP molecules to form a salt bridge with AVP, the function of NP as a carrier proetin for AVP would be impaired which leads to acceleration proteolytic degradation. Conclusion The nucleotides deletion in the coding region for neurophysin Ⅱ gene appears to be one of the causes of autosomal dominant neurohypophyseal diabetes insipidus in Chinese.%目的 探讨中国人的常染色体显性遗传垂体性尿崩症(ADNDI)的分子发病机制。方法 对一个家系中4例ADNDI患者、4例未发病者及1例来自其他家庭的患者的精氨酸加压素-运载蛋白Ⅱ(AVP-NPⅡ)基因外显子1和2进行聚合酶链反应-单链构像多态性(PCR-SSCP)分析及基因测序研究。结果 SSCP分

  14. Improvements in Cataract Surgery

    NARCIS (Netherlands)

    Nibourg, Lisanne Maria

    2016-01-01

    Cataract is the leading cause of blindness and visual impairment in the elderly. It involves lens opacification due to biochemical changes in the lens. Cataract surgery provides restoration of good vision by removal of the opaque lens, followed by implantation of an intraocular lens (IOL) in the rem

  15. Cataract surgery - slideshow

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/presentations/100079.htm Cataract surgery - series—Normal anatomy To use the sharing features on this page, please enable JavaScript. Go to slide 1 out of 5 Go to slide ... 5 Overview The lens of an eye is normally clear. A cataract is when the lens becomes cloudy as you ...

  16. Training a cataract surgeon

    Directory of Open Access Journals (Sweden)

    M Babar Qureshi

    2014-07-01

    Full Text Available Training in cataract surgery is one of the key factors needed to ensure high quality cataract surgery with good visual outcomes and patient satisfaction. The training has to impart the right skills to the right person by the right trainer and in the right environment.

  17. Mapping of Gene Underlying Autosomal Dominant Non-syndromic Hearing Loss(DFNA)%常染色体显性遗传非综合征型耳聋致病基因定位研究

    Institute of Scientific and Technical Information of China (English)

    孙悍军; 袁慧军; 韩东一; 贺林; 陶然; 程静; 杨淑芝; 曹菊阳; 于黎明; 洪梦迪; 冯国鄞; 戴朴

    2006-01-01

    耳聋具有高度的遗传异质性, 迄今已定位了51个常染色体显性遗传非综合征型耳聋(autosomal dominant non-syndromic sensorineural hearing loss, DFNA)基因位点, 20个DFNA相关基因被克隆.文章收集了一个DFNA巨大家系, 家系中有血缘关系的家族成员共170人, 对73名家族成员进行了详细的病史调查、全身检查和耳科学检查, 提示39人有不同程度的迟发性感音神经性听力下降, 未见前庭及其他系统的异常.应用ABI公司382个常染色体微卫星多态标记进行全基因组扫描连锁分析, 将该家系致聋基因定位于14q12-13处D14S1021-D14S70之间约7.6 cM (3.18 Mb)的区域, 最大LOD值为6.69 (D14S1040), 与已知DFNA9位点有4.7 cM (2.57 Mb)的重叠区, DFNA9致病基因COCH位于重叠区域内.下一步拟进行COCH基因的突变筛查, 以揭示该家系耳聋的分子致病机制.

  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

    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.

  19. Combination of Whole Genome Sequencing, Linkage and Functional Studies Implicates a Missense Mutation in Titin as a Cause of Autosomal Dominant Cardiomyopathy with Features of Left Ventricular Non-Compaction

    Science.gov (United States)

    Hooper, Charlotte; Ormondroyd, Liz; Pagnamenta, Alistair; Lise, Stefano; Salatino, Silvia; Knight, Samantha JL; Taylor, Jenny C.; Thomson, Kate L.; Arnold, Linda; Chatziefthimiou, Spyros D.; Konarev, Petr V.; Wilmanns, Matthias; Ehler, Elisabeth; Ghisleni, Andrea; Gautel, Mathias; Blair, Edward; Watkins, Hugh; Gehmlich, Katja

    2016-01-01

    Background High throughput next generation sequencing techniques have made whole genome sequencing accessible in clinical practice, however, the abundance of variation in the human genomes makes the identification of a disease-causing mutation on a background of benign rare variants challenging. Methods and Results Here we combine whole genome sequencing with linkage analysis in a three-generation family affected by cardiomyopathy with features of autosomal dominant left-ventricular non-compaction cardiomyopathy. A missense mutation in the giant protein titin is the only plausible disease-causing variant that segregates with disease amongst the eight surviving affected individuals, with interrogation of the entire genome excluding other potential causes. This A178D missense mutation, affecting a conserved residue in the second immunoglobulin-like domain of titin, was introduced in a bacterially expressed recombinant protein fragment and biophysically characterised in comparison to its wild-type counterpart. Multiple experiments, including size exclusion chromatography, small angle X-ray scattering and circular dichroism spectroscopy suggest partial unfolding and domain destabilisation in the presence of the mutation. Moreover, binding experiments in mammalian cells show that the mutation markedly impairs binding to the titin ligand telethonin. Conclusions Here we present genetic and functional evidence implicating the novel A178D missense mutation in titin as the cause of a highly penetrant familial cardiomyopathy with features of left-ventricular non-compaction. This expands the spectrum of titin’s roles in cardiomyopathies. It furthermore highlights that rare titin missense variants, currently often ignored or left un-interpreted, should be considered to be relevant for cardiomyopathies and can be identified by the approach presented here. PMID:27625337

  20. 广东地区视网膜色素变性两大家系RHO基因突变分析%Analysis of RHO gene mutation for two autosomal dominant retinitis pigmentosa families in Guangdong Province

    Institute of Scientific and Technical Information of China (English)

    徐志勇; 胡玉华; 陈璐; 黄小菊; 张阮章; 王沙燕

    2009-01-01

    目的 分析广东地区两个常染色体显性遗传视网膜色素变性(autosomal dominant retinRis pigmento-sa,ADRP)家系视紫红质(rhodopsin,RHO)基因突变,探讨基因突变与临床表型的关系.方法 收集广东地区两个常染色体显性遗传视网膜色素变性家系的临床资料,对家系成员进行视力、视野、眼底镜检查;应用聚合酶链反应(PCR)和直接测序技术,对两个家系所有现存成员进行RHO基因检测.结果 发现一家系患者为P347S杂合性突变.另一家系患者存在P171L杂合性突变,两家系的临床表现为发病早,病情进展快,表型较严重,该两家系正常成员均未发现RHO基因突变.结论 RHO基因的P347S与P171L突变分别为该两家系视网膜色素变性的病因.该两种突变均导致较严重的临床表型,与分子基础一致.

  1. Analysis of data from the ERA-EDTA Registry indicates that conventional treatments for chronic kidney disease do not reduce the need for renal replacement therapy in autosomal dominant polycystic kidney disease.

    Science.gov (United States)

    Spithoven, Edwin M; Kramer, Anneke; Meijer, Esther; Orskov, Bjarne; Wanner, Christoph; Caskey, Fergus; Collart, Frederic; Finne, Patrik; Fogarty, Damian G; Groothoff, Jaap W; Hoitsma, Andries; Nogier, Marie-Béatrice; Postorino, Maurizio; Ravani, Pietro; Zurriaga, Oscar; Jager, Kitty J; Gansevoort, Ron T

    2014-12-01

    Autosomal dominant polycystic kidney disease (ADPKD) is a major cause of end-stage kidney failure, but is often identified early and therefore amenable to timely treatment. Interventions known to postpone the need for renal replacement therapy (RRT) in non-ADPKD patients have also been tested in ADPKD patients, but with inconclusive results. To help resolve this we determined changes in RRT incidence rates as an indicator for increasing effective renoprotection over time in ADPKD. We analyzed data from the European Renal Association-European Dialyses and Transplant Association Registry on 315,444 patients starting RRT in 12 European countries between 1991 and 2010, grouped into four 5-year periods. Of them, 20,596 were due to ADPKD. Between the first and last period the mean age at onset of RRT increased from 56.6 to 58.0 years. The age- and gender-adjusted incidence rate of RRT for ADPKD increased slightly over the four periods from 7.6 to 8.3 per million population. No change over time was found in the incidence of RRT for ADPKD up to age 50, whereas in recent time periods the incidence in patients above the age of 70 clearly increased. Among countries there was a significant positive association between RRT take-on rates for non-ADPKD kidney disease and ADPKD. Thus, the increased age at onset of RRT is most likely due to an increased access for elderly ADPKD patients or lower competing risk prior to the start of RRT rather than the consequence of effective emerging renoprotective treatments for ADPKD.

  2. 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.

  3. Surgery for Congenital Cataract

    Directory of Open Access Journals (Sweden)

    David Yorston FRCS FRCOphth

    2004-01-01

    Full Text Available The management of congenital cataract is very different to the treatment of a routine age-related cataract. In adults, surgery may be delayed for years without affecting the visual outcome. In infants, if the cataract is not removed during the first year of life, the vision will never be fully regained after surgery. In adults, if the aphakia is not corrected immediately, it can be corrected later. In young children, if the aphakia is not corrected, the vision will never develop normally.

  4. Transplantation of umbilical cord mesenchymal stem cells for treatment of autosomal dominant spinocerebellar ataxias in 12 cases%脐带间充质干细胞治疗脊髓小脑性共济失调12例

    Institute of Scientific and Technical Information of China (English)

    邱云; 汪铮; 路红社; 许鹏; 陈文怡; 路延光; 丁永红

    2012-01-01

    BACKGROUND: There is no study addressing transplantation of umbilical cord mesenchymal stem cells for the treatment of spinocerebellar ataxia.OBJECTIVE: To study the clinical effect of human umbilical cord stem cells transplantation in the treatment of autosomal dominant spinocerebellar ataxias. METHODS: Spinocerebellar ataxias patients selected from Stem Transplantation Center of the 455 Hospital of Chinese PLA were treated with umbilical cord mesenchymal stem cells transplantation via intrathecal injection. The number of umbilical cord mesenchymal stem cells was 107 per transplantation, once per week, for 4 weeks.RESULTS AND CONCLUSION: Both the total score of the International Cooperative Ataxia Rating Scale and Activities of Daily Living score were significantly decreased at 1 month after transplantation compared with before treatment (P < 0.05). The nerve function was significantly improved and the total effective rate was up to 16.7%. Experimental findings indicate that, transplantation of umbilical cord mesenchymal stem cells via intrathecal injection is a feasible and effective treatment to ameliorate the clinical efficacy of spinocerebellar ataxias patients and improve their quality of life.%背景:目前尚未见应用脐带间充质干细胞治疗脊髓小脑性共济失调的报道.目的:观察脐带间充质干细胞治疗脊髓小脑性共济失调的临床效果.方法:选择2010-09/12解放军455医院干细胞移植中心收治的12例脊髓小脑共济失调患者,给予脐带间充质干细胞鞘内注射,每次107个细胞,1次/周,4次为1个疗程.结果与结论:患者治疗后1个月与治疗前比较国际合作共济失调评分量表评分及日常生活量表评分均明显降低(P < 0.05),提示患者的神经功能显著改善,总有效率为16.7%.说明脐带间充质干细胞鞘内注射治疗可以在一定程度上改善脊髓小脑性共济失调患者的临床症状,提高患者生活质量.

  5. Síndrome hereditario de hiperferritinemia y catarata Hereditary syndrome of hyperferritinemia and cataract

    Directory of Open Access Journals (Sweden)

    J. Andonegui

    2007-08-01

    Full Text Available Se describe a una familia con el síndrome hereditario de hiperferritinemia y catarata. La herencia es autonómica dominante y las características clínicas de este síndrome son cataratas familiares de aparición temprana y aumento de los niveles séricos de ferritina, siendo normales el resto de estudios relacionados con el hierro y de parámetros hematológicos. Es importante difundir el conocimiento de esta entidad para diagnosticar nuevos casos y evitar pruebas diagnósticas innecesarias o tratamientos inadecuados.This report describes a family with hereditary hyperferritinemia cataract syndrome. Inheritance is autosomal dominant and clinical characteristics of this syndrome are familial cataracts of early development and elevated serum ferritin levels but otherwise normal iron studies and haematological parameters. It is important to increase awareness of this entity in order to diagnose new cases and avoid unnecessary diagnostic tests and inadequate treatments.

  6. Discriminative Features in Three Autosomal Recessive Cutis Laxa Syndromes: Cutis Laxa IIA, Cutis Laxa IIB, and Geroderma Osteoplastica

    Directory of Open Access Journals (Sweden)

    Ariana Kariminejad

    2017-03-01

    Full Text Available Cutis laxa is a heterogeneous condition characterized by redundant, sagging, inelastic, and wrinkled skin. The inherited forms of this disease are rare and can have autosomal dominant, autosomal recessive, or X-linked inheritance. Three of the autosomal recessive cutis laxa syndromes, namely cutis laxa IIA (ARCL2A, cutis laxa IIB (ARCL2B, and geroderma osteodysplastica (GO, have very similar clinical features, complicating accurate diagnosis. Individuals with these conditions often present with cutis laxa, progeroid features, and hyperextensible joints. These conditions also share additional features, such as short stature, hypotonia, and congenital hip dislocation, but the severity and frequency of these findings are variable in each of these cutis laxa syndromes. The characteristic features for ARCL2A are abnormal isoelectric focusing and facial features, including downslanting palpebral fissures and a long philtrum. Rather, the clinical phenotype of ARCL2B includes severe wrinkling of the dorsum of the hands and feet, wormian bones, athetoid movements, lipodystrophy, cataract and corneal clouding, a thin triangular face, and a pinched nose. Normal cognition and osteopenia leading to pathological fractures, maxillary hypoplasia, and oblique furrowing from the outer canthus to the lateral border of the supraorbital ridge are discriminative features for GO. Here we present 10 Iranian patients who were initially diagnosed clinically using the respective features of each cutis laxa syndrome. Each patient’s clinical diagnosis was then confirmed with molecular investigation of the responsible gene. Review of the clinical features from the cases reported from the literature also supports our conclusions.

  7. Cataract Surgery Tool

    Science.gov (United States)

    1977-01-01

    The NASA-McGannon cataract surgery tool is a tiny cutter-pump which liquefies and pumps the cataract lens material from the eye. Inserted through a small incision in the cornea, the tool can be used on the hardest cataract lens. The cutter is driven by a turbine which operates at about 200,000 revolutions per minute. Incorporated in the mechanism are two passages for saline solutions, one to maintain constant pressure within the eye, the other for removal of the fragmented lens material and fluids. Three years of effort have produced a design, now being clinically evaluated, with excellent potential for improved cataract surgery. The use of this tool is expected to reduce the patient's hospital stay and recovery period significantly.

  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. Molecular genetics of cataract.

    Directory of Open Access Journals (Sweden)

    Kannabiran Chitra

    2000-01-01

    Full Text Available Studies on hereditary congenital cataracts have led to the identification of genes involved in formation of these cataracts. Knowledge of the structure and function of a particular gene and the effect of disease-associated mutations on its function are providing insights into the mechanisms of cataract. Identification of the disease gene requires both the relevant clinical data as well as genetic data on the entire pedigree in which the disease is found to occur. Genes for hereditary cataract have been mapped by genetic linkage analysis, in which one examines the inheritance pattern of DNA markers throughout the genome in all individuals of the pedigree, and compares those with the inheritance of the disease. Cosegregation of a set of markers with disease implies that the disease gene is present at the same chromosomal location as those markers. The genes so far identified for hereditary cataracts in both humans and animal models encode structural lens proteins, gap junction proteins, membrane proteins and regulatory proteins involved in lens development. Understanding of the mechanisms of hereditary cataract may also help us understand the manner in which environmental and nutritional factors act on the lens to promote opacification.

  10. Cataract and Cataract Surgery: Nationwide Prevalence and Clinical Determinants.

    Science.gov (United States)

    Park, Sang Jun; Lee, Ju Hyun; Kang, Se Woong; Hyon, Joon Young; Park, Kyu Hyung

    2016-06-01

    This study aimed to investigate the prevalence and clinical determinants of cataract and cataract surgery in Korean population. The 2008-2012 Korean National Health and Nutrition Examination Survey was analyzed, which included 20,419 participants aged ≥ 40 years. The survey is a multistage, probability-cluster survey, which can produce nationally representative estimates. Prevalence of cataract and cataract surgery was estimated. Clinical determinants for those were investigated using logistic regression analyses (LRAs). The prevalence of cataract was 42.28% (95% confidence interval [CI], 40.67-43.89); 40.82% (95% CI, 38.97-42.66) for men and 43.62% (95% CI, 41.91-45.33) for women (P = 0.606). The prevalence of cataract surgery was 7.75% (95% CI, 7.30-8.20); 6.38% (95% CI, 5.80-6.96) for men and 9.01% (95% CI, 8.41-9.61) for women (P Cataract was associated with older age (P Cataract surgery was consistently associated with older age, occupation, DM, asthma, and anemia in two LRAs, which compared participants with cataract surgery to those without cataract surgery and those having a cataract but without any cataract surgery, respectively. Hypertension, arthritis, and dyslipidemia were associated with cataract surgery at least in one of these LRAs. These results suggest that there are 9.4 million individuals with cataract and 1.7 million individuals with cataract surgery in Korea. Further studies are warranted to reveal the causality and its possible mechanism of developing/exacerbating cataract in novel determinants (i.e., anemia, asthma, and arthritic conditions) as well as well-known determinants.

  11. Methodology for studies on medical therapy of cataracts : cataract II

    Directory of Open Access Journals (Sweden)

    Sharma Y

    1989-01-01

    Full Text Available The methodology for testing any possible effect of potential anti-cataract agents is described. This is based on slit lamp and ophthalmoscopic cataract classification and on visual acuity. The difficulties encountered in such studies are highlighted. The presented methodology is suggested to be fairly adequate in assessing usefulness of any possible medical therapy of cataracts.

  12. The Molecular Pathogenesis of Autosomal Dominant Optic Atrophy%常染色体显性视神经萎缩的分子遗传学研究进展

    Institute of Scientific and Technical Information of China (English)

    张娟娟; 周翔天; 瞿佳; 管敏鑫

    2008-01-01

    Autosomal dominant optic atrophy (ADOA), also called Kjer optic neuropathy, is the most common form of inherited optic neuropathy with a prevalence between 1: 10 000 and 1 : 50 000. The optic atrophy often occurs in the childhood (the average age-of-onset: 7 years old) and with an insidious onset of variable visual loss, temperal optic nerve pallor, central or caecocentral visual field scotoma and dyschromatopsia (often appears tetartanopia). Histopathological studies suggest that the underlying defect is retinal ganglion cell degeneration. Mutations in OPA1 encoding a conserved mitochondrial dynamin-related GTPase are the major cause of ADOA. 117 OPA1 ADOA-associated mutations consisted of 31.6% of deletions/insertions, 16.2% of nonsense, 25.6% of missense and 28. 8% of splicing mutations. The majority of mutations reside at the ceding sequence of this gene, especially in the GTPase domain. Other ADOA-associated genes were OPA3 (19q13. 2-q13.3), OPA4 (18q12.2-q12.3) and OPA5 (22q12.1-q13.1). The variable phenotypes of vision loss suggest the involvement of other genetic factors, personal factors and environmental factors in the pathogcnesis of ADOA.%常染色体显性视神经萎缩常在儿童期发病,发病率约1:10 000~1:50 000,表现为隐匿性渐进性视力减退,双颞侧视盘苍白,中心或旁中心暗点,色觉障碍(常表现为蓝黄色盲).组织病理学表现为:视网膜神经节细胞退行性变.OPA1编码一种保守的动力相关GTPase,OPA1突变是ADOA发病的主要原因,目前已发现117个ADOA相关OPA1突变,包括:31.6%缺失和插人突变,16.2%无义突变,25.6%错义突变和28.8%剪接突变.这些突变分布于OPA1基因编码区,但多数位于GTPase区.另外,本病还与OPA3(19q13.2-q13.3)、OPA4(18q12.2-q12.3)及OPA5(22q12.1-q13.1)基因突变有关.个体间的表型差异表明:其他遗传因素、个人因素以及环境因素可能与ADOA发病有关.

  13. Combined cataract and strabismus surgery.

    Science.gov (United States)

    Gayton, J L; Ledford, J K

    1993-08-01

    A patient with cataracts and congenital exotropia underwent combined cataract and strabismus surgery OU. A lateral rectus recession plus an extracapsular cataract extraction with intraocular lens implantation was done OD first; three months later, this procedure was repeated OS. The patient's postoperative course was benign in both cases, and her strabismus resolved after the second operation. A combined surgical approach to cataracts and strabismus (where only a single muscle is involved) was safe and useful in restoring this patient's vision, binocularity, and appearance.

  14. 晶状体蛋白与先天性白内障%Crystallin and congenital cataract

    Institute of Scientific and Technical Information of China (English)

    鞠宏; 赵堪兴

    2009-01-01

    Congenital cataract is responsible for approximately one tenth of childhood blindness worldwide.Generally,cataract includes three inheriting types:autosomal dominant,autosomal recessive or X-linked.The identified genes so far for hereditary cataracts in both human and animal model mainly include encoding structural lens protein,gap junction protein,membrane protein and regulatory protein involved in lens development.Crystallins are the major structural protein of the lens.Mutation in the crystallin genes can result in lens opacity.Understanding of the mechanism of hereditary cataract may also be helpful for us to understand the involvement of environmental and nutritional factors in the process of lens opacification.The function of the crystallins proteins,the mutations in crystallin genes and associated phenotypes are summarized.%先天性白内障是全世界约1/10盲童失明的原因,绝大多数先天性白内障为单基因遗传病,其遗传方式包括常染色体显性遗传、常染色体隐性遗传和X连锁遗传3种.迄今为止在人类及其他动物定位的遗传性先天性白内障的致病基因主要包括编码晶状体结构蛋白、缝隙连接蛋白、膜蛋白、晶状体发育中的调节蛋白的基因.晶状体蛋白是晶状体中最主要的成分,其编码基因的突变与先天性白内障的发生密切相关.了解遗传性先天性白内障的发病机制有助于理解环境及营养因素在晶状体混浊中的作用.就晶状体蛋白的功能、晶状体蛋白基因突变及其导致的先天性白内障表型进行综述.

  15. Cataract surgery and anticoagulants

    NARCIS (Netherlands)

    Koopmans, SA; VanRij, G

    1996-01-01

    A questionnaire was sent to 240 members of the Netherlands Intraocular implant Club (NIOIC) to register their policy followed in 1993 with regard to anticoagulant therapy (ACT) and the use of aspirin in patients having cataract surgery. Ninety-one (32%) forms were suitable for analysis. Most eye sur

  16. Endophthalmitis following cataract extraction.

    Science.gov (United States)

    McClellan, K; Coster, D J; Badenoch, P R; Sanders, R; Chandraratnam, E; Kupa, A

    1987-02-01

    We describe a case of bacterial endophthalmitis complicating routine cataract extraction and intraocular lens implantation in a 91-year-old woman. The ocular and systemic factors that may have predisposed to intraocular infection in this case, and the possibility of predicting these pre-operatively, are discussed.

  17. 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.

  18. [Autosomal recessive polycystic kidney].

    Science.gov (United States)

    Todorov, V; Penkova, S; Lalev, I

    1990-01-01

    A case of a 22 years old woman with autosomal-recessive form of kidney polycystosis is presented. The diagnosis was made in early childhood. A combination of renal anomaly and hepatic fibrosis with manifestations of portal hypertension was present. No deviations from the other internal organs were found. At the age of 12 she entered into the stage of chronic renal failure. The last five years she is on dialysis treatment. She had survived several acute bleedings from esophageal varices. The authors are of the opinion that the case is of interest since patients with autosomal-recessive renal polycystosis very rarely reach majority.

  19. Causes analysis of 652 hospital stays in patients with autosomal dominant polycystic kidney disease%常染色体显性多囊肾病患者652次住院原因分析

    Institute of Scientific and Technical Information of China (English)

    戎殳; 李林; 孙丽君; 徐成钢; 郁胜强; 赵学智; 叶朝阳; 梅长林; 马熠熠; 陈冬平; 张彤; 孙海棚; 贺靓靓; 李兰君; 陈舟; 程烨

    2012-01-01

    Objective To analyze the causes of 652 hospitalizations in the patients with autosomal dominant polycystic kidney disease (ADPKD).Methods The medical records of all ADPKD inpatients in our hospital from January 1,1990 to December 31,2010 were collected.The differences of hospitalization causes in different age,gender and period were analyzed.Results (1)In 652 hospitalizations,the most common cause was lumbar pain (15.2%),followed by cystic bleeding (14.6%),aggravating renal failure (10.1%),dialysis-related problems (9.4%),renal transplant related issues (8.3%),renal replacement therapy for ESRD (8.0%),urinary tract infection (6.4%),end stage renal failure (5.8%),hypertension (4.1%),renal cyst volume enlargement (3.7%),finding polycystic kidney disease (2.1%),urinary lithiasis (1.8%) and others (10.4%).(2)Younger patients were admitted into hospital because of polycystic kidney bleeding and finding PKD.With the increase of patients age,hospitalization due to dialysis-related problems increased,while many middle-aged patients were hospitalized because of back pain.(3)Male patients were admitted into hospital for aggravating renal failure,ESRD,kidney transplantation-related problems and urinary lithiasis,while female patients mainly for lumbar pain,dialysis-related problems and urinary tract infection.(4)The proportion was significantly reduced with time of finding PKD,renal failure and polycystic kidney bleeding,the proportion of renal cysts increasing and aggravating renal failure increased,there was a significant increase in the proportion of patients with hypertension,while a significant decrease in the proportion of patients with uncontrolled hypertension,and the average SBP was also significantly reduced.Conclusions The highest rate of hospitalization of ADPKD patients is in 40 to 60 age group.Cause of admission varies with age and gender,and changes with the change of time.Over the past decade,the proportion of hospitalization due to

  20. Identification of a novel missense mutation of MIP in a Chinese family with congenital cataracts by target region capture sequencing

    Science.gov (United States)

    Jiang, Bo; chen, Yanhua; Xu, Baisheng; Hong, Nan; Liu, Rongrong; Qi, Ming; Shen, Liping

    2017-01-01

    Congenital cataract is both clinically diverse and genetically heterogeneous. To investigate the underlying genetic defect in three-generations of a Chinese family with autosomal dominant congenital cataracts, we recruited family members who underwent comprehensive ophthalmic examinations. A heterozygous missense mutation c.634G > C (p.G212R) substitution was identified in the MIP gene through target region capture sequencing. The prediction results of PolyPhen-2 and SIFT indicated that this mutation was likely to damage the structure and function of MIP. Confocal microscopy images showed that the intensity of the green fluorescent signal revealed much weaker signal from the mutant compared to the wild-type MIP. The expressed G212R-MIP was diminished and almost exclusively cytoplasmic in the HeLa cells; whereas the WT-MIP was stable dispersed throughout the cytoplasm, and it appeared to be in the membrane structure. Western blot analysis indicated that the protein expression level of the mutant form of MIP was remarkably reduced compared with that of the wild type, however, the mRNA levels of the wild-type and mutant cells were comparable. In conclusion, our study presented genetic and functional evidence for a novel MIP mutation of G212R, which leads to congenital progressive cortical punctate with or without Y suture. PMID:28059152

  1. Congenital Cataract-Causing Mutation G129C in γC-Crystallin Promotes the Accumulation of Two Distinct Unfolding Intermediates That Form Highly Toxic Aggregates.

    Science.gov (United States)

    Xi, Yi-Bo; Chen, Xiang-Jun; Zhao, Wei-Jie; Yan, Yong-Bin

    2015-08-28

    Cataract is a lens opacification disease prevalent worldwide. Cataract-causing mutations in crystallins generally lead to the formation of light-scattering particles in the lens. However, it remains unclear for the detailed structural and pathological mechanisms of most mutations. In this study, we showed that the G129C mutation in γC-crystallin, which is associated with autosomal dominant congenital nuclear cataract, perturbed the unfolding process by promoting the accumulation of two distinct aggregation-prone intermediates under mild denaturing conditions. The abnormally accumulated intermediates escaped from the chaperone-like function of αA-crystallin during refolding. Molecular dynamics simulations indicated that the mutation altered domain pairing geometry and allowed the penetration of extra solvent molecules into the domain binding interface, thereby weakening domain binding energy. Under mild denaturation conditions, the increased domain movements may facilitate the formation of non-native oligomers via domain swapping, which further assembled into amyloid-like fibrils. The intermediate that appeared at 1.6M guanidine hydrochloride was more compact and less aggregatory than the one populated at 0.9 M guanidine hydrochloride, which was caused by the increased solvation of acidic residues in the ion-pairing network via the competitive binding of guanidinium ions. More importantly, both the amyloid-like fibrils preformed in vitro and intracellular aggresomes formed by exogenously overexpressed mutant proteins significantly inhibited cell proliferation and induced cell death. The combined data from spectroscopic, structural and cellular studies strongly suggest that both the formation of light-scattering aggregates and the toxic effects of the aggregates may contribute to the onset and development of cataract.

  2. Three cases of extracapsular cataract extraction for radiation cataract

    Energy Technology Data Exchange (ETDEWEB)

    Hirokane, Kenji; Kosaka, Toshiya; Nii, Hiroki; Kiuchi, Yoshiaki; Nakano, Kensuke; Choshi, Kanji [Hiroshima Univ. (Japan). School of Medicine

    1996-02-01

    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. "Ant-egg" cataract revisited

    DEFF Research Database (Denmark)

    Clemmensen, Kåre; Enghild, Jan J; Ivarsen, Anders;

    2017-01-01

    PURPOSE: Hereditary congenital cataract varies immensely concerning location and form of the lens opacities. A specific and very rare phenotype is called "ant-egg" cataract first described in 1900. "Ant-eggs" have previously been examined using light microscopy, backscattered electron imaging and X......-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......-egg" structures in "ant-egg" cataract. Eighteen of these proteins are not natively found in the human lens. Moreover, "ant-eggs" do not vary over time, after cataract extraction, regarding size and location....

  4. Virtual Mentor Cataract Surgery Trainer

    Science.gov (United States)

    2010-09-01

    TITLE: Virtual Mentor Cataract Surgery Trainer PRINCIPAL INVESTIGATOR: Principal Investigator: John I. Loewenstein MD Co-Investigator: Bonnie A...AND SUBTITLE Virtual Mentor Cataract Surgery Trainer 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-08-1-0531 5c. PROGRAM ELEMENT NUMBER...AVAILABILITY STATEMENT Approved for public release; distribution unlimited 13. SUPPLEMENTARY NOTES 14. ABSTRACT The Virtual Mentor Cataract Surgery

  5. Cataracts and macular degeneration.

    Science.gov (United States)

    Shoch, D

    1979-09-01

    The intraocular lens restores general vision and some degree of independence and mobility to patients with dense cataracts and macular degeneration. The patient, however, must be repeatedly warned that fine central vision, particularly reading, will not be possible after the surgery. An aphakic spectacle leaves such patients a narrow band of vision when superimposed over the macular lesion, and contact lenses are too small for the patient to manage insertion without help.

  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. 先天性非进展性常染色体显性遗传非综合症型耳聋家系临床表型特征分析%Phenotype characteristics of a Chinese family with congenital, stable, autosomal dominant non-syndromic sensorineural hearing loss

    Institute of Scientific and Technical Information of China (English)

    郭亿莲; 赖海彪; 袁慧军; 李征玥; 何琦; 孙一帆; 徐庆文; 周小军; 张丽娟; 王明松; 孔祥廉

    2011-01-01

    目的 一个连续三代的常染色体显性遗传先天性非进展性非综合症型耳聋家系的临床听力学特征及遗传规律.方法 对耳聋家系成员进行病史采集、体格检查、纯音测听、声导抗、听性脑干反应检测,其中一名患者进行颞骨CT扫描检查.绘制遗传图谱并进行遗传学特征分析.结果 该家系成员共计18人,耳聋患者11人,其中一例为氨基糖苷类药物致聋患者.该耳聋家系每代及男女均有发病,非药物致聋患者均表现为语前聋、平稳型、全频中度听力下降,听力曲线呈平坦型.结论 该家系遗传方式符合常染色体显性遗传规律,表现为全频中度感音神经性耳聋.该研究为下一步的致聋基因的定位与鉴定奠定了良好的工作基础.%Objective To study the phenotypes and genetic characteristics of a three-generation Chinese family with autosomal dominant inherited progressive nonsyndromic hearing loss. Methods Pedigree was drawn after the investigation. Eighteen family members were examined including detailed audiology tesing (pure tone assay, acoustic immittance testing and auditory brainstem response audiometry). One patient received temporal bone CT. Results This family was comprised of 18 members, of whom 11 were affected. One patient had a history of using aminoglycosides. The pattern of inheritance of this family was autosomal dominant based on the investigation information. The affected members showed pre-lingual, stable, bilateral moderate sensorineural hearing impairment involving all frequencies. The audiograms showed generally flat hearing loss. Conclusion Pedigree analysis suggests an autosomal dominant hereditary pattern in this family. The information from this study will facilitate linkage analysis and positional cloning for identifying the causative gene in this family.

  8. Dominant cystoid macular dystrophy

    NARCIS (Netherlands)

    Saksens, N.T.M.; Huet, R.A.C. van; Lith-Verhoeven, J.J. van; Hollander, A.I. den; Hoyng, C.B.; Boon, C.J.

    2015-01-01

    OBJECTIVE: To describe the clinical characteristics and long-term follow-up in patients with autosomal dominant cystoid macular dystrophy (DCMD). DESIGN: Retrospective case series. PARTICIPANTS: Ninety-seven patients with DCMD. METHODS: Extensive ophthalmic examination, including visual acuity (VA),

  9. The clinical phenotype analysis of 116 congenital cataract patients in Yunnan province%云南省116例先天性白内障的临床形态分析

    Institute of Scientific and Technical Information of China (English)

    李娟娟; 马璇; 胡竹林

    2011-01-01

    Background Congenital cataract is the major cause of blindness in children with plentiful clinical manifestations and closely linked with genetics. Objective Present study was to investigate the classification of congenital cataract in Yunnan province.Methods The manifestation characteristics of 184 eyes of 116 patients with congenital cataract in Yunnan province were analyzed.The relationship of performance of various types of congenital cataract between phenotype and hereditary feature were explored. Results All of the 116 congenital cataract eyes from 116 patients were divided into ten types based on the clinical appearance,including the complete cataract,nuclear cataract,posterior polar cataract,anterior polar cataract,coralliform cataract,coronary cataract,pulverulent cataracts,lamellar cataract and blue cataract.Bilateral nuclear cataract and unilateral entire cataract is most prevalent in these patients.Blue cataract and coralliform cataract belong to the less types.Forty-four in 116 cases were found to have the hereditary history and determined as autosomal dominant inheritance.Sporadic cases were determined in 72 cases.Conclusions The analysis of phenotype of the hereditary congenital cataract offers some clues to the classification of congenital cataract.%背景 先天性白内障是儿童主要的致盲眼病之一,其临床表现多样,并与遗传学有着密切联系.目的 探讨云南省先天性白内障患者的临床形态特点.方法 回顾性分析2005年1月至2010年1月在云南省红十字会医院眼科诊断和治疗的先天性白内障患者116例184眼,裂隙灯下检查患眼前后节,根据晶状体混浊的部位、形态等进行分类,分析晶状体混浊的形态学特点及各类型的发病情况,并探讨先天性白内障表现型和遗传型之间的关系.结果116例患者按晶状体混浊的临床形态特点分为10种类型,包括全白内障、核性白内障、后极性白内障、前极性白内障、缝性白内

  10. The clinical characteristics of a pedigree with incompletely penetrated autosomal dominant hereditary spastic paraplegia and its exclusion analysis of genetic loci%不完全外显的遗传性痉挛性截瘫一家系临床与致病基因排除定位分析

    Institute of Scientific and Technical Information of China (English)

    赵国华; 任志军; 刘小民; 李书剑; 郭鹏; 沈璐; 夏昆; 唐北沙

    2008-01-01

    Objective To describe the clinical features of a big family with ineompletely penetrated autosomal dominant hereditary spastic paraplegia(SPG) and perform the exclusion analysis of genetic loci.Methods The clinical information of this SPG family was analyzed retmspecfively.Exclusion analysis of the known autosomal dominant SPG loci was performed by using rnltiplex fluorescence PCR, capillary electrophoresis and Linkage package. Results There were eleven affected members available in this SPG family and the age at onset ranged from 2 to 10 years.The first symptoms were a bilateral,symmetrical,progressive lower limb weakness and spasticity.Patients presented with spastieity and hyperrdlexia,positive Babinski sign and scissors gait,and the upper limbs were involved more seveiely than the lower limbs.No urinary inconsistence,sensory impairment,nystagmus and dementia were found.Genetic analyfis showed that this family was consistent with autosomal dominant inheritance.The linkage analysis and mutation analysis revealed this family was not linked to the known autosomal dominant loci.Conclusion This SPG family had typical"pure"clinical symptoms.The age at onset Was early and the signs in the upper limbs were more obvious than those in the lower limbs.The result of linkage analysis shows that this family represents a new SPG subtype.%目的 描述一个遗传了4代的不完全外显的遗传性痉挛性截瘫(hereditary spastic paraplegia,SPG)大家系的临床特征,并进行致病基因排除定位分析.方法 对SPG家系内11例患者的临床资料进行回顾性分析,并采用荧光多重PCR、毛细管凝胶电泳、Linkage软件包,选择对已定位常染色体显性遗传致病基因位点附近微卫星标记进行连锁分析.结果 该SPG家系的11例患者的发病年龄2~10岁,表现为缓慢进展的双下肢僵硬无力,四肢肌张力轻度增高,双上肢为主的腱反射亢进,剪刀步态和病理征阳性,无小便失禁或尿频、感觉障

  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. Congenital Cataract Screening

    Science.gov (United States)

    Rajavi, Zhale; Sabbaghi, Hamideh

    2016-01-01

    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. PMID:27621790

  13. Manual small incision cataract surgery in eyes with white cataracts

    Directory of Open Access Journals (Sweden)

    Venkatesh Rengaraj

    2005-01-01

    Full Text Available PURPOSE: To assess the safety and efficacy of Manual Small Incision Cataract Surgery (MSICS in cases of white cataract with the use of trypan blue as an adjunct for performing continuous curvilinear capsulorthexis (CCC. MATERIALS AND METHODS: Prospective observational study on 100 consecutive eyes of 100 patients with white cataract who had undergone MSICS with trypan blue assisted CCC. The nucleus was prolapsed into anterior chamber by using a sinskey hook and extracted out of the eye using irrigating vectis. Intraoperative and postoperative findings (according to OCTET classification as well as postoperative visual outcomes were used as main measures to report the safety and efficacy of the surgery. RESULTS: Of the 100 eyes, 16 had intumescent, 67 had mature and 17 had hypermature cataract. Intraoperatively CCC was incomplete in 4 eyes (4% and had to be converted to canopener capsulotomy. None of the eyes had posterior capsular rupture or zonular dialysis and no eyes were converted to conventional Extra Capsular Cataract Extraction (ECCE. Postoperatively, 6 eyes (6% developed corneal oedema with >10 Descemets folds and 7 eyes (7% had corneal oedema with < 10 Descemets folds. Mild iritis was seen in 6 eyes (6% and moderate iritis with fibrin membrane was seen in 3 eyes (3%. Iridodialysis was observed in 1 eye (1%. Of the 99 patients (99% categorised under good visual outcomes category, 94 patients (94% had a best-corrected visual acuity of 6/9 or better on the 40th post-operative day. CONCLUSION: In developing countries like India where phacoemulsification may not be affordable to a majority of those requiring cataract surgery, MSICS proves to be a safe and efficacious alternative for white cataracts especially with the adjunctive use of trypan blue dye.

  14. 珊瑚状先天性白内障一家系致病基因筛查与鉴定%Gene mapping and analysis of genes in a Chinese family with congenital coralliform cataract

    Institute of Scientific and Technical Information of China (English)

    巩雪; 宋籽浔; 肖伟

    2016-01-01

    •AIM:To detect the causative mutation for congenital coralliform cataracts in a Chinese family.•METHODS:Peripheral blood samples were collected and genomic DNA was extracted.We chose four candidate genes associated with congenital coralliform cataract including GJA3,GJA8,CRYGC and CRYGD.After genomic polymerase chain reaction ( PCR ) performed, we sequenced the coding exons and their flanking intronic sequences of four candidate genes.•RESULTS:We ascertained a three-generation Chinese family with autosomal dominant coralliform congenital cataracts.Mutation screenings were performed for all four candidate genes, and a heterozygous variant, c.70C>A, was identified in exon 2 of CRYGD.• CONCLUSION: Our result demonstrates that a heterozygous mutation of CRYGD is responsible for the autosomal dominant congenital coralliform cataract in a three-generation Chinese pedigree.%目的:对一个珊瑚状先天性白内障家系进行致病基因的筛查。方法:采集家系中2例患者和1例正常对照者的外周静脉血,提取基因组DNA。选择与珊瑚状白内障相关的候选基因GJA3、GJA8、CRYGC及CRYGD设计引物,进行聚合酶链反应( PCR)扩增候选基因,并对扩增片段进行Sanger测序。结果:该家系疾病表型为珊瑚状白内障,呈常染色体显性遗传。通过对扩增产物测序,发现家系内患者CRYGD第2个外显子第70位有1个C>A碱基的杂合突变( c.70C>A),正常对照未见该点突变。结论:CRYGD基因的错义突变c.70C>A是该珊瑚状白内障家系的致病原因。

  15. A mutation in the FOXE3 gene causes congenital primary aphakia in an autosomal recessive consanguineous Pakistani family

    DEFF Research Database (Denmark)

    Anjum, Iram; Eiberg, Hans; Baig, Shahid Mahmood;

    2010-01-01

    PURPOSE: Aphakia is the complete absence of any lens in the eye, either due to surgical removal of the lens as a result of a perforating wound or ulcer, or due to a congenital anomaly. The purpose of this study was to elucidate the molecular genetics for a large consanguineous Pakistani family...... with a clear aphakia phenotype. METHODS: The initial homozygosity screening of the family was extended to all the known autosomal recessive cataract loci in order to exclude the possibility of surgical cataract removal leading to aphakia. The screening was performed using polymorphic nucleotide repeat markers...

  16. A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder?

    Science.gov (United States)

    Aldea, Anna; Campistol, Josep M; Arostegui, Juan I; Rius, Josefa; Maso, Montserrat; Vives, Jordi; Yagüe, Jordi

    2004-01-01

    Familial Mediterranean fever (FMF) is an autosomal recessive disease characterized by recurring short attacks of fever and serositis. Secondary AA amyloidosis is the worst complication of the disease and often determines the prognosis. The MEFV gene, on chromosome 16p13.3, is responsible for the disease and around 30 mutations have been reported to date. Colchicine is the standard FMF treatment today, and prevents both attacks and amyloid deposition in 95% of patients. Here we describe a three-generation Spanish kindred with five family members affected by a severe periodic inflammatory disorder associated with renal AA amyloidosis and colchicine unresponsiveness. Clinical diagnosis of definite FMF disease was made based on the Tel-Hashomer criteria set. Genetic analyses revealed that all subjects were heterozygous for the new H478Y MEFV variant, segregating with the disease. In addition, mutations in the TNFRSF1A and CIAS1/PYPAF1/NALP3 genes, related to the dominantly inherited autoinflammatory periodic syndromes, were ruled out. However, the dominant inheritance of the disease, the long fever episodes with a predominant joint involvement, and the resistance to colchicine in these patients raise the question of whether the periodic syndrome seen in this kindred is a true FMF disease with unusual manifestations or rather another MEFV-associated periodic syndrome. We conclude that the new H478Y MEFV mutation is the dominant pathological variant causing the inflammatory periodic syndrome in this kindred and that full-length analyses of the MEFV gene are needed to obtain an adequate diagnosis of patients with clinical suspicion of a hereditary periodic fever syndrome, especially those from non-ancestral populations.

  17. Clinical genetics and gene mapping studies on a family in the area of northeast with hereditary cataract%东北地区一遗传性白内障家系的临床遗传学及基因定位研究

    Institute of Scientific and Technical Information of China (English)

    张天晓; 马立威; 赵江月; 张学; 张劲松

    2013-01-01

    目的:分析一先天性核型白内障家系的遗传方式及致病基因所在位置.方法:收集一个3代遗传性白内障家系成员的临床资料;提取家系成员外周血DNA,选取62个态性微卫星标记进行连锁分析.应用LINKAGE软件 (version5.2) 中的MLINK程序计算两点连锁LOD值,并人工构建家系成员的单体型.结果:确定该家系为一常染色体显性遗传性白内障大家系,在微卫星标记D22S689可获得最大LOD值2.71(θ=0时),单体型提示该家系表型可能与染色体22q11.2-12.1区域连锁.该区域含有CRYBB1,CRYBB2,CRYBB3,CRYBA44个候选基因.结论:本研究先天性核型白内障家系符合常染色体显性遗传规律,其致病基因定位于22q11.2-12.1区域.%AIM: To map the causal gene of congenital nuclear cataract in a family in the area of northeast.METHODS: We investigated there generations of a Chinese family affected with hereditary cataract. Peripheral blood samples were collected from all of the family members, and genomic DNA was then extracted from the blood samples. Linkage analysis was performed using 62microsatellite markers. Two-point LOD scores (Z) were calculated using the LINKAGE programs (ver. 5.2). Haplotypes were constructed according to the allele information.RESULTS: The affected members in this family showed classic phenotype of autosomal dominant congenital cataract. The maximum two-point LOD score of 2. 71 was obtained for marker D22S689 (θ= 0). Haplotype analysis traced the disease gene on chromosome 22q11.2-12.1, containing CRYBB1, CRYBB2, CRYBB3, CRYBA4 genes.CONCLUSION: The occurrence of congenital nuclear cataract consistents with the autosomal dominant inherited regular, and the causal gene of congenital nuclear cataract localize at 22q11.2-12.1 in this family.

  18. Topical sulindac therapy in diabetic senile cataracts : cataract IV

    Directory of Open Access Journals (Sweden)

    Sharma Y

    1989-01-01

    Full Text Available Sulindac, a non-steroidal anti-inflammatory drug has been found to be a potent inhibitor of enzyme aldose reductase. We used sulindac topically in diabetic senile cataract patients to note if it effects the progression of cataracts. More of sulindac treated eyes maintained initial vision and fewer eyes had visual loss of up to two lines or more as compared to control eyes. The extent and density of different opacities showed less progression in sulindac treated eyes but it was not statistically significant except that the ophthalmoscopically observed density of opacity showed statistically very significant lesser mean increase in sulindac treated eyes. We suggest that sulindac is a potential drug which should be further evaluated in large double blind photodocumented studies in diabetic senile cataracts.

  19. 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...

  20. Pain determinants of pain in autosomal dominant polycystic kidney disease

    Directory of Open Access Journals (Sweden)

    José Luiz Nishiura

    2013-09-01

    Full Text Available Pain is the most common symptom reported by ADPKD patients, afflicting approximately 60% of cases and may result from renal hemorrhage, calculi, urinary tract infections, cyst rupture, or due to stretching of the capsule or traction of the renal pedicle. We have recently investigated pain patterns in AD-PKD patients using a translated version of a pain questionnaire specific for AD-PKD population. The questionnaire revealed that 67% patients with ADPKD exhibited some type of pain. The findings of that study emphasized that pain appeared early in the course of ADPKD, when patients still exhibited preserved renal function. In the present study, a multivariate logistic regression analysis disclosed that renal volume (9-fold increased risk and nephrolithiasis (4-fold increased risk were the most important determinant factors for pain in ADPKD patients with preserved renal function, after adjustments for the presence of hypertension and duration of the disease.

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

    Science.gov (United States)

    ... with ADNFLE have experienced psychiatric disorders (such as schizophrenia), behavioral problems, or intellectual disability. It is unclear ... Changes Mutations in the CHRNA2 , CHRNA4 , and CHRNB2 genes can cause ADNFLE . These genes provide instructions for ...

  2. A CASE OF AUTOSOMAL DOMINANT BILATERAL FAMILIAL ANIRIDIA

    Directory of Open Access Journals (Sweden)

    Srinivas M

    2014-04-01

    Full Text Available Aniridia are rare developmental anomalies present in 1.8/100, 000 live births. Aniridia occurs due to abnormal neuroectodermal development secondary to mutations in paired box gene 6 (PAX6 on band p13 of chromosome 11 which regulates eye development. Aniridia may be congenital or traumatic. It may occur in isolation or be associated with a number of syndromes such as WAGR. Two third of cases are familial and one third is sporadic. We report a family of aniridia with different clinical spectrum of features.

  3. Progeria (Hutchison-Gilford syndrome) in siblings: in an autosomal recessive pattern of inheritance.

    Science.gov (United States)

    Raghu, T Y; Venkatesulu, G A; Kantharaj, G R; Suresh, T; Veeresh, V; Hanumanthappa, Y

    2001-01-01

    Progeria is an autosomal dominant, premature aging syndrome. Six and three year old female siblings had sclerodermatous 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.

  4. 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.

  5. 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...

  6. Blindness in schoolchildren: importance of heredity, congenital cataract, and prematurity.

    Science.gov (United States)

    Phillips, C I; Levy, A M; Newton, M; Stokoe, N L

    1987-08-01

    Of 99 children in the Royal Blind School, Edinburgh (which serves Scotland and part of N E England), 15 had optic atrophy (hydrocephalus 4, intracranial haemorrhage 2, prematurity 2, fetal distress 2, birth asphyxia 2, cerebral atrophy 1, cardiac arrest during hernia operation 1, and leukaemia 1). Fourteen had congenital cataract, 12 congenital retinal aplasia (Leber's congenital amaurosis) and 11 retinopathy of prematurity. There were small numbers in many other diagnostic categories, including three with non-accidental head injury. Mental retardation, spasticity, and nystagmus were frequent other correlates in all diagnostic categories. 'Very probably hereditary' was a conservative attribution in 36, while 'probable' seemed appropriate for 12-that is, almost 48% were hereditary. Only about 11 cases might have been prevented through genetic counselling, which testifies to the frequency of autosomal recessive hereditary disease, although no parents were consanguineous.

  7. Ultrasound diagnosis of bilateral cataracts in a fetus with possible cerebro-ocular congential muscular dystrophy during the routine second trimester anomaly scan.

    Science.gov (United States)

    Drought, Alexandra; Wimalasundera, Ruwan; Holder, Susan

    2015-08-01

    The finding of bilateral congenital cataracts in the fetus is rare. We report bilateral congenital cataracts detected during the routine second trimester anomaly scan, which subsequently were found to be associated with other congenital anomalies and the parents opted for a termination of pregnancy. At post-mortem, Muscle-Eye Brain disease or Walker-Warburg Syndrome was considered likely, which are autosomal recessive congenital muscular dystrophy disorders associated with cerebral, cerebellar, muscle and eye anomalies. On ultrasound, bilateral cataracts appear as echogenic, solid areas within the fetal orbits. The examination of the fetal face and orbits plays an important role in confirming fetal well-being antenatally. We propose that it should become a routine part of the structural survey of fetal anatomy during the obstetric anomaly scan. This is especially important in pregnancies previously affected by fetal cataracts or pregnancies at risk of rare genetic syndromes.

  8. Gonadal mosaicism as a rare cause of autosomal recessive inheritance.

    Science.gov (United States)

    Anazi, S; Al-Sabban, E; Alkuraya, F S

    2014-03-01

    Autosomal recessive diseases are typically caused by the biparental inheritance of familial mutant alleles. Unusual mechanisms by which the recessiveness of a mutant allele is unmasked include uniparental isodisomy and the occurrence of a de novo chromosomal rearrangement that disrupts the other allele. Gonadal mosaicism is a condition in which a postfertilization mutation is confined to the gamete precursors and is not detected in somatic tissues. Gonadal mosaicism is known to give the impression of autosomal recessive inheritance when recurrence of an autosomal-dominant condition among offspring of phenotypically normal parents is observed. Here, we report an extremely rare event in which maternal gonadal mosaicism for a recessive mutation in COL4A4 caused the recurrence of Alport syndrome within a consanguineous family. Such rare occurrence should be taken into account when analyzing pedigrees both for clinical and research purposes.

  9. 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.

  10. Quality of care from the perspective of the cataract patient: QUOTE Cataract Questionnaire.

    NARCIS (Netherlands)

    Nijkamp, M.D.; Sixma, H.J.; Afman, H.; Hiddema, F.; Koopmans, S.A.; Borne, B. van den; Hendrikse, F.; Nuijts, R.M.M.A.

    2002-01-01

    PURPOSE: To examine the potential of a questionnaire (QUOTE Cataract) to measure quality of care from the perspective of cataract patients in quality-assurance or improvement programs. SETTING: Department of Ophthalmology, University Hospital Maastricht, Maastricht, University Hospital Groningen, Gr

  11. Quality of care from the perspective of the cataract patient - QUOTE Cataract Questionnaire

    NARCIS (Netherlands)

    Nijkamp, MD; Sixma, HJ; Afman, H; Hiddema, F; Koopmans, SA; van den Borne, B; Hendrikse, F; Nuijts, RMMA

    2002-01-01

    Purpose: To examine the potential of a questionnaire (QUOTE Cataract) to measure quality of care from the perspective of cataract patients in quality-assurance or improvement programs. Setting. Department of Ophthalmology, University Hospital Maastricht, Maastricht, University Hospital Groningen, Gr

  12. Cataract and ionizing radiation; Cataracte et rayonnements ionisants

    Energy Technology Data Exchange (ETDEWEB)

    Wassilieff, S. [Ecole des Applications Militaires de l' Energie Atomique, 50 - Cherbourg Octeville (France)

    2009-10-15

    The radiation-induced cataract has been up to now considered as a quite rare pathology, needing high-dose radiations (beyond a dose threshold roughly estimated at 2 Grays to the lens) consisting mainly in head tumour radiotherapy complications. Several new studies on different exposed populations such as astronauts, japanese atomic bomb survivors, people undergoing X-ray examinations, Chernobyl accident 'liquidators' as well as data from animal experiments, suggest that dose threshold for detectable opacities as well as for clinical posterior sub-capsular cataract occurring, might be far lower than those previously assumed. Even the existence of a dose threshold is no longer an absolute certitude insofar as radiation-induced cataract pathogenesis might consist not really in a deterministic effect (direct tissue harmful effect, killing or seriously injuring a critical population of cells) as believed until now, but rather in a stochastic effect (genomic damage in target-cells, altered cell division, abnormal lens fiber cell differentiation). More practically, these new data may lead us to reconsider radioprotection of specifically exposed populations: mainly patients and workers. Regarding workers, labour legislation (lens equivalent dose limit of 150 mSv during 12 consecutive months) might be, in the medium term, reassessed downwards. (author)

  13. Pre-cataract surgery test using speckle pattern

    Science.gov (United States)

    Jutamulia, Suganda; Wihardjo, Erning; Widjaja, Joewono

    2016-11-01

    A laser diode device for pre cataract surgery test is proposed. The operation is based on the speckle generated on the retina by the cataract lens, when the cataract lens is illuminated with a coherent laser light.

  14. Associação entre aneurismas de aorta abdominal infrarrenal e doença renal policística autossômica dominante: relato de caso Association between infrarenal abdominal aortic aneurysm and autosomal dominant polycystic kidney disease: a case report

    Directory of Open Access Journals (Sweden)

    Milton Alves das Neves Junior

    2009-06-01

    Full Text Available A doença renal policística dominante é uma das doenças renais hereditárias mais comuns, podendo apresentar manifestações extrarrenais vasculares de importância clínica, como aneurismas intracranianos, aneurismas aórticos e dissecções arteriais. Relatamos o caso de um paciente masculino, com 66 anos de idade, renal crônico não-dialítico por doença renal policística dominante, com aneurisma de aorta abdominal infrarrenal assintomático, diagnosticado por ultrassonografia de rotina e operado eletivamente com sucesso. A doença renal policística dominante é uma síndrome genética, associada aos genes PDK1 e PDK2 no cromossomo 16. A expressão desses genes na parede dos vasos leva ao seu enfraquecimento, favorecendo a formação de aneurismas. A produção de metaloproteinases pelos túbulos renais também estaria relacionada às doenças vasculares desses pacientes. Tais doenças se apresentam como importantes fatores de mortalidade precoce e morbidade dos portadores de doença renal policística dominante e, como usualmente são assintomáticas, justifica-se o uso de propedêutica armada e tratamento precoce.Autosomal dominant polycystic kidney disease (ADPKD is one of the most common hereditary renal diseases, which may present important clinical extrarenal vascular manifestations, such as intracranial and aortic aneurysms and artery dissections. We report the case of a 66-year-old male chronic renal out-of-dialysis patient, with dominant polycystic kidney disease, presenting an asymptomatic infrarenal abdominal aortic aneurysm diagnosed by routine ultrasonography, submitted to successful elective surgery. ADPKD is a genetic syndrome, associated with PDK1 and PDK2 genes on chromosome 16. The expression of these genes in the vessel walls leads to vessel wall weakening, favoring aneurysm formation. In addition, metalloproteinase production by kidney tubules could be related to vascular diseases in ADPKD patients. These are

  15. 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...... to cataract surgery. METHODS: We included 26 ophthalmic trainees (no cataract surgery experience), 11 experienced cataract surgeons (>4000 cataract procedures) and five vitreoretinal surgeons. All subjects completed 13 different modules twice. Simulator metrics were used for the assessments. RESULTS: Total...... module score on seven of 13 modules showed significant discriminative ability between the novices and experienced cataract surgeons. The intermodule reliability coefficient was 0.76 (p

  16. 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 a

  17. Vitrectomy as a Risk Factor for Complicated Cataract Surgery.

    Science.gov (United States)

    Fenberg, Moss J; Hainsworth, Kenneth J; Rieger, Frank G; Hainsworth, Dean P

    2016-01-01

    A retrospective review of 98 cases of complicated cataract surgery and/or delayed intraocular lens (IOL) dislocation examined the relationship between vitrectomy and cataract surgery complications. Nine (9.2%) of the 98 patients had a history of vitrectomy, before or after cataract surgery, and each had complicated cataract surgery. Six patients who underwent vitrectomy before cataract surgery experienced intraoperative complications. Three patients in whom vitrectomy was performed after uneventful cataract surgery subsequently had delayed IOL dislocation.

  18. 一个迟发性非综合征型常染色体显性遗传性聋家系表型特征及致病基因初步探讨%A Preliminary Study of Phenotypic Characteristics and Causative Genes in a Family with Late-onset Nonsyndromic Autosomal Dominant Hereditary Hearing Loss

    Institute of Scientific and Technical Information of China (English)

    王鸿涵; 刘亚兰; 卢焰梅; 贺楚峰; 冯永; 王行炜; 梅凌云; 陈红胜; 蒋璐; 门美超; 张华; 李海波

    2012-01-01

    Objective To analyze the clinical phenotype of a pedigree with late - onset hereditary hearing loss, and investigate the disease- causing genes of this family. Methods The detailed medical history information of the participants in a large Hunan Province family with hereditary hearing loss were collected. Physical and augdio logical examination were administered.Two individuals were carried out Computed tomography (CT) scan of the temporal bone, The participants' inrormation was sorted, out and the geoalogica tree map was charted. Alter revie wiog the literature, we speculated oo geoes that could lead to desfness sccordiog to pheootype of this family. Some candidate geoes codiog regioo were amplified by polymerase chain reaction (PCR) using geocmic DNA which was extracted from the proband's peripheral blood. PCR products were purified by exopeptidase. Ao ABI 3730XL geoetic soslyzer was used for direct sequeociog, and data was analyzed usiog DNASTAR-Lasergeoe SeqMan Pro software. Results The family tree showed that this was 30 autosomal domioant non-syodromic deafoess pedigree. Clioical fea tures were remarkably similar amoog subjects. All of them were operated oo for "buzz-like" tinnitus between 9 and 25 years old, and then for bilateral hearing loss. Pure tone audiometry examination showed the hearing loss be gan at the higher frequencies,then the lower frequencies with the aggravation of hearing loss. Conclusion Pedigree analysis suggested this family conformed to the characteristics of autosomal dominant hereditary pattern. The causa tive gene of this family needs more exploration.%目的 分析一个迟发性遗传性聋大家系的临床表型,探讨该家系耳聋患者的致病基因.方法 对一个湖南籍耳聋大家系成员进行详细的病史资料采集、体格检查、听力学检查,其中两名患者做了颞骨CT检查.绘制家系图.以先证者外周血基因组DNA为模板对候选致病基因进行涵盖全部编码序列聚

  19. Novel FAM126A mutations in hypomyelination and congenital cataract disease.

    Science.gov (United States)

    Traverso, M; Assereto, S; Gazzerro, E; Savasta, S; Abdalla, E M; Rossi, A; Baldassari, S; Fruscione, F; Ruffinazzi, G; Fassad, M R; El Beheiry, A; Minetti, C; Zara, F; Biancheri, R

    2013-09-27

    Hypomyelination and congenital cataract (HCC, OMIM #610532) is a rare autosomal recessive disorder due to FAM126A mutations characterized by congenital cataract, progressive neurologic impairment, and myelin deficiency in the central and peripheral nervous system. We have identified two novel mutations in three affected members of two unrelated families. Two sibs harbouring a microdeletion causing a premature stop in the protein showed the classical clinical and neuroradiologic HCC picture. The third patient carrying a missense mutation showed a relatively mild clinical picture without peripheral neuropathy. A residual amount of hyccin protein in primary fibroblasts was demonstrated by functional studies indicating that missense mutations are likely to have less detrimental effects if compared with splice-site mutations or deletions that cause the full-blown HCC phenotype, including peripheral nervous system involvement.

  20. 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.

  1. Association between metabolic syndrome and agerelated cataract

    Institute of Scientific and Technical Information of China (English)

    Sangshin; Park; Eun-Hee; Lee

    2015-01-01

    ·AIM: To determine the effect of metabolic syndrome on age-related cataract formation.·METHODS: We analyzed data for 2852 subjects [41.8%men and 58.2% women; mean(±SD) age, 52.9 ±13.9y],taken from the Korea National Health and Nutrition Examination Survey 2008. Metabolic syndrome was diagnosed by criteria proposed by the Joint Interim Societies. Cataract was diagnosed by using the Lens Opacities Classification System III. The association between metabolic syndrome and cataract was determined using age-adjusted and multivariable logistic regression analyses.· RESULTS: In multivariable analyses, men with metabolic syndrome had a 64% increased risk of nuclear cataract [odds ratio(OR), 1.64; 95% confidence interval(CI), 1.12-2.39]. Women with metabolic syndrome had a56% increased risk of cortical cataract(OR, 1.56; 95% CI,1.06-2.30). Men and women with metabolic syndrome had a 46%(OR, 1.46; 95% CI, 1.01-2.12) and 49%(OR,1.49; 95% CI, 1.07-2.08) increased risk of any cataract,respectively. The prevalence of nuclear and any cataract significantly increased with an increasing number of disturbed metabolic components in men, and prevalence of all types of cataracts increased in women. Men using hypoglycemic medication had an increased risk of nuclear(OR, 2.62; 95% CI, 1.41-4.86) and any(OR, 2.27;95% CI, 1.14-4.51) cataract, and women using antidyslipidemia medication had an increased risk of cortical(OR, 2.18; 95% CI, 1.12-4.24) and any(OR, 2.21;95% CI, 1.14-4.26) cataract.·CONCLUSION: Metabolic syndrome and its components,such as abdominal obesity, high blood pressure, andimpaired fasting glucose, are associated with age-related cataract formation in the Korean population.

  2. Lack of association of the WRN C1367T polymorphism with senile cataract in the Israeli population

    Science.gov (United States)

    Ehrenberg, M.; Dratviman-Storobinsky, O.; Avraham-Lubin, B.R.

    2010-01-01

    Purpose Werner syndrome is an autosomal recessive disease of premature aging caused by a polymorphic C1367T mutation in the Werner (WRN) gene. Although there are differences between the pathobiology of normal aging and the phenotype of Werner syndrome, the clinical age-related changes are similar. The aim of the study was to investigate the incidence of the C1367T (rs1346044) polymorphism in patients with age-related cataract. Methods The study group consisted of 81 patients with senile cataract undergoing cataract extraction surgery. Data on age, sex, and medical history of microvascular disease and cancer were obtained from the medical files. Anterior lens capsule material was collected during surgery. DNA was extracted, amplified by polymerase chain reaction, and screened for the C1367T polymorphism in WRN using restriction enzymes followed by sequencing. Results There were 33 male and 48 female patients of mean age 74.3±9 years. Genotypic frequencies were 67% for TT and 33% for TC. None of the patients had the CC genotype. Ten patients had a history of myocardial infarct, 8 cerebrovascular accident, and 8 various tumors. The distribution of these morbidities was similar in the two genotype groups. Conclusions The distribution of the C1367T WRN polymorphism in patients with senile cataract is similar to that in the normal population. Cataract formation in the elderly is not linked to a WRN mutation. PMID:20808731

  3. 伴听觉症状的家族性颞叶外侧癫痫的临床特点及LGI1基因突变检测%Clinical characteristics and LGII gene mutation analysis on an autosomal dominant lateral temporal lobe epilepsy

    Institute of Scientific and Technical Information of China (English)

    席志芹; 王学峰; 吕洋; 王亮; 肖飞; 关立峰

    2009-01-01

    Objective To report the clinical and genetic study of a new Chinese family with autosomal dominant lateral temporal lobe epilepsy (ADLTE).Methods The living affected members underwent a full clinical,neurophysiological,electroencephalogram (EEG),and magnetic resonance imaging (MRI) study.Genetic analysis was performed by LGI1 DNA sequence analysis.Results The clinical feature of the patients was coincidence well with the definition of ADLTE by International league Against Epilepsy in 2001.The living affected members had an adult or children onset of drug-responsive tonic-clonic seizures or complex partial seizures constantly preceded by auditory or visional aura.Routine EEG revealed no focal abnormalities over both temporal regions.MRI detected no structural abnormality.Analysis of LGI1 gene showed no mutation in all affected members.Conclusion This kindred has typical clinical manifestations of ADLTE.The pathogenesis has no association with mutation of the exons of LGIl gene.%目的 研究伴听觉症状的常染色体显性遗传颞叶外侧癫痫(ADLTE)一家系相关基因富亮氨酸胶质瘤失活基因1(LGll)的突变,探讨该综合征的临床特征及基因基础.方法 对该家系进行详细的病史询问和遗传学调查,采集患者和家属血液,按受累同胞对配对法对LGIl基因的8个外显子分别设计引物,用聚合酶链反应(PCR)结合DNA测序,检测该家系中有无LGIl基因外显子突变.结果 家系中所有患者符合国际抗癫痫联盟2001年新癫痫综合征标准中ADLTE典型表现,头颅MRI正常,PCR结合DNA序列分析LGIl基因8个外显子未发现突变.结论 该家系临床表现与ADLTE相同,但其发病不是由已知的LGIl基因外显子突变所致.

  4. 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

  5. Clinical features and gene mutations of Chinese patients with autosomal dominant Charcot-Marie-Tooth disease%常染色体显性遗传腓骨肌萎缩症的临床与基因突变特点

    Institute of Scientific and Technical Information of China (English)

    郭鹏; 宋福聪; 王相斌; 冯文霞; 胡志强; 唐北沙; 夏昆

    2011-01-01

    Objective To analyze the characteristics of the clinical features and the gene mutations between Chinese patients with autosomal dominant Charcot-Marie-Tooth disease. Methods The clinical manifestations, electrophysiological and pathological investigations of patients with autosomal dominant Charcot-Marie-Tooth were analyzed retrospectively. One hundred and six CMT patients underwent mutation analysis of PMP22 duplication and PMP22, MPZ, SIMPLE, EGR2, RAB7,NEFL,MFN2,Hsp27 and Hsp22. Results CMT1A was caused by PMP22 duplication,and CMT1B was caused by MPZ mutation. In those patients,the age of onset were earlier. The most frequently first symptom was weakness and atrophy in lower limbs with hypesthesia. Physical examination showed distal limb weakness and wasting,and taplipes cavus in all of them. Electromyogram and nerve conduction velocity showed slow nerve conduction. Pathological examination showed demye-lination. CMT2A2 was caused by MFN2 mutation,CMT2F wag caused by Hsp27 mutation,and CMT2L was caused by Hsp22 mutation. Compared with CMT1 ,patients of CMT2 were less frequent,the age of onset were later,motor disability was more sever than sensory disability. Electromyogram and nerve conduction velocity was normal. Pathological examination showed axonal denaturation. Conclusions In this study, the results of the mutation screening were consistent with the clinical features. Mutation screening has the character of high accuracy,little harm and can help to diagnosis earlier,so it suggestes to be performed widely in the clinic especially to the patients who has family history or to the lineal relatives.%目的:探讨常染色体显性遗传腓骨肌萎缩症(CMT)患者的临床与基因突变的特点。方法:对43个常染色体显性遗传CMT家系共106例患者的临床表现、电生理和病理特点进行回顾性分析,并进行PMP22的大片段重复突变和PMP22、MPZ、SIMPLE、EGR2、RAB7、NEFL、MFN2、Hsp27及Hsp22

  6. Monitoring Cataract Surgical Outcomes: 'Hand Written' Registration Method

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    Colin Cook

    2002-01-01

    Full Text Available The purpose of this hand written method of monitoring cataract surgery outcomes is to provide a practical method, assisting cataract surgeons and programme managers to monitor qualitatively the results of their cataract surgery. Such monitoring is the key to improving the quality and results of our cataract surgery.The hand registered method is quick, simple, and friendly to use!

  7. Quality of care from the perspective of the cataract patient : the reliability and validity of the QUOTE-Cataract

    NARCIS (Netherlands)

    Nijkamp, MD; Sixma, HJM; Afman, H; Hiddema, F; Koopmans, SA; van den Borne, B; Hendrikse, F; Nuijts, RMMA

    2002-01-01

    Background/aims: To assess reliability and validity of the QUOTE-cataract, a questionnaire that measures the quality of care from the perspective of cataract patients. Methods: The QUOTE-cataract was tested in a multicentre study among 540 cataract patients in three different hospitals. Reliability

  8. Quality of care from the perspective of the cataract patient: the reliability and validity of the QUOTE-Cataract.

    NARCIS (Netherlands)

    Nijkamp, M.D.; Sixma, H.J.M.; Afman, H.; Hiddema, F.; Koopmans, S.A.; Borne, B. van den

    2002-01-01

    Background/aims: To assess reliability and validity of the QUOTE-Cataract, a questionnaire that measures the quality of care from the perspective of cataract patients. Methods: The QUOTE-Cataract was tested in a multicentre study among 540 cataract patients in three different hospitals. Reliability

  9. Childhood Cataract: Magnitude, Management, Economics and Impact

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    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.

  10. [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.

  11. 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

  12. 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.

  13. Improving cataract services in the Indian context

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    Gudlavalleti VS Murthy

    2014-04-01

    Full Text Available In many countries, the number of cataract operations performed is inadequate to deal even with the people who have newly become blind from cataract, let alone those who are already blind or visually impaired. There is, therefore, a backlog of cases needing surgery. This could be due to low surgical capacity (people are on a waiting list or to a lack of demand for cataract surgery (people haven’t come forward for the services they need and there is therefore no waiting list.

  14. Working with patients to optimise cataract outcomes

    Directory of Open Access Journals (Sweden)

    Nick Astbury

    2016-10-01

    Full Text Available One of the delights of ophthalmology is to witness the joy on the face of a patient with cataract when the dressing is taken off and sight has been restored. Unfortunately, for some patients, the result does not live up to their expectations. Despite cataract surgery being one of the most successful surgical interventions available, there is evidence that the visual outcome of cataract surgery in sub-Saharan Africa is not always good (defined as a VA of 6/18 or better. The proportion of good outcomes range from only 23% up to 70%, failing to reach the WHO target of 85% or better.

  15. Progresión de la Poliquistosis renal autosómica dominante: Influencia de polimorfismos de genes de sintasa endotelial del óxido nítrico (ecNOS y del sistema renina-angiotensina Glomerular filtration rate decline in autosomic dominant polycystic kidney disease. Influence of endothelial NO synthase (ecNOS and renin angiotensin system gene polymorphisms

    Directory of Open Access Journals (Sweden)

    Pablo Azurmendi

    2004-04-01

    Full Text Available La velocidad de progresión (VdP de la poliquistosis renal autosómica dominante (PQRAD es variable. Estudiamos la asociación de los polimorfismos AGTM235T (angiotensinógeno, AT1A1166C (ATR1 y ecNOSGlu298Asp (NO sintasa endotelial con la VdP en 88 pacientes. VdP fue estimada por 1/Cr pl vs edad. Consideramos edades de Cr pl 2 y 6 mg/dl como comienzo de progresión (E2 y arribo a insuficiencia renal crónica terminal (E6, respectivamente. Los polimorfismos se estudiaron por PCR-RFLP. El grupo en su totalidad presentó VdP (ml/min/año de 6.9±0.5, E2 y E6 de 48.9±1.3 y 55.0±1.4 años y tensión arterial media (TAM de 111.2±1.2 mmHg. Según E6 observamos dos grupos (£ y > a 55 años. En £ 55 (fenotipo PKD1, n=42, E2 y E6 del genotipo CC de AT1A1166C fueron 36.0±1.2 y 41.4±0.9 años vs. AA-AC (42.8±1.0 y 47.5±0.8, p Glomerular filtration rate decline (GFRd is variable in autosomic dominant polycystic kidney disease (ADPKD. In 88 ADPKD patients, GFRd was assessed by 1/S Cr and compared with the association to AT1A1166C (AT1R, AGTM235T (angiotensinogen and ecNOSGlu298Asp (NO endothelial synthase polymorphisms. Age at S Cr values of 2 and 6 mg/dl were assumed as beginning of progressive phase (A2 and end-stage-renal disease (A6, respectively. Polymorphisms were studied by PCR-RFLP. The group as a whole showed GFRd (ml/min/year of 6.9±0.5; A2 and A6 of 48.9±1.3 and 55.0±1.4 years and mean arterial pressure of 111.2±1.2 mmHg. When A6 was considered, two populations were defined (£ and > 55 years. In £ 55 (assumed as PKD1 phenotype (n=42, A2 and A6 of the AT11166CC genotype were 36.0±1.2 and 41.4±0.9 years vs AA-AC (42.8±1.0 and 47.5±0.8, p<0.001. A2 and A6 of the ecNOS298Asp/Asp genotype were 34.8±1.5 and 41.1±0.6 years vs. Glu/Glu-Glu/Asp (42.4±0.9 and 47.1±0.8, p<0.02. In AGT235TT genotype, GFRd was 12.4±2.2 ml/min/year vs MM-MT (7.9±0.7, p<0.03. This difference was also observed when all ADPKD patients were considered (TT

  16. 一个常染色体显性遗传Emery-Dreifuss型肌营养不良家系的基因突变分析%Mutation analysis of a Chinese family with autosomal dominant Emery-Dreifuss muscular dystrophy

    Institute of Scientific and Technical Information of China (English)

    袁军辉; 胡静; 赵哲; 沈宏锐; 李娜; 邴琪

    2010-01-01

    Objective To investigate the clinical, pathological and genetic characteristics in a family with autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD). Methods Clinical data and skeletal muscle specimens were collected from two patients (the proband and her daughter) for pathological analysis. DNA samples of the proband and her family members (7 persons from 3 generations) were obtained for PCR amplification and direct DNA sequencing of the lamin A/C (LMNA) gene. Haplotype analysis was performed after the identification of mutation. Results The proband had typical clinical manifestation of EDMD: joint contracture, progressive muscle weakness and atrophy and cardiac conduction dysfunction. Muscular pathology revealed myopathic changes combined with slight neuropathic changes. A heterozygous missense mutation 1583 (C→G) (T528R) was identified in exon 9 of the LMNA gene in the two patients, but not in other family members. Haplotype analysis indicated that the proband and her daughter shared the same causative haplotype. Conclusion This is the first report of the phenotype and genotype of AD-EDMD in Chinese.%目的 探讨一个常染色体显性遗传Emery-Dreifuss型肌营养不良(Emery-Dreifuss muscular dystrophy,EDMD)家系的临床、病理及遗传学特点.方法 收集家系中2例患者(先证者及女儿)的临床资料及骨骼肌标本,行组织化学染色病理分析;收集先证者及家系成员(3代7人)血液DNA标本,采用聚合酶链反应和DNA直接测序方法 对LMNA基因进行突变检测;明确基因变异位点后对家系行单倍型分析.结果 先证者具有典型的EDMD临床表现:关节挛缩、进行性加重的肌无力和肌萎缩、心脏传导异常;骨骼肌活检病理示肌源性合并轻度神经源性改变;2例患者LMNA基因第9外显子发现杂合错义突变1583(C→G)(T528R),表型正常的其他家系成员未发现该突变;单倍型分析显示先证者及女儿具有相同的致病单倍型.结论

  17. Glaucoma after Congenital Cataract Surgery

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    Mahmoodreza Panahi Bazaz

    2014-05-01

    Full Text Available Purpose: To determine the incidence and risk factors associated with glaucoma following congenital cataract surgery (CCS in children under age of 15 Methods: This prospective cohort (since 2006 consisted of children less than 15 years of age who underwent cataract surgery with or without intraocular lens (IOL implantation. The role of the following factors on the development of glaucoma after CCS including age at surgery, gender, laterality of the cataract, IOL implantation, congenital ocular anomalies, intra- and postoperative complications, length of follow-up, central corneal thickness (CCT as well as the effect of the age of onset, time to development of glaucoma, and response to treatment were evaluated. Results: Overall, 161 eyes of 96 patients were included in this study of which 28 eyes developed glaucoma. Incidence of glaucoma was 17.4%. Mean±SD age at surgery was 9.3±6.9 (range, 1-24 months in glaucomatous and 40.4±41.1 (range, 1 m-13.6 year months in non-glaucomatous group (p<0.001. All glaucoma patients had the operation under two years of age. In group 1, 9 (60% and in group 2, 24 (30% patients were female (p=0.001. In group 1, 17 eyes (60.7% and in the group 2, 41 eyes (30.8% were aphakic (p=0.001. Mean time to diagnosis of glaucoma was 111.2 days (range 30-1200 days. Mean follow-up time was 3.1 years (range, 1-6 years. In 22 (78.6% eyes glaucoma was diagnosed within six months after surgery. Glaucoma was controlled with medications in 23 eyes (82% and with surgery in five eyes. Conclusion: In this study the incidence of glaucoma after CCS was 17.4% over a follow-up period of six years. Younger age at the time of lensectomy increases the risk of secondary glaucoma. IOL implantation may protect against glaucoma. Female gender was affected more than male.

  18. 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.

  19. Cataract

    Science.gov (United States)

    ... to the other. Common symptoms are Blurry vision Colors that seem faded Glare - headlights, lamps or sunlight ... the cloudy lens and replacing it with an artificial lens. Wearing sunglasses and a hat with a ...

  20. Cataract

    Science.gov (United States)

    ... activities such as driving, reading, or looking at computer or video screens, even with glasses. Some people ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  1. Cataracts

    Science.gov (United States)

    ... Uveitis Focus On Pediatric Ophthalmology Education Center Oculofacial Plastic Surgery Center Laser Surgery Education Center Redmond Ethics Center ... Uveitis Focus On Pediatric Ophthalmology Education Center Oculofacial Plastic Surgery Center Laser Surgery Education Center Redmond Ethics Center ...

  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. Intraocular lens employed for cataract surgery

    Science.gov (United States)

    Roszkowska, A. M.; Torrisi, L.

    2014-04-01

    The aim of this paper is to illustrate the techniques of cataract surgery with implantation of intraocular lenses and some physical properties of the used materials. The new technology, coupled with extensive experience and the studied cases, permits to increase the standardization and accuracy of the engravings, by reducing the use and handling of surgical instruments inside the eye. At present it is possible to replace the cataract with crystalline lenses based on biopolymers such as PMMA, silicone, acrylic hydrophilic and hydrophobic acrylic. These materials are increasingly able to replace the natural lens and to ensure the fully functional of the eye. The role of femtosecond lasers in cataract surgery, to assist or replace several aspects of the manual cataract surgery, are discussed.

  4. 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

  5. Autosomal recessive hereditary auditory neuropathy

    Institute of Scientific and Technical Information of China (English)

    王秋菊; 顾瑞; 曹菊阳

    2003-01-01

    Objectives: Auditory neuropathy (AN) is a sensorineural hearing disorder characterized by absent or abnormal auditory brainstem responses (ABRs) and normal cochlear outer hair cell function as measured by otoacoustic emissions (OAEs). Many risk factors are thought to be involved in its etiology and pathophysiology. Three Chinese pedigrees with familial AN are presented herein to demonstrate involvement of genetic factors in AN etiology. Methods: Probands of the above - mentioned pedigrees, who had been diagnosed with AN, were evaluated and followed up in the Department of Otolaryngology Head and Neck Surgery, China PLA General Hospital. Their family members were studied and the pedigree diagrams were established. History of illness, physical examination,pure tone audiometry, acoustic reflex, ABRs and transient evoked and distortion- product otoacoustic emissions (TEOAEs and DPOAEs) were obtained from members of these families. DPOAE changes under the influence of contralateral sound stimuli were observed by presenting a set of continuous white noise to the non - recording ear to exam the function of auditory efferent system. Some subjects received vestibular caloric test, computed tomography (CT)scan of the temporal bone and electrocardiography (ECG) to exclude other possible neuropathy disorders. Results: In most affected subjects, hearing loss of various degrees and speech discrimination difficulties started at 10 to16 years of age. Their audiological evaluation showed absence of acoustic reflex and ABRs. As expected in AN, these subjects exhibited near normal cochlear outer hair cell function as shown in TEOAE & DPOAE recordings. Pure- tone audiometry revealed hearing loss ranging from mild to severe in these patients. Autosomal recessive inheritance patterns were observed in the three families. In Pedigree Ⅰ and Ⅱ, two affected brothers were found respectively, while in pedigree Ⅲ, 2 sisters were affected. All the patients were otherwise normal without

  6. Cataract blindness in the developing world: is there a solution?

    Science.gov (United States)

    Isaacs, Robert; Ram, Jagat; Apple, David

    2004-01-01

    Cataracts are the leading cause of blindness worldwide, accounting for half of the world's 40 million blind. The majority of the world's 20 million cataract blind live in the developing world. About 5 million new cases of cataract blindness occur each year. Only a small percentage of persons in the Third World who develop cataracts receive cataract surgery. Cataract blindness causes severe economic and social problems in these countries. Because of increased longevity and population growth in the Third World, the number of untreated cataract cases is escalating rapidly. Governmental, non-governmental and service club organizations have put extraordinary effort and resources into reversing the trend of increasing cataract blindness, but much work still needs to be done. Current surgical methods used in the Third World have not yet succeeded in reducing the backlog of cataracts, due in part to either their prohibitive cost or poor results. Extra capsular cataract extraction (ECCE) with placement of a posterior chamber intraocular lens (PC-IOL) is the hope for preferred method of treatment. This paper discusses a largely overlooked method of cataract surgery which may be an additional, cost-effective and efficacious means of providing good sight rehabilitation. Combining intracapsular cataract extraction, currently the most common method used in the rural developing world, with anterior chamber intraocular lens implantation (ICCE AC-IOL), may prove effective in reducing the cataract backlog in developing countries.

  7. Hereditary and histologic characteristics of the CF1/b cac mouse cataract model.

    Science.gov (United States)

    Kondo, Tomohiro; Nagai, Hiroaki; Kawashima, Takamune; Taniguchi, Yusuke; Koyabu, Nozomu; Takeshita, Ai; Kusakabe, Ken-Takeshi; Okada, Toshiya

    2014-10-01

    A substrain of mice originating from the CF1 strain (an outbred colony) reared at Osaka Prefecture University (CF1/b cac mice) develops cataracts beginning at 14 d old. Affected mice were fully viable and fertile and had developed cataracts by 22 d of age. The incidence of cataracts did not differ between male and female mice. Histologically, 14-wk-old CF1/b cac mice showed vacuolated lens epithelial cells, swollen lens fibers, many pyknotic nuclei, and vacuolation of the lens cortex. To elucidate the mode of inheritance, we analyzed heterozygous mutants hybrids generated from CF1/b cac and wildtype BALB/c mice and the offspring of the backcrossed heterozygous mutants. None of the heterozygous mutants was affected, but the ratio of affected to unaffected mice was 1:3 among the offspring of the heterozygous mutants. The initial genomewide screen of 20 affected backcrossed offspring (CF1/b cac × [CF1/b cac × BALB/c]) indicated that the mutant gene resides on chromosome 16. For further mapping, we used affected progeny of CF1/b cac × (CF1/b cac × MSM/Ms) mice. We concluded that the cataracts in CF1/b cac mice are inherited through an autosomal recessive mutation and that the mutant gene is located on mouse chromosome 16 between D16Mit5 and D16Mit92 and between D16Mit92 and D16Mit201. The mapping of the mutant gene of the CF1/b cac mice to mouse chromosome 16 provides the positional information necessary to identify the candidate gene responsible for the CF1/b cac phenotype.

  8. Cataract blindness, surgical coverage, outcome, and barriers to uptake of cataract services in Plateau State, Nigeria

    Directory of Open Access Journals (Sweden)

    Ojo P Odugbo

    2012-01-01

    Full Text Available Purpose: The purpose was to estimate the prevalence of blindness due to cataract, assess visual outcomes of cataract surgery, and determine the cataract surgical coverage rate and barriers to uptake of services among individuals aged 50 years or older in Plateau State, Nigeria. Materials and Methods: A population-based, cross-sectional survey of 4200 adults 50 years or older was performed. Multistage stratified random sampling, with probability proportional to size was used to select a representative sample. The Rapid Assessment of Cataract Surgical Services protocol was used. Statistical significance was indicated by (P 0.05. The prevalence of monocular blindness due to cataract was 5.9% (95% CI: 5.2-6.6%. The cataract surgical coverage for subjects with visual acuity (VA less 3/60 was 53.8% in the entire cohort; 60.5% for males and 48% for females (χ2 = 2.49, P > 0.05. The couching coverage for subjects who were blind was 12%. A total of 180 eyes underwent surgical intervention (surgery or couching for cataract, of which, 48 (26.7% eyes underwent couching. The prevalence of bilateral (pseudo aphakia was 1.5%, (95% CI: 1.2-1.9% and 2.7% (95% CI: 2.2-3.2% for unilateral (pseudo aphakia. Visual outcomes of the 180 eyes that underwent surgical intervention were good (VA ≥ 6/18 in 46 (25.6% eyes and poor (VA < 6/60 in 105 (58.3% eyes. Uncorrected aphakia was the most common cause of poor outcome (65.1%. Most subjects who underwent cataract surgery were not using spectacles 74 (71.2%. Cost and lack of awareness were the main barriers to uptake of cataract surgery services. Conclusion: Couching remains a significant challenge in Nigeria. The outcomes of cataract surgery are poor with the lack of aphakic correction being the main cause of the poor outcomes.

  9. 常染色体显性遗传性脑动脉病伴皮层下梗死和白质脑病的颅脑MRI表现%The cranial MRI appearance of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy in a family

    Institute of Scientific and Technical Information of China (English)

    张金平; 孙冰莲; 余永强; 潘华; 汤永祥; 钱振; 高萍; 刘丰; 李惠芬

    2008-01-01

    目的 提高对常染色体显性遗传性脑动脉病伴皮层下梗死和白质脑病(CADASIL)的颅脑MRI表现的认识.方法 对一家系2代5例患者进行头颅常规MR和MR血管成像(MRA)检查.对经Notch3基因检查或皮肤组织活检超微病理检查确诊的3例和经MRI与临床诊断的1例CADASIL的MRI资料进行分析.结果 MR检查的5例中4例CADASIL均获得明确诊断,1例排除诊断.4例CADASIL均见两侧颞叶、额叶和顶叶大致对称性皮层下与侧脑室旁白质病灶,呈长T1、长T2信号,但枕叶累及甚少且皮层不受累;O'Sullivan征阳性4例,皮层下腔隙性损害(SLLs)征阳性2例;3例半卵圆中心可见多发圆形或卵圆形囊性梗死即"黑洞",4例均见多发圆点状血管周间隙即"胡椒罐盖"样征象;4例全部显示胼胝体单发或多发斑片状显著长T1、长T2信号,其中2例伴萎缩;内囊前肢与外囊均受累,呈"人"字征;基底节和脑干可见单发或多发陈旧性腔隙性梗死灶;1例伴右侧小脑小片状梗死灶;4例全部有轻度至中度的脑干、小脑和大脑萎缩;MRA颅内Ⅰ-Ⅲ级较大动脉均未见明显异常.结论 CADASIL的颅脑MRI表现具有一定的特征性,可为CADASIL的初诊和筛选提供重要依据.%Objective To recognize the cranial MRI appearance in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy(CADASIL). Methods Five patients with CADASIL from two generations in a family underwent routine MRI and MRA examinations.Three patients with CADASIL were confirmed by the Notch3 genetic testing and the vascular pathological Results and one was diagnosed on basis of MR and clinical manifestations. The imaging data from 4 patients with CADASIL were analyzed.Results Four cases achieved preliminary diagnosis of CADASIL and one was excluded by MRI.In 4 patients with CADASIL,bilateral symmetrical,confluent white matter lesions in the subcortical and Deriventricular regions were seen frequently

  10. A retrospective study on management of gross hematuria in autosomal dominant polycystic kidney disease patients%常染色体显性多囊肾病患者并发肉眼血尿治疗方法的回顾研究

    Institute of Scientific and Technical Information of China (English)

    马熠熠; 陈冬平; 梅长林; 郁胜强; 戎殳; 张彤; 李林

    2012-01-01

    目的 寻找治疗常染色体显性多囊肾病(ADPKD)并发肉眼血尿的理想疗法.方法 1993年以来曾在我科住院治疗以及目前在我科多囊肾病专科门诊定期就诊随访的ADPKD患者为对象.收集ADPKD患者出现肉眼血尿时的平均年龄、性别构成、肾功能水平、诱发因素、治疗方案、症状持续时间、血小板计数、凝血参数、肾脏囊肿大小等资料,分别以不同的肉眼血尿诱发因素及治疗方案进行分组,比较其各指标间的差异.结果 共筛选出ADPKD患者905例.279例(男150例,女129例)曾有肉眼血尿病史,其中146例能提供完整的病史和治疗经过,而只有101例能提供相关的实验室检查结果.在这101例中,肉眼血尿可出现在慢性肾脏病(CKD)任何一期;GFR为(56.4±44.1)ml·min-1·(1.73 m2)-1;症状持续时间(8.8±8.0)d;男、女患者症状持续时间差异无统计学意义[(8.2±7.3)d比(9.5±8.8)d,P=0.426);凝血参数均在正常参考范围内,其中91例患者血小板计数正常.不同诱发因素导致的肉眼血尿持续时间差异有统计学意义(P<0.05).卧床休息组症状持续时间显著短于其他组患者(P<0.05).各组间血小板计数、凝血酶时间和国际标准化比值等差异无统计学意义.结论 对出现肉眼血尿的ADPKD患者应首先明确其诱因.卧床休息应作为核心治疗措施.在考虑使用止血药物时建议使用抗纤维蛋白溶解类药物,不需要预防性使用抗生索.%Objective To seauch the ideal management for gross hematuria in autosomal dominant polycystic kidney disease (ADPKD).Methods ADPKD patients who were ever hospitalized and followed up in our department since 1993 were enrolled in the study.Demographic and clinical data were colloected,such as gender,age of gross hematuria,level of renal function,causative factors,management strategies,duration of gross hematuria,blood platelet count,activated partial thromboplastin time,prothrombin time

  11. 先天性白内障一家系晶状体蛋白突变基因筛查%Screen of crystallin protein mutation genes in a hereditary congenital cataract family

    Institute of Scientific and Technical Information of China (English)

    李娟娟; 黎铧; 胡竹林

    2010-01-01

    With the development of biological techniques,the study on the pathogenesis of disease-causing genes of congenital cataracts has substantial progress.Some positive results of screen of mutation gene in congenital cataract family has been reported,but the report of negative result is rate.ObjectiveThe present study attempts to screen the mutation of CRYAA,CRYAB,CRYA1/A3,CRYBB2,CRYGC and CRYGD gene in a Chinese family with autosomal dominant congenital cataract. MethodsThe periphery blood samples were exacted from 8 patients of 4 generations of with congenital cataract in this family.The complete coding region and intron spliced sites of CRYAA,CRYAB,CRYA1/A3,CRYBB2,CRYGC and CRYGD were amplified with polymerase chain reaction (PCR),and the products of PCR were directly sequenced.The control blood samples were from 10 normal subjects.This study followed the Declaration of Helsinki.Written informed consent was obtained from all of the patients.ResultsThe patients were found in each generation in this family and the mode of inheritance was in accordance with the characteristic of autosomal dominant inheritance.The sequence of amplified genetic fragments of CRYAA,CRYAB,CRYA1/A3,CRYBB2,CRYGC and CRYGD genes were inaccordance with those of normal subjects and GeneBank.No any mutation loci was found in all of the patients of this family.ConclusionCRYAA,CRYAB,CRYA1/A3,CRYBB2,CRYGC and CRYGD genes is not the causing-disease genes in this family.%目的 对先天性白内障一家系进行晶状体蛋白致病基因的初步筛查.方法 通过聚合酶链反应(PCR)对先天性白内障一家系中4代8例患者进行CRYAA、CRYAB、CRYA1/A3、CRYBB2、CRYGC和CRYGD 6个候选基因的外显子及内含子扩增,扩增产物进行直接测序,测序结果与GeneBank中原始序列进行BLAST比对分析.结果 该家系每代均有先天性白内障患者,遗传方式为常染色体显性遗传.该家系的CRYAA、CRYAB、CRYA1/A3、CRYBB2、CRYGC和CRYGD 6个晶状体蛋白

  12. PVEP in Patients with Different Types of Congenital Cataract

    Institute of Scientific and Technical Information of China (English)

    1994-01-01

    The preoperative and postoperative PVEP in 79 eyes of 45 patients with three types of congenital namely lamellar cataract, nuclear cataract and total cataract was studied. The results showed that visual acuity of patients who could be cooperatively examined was improved significantly after operation. The examination of PVEP revealed that more abnormal wave-formes were found in total cataract group before operation. P1 latencies of low and medium spatial frequencies (140', 70', and 35') became much longe...

  13. Parinaud's oculoglandular syndrome and possibly causing cortical cataract

    Directory of Open Access Journals (Sweden)

    Mariana Heid Rocha Hemerly

    2014-06-01

    Full Text Available According to the World Health Organization, cataract is the leading cause of blindness and visual impairment throughout the world. However, the etiology of cataracts often remains unknown. This report describes the development of cortical cataract in a patient after Parinaud's oculoglandular syndrome caused by the fungus Sporothrix schenckii.

  14. 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.

  15. Parinaud's oculoglandular syndrome and possibly causing cortical cataract

    OpenAIRE

    Mariana Heid Rocha Hemerly; Marcelo Berno Mattos; Fábio Petersen Saraiva; Fellipe Berno Mattos

    2014-01-01

    According to the World Health Organization, cataract is the leading cause of blindness and visual impairment throughout the world. However, the etiology of cataracts often remains unknown. This report describes the development of cortical cataract in a patient after Parinaud's oculoglandular syndrome caused by the fungus Sporothrix schenckii.

  16. 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.

  17. [Cataract surgery - essentials for the general practitioner].

    Science.gov (United States)

    Amstutz, Ch; Thiel, M A; Kaufmann, Claude

    2010-08-11

    Age-related cataracts are mainly caused by life-long accumulation of oxidative stress on the lens fibres. Symptoms include reduced visual acuity, requiring more light for reading, and glare. The only treatment that provides a cure for cataracts is surgery. Phacoemulsification represents the preferred method of lens removal. It involves fragmentation of the lens using ultrasound and insertion of an artificial intraocular lens. The preoperative assessment the general practitioner provides to surgeon and anesthesia team has an important share in the low complication rate of the procedure in the event of co-existing systemic disease. Growing patient expectation for spectacle independence following cataract surgery is met to some extent using techniques for astigmatism control and presbyo-pia-correcting intraocular lenses.

  18. Methylphenidate (Ritalin)-associated cataract and glaucoma.

    Science.gov (United States)

    Lu, Chao-Kung; Kuang, Tung-Mei; Chou, Joe Ching-Kuang

    2006-12-01

    Methylphenidate hydrochloride (Ritalin) is the drug of choice for attention deficit hyperactivity disorder (ADHD). However, an association of Ritalin with glaucoma has been reported. We report a case of Ritalin-associated cataract and glaucoma. A 10-year-old boy was diagnosed with ADHD and had received methylphenidate hydrochloride, 60 mg/day for 2 years. He presented with blurred vision. Best-corrected visual acuity was 6/60 in both eyes. Ocular examinations revealed intraocular pressure (IOP) of 30 mmHg under medication, dense posterior subcapsular opacity of lens, pale disc with advanced cupping, and marked constriction of visual field. Despite maximal anti-glaucomatous medication, IOP still could not be controlled. The patient then received combined cataract and glaucoma surgery. Visual acuity improved and IOP was within normal limits in both eyes postoperatively. Large dose of methylphenidate may cause cataract and glaucoma. The mechanism remains unclear. Doctors should be aware of the possible ocular side effects of methylphenidate.

  19. Reversible monocular cataract simulating amaurosis fugax.

    Science.gov (United States)

    Paylor, R R; Selhorst, J B; Weinberg, R S

    1985-07-01

    In a patient having brittle, juvenile-onset diabetes, transient monocular visual loss occurred repeatedly whenever there were wide fluctuations in serum glucose. Amaurosis fugax was suspected. The visual loss differed, however, in that it persisted over a period of hours to several days. Direct observation eventually revealed that the relatively sudden change in vision of one eye was associated with opacification of the lens and was not accompanied by an afferent pupillary defect. Presumably, a hyperosmotic gradient had developed with the accumulation of glucose and sorbitol within the lens. Water was drawn inward, altering the composition of the lens fibers and thereby lowering the refractive index, forming a reversible cataract. Hypoglycemia is also hypothesized to have played a role in the formation of a higher osmotic gradient. The unilaterality of the cataract is attributed to variation in the permeability of asymmetric posterior subcapsular cataracts.

  20. Mini-rhexis for white intumescent cataracts

    Directory of Open Access Journals (Sweden)

    Newton Kara-Junior

    2009-04-01

    Full Text Available PURPOSE: To compare the intraoperative safety of two techniques of capsulorhexis for intumescent white cataracts: traditional one-stage continuous curvilinear capsulorhexis and two-stage continuous curvilinear capsulorhexis. METHODS: This prospective comparative randomized study included two groups: the 1-CCC group (11 patients received traditional one-stage continuous curvilinear capsulorhexis with 5-6 mm diameter, and the 2-CCC (13 patients group received a deliberately small continuous curvilinear capsulorhexis that was secondarily enlarged, or a two-stage continuous curvilinear capsulorhexis. Patients were stratified according to cataract subset, which was characterized echographically. Six patients were considered as type 1, fifteen as type 2 and three as type 3. Type 1 included intumescent white cataracts with cortex liquefaction and extensive internal acoustic reflections, type 2 included white cataracts with voluminous nuclei, a small amount of whitish solid cortex, and minimal internal acoustic reflections, and type 3 included white cataracts with fibrous anterior capsules and few internal echo spikes. RESULTS: With the one-stage technique, 46.15% of patients had leakage of the liquefied cortex; in addition, the surgeon perceived high intracapsular pressure in 61.53% of cases. Anterior capsule tears occurred in 23.07% of cases, discontinuity of capsulorhexis in 30.79% of cases and no posterior capsular rupture occurred. With the two-stage technique, leakage of the liquefied cortex occurred in 45.45% of cases; additionally, the surgeon perceived high intracapsular pressure in 36.36% of cases. No anterior capsule tears, discontinuity of capsulorhexis or posterior capsular rupture occurred. Considering each cataract subset, there was a higher incidence of leakage for type 2 as compared to types 1 and 3. CONCLUSIONS: Two-stage continuous curvilinear capsulorhexis helps prevent unexpected radial tears of the initial capsulotomy from high

  1. Sensory exotropia subsequent to senile cataract

    Institute of Scientific and Technical Information of China (English)

    LOU Ding-hua; XU Ye-sheng; LI Yu-min

    2005-01-01

    To evaluate the phacoemulsification and intraocular lens implantation in patients with sensory exotropia subsequent to senile cataract. The authors prospectively studied the role of phacoemulsification and intraocular lens implantation on 25 patients by observing visual acuity, ocular alignment, binocular vision and diplopia pre-, 1 month post- and 3 months post-operation. The patients underwent follow-up for three months. Postoperatively, one patient had a corrected visual acuity of 20/50, and 24 patients had 20/40 or better. The ocular alignment, binocular vision and diplopia were resolved spontaneously. Phacoemulsification and intraocular lens implantation performed together is effective on sensory exotropia subsequent to senile cataract.

  2. Outsourced cataract surgery and postoperative endophthalmitis

    DEFF Research Database (Denmark)

    Solborg Bjerrum, Søren; Kiilgaard, Jens F; Mikkelsen, Kim Lyngby;

    2013-01-01

    To compare the risk of postoperative endophthalmitis (PE) after cataract surgery at eye departments in public hospitals and private hospitals/eye clinics and to evaluate if the Danish National Patient Registry (NPR) is a reliable database to monitor the PE risk.......To compare the risk of postoperative endophthalmitis (PE) after cataract surgery at eye departments in public hospitals and private hospitals/eye clinics and to evaluate if the Danish National Patient Registry (NPR) is a reliable database to monitor the PE risk....

  3. [Appropriate cataract surgery training can promote work of blindness prevention].

    Science.gov (United States)

    Zhang, Mingzhi

    2014-03-01

    Cataract is the first blinding eye disease in the world and China. However, due to various reasons, cataract surgery rate (CSR) in China is much lower than in developed countries and even some developing countries. Properly and standardized training of cataract surgery for ophthalmologists from primary hospital and young eye doctors is one of the key point to improve CSR. For above, we had explored actively to establish an appropriate and suitable training model of cataract surgery. Ophthalmologist in primary hospital can provide high quality medical services to cataract patients in accordance with their own conditions after training and promote the sustainable development of blindness prevention work.

  4. Metabolism and serum levels of tryptophan in senile cataract patients.

    Science.gov (United States)

    Costa, C; Angi, M R; De Carli, M; Vanzan, S; Allegri, G

    1982-03-30

    In order to clarify the role of tryptophan in the patogenesis of senile cataract, we have studied the serum total and free levels of tryptophan in cataract patients as compared with age and sex-matched controls, and the urinary excretion of 10 metabolites after oral load of the amino acid. This excretion increases in the cataract group both as total per cent and as kynurenine. No difference has been found in the free and total serum tryptophan between normal subjects and cataract patients. A possible role of the kynurenines in the pathogenesis of senile cataract is suggested.

  5. 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…

  6. 先天性白内障一家系的致病基因研究%Gene mutation analysis of a Chinese family with congenital cataract

    Institute of Scientific and Technical Information of China (English)

    郑青青; 李文伟; 沈婷; 洪朝阳

    2015-01-01

    Objective To identify the pathogenic gene of congenital cataract in a Chinese family. Methods In a three- generation Chinese family 4 members were affected by congenital cataract in both eyes. Ten individuals from this family underwent ophthalmologic and physical examination in Zhejiang Provincial People's Hospital. The DNA was extracted from pe-riphery blood samples and amplified by PCR. The PCR products were sequenced and analyzed to detect mutations of 18 autoso-mal dominant congenital contact- related genes (CRYAA, CRYAB, CRYBA1, CRYBA2, CRYBA4, CRYBB1, CRYBB2, CRYGC, CRYGD, CRYGS, GJA3, GJA8, MIP, BFSP, HSF4, PITX3, EPHA2 and PAX6). Results The congenital cataract in this family is pulverulent type. A C→T mutation at 6 base in the first exon of CRYAA gene was detected, which was coding the same amino acid (asparaginic acid). Al the patients in this family had this mutation, while the mutation was not detected in normal family mem-bers. Conclusion The study identifies a mutation in CRYAA, which may contribute to the pathogenesis of congenital cataract in this family.%目的:对一个来自浙江省杭州地区的三代先天性白内障家系进行常染色体显性遗传基因的突变分析,以寻找其可能的致病基因及突变位点。方法该家系共10例成员,其中包括4例患者。10例家系成员在浙江省人民医院眼科中心接受眼科专科检查及全身检查,以排除存在白内障以外的眼部及全身疾患。10例家系成员各抽取外周血5ml,提取基因组DNA。针对国内外文献报道的与常染色体显性遗传先天性白内障相关的18个基因(CRYAA、CRYAB、CRYBA1、CRYBA2、CRYBA4、CRYBB1、CRYBB2、CRYGC、CRYGD、CRYGS、GJA3、GJA8、MIP、BFSP、HSF4、PITX3、EPHA2、PAX6)设计引物,进行PCR扩增,对扩增产物进行测序和序列分析,了解这10例家系成员的以上基因是否存在相应的序列。结果临床眼科检查显示该家系先天性白内障类型

  7. Vision. Realignment of cones after cataract removal.

    Science.gov (United States)

    Smallman, H S; MacLeod, D I; Doyle, P

    2001-08-01

    Through unique observations of an adult case of bilateral congenital cataract removal, we have found evidence that retinal photoreceptors will swiftly realign towards the brightest regions in the pupils of the eye. Cones may be phototropic, actively orientating themselves towards light like sunflowers in a field.

  8. Cataract surgery following KAMRA presbyopic implant

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    Tan TE

    2013-09-01

    Full Text Available Tien-En Tan,1,2 Jodhbir S Mehta2–4 1Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 2Singapore National Eye Centre, Singapore; 3Singapore Eye Research Institute, Singapore; 4Department of Clinical Sciences, Duke-NUS Graduate Medical School, Singapore Abstract: Intrastromal corneal inlays are an emerging treatment for presbyopic patients. The KAMRA™ small aperture inlay was the first such inlay to receive Conformité Européenne (CE marking in 2005. It has been shown to improve uncorrected near and intermediate visual acuity without adversely affecting uncorrected distance visual acuity. Due to the age of presbyopic patients, they may eventually develop cataracts. In two such cases, we found that cataract surgery with the KAMRA implant left in place was not technically more difficult, and that the surgical procedure could be improved by additional ocular rotations to improve visualization. Biometry readings were reliable, and it appeared that the SRK/T formula was accurate for calculation of intraocular lens power. Cataract surgery with the KAMRA implant left in situ is a viable option for patients. Keywords: cataract surgery, KAMRA, corneal inlay, AcuTarget, presbyopia

  9. Current developments in equine cataract surgery.

    Science.gov (United States)

    McMullen, R J; Utter, M E

    2010-03-01

    The purpose of this review is to discuss the evolution of equine cataract surgery over the past 50 years to its current stage. Equine cataract surgery is performed similarly compared with the techniques used in human ophthalmology and in other veterinary species. However, enough differences exist to make surgical lens removal and intraocular lens implantation in the horse an intrinsically unique endeavour. Due to the size of the adult equine globe, the introduction of species-specific instrumentation has provided the cornerstone to many of the changes made regarding surgical technique over the last 15-20 years. The continuing development of an equine specific, foldable intraocular lens implant (IOL) has provided much needed data supporting the use of such lenses in the horse to improve upon the post operative visual outcome. Finally, the methods utilised to assess visual capacity and the effects of intraocular lens implantation on the globe (e.g. ocular ultrasonography, electroretinography and streak retinoscopy) are gradually becoming more important in preoperative patient assessment and IOL development in the horse. It is the hope of the authors that a broader group of equine veterinarians will become aware of the many changes that have taken place in equine cataract surgery over the last half-century. Although aspiration was implemented nearly 40 years ago in foals for the treatment of congenital cataracts, phacofragmentation (phacoemulsification) techniques have only recently become routine in mature horses undergoing lens extraction.

  10. Absence of mutations in four genes encoding for congenital cataract and expressed in the human brain in Tunisian families with cataract and mental retardation

    Directory of Open Access Journals (Sweden)

    Chograni Manèl

    2011-11-01

    Full Text Available Abstract Background To identify the genetic defect associated with autosomal recessive congenital cataract (ARCC, mental retardation (MR and ARCC, MR and microcephaly present in most patients in four Tunisian consanguineous families. Methods We screened four genes implicated in congenital cataract by direct sequencing in two groups of patients; those affected by ARCC associated to MR and those who presented also microcephaly. Among its three genes PAX6, PITX3 and HSF4 are expressed in human brain and one gene LIM2 encodes for the protein MP20 that interact with the protein galectin-3 expressed in human brain and plays a crucial role in its development. All genes were screened by direct sequencing in two groups of patients; those affected by ARCC associated to MR and those who presented also microcephaly. Results We report no mutation in the four genes of congenital cataract and its flanking regions. Only variations that did not segregate with the studied phenotypes (ARCC associated to MR, ARCC associated with MR and microcephaly are reported. We detected three intronic variations in PAX6 gene: IVS4 -274insG (intron 4, IVS12 -174G>A (intron12 in the four studied families and IVS4 -195G>A (intron 4 in two families. Two substitutions polymorphisms in PITX3 gene: c.439 C>T (exon 3 and c.930 C>A (exon4 in one family. One intronic variation in HSF4 gene: IVS7 +93C>T (intron 7 identified in one family. And three intronic substitutions in LIM2 gene identified in all four studied families: IVS2 -24A>G (intron 2, IVS4 +32C>T (intron 4 and c.*15A>C (3'-downstream sequence. Conclusion Although the role of the four studied genes: PAX6, PITX3, HSF4 and LIM2 in both ocular and central nervous system development, we report the absence of mutations in all studied genes in four families with phenotypes associating cataract, MR and microcephaly.

  11. Simultaneous Penetrating Keratoplasty and Cataract Surgery

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    Mohammad-Ali Javadi

    2013-01-01

    Full Text Available Purpose: To determine the clinical outcomes of simultaneous penetrating keratoplasty (PK, cataract removal and intraocular lens implantation (triple procedure, and to compare the safety and efficacy of two different cataract extraction techniques during the course of PK. Methods: This retrospective comparative study was conducted on patients who had undergone a triple procedure. The technique of cataract extraction was either opensky extracapsular cataract extraction (ECCE or phacoemulsification (PE. In the ECCE group, the posterior chamber intraocular lens (PCIOL was implanted in the ciliary sulcus, while in the PE group PCIOLs were fixated within the capsular bag. Outcome measures included best spectacle corrected visual acuity (BSCVA, refractive results, graft clarity and complications. Results: Seventy-six eyes of 69 consecutive patients with mean age of 61.4±14.2 years were enrolled. Mean follow-up period was 61.4±37.2 months over which mean BSCVA was significantly improved from 1.40±0.68 to 0.44±0.33 LogMAR (P<0.001. Mean postoperative spherical equivalent refractive error was -2.13±3.02 D, which significantly differed from the target refraction (-0.73±0.29 D, P=0.004. At final follow-up, 89.5% of the corneal grafts remained clear. Conclusion: The triple procedure is a safe and effective approach to restore vision in patients with coexisting corneal pathologies and cataracts. However, unacceptable postoperative refractive error can be anticipated.

  12. Fine genetic mapping of a gene for autosomal recessive retinitis pigmentosa on chromosome 6p21

    Energy Technology Data Exchange (ETDEWEB)

    Shugart, Yin Y.; Banerjee, P.; Knowles, J.A. [Columbia Univ., New York, NY (United States)] [and others

    1995-08-01

    The inherited retinal degenerations known as retinitis pigmentosa (RP) can be caused by mutations at many different loci and can be inherited as an autosomal recessive, autosomal dominant, or X-linked recessive trait. Two forms of autosomal recessive (arRP) have been reported to cosegregate with mutations in the rhodopsin gene and the beta-subunit of rod phosphodiesterase on chromosome 4p. Genetic linkage has been reported on chromosomes 6p and 1q. In a large Dominican family, we reported an arRp gene near the region of the peripherin/RDS gene. Four recombinations were detected between the disease locus and an intragenic marker derived from peripherin/RDS. 26 refs., 2 figs., 1 tab.

  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. Manual cataract extraction via a subconjunctival limbus oblique incision for mature cataracts

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    J Yang

    2014-01-01

    Full Text Available Aims: To report the technique and outcomes of sutureless manual cataract extraction via a subconjunctival limbus oblique incision for mature cataracts. Materials and Methods: This retrospective study comprised of 112 eyes of 83 patients with mature cataract who all had manual cataract extraction via a subconjunctival limbus oblique incision. A transconjunctival tunnel is fashioned with a 3.0 mm keratome, 0.5 mm behind the limbal vascular arcades. A limbal tunnel, with a transverse extent of 9 mm in the cornea and 7.0 mm in the limbus, is created beneath the conjunctival/Tenon′s tissue using an angled bevel-up crescent blade. Outcome measures included visual acuity, intraoperative complications, surgically induced astigmatism, endothelial cell loss rate and surgery time. Results: Self-sealing wound was achieved in 112 eyes (98.2%. The nucleus was delivered in whole in 108 eyes (96.4%. Intraoperative complications included hyphema in 3 eyes (2.7%, iridodialysis in 2 eyes 1.8%, posterior capsular rupture and zonular dialysis in 2 eyes (1.8%. At the 3-month follow-up, 91% patients achieved a best-corrected visual acuity of 20/20 or better, the mean of surgically induced astigmatism was -0.62 ± 0.41 Diopters and endothelial cell loss was 4.2%. Average surgical time was 3.75 min per case. Conclusion: This subconjunctival limbus oblique incision has the potential to serve as safe and effective technique for mature cataracts.

  15. Editorial: Improving cataract outcomes through good postoperative care

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    Nick Astbury

    2016-10-01

    Full Text Available Cataract surgery is one of the most successful and frequently performed operations worldwide, and yet cataract remains the commonest cause of global blindness. This is in part due to the shortage and uneven distribution of trained personnel in some countries. More worryingly, a high rate of cataract blindness also reflects poor visual outcomes after surgery, as has been documented in many RAAB (rapid assessment of avoidable blindness studies.

  16. Explicit criteria for prioritization of cataract surgery

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    Escobar Antonio

    2006-03-01

    Full Text Available Abstract Background Consensus techniques have been used previously to create explicit criteria to prioritize cataract extraction; however, the appropriateness of the intervention was not included explicitly in previous studies. We developed a prioritization tool for cataract extraction according to the RAND method. Methods Criteria were developed using a modified Delphi panel judgment process. A panel of 11 ophthalmologists was assembled. Ratings were analyzed regarding the level of agreement among panelists. We studied the effect of all variables on the final panel score using general linear and logistic regression models. Priority scoring systems were developed by means of optimal scaling and general linear models. The explicit criteria developed were summarized by means of regression tree analysis. Results Eight variables were considered to create the indications. Of the 310 indications that the panel evaluated, 22.6% were considered high priority, 52.3% intermediate priority, and 25.2% low priority. Agreement was reached for 31.9% of the indications and disagreement for 0.3%. Logistic regression and general linear models showed that the preoperative visual acuity of the cataractous eye, visual function, and anticipated visual acuity postoperatively were the most influential variables. Alternative and simple scoring systems were obtained by optimal scaling and general linear models where the previous variables were also the most important. The decision tree also shows the importance of the previous variables and the appropriateness of the intervention. Conclusion Our results showed acceptable validity as an evaluation and management tool for prioritizing cataract extraction. It also provides easy algorithms for use in clinical practice.

  17. Prevalence of corneal astigmatism before cataract surgery.

    Science.gov (United States)

    Mohammadi, Mehran; Naderan, Mohammad; Pahlevani, Rozhin; Jahanrad, Ali

    2016-12-01

    The purpose of this study was to describe and analyze the prevalence and pattern of corneal astigmatism in cataract surgery candidates. In a prospective cross-sectional study, preoperative demographics, and keratometric and refractive values of cataract surgery candidates were collected from January 2013 to December 2014. Axial length (AL) and flat and steep keratometry measurements were optically measured by a partial coherence interferometry device (IOLMaster). This study consisted of 2156 eyes of 1317 patients with a mean age of 64.92 ± 11.48 (SD) (30-88 years). The mean of AL was 23.33 ± 1.37 mm, and the mean of corneal astigmatism was 1.12 ± 1.10 diopter (D) (range 0.0-7.00), in all patients. Furthermore, the mean of flat and steep keratometry were 43.70 ± 1.70 and 44.83 ± 1.79 D, respectively. Corneal astigmatism was 1.50 D or less in 1590 eyes (73.7 %), more than 1.50 D in 566 eyes (26.2 %), 3.00 D or more in 161 eyes (7.4 %), WTR in 796 eyes (36.9 %), ATR in 1010 eyes (46.8 %), and oblique in 350 eyes (16.2 %). ATR astigmatism axis significantly increased with the increase in age. Corneal astigmatism of most cataract surgery candidates fell between 0.50 and 1.50 D. The results of our study however is confined to our demographics might provide useful data for cataract patients, surgeons, and intraocular lens manufacturers for different purposes.

  18. A PROSPECTIVE STUDY OF TRAUMATIC CATARACT AND ITS VISUAL OUTCOME

    Directory of Open Access Journals (Sweden)

    Siddharam S

    2014-06-01

    Full Text Available : INTRODUCTION: Ocular trauma is the leading cause of unilateral blindness all over the world.[1] The incidence of ocular trauma varies in different parts of the world. From India, the reported incidence is 20.53%.[2] Any strategy for prevention requires knowledge of the cause of injury, which may enable more appropriate targeting of resources towards preventing such injuries.[3] Eye trauma represents a large, potentially preventable burden on both victims and society as a whole. Traumatic cataracts occur secondary to blunt or penetrating ocular trauma, Infrared energy (glass-blower's cataract, electric shock and ionizing radiation are other rare causes of traumatic cataracts.[4] It form a separate category of cataracts as they present with other ocular morbidity like corneal tears, iris injury, vitreous hemorrhage and retinal tears; and they are to some extent, preventable. The methods used to evaluate the visual outcome in eyes managed for traumatic cataracts and senile cataracts are similar, but the damage to other ocular tissues owing to trauma may compromise the visual gain in eyes treated surgically for traumatic cataracts.[5] Hence, the success rates may differ between eyes with these two types of cataract. The aim of this study was to evaluate the final visual outcome of a patient with surgical extraction of traumatic cataract along with demographic features and modes of trauma.

  19. Measuring aniseikonia using scattering filters to simulate cataract

    Science.gov (United States)

    Wilson, Jason

    2011-12-01

    The relationship between anisometropia and aniseikonia (ANK) is not well understood. Ametropic cataract patients provide a unique opportunity to study this relationship after undergoing emmetropizing lens extraction. Because light scatter may affect ANK measurement in cataract patients, its effect should also be evaluated. The Basic Aniseikonia Test (BAT) was evaluated using afocal size lenses to produce specific changes in retinal height. Several light scattering devices were then evaluated to determine which produced effects most similar to cataract. Contrast sensitivity and visual acuity (VA) losses were measured with each device and compared to those reported in cataract. After determining the most appropriate light scattering device, twenty healthy patients with normal visual function were recruited to perform the BAT using the filters to simulate cataract. Cataract patients were recruited from Vision America and the University of Alabama at Birmingham School of Optometry. Patients between 20 and 75 years of age with at least 20/80 VA in each eye, ≥ 2D ametropia, and normal binocular function were recruited. Stereopsis and ANK were tested and each patient completed a symptom questionnaire. ANK measurements using afocal size lenses indicated that the BAT underestimates ANK, although the effect was minimal for vertical targets and darkened surroundings, as previously reported. Based on VA and contrast sensitivity loss, Vistech scattering filters produced changes most similar to cataract. Results of the BAT using Vistech filters demonstrated that a moderate cataract but not a mild cataract may affect the ANK measurement. ANK measurements on cataract patients indicated that those with ≥ 2 D ametropia in each eye may suffer from induced ANK after the first cataract extraction. With upcoming healthcare reform, unilateral cataract extraction may be covered, but not necessarily bilateral, depending on patient VA in each eye. However, a questionnaire about symptoms

  20. Additivity dominance

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    Paul Rozin

    2009-10-01

    Full Text Available Judgments of naturalness of foods tend to be more influenced by the process history of a food, rather than its actual constituents. Two types of processing of a ``natural'' food are to add something or to remove something. We report in this study, based on a large random sample of individuals from six countries (France, Germany, Italy, Switzerland, UK and USA that additives are considered defining features of what makes a food not natural, whereas ``subtractives'' are almost never mentioned. In support of this, skim milk (with major subtraction of fat is rated as more natural than whole milk with a small amount of natural vitamin D added. It is also noted that ``additives'' is a common word, with a synonym reported by a native speaker in 17 of 18 languages, whereas ``subtractive'' is lexicalized in only 1 of the 18 languages. We consider reasons for additivity dominance, relating it to omission bias, feature positive bias, and notions of purity.

  1. Genetics Home Reference: autosomal recessive cerebellar ataxia type 1

    Science.gov (United States)

    ... Genetics Home Health Conditions ARCA1 autosomal recessive cerebellar ataxia type 1 Enable Javascript to view the expand/ ... Open All Close All Description Autosomal recessive cerebellar ataxia type 1 ( ARCA1 ) is a condition characterized by ...

  2. A COMPARATIVE STUDY OF THE AMOUNT OF ASTIGMATISM FOLLOWING CONVENTIONAL EXTRACAPSULAR CATARACT EXTRACTION AND MANUAL SMALL INCISION CATARACT SURGERY

    Directory of Open Access Journals (Sweden)

    Rajkumari Bigyabati

    2016-06-01

    Full Text Available BACKGROUND Cataract is the principal cause of avoidable blindness in India and throughout the world. Surgical removal of the cataractous lens remains the only effective treatment for management of cataract blindness. The success of cataract surgery is determined by best and earliest visual recovery. But the occurrence of postoperative astigmatism has become a major hurdle in achieving this goal. AIMS The study was designed to compare the amount of astigmatism following conventional extracapsular cataract extraction (ECCE and manual small incision cataract surgery (SICS. MATERIALS AND METHODS The study was carried out in 100 eyes of 75 patients aged between 50 and 80 years admitted for cataract surgery. Out of these, 50 eyes were operated by conventional extracapsular cataract extraction and 50 eyes by manual small incision cataract surgery. The patients were followed up at 2 nd , 4 th , 6 th and 8 th weeks. At each follow-up visual acuity, refraction and acceptance and keratometry were recorded and the findings analysed for astigmatism. RESULTS In the current study, the mean (SD astigmatism developed at the end of the 2 nd , 4 th and 6 th of follow-up was significantly lower in the SICS group as compared to the ECCE group (P<0.000. At the end of 8 weeks of follow-up, the mean (SD astigmatism of the SICS group was 0.64±0.56 D as compared to the mean (SD of the ECCE group of 1.39±86 D and the difference was found to be significant (p<0.014. CONCLUSION The current study concludes that manual small incision cataract surgery is a better technique to control postoperative astigmatism than conventional extracapsular cataract extraction.

  3. Outcomes of Cataract Surgery Following Treatment for Retinoblastoma

    Science.gov (United States)

    Kim, Hyeong Min; Lee, Byung Joo; Kim, Jeong Hun

    2017-01-01

    Purpose To evaluate the long-term visual outcomes and complications of cataract surgery in eyes previously treated for retinoblastoma. Methods We reviewed the medical records of patients who underwent cataract extraction and intraocular lens implantation at Seoul National University Children's Hospital for a secondary cataract that developed after retinoblastoma treatment. Results During the period between 1990 and 2014, 208 eyes of 147 patients received eye-salvaging treatment (radiotherapy, chemotherapy, and local therapy) for retinoblastoma at Seoul National University Children's Hospital. Among these eyes, a secondary cataract was detected in 17 eyes of 14 patients, and five eyes of five patients underwent cataract surgery. The median age of cataract formation was 97 months (range, 38 to 153 months). The medial interval between the diagnosis of retinoblastoma and cataract formation was 79 months (range, 29 to 140 months). All patients received posterior chamber intraocular lens insertion after irrigation and aspiration of the lens through a scleral tunnel incision. Anterior vitrectomy and posterior capsulotomy were performed in two eyes and a laser capsulotomy was subsequently performed in one eye. No intraoperative and postoperative complications occurred. The median follow-up after surgery was 36 months (range, 14 to 47 months). The final best corrected visual acuities were improved in all five eyes. No intraocular tumor recurrences or metastases occurred. Conclusions After retinoblastoma regression, cataract extraction in our series was not associated with tumor recurrence or metastasis. Visual improvement was noted in every patient. PMID:28243024

  4. Results of Cataract Outreach Services in a State of Nigeria

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    Abdu Lawan

    2010-06-01

    Full Text Available AIM: A blindness prevalence survey in 1996 indicated that estimates of 40000 are blind from cataracts in Kano state, northwestern Nigeria. Many more were severely visually impaired. Eye care personnel and other resources for eye care delivery are located at the state capital. The state Ministry of Health organized an outreach program. The aim was to operate on 750 cataract patients and measure the visual acuity at two weeks follow up. METHOD: Patients were registered and examined. Cataract patients with accurate four quadrant light projection, briskly reacting pupils and normal intra ocular pressures were selected and had manual extra capsular cataract extraction with posterior chamber intra ocular lens implantation. Post operative medications were administered. Patients were reviewed at 2 weeks follow up after discharge during which their visual acuity was measured and recorded. RESULTS: 868 cataract patients were operated. Thirty two percent of the patients were blind before surgery and 77% of these had bilateral cataracts. The proportion of those who had posterior chamber intra ocular lens (PC IOL was 85%. The proportion of patients who regained normal vision was 43% and overall, 94% had vision of 6/60 or, better after surgery compared with 20% in this category before surgery, (WHO vision category 0 and 1. CONCLUSION: Cataract outreach service is essential in reducing cataract blindness. There is need to follow up patients although the vision recorded for this study was obtained at two weeks follow up. [TAF Prev Med Bull 2010; 9(3.000: 225-228

  5. Congenital cataract screening in maternity wards is effective

    DEFF Research Database (Denmark)

    Magnusson, Gunilla; Bizjajeva, Svetlana; Haargaard, Birgitte;

    2013-01-01

    screening policy. Response frequency was 96% (122/127). Data were derived from The Pediatric Cataract Register, PECARE Sweden. All Swedish children diagnosed with congenital cataract and operated on before 1 year of age between January 2007 and December 2009 were included. Statistical comparison...

  6. Blindness and cataract surgical services in Atsinanana region, Madagascar

    Directory of Open Access Journals (Sweden)

    Jean-Baptiste Randrianaivo

    2014-01-01

    Conclusions: Although the survey included only people with reasonable access, the main cause of visual impairment was still cataract. The incidence of cataract is such that it ought to be possible to eliminate it as a cause of visual impairment, but changes in service delivery at hospitals and strategies to improve access will be necessary for this change.

  7. Radiation hybrid mapping of cataract genes in the dog

    NARCIS (Netherlands)

    Hunter, L; Sidjanin, D; Johnson, J; Zangerl, B; Galibert, F; Andre, C; Kirkness, E; Talamas, E; Acland, G; Aguirre, G

    2006-01-01

    Purpose: To facilitate the molecular characterization of naturally occurring cataracts in dogs by providing the radiation hybrid location of 21 cataract-associated genes along with their closely associated polymorphic markers. These can be used for segregation testing of the candidate genes in canin

  8. Barriers to cataract surgery in Africa: A systematic review

    Directory of Open Access Journals (Sweden)

    Shaheer Aboobaker

    2016-01-01

    Full Text Available Cataract remains the leading cause of blindness in Africa. We performed a systematic literature search of articles reporting barriers to cataract surgery in Africa. PubMed and Google Scholar databases were searched with the terms "barriers, cataract, Africa, cataract surgery, cataract surgical coverage (CSC, and rapid assessment of avoidable blindness (RAAB." The review covered from 1999 to 2014. In RAAB studies, barriers related to awareness and access were more commonly reported than acceptance. Other type of studies reported cost as the most common barrier. Some qualitative studies tended to report community and family dynamics as barriers to cataract surgery. CSC was lower in females in 88.2% of the studies. The variability in outcomes of studies of barriers to cataract surgery could be due to context and the type of data collection. It is likely that qualitative data will provide a deeper understanding of the complex social, family, community, financial and gender issues relating to barriers to uptake of cataract surgery in Africa.

  9. Cataracts and microphthalmia caused by a Gja8 mutation in extracellular loop 2.

    Directory of Open Access Journals (Sweden)

    Chun-Hong Xia

    Full Text Available The mouse semi-dominant Nm2249 mutation displays variable cataracts in heterozygous mice and smaller lenses with severe cataracts in homozygous mice. This mutation is caused by a Gja8(R205G point mutation in the second extracellular loop of the Cx50 (or α8 connexin protein. Immunohistological data reveal that Cx50-R205G mutant proteins and endogenous wild-type Cx46 (or α3 connexin proteins form diffuse tiny spots rather than typical punctate signals of normal gap junctions in the lens. The level of phosphorylated Cx46 proteins is decreased in Gja8(R205G/R205G mutant lenses. Genetic analysis reveals that the Cx50-R205G mutation needs the presence of wild-type Cx46 to disrupt lens peripheral fibers and epithelial cells. Electrophysiological data in Xenopus oocytes reveal that Cx50-R205G mutant proteins block channel function of gap junctions composed of wild-type Cx50, but only affect the gating of wild-type Cx46 channels. Both genetic and electrophysiological results suggest that Cx50-R205G mutant proteins alone are unable to form functional channels. These findings imply that the Gja8(R205G mutation differentially impairs the functions of Cx50 and Cx46 to cause cataracts, small lenses and microphthalmia. The Gja8(R205G mutation occurs at the same conserved residue as the human GJA8(R198W mutation. This work provides molecular insights to understand the cataract and microphthalmia/microcornea phenotype caused by Gja8 mutations in mice and humans.

  10. Cataracts and microphthalmia caused by a Gja8 mutation in extracellular loop 2.

    Science.gov (United States)

    Xia, Chun-Hong; Chang, Bo; Derosa, Adam M; Cheng, Catherine; White, Thomas W; Gong, Xiaohua

    2012-01-01

    The mouse semi-dominant Nm2249 mutation displays variable cataracts in heterozygous mice and smaller lenses with severe cataracts in homozygous mice. This mutation is caused by a Gja8(R205G) point mutation in the second extracellular loop of the Cx50 (or α8 connexin) protein. Immunohistological data reveal that Cx50-R205G mutant proteins and endogenous wild-type Cx46 (or α3 connexin) proteins form diffuse tiny spots rather than typical punctate signals of normal gap junctions in the lens. The level of phosphorylated Cx46 proteins is decreased in Gja8(R205G/R205G) mutant lenses. Genetic analysis reveals that the Cx50-R205G mutation needs the presence of wild-type Cx46 to disrupt lens peripheral fibers and epithelial cells. Electrophysiological data in Xenopus oocytes reveal that Cx50-R205G mutant proteins block channel function of gap junctions composed of wild-type Cx50, but only affect the gating of wild-type Cx46 channels. Both genetic and electrophysiological results suggest that Cx50-R205G mutant proteins alone are unable to form functional channels. These findings imply that the Gja8(R205G) mutation differentially impairs the functions of Cx50 and Cx46 to cause cataracts, small lenses and microphthalmia. The Gja8(R205G) mutation occurs at the same conserved residue as the human GJA8(R198W) mutation. This work provides molecular insights to understand the cataract and microphthalmia/microcornea phenotype caused by Gja8 mutations in mice and humans.

  11. Long-Term Results of Cataract Surgery in Patients with Unilateral Childhood Cataract

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    Suzan Güven Yılmaz

    2012-03-01

    Full Text Available Pur po se: To evaluate the long-term visual outcome and to determine the surgical complications after cataract surgery in patients with unilateral childhood cataract. Ma te ri al and Met hod: We retrospectively reviewed the records of 18 cases with unilateral childhood cataract who had undergone cataract surgery before the age of seven. Primary intraocular lens (IOL implantation was made in children who were older than 1 year of age. Secondary IOL implantation was made after 18 months in children who were operated before the age of 1 year and were left aphakic. Occlusion therapy was performed to all children for amblyopia postoperatively. Visual acuity and complications were evaluated in a mean follow-up period of 4.8 years. Re sults: The mean age of the 18 patients (9 female/9 male at the time of surgery was 43.6±33.7(1-84 months. Eleven (61% patients had cataract surgery after 1 year of age. Secondary IOL implantation was performed at mean 28th month in 4 of 7 aphakic patients (57% who had cataract surgery before one year of age. In 3 (43% aphakic patients, secondary IOL implantation could not be performed because of ocular pathologies such as microophthalmia. Final visual acuity was 0.5 or better in 7 eyes (39%, between 0.1 and 0.5 in 6 eyes (33%, and worse than 0.1 - in 5 eyes (28%. Of 5 eyes that had visual acuity worse than 0.1, 4 (80% had at least one additional ocular pathology such as microphthalmia, strabismus and nystagmus. Nd:YAG laser posterior capsulotomy was performed at mean 8th month in 7 of 8 (87% children whose posterior capsules were left intact at surgery. Dis cus si on: Favorable visual outcomes can be achieved with surgical intervention and complementary amblyopia treatment in children with unilateral cataract. Preoperative microphthalmia, nystagmus and strabismus are not entirely an obstacle to visual development, but they are important factors leading to low visual acuity. (Turk J Ophthalmol 2012; 42: 103-10

  12. Surgical options for correction of refractive error following cataract surgery.

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    Abdelghany, Ahmed A; Alio, Jorge L

    2014-01-01

    Refractive errors are frequently found following cataract surgery and refractive lens exchange. Accurate biometric analysis, selection and calculation of the adequate intraocular lens (IOL) and modern techniques for cataract surgery all contribute to achieving the goal of cataract surgery as a refractive procedure with no refractive error. However, in spite of all these advances, residual refractive error still occasionally occurs after cataract surgery and laser in situ keratomileusis (LASIK) can be considered the most accurate method for its correction. Lens-based procedures, such as IOL exchange or piggyback lens implantation are also possible alternatives especially in cases with extreme ametropia, corneal abnormalities, or in situations where excimer laser is unavailable. In our review, we have found that piggyback IOL is safer and more accurate than IOL exchange. Our aim is to provide a review of the recent literature regarding target refraction and residual refractive error in cataract surgery.

  13. Cataract extraction after brachytherapy for malignant melanoma of the choroid

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    Fish, G.E.; Jost, B.F.; Snyder, W.I.; Fuller, D.G.; Birch, D.G. (Texas Retina Associates, Dallas (USA))

    1991-05-01

    Thirteen eyes of 55 consecutive patients treated with brachytherapy for malignant melanoma of the choroid developed postirradiation cataracts. Cataract development was more common in older patients and in patients with larger and more anterior tumors. Eleven eyes had extracapsular cataract extraction and intraocular lens implantation. Initial visual improvement occurred in 91% of eyes, with an average improvement of 5.5 lines. Visual acuity was maintained at 20/60 or better in 55% of the eyes over an average period of follow-up of 24 months (range, 6 to 40 months). These data suggest that, visually, cataract extraction can be helpful in selected patients who develop a cataract after brachytherapy for malignant melanoma of the choroid.

  14. Effect of coffee (caffeine against human cataract blindness

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    Varma SD

    2016-01-01

    Full Text Available Shambhu D VarmaDepartment of Ophthalmology and Visual Sciences, Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD, USAAbstract: Previous biochemical and morphological studies with animal experiments have demonstrated that caffeine given topically or orally to certain experimental animal models has significant inhibitory effect on cataract formation. The present studies were undertaken to examine if there is a correlation between coffee drinking and incidence of cataract blindness in human beings. That has been found to be the case. Incidence of cataract blindness was found to be significantly lower in groups consuming higher amounts of coffee in comparison to the groups with lower coffee intake. Mechanistically, the caffeine effect could be multifactorial, involving its antioxidant as well as its bioenergetic effects on the lens.Keywords: caffeine, cataract, cataract blindness, cataractogenic process, intraocular pressure, vision impairment

  15. Outcomes of Cataract Surgery in Vitrectomized Eyes

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    Nilüfer Koçak

    2013-01-01

    Full Text Available Pur po se: To evaluate the intraoperative complications and postoperative visual outcomes of phacoemulsification surgery for the secondary cataract in vitrectomized eyes. Ma te ri al and Met hod: We retrospectively evaluated 51 previously vitrectomized eyes of 51 patients who had undergone phacoemulsification and intraocular lens (PHACO+IOL implantation surgery. PHACO+IOL surgery was performed in our clinic between October 2008 and May 2011. Intraoperative complications and postoperative best-corrected visual acuity (BCVA outcomes were analyzed. Re sults: In this study, 31 out of 51 eyes had posterior subcapsular cataract. Cataract surgery was performed after a mean of 21.39±26.4 (6- 120, median 10.75 months following PPV. Mean preoperative and postoperative BCVA was measured to be 1.52±0.88 logMAR and 0.74±0.73 logMAR, respectively. In 25 eyes which had been filled with silicon oil, mean BCVA was 1.95±0.91 logMAR preoperatively and 1.15±0.84 logMAR postoperatively. In 18 (35.3% eyes which had been filled with sulfur hexafluoride tamponade, mean BCVA was 1.17±0.47 logMAR preoperatively and 0.38±3.6 logMAR postoperatively. Peroperative zonular dialysis with instable deep anterior chamber occurred in two eyes, and posterior capsular tear occurred in one eye. Four eyes had Nd:YAG capsulotomy due to the posterior capsular opacity during the follow-up period. Dis cus si on: Despite the well-known difficulties encountered in vitrectomized eyes such as zonular weakness, increased mobility of the lens-iris diaphragm, posterior capsular instability and posterior capsular plaques, phacoemulsification in vitrectomized eyes proved to be a safe surgery, and increase in visual acuity can be achieved. (Turk J Ophthalmol 2013; 43: 23-6

  16. Are entry criteria for cataract surgery justified?

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    Daniel Böhringer

    Full Text Available PURPOSE: The German Ophthalmological Society (GOS recently proposed surgical entry criteria, i.e. 300 cataract surgeries. We herein correlate the surgical hands-on experience with the risk of posterior capsule ruptures in order to assess whether this number is appropriate. METHODS: We identified all cataract operations that had been performed at the University Eye Hospital Freiburg since 1995. For each surgeon, we assigned a running number to his/her procedures in the order they had been performed. Thereafter, we excluded all combined procedures and the second eyes. We then selected the 5475 surgical reports between November 2008 and November 2012 for detailed review. We additionally classified each surgery into low- vs. high- à priori risk for posterior capsule ruptures. We fitted a multifactorial logistic regression model to assess the GOS recommendation of 300 surgeries under supervision. In the low-risk group, we additionally visualized the 'typical' learning curve by plotting the posterior capsule ruptures against the respective rank numbers. RESULTS: The odds ratio for posterior capsule ruptures of 'learning-mode' (one of the respective surgeon's 300 first procedures vs. the non-learning-mode was 3.8 (p<0.0001. By contrast, classification into the low-risk group lowered the risk of posterior capsule ruptures three fold (p<0.0001. According to the low-risk plot, the surgeons started with a complication rate of 4% and continuously improved towards 0.5% after 1500 operations. Thereafter, the rate increased again and stabilized around one percent. CONCLUSION: The learning curve with respect to posterior capsule ruptures is surprisingly flat. The GOS entry criterion of 300 cataract procedures is therefore most likely justified. Careful selection of low-risk patients for the training surgeons may help in reducing the rate of posterior capsule ruptures during training.

  17. Cataract and progressing keratoconus — solution?

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    K. B. Pershin

    2015-01-01

    Full Text Available Purpose: To develop an uniform method of the treatment for patients with progressive keratoconus (stage 1‑2 and cataract. Patients and methods: 4 patients (5 eyes with cataract and progressive keratoconus stage 1‑2 were enrolled in the study. Mean age was 42 years. In