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Sample records for autosomal dominant retinitis

  1. 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.

  2. 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....

  3. 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.

  4. 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.

  5. 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,

  6. 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

  7. 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.

  8. 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.

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

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    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.

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

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    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.

  11. 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...

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

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    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.

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

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    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.

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

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

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    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

  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. 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.

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    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.

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

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    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.

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

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    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.

  20. 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.

  1. 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.

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

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    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.

  3. 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...

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. MRI of autosomal dominant pure spastic paraplegia

    Energy Technology Data Exchange (ETDEWEB)

    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.

  9. 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.

  10. 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.

  11. 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

  12. 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

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

    Science.gov (United States)

    ... 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 ...

  14. [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

  15. 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,

  16. [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.

  17. 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.

  18. 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.

  19. 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...

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

    Science.gov (United States)

    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.

  1. 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.

  2. 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.

  3. 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.

  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. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. [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.

  15. 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.

  16. 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

  17. 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.

  18. 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.

  19. AUTOSOMAL DOMINANT HYPOCALCEMIA (HYPOPARATHYROIDISM TYPES 1 AND 2

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    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.

  20. 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

  1. Genotype-phenotype heterogeneity of ganglion cell and inner plexiform layer deficit in autosomal-dominant optic atrophy

    DEFF Research Database (Denmark)

    Rönnbäck, Cecilia; Nissen, Claus; Almind, Gitte J;

    2015-01-01

    PURPOSE: To describe the thickness of the combined ganglion cell and inner plexiform layers (GC-IPL) and the peripapillary retinal nerve fibre layer (RNFL) in patients with OPA1 c.983A>G or c.2708_2711delTTAG autosomal-dominant optic atrophy (ADOA). METHODS: The study included 20 individuals with c...... measurement and high-definition optical coherence tomography. RESULTS: There was overlap in GC-IPL thickness in subjects younger than 20-30 years between the two new groups of ADOA patients and controls. Numerical decreases in GC-IPL thickness with age did not reach statistical significance in individuals...

  2. 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.

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

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    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.

  4. 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)....

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

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    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.

  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. Homozygosity Mapping in Leber Congenital Amaurosis and Autosomal Recessive Retinitis Pigmentosa in South Indian Families.

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    Sundaramurthy Srilekha

    Full Text Available Leber congenital amaurosis (LCA and retinitis pigmentosa (RP are retinal degenerative diseases which cause severe retinal dystrophy affecting the photoreceptors. LCA is predominantly inherited as an autosomal recessive trait and contributes to 5% of all retinal dystrophies; whereas RP is inherited by all the Mendelian pattern of inheritance and both are leading causes of visual impairment in children and young adults. Homozygosity mapping is an efficient strategy for mapping both known and novel disease loci in recessive conditions, especially in a consanguineous mating, exploiting the fact that the regions adjacent to the disease locus will also be homozygous by descent in such inbred children. Here we have studied eleven consanguineous LCA and one autosomal recessive RP (arRP south Indian families to know the prevalence of mutations in known genes and also to know the involvement of novel loci, if any. Complete ophthalmic examination was done for all the affected individuals including electroretinogram, fundus photograph, fundus autofluorescence, and optical coherence tomography. Homozygosity mapping using Affymetrix 250K HMA GeneChip on eleven LCA families followed by screening of candidate gene(s in the homozygous block identified mutations in ten families; AIPL1 - 3 families, RPE65- 2 families, GUCY2D, CRB1, RDH12, IQCB1 and SPATA7 in one family each, respectively. Six of the ten (60% mutations identified are novel. Homozygosity mapping using Affymetrix 10K HMA GeneChip on the arRP family identified a novel nonsense mutation in MERTK. The mutations segregated within the family and was absent in 200 control chromosomes screened. In one of the eleven LCA families, the causative gene/mutation was not identified but many homozygous blocks were noted indicating that a possible novel locus/gene might be involved. The genotype and phenotype features, especially the fundus changes for AIPL1, RPE65, CRB1, RDH12 genes were as reported earlier.

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

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    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.

  10. 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...

  11. 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.

  12. Mutation Analysis Identifies GUCY2D as the Major Gene Responsible for Autosomal Dominant Progressive Cone Degeneration

    Science.gov (United States)

    Kitiratschky, Veronique B. D.; Wilke, Robert; Renner, Agnes B.; Kellner, Ulrich; Vadalà, Maria; Birch, David G.; Wissinger, Bernd; Zrenner, Eberhart; Kohl, Susanne

    2017-01-01

    Purpose Heterozygous mutations in the GUCY2D gene, which encodes the membrane-bound retinal guanylyl cyclase-1 protein (RetGC-1), have been shown to cause autosomal dominant inherited cone degeneration and cone–rod degeneration (adCD, adCRD). The present study was a comprehensive screening of the GUCY2D gene in 27 adCD and adCRD unrelated families of these rare disorders. Methods Mutation analysis was performed by direct sequencing as well as PCR and subsequent restriction length polymorphism analysis (PCR/RFLP). Haplotype analysis was performed in selected patients by using microsatellite markers. Results GUCY2D gene mutations were identified in 11 (40%) of 27 patients, and all mutations clustered to codon 838, including two known and one novel missense mutation: p.R838C, p.R838H, and p.R838G. Haplotype analysis showed that among the studied patients only two of the six analyzed p.R838C mutation carriers shared a common haplotype and that none of the p.R838H mutation carriers did. Conclusions GUCY2D is a major gene responsible for progressive autosomal dominant cone degeneration. All identified mutations localize to codon 838. Haplotype analysis indicates that in most cases these mutations arise independently. Thus, codon 838 is likely to be a mutation hotspot in the GUCY2D gene. PMID:18487367

  13. 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

  14. 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.

  15. 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...

  16. 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...

  17. 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

  18. 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...

  19. 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

  20. 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

  1. 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

  2. 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...

  3. 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...

  4. 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...

  5. 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,

  6. Retinal arterial but not venous tortuosity correlates with facioscapulohumeral muscular dystrophy severity

    NARCIS (Netherlands)

    Longmuir, Susannah Q.; Mathews, Katherine D.; Longmuir, Reid A.; Joshi, Vinayak; Olson, Richard J.; Abramoff, M.D.

    2010-01-01

    Background Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease beginning with facial and shoulder girdle weakness with variable progression. Exudative retinal detachment, retinal vessel irregularities on fluorescein angiography, and retinal vessel tortuosity have been foun

  7. Panel-based NGS Reveals Novel Pathogenic Mutations in Autosomal Recessive Retinitis Pigmentosa.

    Science.gov (United States)

    Perez-Carro, Raquel; Corton, Marta; Sánchez-Navarro, Iker; Zurita, Olga; Sanchez-Bolivar, Noelia; Sánchez-Alcudia, Rocío; Lelieveld, Stefan H; Aller, Elena; Lopez-Martinez, Miguel Angel; López-Molina, Ma Isabel; Fernandez-San Jose, Patricia; Blanco-Kelly, Fiona; Riveiro-Alvarez, Rosa; Gilissen, Christian; Millan, Jose M; Avila-Fernandez, Almudena; Ayuso, Carmen

    2016-01-25

    Retinitis pigmentosa (RP) is a group of inherited progressive retinal dystrophies (RD) characterized by photoreceptor degeneration. RP is highly heterogeneous both clinically and genetically, which complicates the identification of causative genes and mutations. Targeted next-generation sequencing (NGS) has been demonstrated to be an effective strategy for the detection of mutations in RP. In our study, an in-house gene panel comprising 75 known RP genes was used to analyze a cohort of 47 unrelated Spanish families pre-classified as autosomal recessive or isolated RP. Disease-causing mutations were found in 27 out of 47 cases achieving a mutation detection rate of 57.4%. In total, 33 pathogenic mutations were identified, 20 of which were novel mutations (60.6%). Furthermore, not only single nucleotide variations but also copy-number variations, including three large deletions in the USH2A and EYS genes, were identified. Finally seven out of 27 families, displaying mutations in the ABCA4, RP1, RP2 and USH2A genes, could be genetically or clinically reclassified. These results demonstrate the potential of our panel-based NGS strategy in RP diagnosis.

  8. Mutation Spectrum of EYS in Spanish Patients with Autosomal Recessive Retinitis Pigmentosa

    Science.gov (United States)

    Barragán, Isabel; Borrego, Salud; Pieras, Juan Ignacio; Pozo, María González-del; Santoyo, Javier; Ayuso, Carmen; Baiget, Montserrat; Millan, José M; Mena, Marcela; El-Aziz, Mai M Abd; Audo, Isabelle; Zeitz, Christina; Littink, Karin W; Dopazo, Joaquín; Bhattacharya, Shomi S; Antiñolo, Guillermo

    2010-01-01

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal dystrophies characterised ultimately by the loss of photoreceptor cells. We have recently identified a new gene (EYS) encoding an ortholog of Drosophila spacemaker (spam) as a commonly mutated gene in autosomal recessive RP. In the present study, we report the identification of 73 sequence variations in EYS, of which 28 are novel. Of these, 42.9% (12/28) are very likely pathogenic, 17.9% (5/28) are possibly pathogenic, whereas 39.3% (11/28) are SNPs. In addition, we have detected 3 pathogenic changes previously reported in other populations. We are also presenting the characterisation of EYS homologues in different species, and a detailed analysis of the EYS domains, with the identification of an interesting novel feature: a putative coiled-coil domain. Majority of the mutations in the arRP patients have been found within the domain structures of EYS. The minimum observed prevalence of distinct EYS mutations in our group of patients is of 15.9% (15/94), confirming a major involvement of EYS in the pathogenesis of arRP in the Spanish population. Along with the detection of three recurrent mutations in Caucasian population, our hypothesis of EYS being the first prevalent gene in arRP has been reinforced in the present study. © 2010 Wiley-Liss, Inc. PMID:21069908

  9. 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.

  10. X-linked dominant cone-rod degeneration: Linkage mapping of a new locus for retinitis pigmentosa (RP15) to Xp22.13-p22.11

    Energy Technology Data Exchange (ETDEWEB)

    McGuire, R.E.; Sullivan, L.S.; Daiger, S.P. [Univ. of Texas-Houston Health Science Center, TX (United States)] [and others

    1995-07-01

    Retinitis pigmentosa is the name given to a heterogeneous group of hereditary retinal degenerations characterized by progressive visual field loss, pigmentary changes of the retina, abnormal electroretinograms, and, frequently, night blindness. In this study, we investigated a family with dominant cone-rod degeneration, a variant form of retinitis pigmentosa. We used microsatellite markers to test for linkage to the disease locus and exluded all mapped autosomal loci. However, a marker from the short arm of the X chromosome, DXS989, showed 0% recombination to the disease locus, with a maximum lod (log-odds) score of 3.3. On the basis of this marker, the odds favoring X-linked dominant versus autosomal dominant inheritance are > 10{sup 5}:1. Haplotype analysis using an additional nine microsatellite markers places the disease locus in the Xp22.13-p22.11 region and excludes other X-linked disease loci causing retinal degeneration. The clinical expression of the retinal degeneration is consistent with X-linked dominant inheritance with milder, variable effects of Lyonization affecting expression in females. On the basis of these data we propose that this family has a novel form of dominant, X-linked cone-rod degeneration with the gene symbol {open_quotes}RP15{close_quotes}. 17 refs., 2 figs., 4 tabs.

  11. 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

  12. 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.

  13. [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.

  14. 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.

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

    Science.gov (United States)

    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.

  16. 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.

  17. Identification of the CRB1 gene and analysis of its role in autosomal recessive retinal dystrophies

    NARCIS (Netherlands)

    Hollander, Antonia Ingrid den

    2002-01-01

    Inherited retinal dystrophies generally lead to severe visual impairment early in life. Most genes involved in retinal dystrophies are expressed exclusively or predominantly in the retina or the RPE. To identify candidate genes for inherited retinal dystrophies, we isolated

  18. 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.

  19. 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

  20. 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

  1. 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.

  2. 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

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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...

  8. [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.

  9. 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.

  10. [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.

  11. 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.

  12. 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.

  13. 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.

  14. Mutations in C8orf37, encoding a ciliary protein, are associated with autosomal-recessive retinal dystrophies with early macular involvement.

    NARCIS (Netherlands)

    Estrada-Cuzcano, A.; Neveling, K.; Kohl, S.; Banin, E.; Rotenstreich, Y.; Sharon, D.; Falik-Zaccai, T.C.; Hipp, S.; Roepman, R.; Wissinger, B.; Letteboer, S.J.F.; Mans, D.A.; Blokland, E.A.W.; Kwint, M.P.; Gijsen, S.J.; Huet, R.A.C. van; Collin, R.W.J.; Scheffer, H.; Veltman, J.A.; Zrenner, E.; Hollander, A.I. den; Klevering, B.J.; Cremers, F.P.M.

    2012-01-01

    Cone-rod dystrophy (CRD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. By using homozygosity mapping in an individual with autosomal-recessive (ar) RP from a consanguineous family, we identified three sizeable homozygous regions, together

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  1. 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

  2. Animals deficient in C2Orf71, an autosomal recessive retinitis pigmentosa-associated locus, develop severe early-onset retinal degeneration.

    Science.gov (United States)

    Kevany, Brian M; Zhang, Ning; Jastrzebska, Beata; Palczewski, Krzysztof

    2015-05-01

    Genetic mapping was recently used to identify the underlying cause for a previously uncharacterized cohort of autosomal recessive retinitis pigmentosa cases. Genetic mapping of affected individuals resulted in the identification of an uncharacterized gene, C2Orf71, as the causative locus. However, initial homology searches failed to reveal similarities to any previously characterized protein or domain. To address this issue, we characterized the mouse homolog, BC027072. Immunohistochemistry with a custom polyclonal antibody showed staining localized to the inner segments (IS) of photoreceptor cells, as well as the outer segments (OS) of cone cells. A knockout mouse line (BC(-/-)) was generated and demonstrated that loss of this gene results in a severe, early-onset retinal degeneration. Histology and electron microscopy (EM) revealed disorganized OS as early as 3 weeks with complete loss by 24 weeks of age. EM micrographs displayed packets of cellular material containing OS discs or IS organelles in the OS region and abnormal retinal pigmented epithelium cells. Analyses of retinoids and rhodopsin levels showed retinal degenerations. Although its function remains unknown, this protein appears essential for normal OS development/maintenance and vision in humans and mice. RNAseq data are available in the GEO database under accession: GSE63810.

  3. 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.

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

    Directory of Open Access Journals (Sweden)

    Walter O. Arruda

    1991-09-01

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

  5. [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.

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

    Directory of Open Access Journals (Sweden)

    Kambiz Yazdanpanah

    2013-01-01

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

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    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

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

    Science.gov (United States)

    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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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

  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. 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.

  2. 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.

  3. 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

  4. 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.

  5. 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.

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

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    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.

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

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    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

  8. 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.

  9. 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

  10. 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

  11. 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...

  12. 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

  13. 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

  14. 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

  15. 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),"…

  16. 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.

  17. 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...

  18. 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.

  19. 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.

  20. 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.

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

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    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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

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

    Directory of Open Access Journals (Sweden)

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

    Directory of Open Access Journals (Sweden)

    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.499T

  9. 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.

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

    Science.gov (United States)

    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

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

    Directory of Open Access Journals (Sweden)

    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.

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

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    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.

  14. A homozygous missense mutation in the IRBP gene (RBP3) associated with autosomal recessive retinitis pigmentosa.

    NARCIS (Netherlands)

    Hollander, A.I. den; McGee, T.L.; Ziviello, C.; Banfi, S.; Dryja, T.P.; Gonzalez-Fernandez, F.; Ghosh, D.; Berson, E.L.

    2009-01-01

    PURPOSE: Interphotoreceptor retinoid-binding protein (IRBP) has been considered essential for normal rod and cone function, as it mediates the transport of retinoids between the photoreceptors and the retinal pigment epithelium. This study was performed to determine whether mutations in the IRBP gen

  15. 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.

  16. 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.

  17. 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.

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

    Science.gov (United States)

    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.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.)

  20. 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.

  1. 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.

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

    Science.gov (United States)

    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

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

    Directory of Open Access Journals (Sweden)

    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.

  4. 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.

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

    Science.gov (United States)

    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

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

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    Andrea eBecchetti

    2015-02-01

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

  7. Autosomal recessive posterior column ataxia with retinitis pigmentosa caused by novel mutations in the FLVCR1 gene.

    Science.gov (United States)

    Shaibani, Aziz; Wong, Lee-Jun; Wei Zhang, Victor; Lewis, Richard Alan; Shinawi, Marwan

    2015-01-01

    Posterior column ataxia with retinitis pigmentosa (PCARP) is an autosomal recessive disorder characterized by severe sensory ataxia, muscle weakness and atrophy, and progressive pigmentary retinopathy. Recently, mutations in the FLVCR1 gene were described in four families with this condition. We investigated the molecular basis and studied the phenotype of PCARP in a new family. The proband is a 33-year-old woman presented with sensory polyneuropathy and retinitis pigmentosa (RP). The constellation of clinical findings with normal metabolic and genetic evaluation, including mitochondrial DNA (mtDNA) analysis and normal levels of phytanic acid and vitamin E, prompted us to seek other causes of our patient's condition. Sequencing of FLVCR1 in the proband and targeted mutation testing in her two affected siblings revealed two novel variants, c.1547G > A (p.R516Q) and c.1593+5_+8delGTAA predicted, respectively, to be highly conserved throughout evolution and affecting the normal splicing, therefore, deleterious. This study supports the pathogenic role of FLVCR1 in PCARP and expands the molecular and clinical spectra of PCARP. We show for the first time that nontransmembrane domain (TMD) mutations in the FLVCR1 can cause PCARP, suggesting different mechanisms for pathogenicity. Our clinical data reveal that impaired sensation can be part of the phenotypic spectrum of PCARP. This study along with previously reported cases suggests that targeted sequencing of the FLVCR1 gene should be considered in patients with severe sensory ataxia, RP, and peripheral sensory neuropathy.

  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.

    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

  9. 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

  10. 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.

  11. 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.

  12. 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:

  13. 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 ...

  14. 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.

  15. 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...

  16. 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...

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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.

  2. Screening for homozygosity by descent in families with autosomal recessive retinitis pigmentosa

    Indian Academy of Sciences (India)

    Kota Lalitha; Subhadra Jalali; Tejas Kadakia; Chitra Kannabiran

    2002-08-01

    Retinitis pigmentosa (RP) is a genetically heterogeneous disease and an important cause of blindness in the state of Andhra Pradesh in India. In an attempt to identify the disease locus in families with the recessive form of the disease, we used the approach of screening for homozygosity by descent in offspring of consanguineous and nonconsanguineous families with RP. Microsatellite markers closely flanking 21 known candidate genes for RP were genotyped in parents and affected offspring to determine whether there was homozygosity at these loci that was shared by affected individuals of a family. This screening approach may be a rapid preliminary method to test known loci for possible cosegregation with disease.

  3. 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.

  4. 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. The search for mutations in the gene for the beta subunit of the cGMP phosphodiesterase (PDEB) in patients with autosomal recessive retinitis pigmentosa

    DEFF Research Database (Denmark)

    Riess, O; Noerremoelle, A; Weber, B

    1992-01-01

    including 196 bp of the 5' region of the PDEB gene have been assessed for mutations by using single-strand conformational polymorphism analysis in 14 patients from 13 unrelated families with autosomal recessive retinitis pigmentosa (ARRP). No disease-causing mutations were found in this group of affected...... individuals of seven different ancestries. However, a frequent intronic and two exonic polymorphisms (Leu489----Gln and Gly842----Gly) were identified. Segregation analysis using these polymorphic sites excludes linkage of ARRP to the PDEB gene in a family with two affected children....

  2. 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.

  3. 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.

  4. 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.

  5. Whole-exome sequencing reveals ZNF408 as a new gene associated with autosomal recessive retinitis pigmentosa with vitreal alterations

    NARCIS (Netherlands)

    Avila-Fernandez, A.; Perez-Carro, R.; Corton, M.; Lopez-Molina, M.I.; Campello, L.; Garanto, A.; Fernandez-Sanchez, L.; Duijkers, L.; Lopez-Martinez, M.A.; Riveiro-Alvarez, R.; Silva, L.R. Da; Sanchez-Alcudia, R.; Martin-Garrido, E.; Reyes, N.; Garcia-Garcia, F.; Dopazo, J.; Garcia-Sandoval, B.; Collin, R.W.J.; Cuenca, N.; Ayuso, C.

    2015-01-01

    Retinitis pigmentosa (RP) is a group of progressive inherited retinal dystrophies that cause visual impairment as a result of photoreceptor cell death. RP is heterogeneous, both clinically and genetically making difficult to establish precise genotype-phenotype correlations. In a Spanish family with

  6. 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.

  7. Whole-exome sequencing reveals a novel frameshift mutation in the FAM161A gene causing autosomal recessive retinitis pigmentosa in the Indian population.

    Science.gov (United States)

    Zhou, Yu; Saikia, Bibhuti B; Jiang, Zhilin; Zhu, Xiong; Liu, Yuqing; Huang, Lulin; Kim, Ramasamy; Yang, Yin; Qu, Chao; Hao, Fang; Gong, Bo; Tai, Zhengfu; Niu, Lihong; Yang, Zhenglin; Sundaresan, Periasamy; Zhu, Xianjun

    2015-10-01

    Retinitis pigmentosa (RP) is a heterogenous group of inherited retinal degenerations caused by mutations in at least 50 genes. To identify genetic mutations underlying autosomal recessive RP (arRP), we performed whole-exome sequencing study on two consanguineous marriage Indian families (RP-252 and RP-182) and 100 sporadic RP patients. Here we reported novel mutation in FAM161A in RP-252 and RP-182 with two patients affected with RP in each family. The FAM161A gene was identified as the causative gene for RP28, an autosomal recessive form of RP. By whole-exome sequencing we identified several homozygous genomic regions, one of which included the recently identified FAM161A gene mutated in RP28-linked arRP. Sequencing analysis revealed the presence of a novel homozygous frameshift mutation p.R592FsX2 in both patients of family RP-252 and family RP-182. In 100 sporadic Indian RP patients, this novel homozygous frameshift mutation p.R592FsX2 was identified in one sporadic patient ARRP-S-I-46 by whole-exome sequencing and validated by Sanger sequencing. Meanwhile, this homozygous frameshift mutation was absent in 1000 ethnicity-matched control samples screened by direct Sanger sequencing. In conclusion, we identified a novel homozygous frameshift mutations of RP28-linked RP gene FAM161A in Indian population.

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. 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.)

  20. 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

  1. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  3. 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.

  4. 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.

  5. RNA interference gene therapy in dominant retinitis pigmentosa and cone-rod dystrophy mouse models caused by GCAP1 mutations

    Directory of Open Access Journals (Sweden)

    Li eJiang

    2014-04-01

    Full Text Available RNA interference (RNAi knockdown is an efficacious therapeutic strategy for silencing genes causative for dominant retinal dystrophies. To test this, we used self-complementary (sc AAV2/8 vector to develop an RNAi-based therapy in two dominant retinal degeneration mouse models. The allele-specific model expresses transgenic bovine GCAP1(Y99C establishing a rapid RP-like phenotype, whereas the nonallele-specific model expresses mouse GCAP1(L151F producing a slowly progressing cone/rod dystrophy (CORD. The late onset GCAP1(L151F-CORD mimics the dystrophy observed in human GCAP1-CORD patients. Subretinal injection of scAAV2/8 carrying shRNA expression cassettes specific for bovine or mouse GCAP1 showed strong expression at one week post-injection. In both allele-specific (GCAP1(Y99C-RP and nonallele-specific (GCAP1(L151F-CORD models of dominant retinal dystrophy, RNAi-mediated gene silencing enhanced photoreceptor survival, delayed onset of degeneration and improved visual function. Such results provide a proof of concept toward effective RNAi-based gene therapy mediated by scAAV2/8 for dominant retinal disease based on GCAP1 mutation. Further, nonallele-specific RNAi knockdown of GCAP1 may prove generally applicable toward the rescue of any human GCAP1-based dominant cone-rod dystrophy.

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. Retinitis pigmentosa

    Directory of Open Access Journals (Sweden)

    Hamel Christian

    2006-10-01

    Full Text Available Abstract Retinitis pigmentosa (RP is an inherited retinal dystrophy caused by the loss of photoreceptors and characterized by retinal pigment deposits visible on fundus examination. Prevalence of non syndromic RP is approximately 1/4,000. The most common form of RP is a rod-cone dystrophy, in which the first symptom is night blindness, followed by the progressive loss in the peripheral visual field in daylight, and eventually leading to blindness after several decades. Some extreme cases may have a rapid evolution over two decades or a slow progression that never leads to blindness. In some cases, the clinical presentation is a cone-rod dystrophy, in which the decrease in visual acuity predominates over the visual field loss. RP is usually non syndromic but there are also many syndromic forms, the most frequent being Usher syndrome. To date, 45 causative genes/loci have been identified in non syndromic RP (for the autosomal dominant, autosomal recessive, X-linked, and digenic forms. Clinical diagnosis is based on the presence of night blindness and peripheral visual field defects, lesions in the fundus, hypovolted electroretinogram traces, and progressive worsening of these signs. Molecular diagnosis can be made for some genes, but is not usually performed due to the tremendous genetic heterogeneity of the disease. Genetic counseling is always advised. Currently, there is no therapy that stops the evolution of the disease or restores the vision, so the visual prognosis is poor. The therapeutic approach is restricted to slowing down the degenerative process by sunlight protection and vitaminotherapy, treating the complications (cataract and macular edema, and helping patients to cope with the social and psychological impact of blindness. However, new therapeutic strategies are emerging from intensive research (gene therapy, neuroprotection, retinal prosthesis.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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....

  17. 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...

  18. 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

  19. 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.

  20. A gene for autosomal dominant progressive cone dystrophy (CORD5) maps to chromosome 17p12-p13

    Energy Technology Data Exchange (ETDEWEB)

    Balciuniene, J.; Holmgren, G.; Forsman, K. [University Hospital, Umea (Sweden)] [and others

    1995-11-20

    Inherited retinal dystrophy is a common cause of visual impairment. Cone dystrophy affects the cone function and is manifested as progressive loss of the central vision, defective color vision, and photophobia. Linkage was demonstrated between progressive cone dystrophy (CORD5) and genetic markers on chromosome 17p12-p13 in a five-generation family. Multipoint analysis gave a maximum lod score of 7.72 at the marker D17S938. Recombinant haplotypes in the family suggest that the cone dystrophy locus is located in a 25-cM interval between the markers D17S926/D17S849 and D17S804/D17S945. Furthermore, one recombination was detected between the disease locus and a microsatellite marker in the candidate gene RCV1, encoding the retinal protein recoverin. Two additional candidate genes encoding retinal guanylate cyclase (GUC2D) and pigment epithelium-derived factor (PEDF) are located at 17p13.1. Moreover, loci for retinitis pigmentosa and Leber congenital amaurosis have been mapped to the same region. Identification of the cone dystrophy locus may be of importance not only for identifying functional genes in the cone system, but also for identifying genes for other retinal disorders. 34 refs., 3 figs., 2 tabs.

  1. Dominant inheritance of retinal ganglion cell resistance to optic nerve crush in mice

    Directory of Open Access Journals (Sweden)

    Schlamp Cassandra L

    2007-03-01

    Full Text Available Abstract Background Several neurodegenerative diseases are influenced by complex genetics that affect an individual's susceptibility, disease severity, and rate of progression. One such disease is glaucoma, a chronic neurodegenerative condition of the eye that targets and stimulates apoptosis of CNS neurons called retinal ganglion cells. Since ganglion cell death is intrinsic, it is reasonable that the genes that control this process may contribute to the complex genetics that affect ganglion cell susceptibility to disease. To determine if genetic background influences susceptibility to optic nerve damage, leading to ganglion cell death, we performed optic nerve crush on 15 different inbred lines of mice and measured ganglion cell loss. Resistant and susceptible strains were used in a reciprocal breeding strategy to examine the inheritance pattern of the resistance phenotype. Because earlier studies had implicated Bax as a susceptibility allele for ganglion cell death in the chronic neurodegenerative disease glaucoma, we conducted allelic segregation analysis and mRNA quantification to assess this gene as a candidate for the cell death phenotype. Results Inbred lines showed varying levels of susceptibility to optic nerve crush. DBA/2J mice were most resistant and BALB/cByJ mice were most susceptible. F1 mice from these lines inherited the DBA/2J phenotype, while N2 backcross mice exhibited the BALB/cByJ phenotype. F2 mice exhibited an intermediate phenotype. A Wright Formula calculation suggested as few as 2 dominant loci were linked to the resistance phenotype, which was corroborated by a Punnett Square analysis of the distribution of the mean phenotype in each cross. The levels of latent Bax mRNA were the same in both lines, and Bax alleles did not segregate with phenotype in N2 and F2 mice. Conclusion Inbred mice show different levels of resistance to optic nerve crush. The resistance phenotype is heritable in a dominant fashion involving

  2. An autosomal recessive leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa maps to chromosome 17q24.2-25.3

    Directory of Open Access Journals (Sweden)

    Bouhouche Ahmed

    2012-03-01

    Full Text Available Abstract Background Single-gene disorders related to ischemic stroke seem to be an important cause of stroke in young patients without known risk factors. To identify new genes responsible of such diseases, we studied a consanguineous Moroccan family with three affected individuals displaying hereditary leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa that appears to segregate in autosomal recessive pattern. Methods All family members underwent neurological and radiological examinations. A genome wide search was conducted in this family using the ABI PRISM linkage mapping set version 2.5 from Applied Biosystems. Six candidate genes within the region linked to the disease were screened for mutations by direct sequencing. Results Evidence of linkage was obtained on chromosome 17q24.2-25.3. Analysis of recombination events and LOD score calculation suggests linkage of the responsible gene in a genetic interval of 11 Mb located between D17S789 and D17S1806 with a maximal multipoint LOD score of 2.90. Sequencing of seven candidate genes in this locus, ATP5H, FDXR, SLC25A19, MCT8, CYGB, KCNJ16 and GRIN2C, identified three missense mutations in the FDXR gene which were also found in a homozygous state in three healthy controls, suggesting that these variants are not disease-causing mutations in the family. Conclusion A novel locus for leucoencephalopathy with ischemic stroke, dysmorphic syndrome and retinitis pigmentosa has been mapped to chromosome 17q24.2-25.3 in a consanguineous Moroccan family.

  3. 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

  4. 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

  5. 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

  6. 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.

  7. 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...

  8. 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...

  9. 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).

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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

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

    Science.gov (United States)

    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.

  16. 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.)

  17. 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.

  18. 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...

  19. 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.

  20. 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

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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

  9. 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.

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

    Institute of Scientific and Technical Information of China (English)

    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.

  11. 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.

  12. 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.

  13. Rgcs1, a dominant QTL that affects retinal ganglion cell death after optic nerve crush in mice

    Directory of Open Access Journals (Sweden)

    Schlamp Cassandra L

    2008-07-01

    Full Text Available Abstract Background Intrinsic apoptosis of neuronal somas is one aspect of neurodegenerative diseases that can be influenced by genetic background. Genes that affect this process may act as susceptibility alleles that contribute to the complex genetic nature of these diseases. Retinal ganglion cell death is a defining feature of the chronic and genetically complex neurodegenerative disease glaucoma. Previous studies using an optic nerve crush procedure in inbred mice, showed that ganglion cell resistance to crush was affected by the Mendelian-dominant inheritance of 1–2 predicted loci. To assess this further, we bred and phenotyped a large population of F2 mice derived from a resistant inbred strain (DBA/2J and a susceptible strain (BALB/cByJ. Results Genome wide mapping of the F2 mice using microsatellite markers, detected a single highly significant quantitative trait locus in a 25 cM (58 Mb interval on chromosome 5 (Chr5.loc34-59 cM. No interacting loci were detected at the resolution of this screen. We have designated this locus as Retinal ganglion cell susceptible 1, Rgcs1. In silico analysis of this region revealed the presence of 578 genes or expressed sequence tags, 4 of which are highly expressed in the ganglion cell layer of the mammalian retina, and 2 of which are suspected susceptibility alleles in chronic neurodegenerative diseases. In addition, 25 genes contain 36 known single nucleotide polymorphisms that create nonsynonymous amino acid changes between the two parental strains. Collectively, this analysis has identified 7 potential candidate genes that may affect ganglion cell death. Conclusion The process of ganglion cell death is likely one of the many facets of glaucoma susceptibility. A novel dominant locus has been identified that affects sensitivity of ganglion cells to optic nerve crush. The allele responsible for this sensitivity may also be a susceptibility allele for glaucoma.

  14. 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

  15. 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

  16. 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...

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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.)

  4. 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.

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

    Science.gov (United States)

    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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. A missense mutation in the alpha-actinin 1 gene (ACTN1 is the cause of autosomal dominant macrothrombocytopenia in a large French family.

    Directory of Open Access Journals (Sweden)

    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.

  13. 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

  14. 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.

  15. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. 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.

  18. 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.

  19. 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.

  20. Cyst infection in hospital-admitted autosomal dominant polycystic kidney disease patients is predominantly multifocal and associated with kidney and liver volume

    Energy Technology Data Exchange (ETDEWEB)

    Balbo, B.E.P. [Divisão de Nefrologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Sapienza, M.T.; Ono, C.R. [Divisão de Medicina Nuclear, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Jayanthi, S.K. [Divisão de Radiologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Dettoni, J.B. [Divisão de Patologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Castro, I.; Onuchic, L.F. [Divisão de Nefrologia, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

    2014-06-13

    Positron-emission tomography/computed tomography (PET/CT) has improved cyst infection (CI) management in autosomal dominant polycystic kidney disease (ADPKD). The determinants of kidney and/or liver involvement, however, remain uncertain. In this study, we evaluated clinical and imaging factors associated with CI in kidney (KCI) and liver (LCI) in ADPKD. A retrospective cohort study was performed in hospital-admitted ADPKD patients with suspected CI. Clinical, imaging and surgical data were analyzed. Features of infected cysts were evaluated by PET/CT. Total kidney (TKV) and liver (TLV) volumes were measured by CT-derived multiplanar reconstruction. CI was detected in 18 patients who experienced 24 episodes during an interval of 30 months (LCI in 12, KCI in 10 and concomitant infection in 2). Sensitivities of CT, magnetic resonance imaging and PET/CT were 25.0, 71.4, and 95.0%. Dysuria (P<0.05), positive urine culture (P<0.01), and previous hematuria (P<0.05) were associated with KCI. Weight loss (P<0.01) and increased C-reactive protein levels (P<0.05) were associated with LCI. PET/CT revealed that three or more infected cysts were present in 70% of the episodes. TKV was higher in kidney-affected than in LCI patients (AUC=0.91, P<0.05), with a cut-off of 2502 mL (72.7% sensitivity, 100.0% specificity). TLV was higher in liver-affected than in KCI patients (AUC=0.89, P<0.01) with a cut-off of 2815 mL (80.0% sensitivity, 87.5% specificity). A greater need for invasive procedures was observed in LCI (P<0.01), and the overall mortality was 20.8%. This study supports PET/CT as the most sensitive imaging method for diagnosis of cyst infection, confirms the multifocal nature of most hospital-admitted episodes, and reveals an association of kidney and liver volumes with this complication.

  1. 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

  2. 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,

  3. Marfan Syndrome Presenting with Bilateral Retinal Detachment

    Directory of Open Access Journals (Sweden)

    Subrata Chakrabarti

    2014-02-01

    Full Text Available Marfan syndrome is an autosomal dominant systemic disorder of the connective tissue. Marfan syndrome affects most organs and tissues, especially the skeleton, lungs, eyes, heart, and the large blood vessels. Eye involvement may be in the form of retinal detachment which is a potentially dangerous manifestation for its sight threatening nature .We report a case where a 17 year old male developed sudden blindness due to spontaneous bilateral retinal detachment. Examination revealed features of Marfan syndrome and was stamped as a case of Marfan syndrome by Ghent criteria . The point to stress upon is that a young male developing spontaneous retinal detachment, a diagnosis of underlying Marfan syndrome should be kept in mind if appropriate clinical stigmata are present. [Natl J Med Res 2014; 4(1.000: 104-105

  4. 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.

  5. Ribozyme uses in retinal gene therapy.

    Science.gov (United States)

    Hauswirth, W W; Lewin, A S

    2000-11-01

    In this chapter we discuss the design, delivery and preclinical testing of mutation-specific ribozymes for the treatment of dominantly inherited retinal disease. We focus particular attention on the initial screening of ribozymes in vitro, because the activity of RNA enzymes in cell-free systems can be used to predict their suitability for animal experiments. Current techniques for delivering genes of interest to cells of the retina using viral vectors are then briefly surveyed emphasizing vector properties that best match to the needs of a ribozyme-based therapy. Using these considerations, analysis of ribozyme gene therapy for an autosomal dominant RP-like disease in a rodent model is outlined emphasizing the desirability of combining biochemical, morphological and electrophysiological measures of therapy. Finally, we describe alternative, perhaps more general, ribozyme approaches that have yet to be tested in the context of retinal disease.

  6. 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 ...

  7. Safranal, a saffron constituent, attenuates retinal degeneration in P23H rats.

    Directory of Open Access Journals (Sweden)

    Laura Fernández-Sánchez

    Full Text Available Saffron, an extract from Crocus sativus, has been largely used in traditional medicine for its antiapoptotic and anticarcinogenic properties. In this work, we investigate the effects of safranal, a component of saffron stigmas, in attenuating retinal degeneration in the P23H rat model of autosomal dominant retinitis pigmentosa. We demonstrate that administration of safranal to homozygous P23H line-3 rats preserves both photoreceptor morphology and number. Electroretinographic recordings showed higher a- and b-wave amplitudes under both photopic and scotopic conditions in safranal-treated versus non-treated animals. Furthermore, the capillary network in safranal-treated animals was preserved, unlike that found in untreated animals. Our findings indicate that dietary supplementation with safranal slows photoreceptor cell degeneration and ameliorates the loss of retinal function and vascular network disruption in P23H rats. This work also suggests that safranal could be potentially useful to retard retinal degeneration in patients with retinitis pigmentosa.

  8. Safranal, a saffron constituent, attenuates retinal degeneration in P23H rats.

    Science.gov (United States)

    Fernández-Sánchez, Laura; Lax, Pedro; Esquiva, Gema; Martín-Nieto, José; Pinilla, Isabel; Cuenca, Nicolás

    2012-01-01

    Saffron, an extract from Crocus sativus, has been largely used in traditional medicine for its antiapoptotic and anticarcinogenic properties. In this work, we investigate the effects of safranal, a component of saffron stigmas, in attenuating retinal degeneration in the P23H rat model of autosomal dominant retinitis pigmentosa. We demonstrate that administration of safranal to homozygous P23H line-3 rats preserves both photoreceptor morphology and number. Electroretinographic recordings showed higher a- and b-wave amplitudes under both photopic and scotopic conditions in safranal-treated versus non-treated animals. Furthermore, the capillary network in safranal-treated animals was preserved, unlike that found in untreated animals. Our findings indicate that dietary supplementation with safranal slows photoreceptor cell degeneration and ameliorates the loss of retinal function and vascular network disruption in P23H rats. This work also suggests that safranal could be potentially useful to retard retinal degeneration in patients with retinitis pigmentosa.

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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 ...

  14. The incidence of HLA-SD antigens in recessive retinitis pigmentosa.

    Science.gov (United States)

    Chen, M C; Marak, G E; Pilkerton, A R

    1978-01-01

    Eighteen patients with recessive retinitis pigmentosa were tissue typed for HLA-SD antigens. There was no evidence that a particular HLA-SD antigen was associated with autosomal recessive retinitis pigmentosa. PMID:638110

  15. 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

  16. 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

  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. 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.

  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. UNILATERAL RETINAL VASCULAR MALFORMATION IN HEREDITARY HEMORRHAGIC TELANGIECTASIA

    Directory of Open Access Journals (Sweden)

    Ananth Bhandary

    2014-07-01

    Full Text Available Hereditary hemorrhagic telangeiectasia (HHT is an autosomal dominant genetic disorder that leads to vascular malformations. It was first recognized in the 19th century as a familial disorder with abnormal vascular structures causing bleeding from the nose and gastrointestinal tract. HHT is characterized by telangiectatic lesions of the nose, lips, lungs, brain, and spinal cord. The reported incidence in Europe and Japan is between 1:5000 and 1:8000; but is widely variable in other regions. It is seen more frequently in whites. Ocular involvement has been reported in patients with HHT. Although conjunctival telangiectasia is the most common manifestation, rarely intraocular vascular lesions such as retinal telangiectasia and arteriovenous malformations in the retina, are seen. We describe a patient with HHT who had an abnormal unilateral retinal vascular abnormality along with tortuous conjunctival vasculature in the other eye, which has not been reported till date

  3. Mutation analysis of codons 345 and 347 of rhodopsin gene in Indian retinitis pigmentosa patients

    Indian Academy of Sciences (India)

    Madhurima Dikshit; Rakhi Agarwal

    2001-08-01

    More than 100 mutations have been reported till date in the rhodopsin gene in patients with retinitis pigmentosa. The present study was undertaken to detect the reported rhodopsin gene point mutations in Indian retinitis pigmentosa patients. We looked for presence or absence of codon 345 and 347 mutations in exon 5 of the gene using the technique of allele-specific polymerase chain reaction by designing primers for each mutation. We have examined 100 patients from 76 families irrespective of genetic categories. Surprisingly, in our sample the very widely reported highly frequent mutations of codon 347 (P → S/A/R/Q/L/T) were absent while the codon 345 mutation V → M was seen in three cases in one family (autosomal dominant form) and in one sporadic case (total two families). This is the first report on codon 345 and 347 mutation in Indian retinitis pigmentosa subjects.

  4. Axonal loss occurs early in dominant optic atrophy

    DEFF Research Database (Denmark)

    Milea, Dan; Sander, Birgit; Wegener, Marianne

    2010-01-01

    Purpose: This study set out to investigate retinal nerve fibre layer (RNFL) thickness and best corrected visual acuity (BCVA) in relation to age in healthy subjects and patients with OPA1 autosomal dominant optic atrophy (DOA). Methods: We carried out a cross-sectional investigation of RNFL...... thickness and ganglion cell layer density in 30 healthy subjects and 10 patients with OPA1 DOA using optical coherence tomography (OCT). We then performed a regression analysis of RNFL thickness and BCVA versus age. Results: Both healthy subjects and DOA patients demonstrated a gradual reduction in RNFL...

  5. A genetic analysis of retinitis pigmentosa

    Directory of Open Access Journals (Sweden)

    Shanker Jayashree

    1993-01-01

    Full Text Available The data consists of sixty probands affected with Retinitis pigmentosa. Syndromic cases were found in five percent of the RP probands. Segregation analysis was carried out on proband sibship data. The ascertainment probability was estimated at 0.5517. Analysis of the data by parental mating types of proband sibships indicated the presence of dominant forms of RP (2.05%. Analysis of proband sibships indicated the presence of low risk families in the Normal x Normal matings (45% and in the consanguineous matings (40%. The hypothesis of recessive inheritance could be confirmed only in multiplex sibships (p = 0.383 +/- 0.0793. Data on proband matings though incomplete conformed in general to autosomal recessive gene hypothesis.

  6. 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.

  7. Search for a correlation between telomere length and severity of retinitis pigmentosa due to the dominant rhodopsin Pro23His mutation

    NARCIS (Netherlands)

    Hartong, Dyonne T.; McGee, Terri L.; Sandberg, Michael A.; Berson, Eliot L.; Asselbergs, Folkert W.; van der Harst, Pim; De Vivo, Immaculata; Dryja, Thaddeus P.

    2009-01-01

    Purpose: Great variation exists in the age of onset of symptoms and the severity of disease at a given age in patients with retinitis pigmentosa ( RP). The final pathway for this disease may involve apoptotic photoreceptor cell death. Telomere length is associated with biologic aging, senescence, an

  8. Neuroprotective effects of the cannabinoid agonist HU210 on retinal degeneration

    OpenAIRE

    Lax Zapata, Pedro; Esquiva Sobrino, Gema; Altavilla, Cesare; Cuenca Navarro, Nicolás

    2014-01-01

    Cannabinoids have been demonstrated to exert neuroprotective effects on different types of neuronal insults. Here we have addressed the therapeutic potential of the synthetic cannabinoid HU210 on photoreceptor degeneration, synaptic connectivity and functional activity of the retina in the transgenic P23H rat, an animal model for autosomal dominant retinitis pigmentosa (RP). In P23H rats administered with HU210 (100 μg/kg, i.p.) from P24 to P90, ERG recordings showed an amelioration of vision...

  9. [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.

  10. 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

  11. PHAKOMATOSIS : INTRESTING CASES OF TUBEROUS SCLEROSIS WITH RETINAL ASTROCYTOMA

    Directory of Open Access Journals (Sweden)

    Srinivasa Rao

    2015-05-01

    Full Text Available NTRODUCTION: Tuberous sclerosis complex (TSC or Morbus Bourneville - Pringle disease is an autosomal dominant phakomatosis, first described by Desiree - Magloire Bourneville in 1880. Tuberous sclerosis is a genetic disorder characterized by the growth of numerous benign tumours in many parts of the body caused by mutations on either of two genes, TSC1 and TSC2. This rare genetic disorder is usually associated with a triad of seizures, mental retardation and cutaneous lesions. Approximately one half of all patients affected by TS develop at least one retinal astrocytoma in one eye. PRESENTATION OF CASES: In the department of ophthalmology, G.S.L M edical C ollege, Rajahmundry, we came across 3 cases of tuberous sclerosis involving multi organ systems. Out of 3 cases, 2 cases were reported to be familial and 1case is sporadic, with a history of epilepsy with angiofibromatosis lesions over the face, multiple ash - leaf lesions over the abdomen, renal angiomyolipomas, multiple subependymal nodules in brain and retinal astrocytic hamartomas in the retina. CONCLUSION: It is important to be cognizant of the likely presence of systemic and ocular pathology in a child with mental retardation and skin lesions. Identification of retinal phakomatosis during ocular evaluation in any suspected case of Tuberous sclerosis can aid in the establishment of the diagnosis of the disease

  12. Temporal retinal nerve fiber loss in patients with spinocerebellar ataxia type 1.

    Directory of Open Access Journals (Sweden)

    Sarah Stricker

    Full Text Available BACKGROUND: Autosomal dominant spinocerebellar ataxia type 1 is an adult onset progressive disorder with well characterized neurodegeneration in the cerebellum and brainstem. Beyond brain atrophy, few data exist concerning retinal and optic nerve involvement. OBJECTIVE: To evaluate retinal changes in SCA1 patients compared to age and gender matched healthy controls. METHODOLOGY/PRINCIPAL FINDINGS: Nine patients with SCA1 were prospectively recruited from the ataxia clinic and were compared to nine age and gender matched healthy controls. Both cohorts received assessment of visually evoked potentials and eye examination by optical coherence tomography to determine retinal nerve fiber layer thickness and total macular volume. While no differences were found in visually evoked potentials, SCA1 patients showed a significant reduction of mean retinal nerve fiber layer thickness (RNFLT compared to healthy controls (84±13 µm vs. 97±8 µm, p = 0.004. Temporal areas showed the most prominent RNFLT reduction with high statistical significances (temporal-inferior: p<0.001, temporal: p<0.001, temporal-superior: p = 0.005 whereas RNFLT in nasal areas was in the range of the control group. From six SCA1 patients an additional macular scan was obtained. The comparison to the corresponding healthy control showed a slight but not significant reduction in TMV (8.22±0.68 mm(3 vs. 8.61±0.41 mm(3, p = 0.15. CONCLUSION: In SCA1 patients, we found evidence for degeneration of retinal nerve fibers. The temporal focus of the observed retinal nerve fiber layer reduction suggests an involvement of the papillo-macular bundle which resembles pathology found in toxic or mitochondrial optic nerve disease such as Leber's hereditary optic neuropathy (LHON or dominant optic atrophy (DOA.

  13. Prevalence of generalized retinal dystrophy in Denmark

    DEFF Research Database (Denmark)

    Bertelsen, Mette; Jensen, Hanne; Bregnhøj, Jesper F;

    2014-01-01

    of this study was to examine the prevalence and diagnostic spectrum of generalized retinal dystrophy in the Danish population. METHODS: A population-based cross-sectional study with data from the Danish Retinitis Pigmentosa Registry that comprises all patients in Denmark with generalized retinal....... RESULTS: Of the 5,602,628 Danish citizens on January 1, 2013, 1622 patients were registered as having a generalized retinal dystrophy and were alive and living in Denmark, corresponding to a prevalence of 1:3,454. In 28% of cases the eye condition was part of a syndrome, while the remaining 72% had eye...... disease only. Aside from simplex cases (45%), the most common hereditary pattern was autosomal recessive (23%). CONCLUSION: This epidemiological survey demonstrates that the prevalence of generalized retinal dystrophy in the Danish population is 1:3454. Many of the dystrophies are the subjects of clinical...

  14. Identification and characterization of autosomal genes that interact with glass in the developing Drosophila eye

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Chaoyong; Liu, Hui; Zhou, Ying; Moses, K. [Univ. of Southern California, Los Angeles, CA (United States)

    1996-04-01

    The glass gene encodes a zinc finger, DNA-binding protein that is required for photoreceptor cell development in Drosophila melanogaster. In the developing compound eye, glass function is regulated at two points: (1) the protein is expressed in all cells` nuclei posterior to the morphogenetic furrow and (2) the ability of the Glass protein to regulate downstream genes is largely limited to the developing photoreceptor cells. We conducted a series of genetic screen for autosomal dominant second-site modifiers of the weak allele glass, to discover genes with products that may regulate glass function at either of these levels. Seventy-six dominant enhancer mutations were recovered (and no dominant suppressors). Most of these dominant mutations are in essential genes and are associated with recessive lethality. We have assigned these mutations to 23 complementation groups that include multiple alleles of Star and hedgehog as well as single alleles of Delta, roughened eye, glass and hairy. Mutations in 18 of the complementation groups are embryonic lethals, and of these, 13 show abnormal adult retinal phenotypes in homozygous clones, usually with altered numbers of photoreceptor cells in some of the ommatidia. 116 refs., 9 figs., 2 tabs.

  15. 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.

  16. 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),

  17. 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

  18. A Nonsense Mutation in PDE6H Causes Autosomal-Recessive Incomplete Achromatopsia.

    NARCIS (Netherlands)

    Kohl, S.; Coppieters, F.; Meire, F.; Schaich, S.; Roosing, S.; Brennenstuhl, C.; Bolz, S.; Genderen, M.M. van; Riemslag, F.C.; Lukowski, R.; Hollander, A.I. den; Cremers, F.P.M.; Baere, E. de; Hoyng, C.B.; Wissinger, B.

    2012-01-01

    Achromatopsia (ACHM) is an autosomal-recessive retinal dystrophy characterized by color blindness, photophobia, nystagmus, and severely reduced visual acuity. Its prevalence has been estimated to about 1 in 30,000 individuals. Four genes, GNAT2, PDE6C, CNGA3, and CNGB3, have been implicated in ACHM,

  19. Novel insights into the molecular pathogenesis of CYP4V2-associated Bietti's retinal dystrophy

    NARCIS (Netherlands)

    Astuti, G.D.N; Sun, V.; Bauwens, M.; Zobor, D.; Leroy, B.P.; Omar, A.; Jurklies, B.; Lopez, I.; Ren, H.; Yazar, V.; Hamel, C.; Kellner, U.; Wissinger, B.; Kohl, S.; Baere, E. De; Collin, R.W.J.; Koenekoop, R.K.

    2015-01-01

    Bietti's crystalline dystrophy (BCD) is a rare, autosomal recessive retinal degenerative disease associated with mutations in CYP4V2. In this study, we describe the genetic and clinical findings in 19 unrelated BCD patients recruited from five international retinal dystrophy clinics. Patients underw

  20. Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration

    NARCIS (Netherlands)

    Nishiguchi, K.M.; Avila-Fernandez, A.; Huet, R.A.C. van; Corton, M.; Perez-Carro, R.; Martin-Garrido, E.; Lopez-Molina, M.I.; Blanco-Kelly, F.; Hoefsloot, L.H.; Zelst-Stams, W.A.G. van; Garcia-Ruiz, P.J.; Val, J. Del; Gioia, S.A. Di; Klevering, B.J.; Warrenburg, B.P.C. van de; Vazquez, C.; Cremers, F.P.M.; Garcia-Sandoval, B.; Hoyng, C.B.; Collin, R.W.J.; Rivolta, C.; Ayuso, C.

    2014-01-01

    OBJECTIVE: To identify the genetic causes underlying autosomal recessive retinitis pigmentosa (arRP) and to describe the associated phenotype. DESIGN: Case series. PARTICIPANTS: Three hundred forty-seven unrelated families affected by arRP and 33 unrelated families affected by retinitis pigmentosa (

  1. 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.

  2. The Finnish lapphund retinal atrophy locus maps to the centromeric region of CFA9

    Directory of Open Access Journals (Sweden)

    Sargan David R

    2007-07-01

    Full Text Available Abstract Background Dogs have the second largest number of genetic diseases, after humans. Among the diseases present in dogs, progressive retinal atrophy has been reported in more than a hundred breeds. In some of them, the mutation has been identified and genetic tests have allowed the identification of carriers, thus enabling a drastic reduction in the incidence of the disease. The Finnish lapphund is a dog breed presenting late-onset progressive retinal atrophy for which the disease locus remains unknown. Results In this study we mapped the progressive retinal atrophy locus in the Finnish lapphund using a DNA pooling approach, assuming that all affected dogs within the breed share the same identical-by descent-mutation as the cause of the disease (genetic homogeneity. Autosomal recessive inheritance was also assumed, after ruling out, from pedigree analysis, dominant and X-linked inheritance. DNA from 12 Finnish lapphund cases was mixed in one pool, and DNA from 12 first-degree relatives of these cases was mixed to serve as the control pool. The 2 pools were tested with 133 microsatellite markers, 3 of which showed a shift towards homozygosity in the cases. Individual genotyping with these 3 markers confirmed homozygosity for the GALK1 microsatellite only (chromosome 9. Further individual genotyping with additional samples (4 cases and 59 controls confirmed the association between this marker and the disease locus (p Conclusion The locus for progressive rod-cone degeneration is known to be close to the GALK1 locus, on the telomeric region of chromosome 9, where the retinal atrophy locus of the Finnish lapphund has been mapped. This suggests that the disease in this breed, as well as in the Swedish lapphund, may correspond to progressive rod-cone degeneration. This would increase the number of known dog breeds having this particular form of progressive retinal atrophy.

  3. Retinitis pigmentosa

    NARCIS (Netherlands)

    Hartong, Dyonne T.; Berson, Eliot L.; Dryja, Thaddeus P.

    2006-01-01

    Hereditary degenerations of the human retina are genetically heterogeneous, with well over 100 genes implicated so far. This Seminar focuses on the subset of diseases called retinitis pigmentosa, in which patients typically lose night vision in adolescence, side vision in young adulthood, and centra

  4. Neuroprotective effects of the cannabinoid agonist HU210 on retinal degeneration.

    Science.gov (United States)

    Lax, Pedro; Esquiva, Gema; Altavilla, Cesare; Cuenca, Nicolás

    2014-03-01

    Cannabinoids have been demonstrated to exert neuroprotective effects on different types of neuronal insults. Here we have addressed the therapeutic potential of the synthetic cannabinoid HU210 on photoreceptor degeneration, synaptic connectivity and functional activity of the retina in the transgenic P23H rat, an animal model for autosomal dominant retinitis pigmentosa (RP). In P23H rats administered with HU210 (100 μg/kg, i.p.) from P24 to P90, ERG recordings showed an amelioration of vision loss, as compared to vehicle-administered animals. Under scotopic conditions, the maximum a-wave amplitudes recorded at P60 and P90 were higher in HU210-treated animals, as compared to the values obtained in untreated animals. The scotopic b-waves were significantly higher in treated animals than in untreated rats at P30, P60 and P90. This attenuation of visual deterioration correlated with a delay in photoreceptor degeneration and the preservation of retinal cytoarchitecture. HU210-treated animals had 40% more photoreceptors than untreated animals. Presynaptic and postsynaptic elements, as well as the synaptic contacts between photoreceptors and bipolar or horizontal cells, were also preserved in HU210-treated P23H rats. These results indicate that HU210 preserves cone and rod structure and function, together with their contacts with postsynaptic neurons, in P23H rats. These data suggest that cannabinoids are potentially useful to delay retinal degeneration in RP patients.

  5. 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.

  6. 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 ...

  7. 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.

  8. 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.

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

    Directory of Open Access Journals (Sweden)

    Raghu Tanjore

    2001-09-01

    Full Text Available Progeria is an autosomal dominant, premature aging syndrome. Six and three year old female siblings had sclcrodermatous changes over the extremities, alopecia, beaked nose, prominent veins and bird-like facies. Radiological features were consistent with features of progeria. The present case highlights rarity of progeria in siblings with a possible autosomal recessive pattern.

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. 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

  15. Rhodopsin gene expression determines rod outer segment size and rod cell resistance to a dominant-negative neurodegeneration mutant.

    Directory of Open Access Journals (Sweden)

    Brandee A Price

    Full Text Available Two outstanding unknowns in the biology of photoreceptors are the molecular determinants of cell size, which is remarkably uniform among mammalian species, and the mechanisms of rod cell death associated with inherited neurodegenerative blinding diseases such as retinitis pigmentosa. We have addressed both questions by performing an in vivo titration with rhodopsin gene copies in genetically engineered mice that express only normal rhodopsin or an autosomal dominant allele, encoding rhodopsin with a disease-causing P23H substitution. The results reveal that the volume of the rod outer segment is proportional to rhodopsin gene expression; that P23H-rhodopsin, the most common rhodopsin gene disease allele, causes cell death via a dominant-negative mechanism; and that long term survival of rod cells carrying P23H-rhodopsin can be achieved by increasing the levels of wild type rhodopsin. These results point to promising directions in gene therapy for autosomal dominant neurodegenerative diseases caused by dominant-negative mutations.

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. Structural modeling of a novel CAPN5 mutation that causes uveitis and neovascular retinal detachment.

    Directory of Open Access Journals (Sweden)

    Alexander G Bassuk

    Full Text Available CAPN5 mutations have been linked to autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV, a blinding autoimmune eye disease. Here, we link a new CAPN5 mutation to ADNIV and model the three-dimensional structure of the resulting mutant protein. In our study, a kindred with inflammatory vitreoretinopathy was evaluated by clinical eye examinations, DNA sequencing, and protein structural modeling to investigate the disease-causing mutation. Two daughters of an affected mother demonstrated symptoms of stage III ADNIV, with posterior uveitis, cystoid macular edema, intraocular fibrosis, retinal neovascularization, retinal degeneration, and cataract. The women also harbored a novel guanine to thymine (c.750G>T, p.Lys250Asn missense mutation in exon 6 of CAPN5, a gene that encodes a calcium-activated cysteine protease, calpain-5. Modeling based on the structures of all known calpains revealed the mutation falls within a calcium-sensitive flexible gating loop that controls access to the catalytic groove. Three-dimensional modeling placed the new mutation in a region adjacent to two previously identified disease-causing mutations, all three of which likely disrupt hydrogen bonding within the gating loop, yielding a CAPN5 with altered enzymatic activity. This is the third case of a CAPN5 mutation leading to inherited uveitis and neovascular vitreoretinopathy, suggesting patients with ADNIV features should be tested for CAPN5 mutations. Structural modeling of novel variants can be used to support mechanistic consequences of the disease-causing variants.

  2. Multimodal Imaging in Hereditary Retinal Diseases

    Directory of Open Access Journals (Sweden)

    Francesco Pichi

    2013-01-01

    Full Text Available Introduction. In this retrospective study we evaluated the multimodal visualization of retinal genetic diseases to better understand their natural course. Material and Methods. We reviewed the charts of 70 consecutive patients with different genetic retinal pathologies who had previously undergone multimodal imaging analyses. Genomic DNA was extracted from peripheral blood and genotyped at the known locus for the different diseases. Results. The medical records of 3 families of a 4-generation pedigree affected by North Carolina macular dystrophy were reviewed. A total of 8 patients with Stargardt disease were evaluated for their two main defining clinical characteristics, yellow subretinal flecks and central atrophy. Nine male patients with a previous diagnosis of choroideremia and eleven female carriers were evaluated. Fourteen patients with Best vitelliform macular dystrophy and 6 family members with autosomal recessive bestrophinopathy were included. Seven patients with enhanced s-cone syndrome were ascertained. Lastly, we included 3 unrelated patients with fundus albipunctatus. Conclusions. In hereditary retinal diseases, clinical examination is often not sufficient for evaluating the patient’s condition. Retinal imaging then becomes important in making the diagnosis, in monitoring the progression of disease, and as a surrogate outcome measure of the efficacy of an intervention.

  3. Inherited Retinal Degenerative Clinical Trial Network. Addendum

    Science.gov (United States)

    2013-10-01

    and the impact of low study drug exposure on efficacy outcomes. Dr. Zill iox also requested that the DSMB discuss the population that would define...autosomal dominant mutations. Dr. Zill iox agreed with not reducing the sample size, noting that tltis request for consideration of sample size reduction

  4. 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

  5. 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

  6. 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.

  7. Loss of Ikbkap Causes Slow, Progressive Retinal Degeneration in a Mouse Model of Familial Dysautonomia

    Science.gov (United States)

    Ramirez, Grisela

    2016-01-01

    Abstract Familial dysautonomia (FD) is an autosomal recessive congenital neuropathy that is caused by a mutation in the gene for inhibitor of kappa B kinase complex-associated protein (IKBKAP). Although FD patients suffer from multiple neuropathies, a major debilitation that affects their quality of life is progressive blindness. To determine the requirement for Ikbkap in the developing and adult retina, we generated Ikbkap conditional knockout (CKO) mice using a TUBA1a promoter-Cre (Tα1-Cre). In the retina, Tα1-Cre expression is detected predominantly in retinal ganglion cells (RGCs). At 6 months, significant loss of RGCs had occurred in the CKO retinas, with the greatest loss in the temporal retina, which is the same spatial phenotype observed in FD, Leber hereditary optic neuropathy, and dominant optic atrophy. Interestingly, the melanopsin-positive RGCs were resistant to degeneration. By 9 months, signs of photoreceptor degeneration were observed, which later progressed to panretinal degeneration, including RGC and photoreceptor loss, optic nerve thinning, Müller glial activation, and disruption of layers. Taking these results together, we conclude that although Ikbkap is not required for normal development of RGCs, its loss causes a slow, progressive RGC degeneration most severely in the temporal retina, which is later followed by indirect photoreceptor loss and complete retinal disorganization. This mouse model of FD is not only useful for identifying the mechanisms mediating retinal degeneration, but also provides a model system in which to attempt to test therapeutics that may mitigate the loss of vision in FD patients. PMID:27699209

  8. Expression of wild-type Rp1 protein in Rp1 knock-in mice rescues the retinal degeneration phenotype.

    Directory of Open Access Journals (Sweden)

    Qin Liu

    Full Text Available Mutations in the retinitis pigmentosa 1 (RP1 gene are a common cause of autosomal dominant retinitis pigmentosa (adRP, and have also been found to cause autosomal recessive RP (arRP in a few families. The 33 dominant mutations and 6 recessive RP1 mutations identified to date are all nonsense or frameshift mutations, and almost exclusively (38 out of 39 are located in the 4(th and final exon of RP1. To better understand the underlying disease mechanisms of and help develop therapeutic strategies for RP1 disease, we performed a series of human genetic and animal studies using gene targeted and transgenic mice. Here we report that a frameshift mutation in the 3(rd exon of RP1 (c.686delC; p.P229QfsX35 found in a patient with recessive RP1 disease causes RP in the homozygous state, whereas the heterozygous carriers are unaffected, confirming that haploinsufficiency is not the causative mechanism for RP1 disease. We then generated Rp1 knock-in mice with a nonsense Q662X mutation in exon 4, as well as Rp1 transgenic mice carrying a wild-type BAC Rp1 transgene. The Rp1-Q662X allele produces a truncated Rp1 protein, and homozygous Rp1-Q662X mice experience a progressive photoreceptor degeneration characterized disorganization of photoreceptor outer segments. This phenotype could be prevented by expression of a normal amount of Rp1 protein from the BAC transgene without removal of the mutant Rp1-Q662X protein. Over-expression of Rp1 protein in additional BAC Rp1 transgenic lines resulted in retinal degeneration. These findings suggest that the truncated Rp1-Q662X protein does not exert a toxic gain-of-function effect. These results also imply that in principle gene augmentation therapy could be beneficial for both recessive and dominant RP1 patients, but the levels of RP1 protein delivered for therapy will have to be carefully controlled.

  9. 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

  10. Retinal remodeling in human retinitis pigmentosa.

    Science.gov (United States)

    Jones, B W; Pfeiffer, R L; Ferrell, W D; Watt, C B; Marmor, M; Marc, R E

    2016-09-01

    Retinitis Pigmentosa (RP) in the human is a progressive, currently irreversible neural degenerative disease usually caused by gene defects that disrupt the function or architecture of the photoreceptors. While RP can initially be a disease of photoreceptors, there is increasing evidence that the inner retina becomes progressively disorganized as the outer retina degenerates. These alterations have been extensively described in animal models, but remodeling in humans has not been as well characterized. This study, using computational molecular phenotyping (CMP) seeks to advance our understanding of the retinal remodeling process in humans. We describe cone mediated preservation of overall topology, retinal reprogramming in the earliest stages of the disease in retinal bipolar cells, and alterations in both small molecule and protein signatures of neurons and glia. Furthermore, while Müller glia appear to be some of the last cells left in the degenerate retina, they are also one of the first cell classes in the neural retina to respond to stress which may reveal mechanisms related to remodeling and cell death in other retinal cell classes. Also fundamentally important is the finding that retinal network topologies are altered. Our results suggest interventions that presume substantial preservation of the neural retina will likely fail in late stages of the disease. Even early intervention offers no guarantee that the interventions will be immune to progressive remodeling. Fundamental work in the biology and mechanisms of disease progression are needed to support vision rescue strategies.

  11. Orthogonal moments for determining correspondence between vessel bifurcations for retinal image registration.

    Science.gov (United States)

    Patankar, Sanika S; Kulkarni, Jayant V

    2015-05-01

    Retinal image registration is a necessary step in diagnosis and monitoring of Diabetes Retinopathy (DR), which is one of the leading causes of blindness. Long term diabetes affects the retinal blood vessels and capillaries eventually causing blindness. This progressive damage to retina and subsequent blindness can be prevented by periodic retinal screening. The extent of damage caused by DR can be assessed by comparing retinal images captured during periodic retinal screenings. During image acquisition at the time of periodic screenings translation, rotation and scale (TRS) are introduced in the retinal images. Therefore retinal image registration is an essential step in automated system for screening, diagnosis, treatment and evaluation of DR. This paper presents an algorithm for registration of retinal images using orthogonal moment invariants as features for determining the correspondence between the dominant points (vessel bifurcations) in the reference and test retinal images. As orthogonal moments are invariant to TRS; moment invariants features around a vessel bifurcation are unaltered due to TRS and can be used to determine the correspondence between reference and test retinal images. The vessel bifurcation points are located in segmented, thinned (mono pixel vessel width) retinal images and labeled in corresponding grayscale retinal images. The correspondence between vessel bifurcations in reference and test retinal image is established based on moment invariants features. Further the TRS in test retinal image with respect to reference retinal image is estimated using similarity transformation. The test retinal image is aligned with reference retinal image using the estimated registration parameters. The accuracy of registration is evaluated in terms of mean error and standard deviation of the labeled vessel bifurcation points in the aligned images. The experimentation is carried out on DRIVE database, STARE database, VARIA database and database provided

  12. 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

  13. 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

  14. 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

  15. Improving the management of Inherited Retinal Dystrophies by targeted sequencing of a population-specific gene panel

    Science.gov (United States)

    Bravo-Gil, Nereida; Méndez-Vidal, Cristina; Romero-Pérez, Laura; González-del Pozo, María; Rodríguez-de la Rúa, Enrique; Dopazo, Joaquín; Borrego, Salud; Antiñolo, Guillermo

    2016-01-01

    Next-generation sequencing (NGS) has overcome important limitations to the molecular diagnosis of Inherited Retinal Dystrophies (IRD) such as the high clinical and genetic heterogeneity and the overlapping phenotypes. The purpose of this study was the identification of the genetic defect in 32 Spanish families with different forms of IRD. With that aim, we implemented a custom NGS panel comprising 64 IRD-associated genes in our population, and three disease-associated intronic regions. A total of 37 pathogenic mutations (14 novels) were found in 73% of IRD patients ranging from 50% for autosomal dominant cases, 75% for syndromic cases, 83% for autosomal recessive cases, and 100% for X-linked cases. Additionally, unexpected phenotype-genotype correlations were found in 6 probands, which led to the refinement of their clinical diagnoses. Furthermore, intra- and interfamilial phenotypic variability was observed in two cases. Moreover, two cases unsuccessfully analysed by exome sequencing were resolved by applying this panel. Our results demonstrate that this hypothesis-free approach based on frequently mutated, population-specific loci is highly cost-efficient for the routine diagnosis of this heterogeneous condition and allows the unbiased analysis of a miscellaneous cohort. The molecular information found here has aid clinical diagnosis and has improved genetic counselling and patient management. PMID:27032803

  16. Characterisation of a C1qtnf5 Ser163Arg knock-in mouse model of late-onset retinal macular degeneration.

    Directory of Open Access Journals (Sweden)

    Xinhua Shu

    Full Text Available A single founder mutation resulting in a Ser163Arg substitution in the C1QTNF5 gene product causes autosomal dominant late-onset retinal macular degeneration (L-ORMD in humans, which has clinical and pathological features resembling age-related macular degeneration. We generated and characterised a mouse "knock-in" model carrying the Ser163Arg mutation in the orthologous murine C1qtnf5 gene by site-directed mutagenesis and homologous recombination into mouse embryonic stem cells. Biochemical, immunological, electron microscopic, fundus autofluorescence, electroretinography and laser photocoagulation analyses were used to characterise the mouse model. Heterozygous and homozygous knock-in mice showed no significant abnormality in any of the above measures at time points up to 2 years. This result contrasts with another C1qtnf5 Ser163Arg knock-in mouse which showed most of the features of L-ORMD but differed in genetic background and targeting construct.

  17. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism

    DEFF Research Database (Denmark)

    Grønskov, Karen; Dooley, Christopher M; Østergaard, Elsebet

    2013-01-01

    in an individual originating from Lithuania. Immunohistochemistry showed localization of C10orf11 in melanoblasts and melanocytes in human fetal tissue, but no localization was seen in retinal pigment epithelial cells. Knockdown of the zebrafish (Danio rerio) homolog with the use of morpholinos resulted...... in substantially decreased pigmentation and a reduction of the apparent number of pigmented melanocytes. The morphant phenotype was rescued by wild-type C10orf11, but not by mutant C10orf11. In conclusion, we have identified a melanocyte-differentiation gene, C10orf11, which when mutated causes autosomal...

  18. ABCA4 gene analysis in patients with autosomal recessive cone and cone rod dystrophies.

    Science.gov (United States)

    Kitiratschky, Veronique B D; Grau, Tanja; Bernd, Antje; Zrenner, Eberhart; Jägle, Herbert; Renner, Agnes B; Kellner, Ulrich; Rudolph, Günther; Jacobson, Samuel G; Cideciyan, Artur V; Schaich, Simone; Kohl, Susanne; Wissinger, Bernd

    2008-07-01

    The ATP-binding cassette (ABC) transporters constitute a family of large membrane proteins, which transport a variety of substrates across membranes. The ABCA4 protein is expressed in photoreceptors and possibly functions as a transporter for N-retinylidene-phosphatidylethanolamine (N-retinylidene-PE), the Schiff base adduct of all-trans-retinal with PE. Mutations in the ABCA4 gene have been initially associated with autosomal recessive Stargardt disease. Subsequent studies have shown that mutations in ABCA4 can also cause a variety of other retinal dystrophies including cone rod dystrophy and retinitis pigmentosa. To determine the prevalence and mutation spectrum of ABCA4 gene mutations in non-Stargardt phenotypes, we have screened 64 unrelated patients with autosomal recessive cone (arCD) and cone rod dystrophy (arCRD) applying the Asper Ophthalmics ABCR400 microarray followed by DNA sequencing of all coding exons of the ABCA4 gene in subjects with single heterozygous mutations. Disease-associated ABCA4 alleles were identified in 20 of 64 patients with arCD or arCRD. In four of 64 patients (6%) only one mutant ABCA4 allele was detected and in 16 patients (25%), mutations on both ABCA4 alleles were identified. Based on these data we estimate a prevalence of 31% for ABCA4 mutations in arCD and arCRD, supporting the concept that the ABCA4 gene is a major locus for various types of degenerative retinal diseases with abnormalities in cone or both cone and rod function.

  19. Retinal oximetry in patients with ischaemic retinal diseases

    DEFF Research Database (Denmark)

    Rilvén, Sandra; Torp, Thomas Lee; Grauslund, Jakob

    2016-01-01

    The retinal oximeter is a new tool for non-invasive measurement of retinal oxygen saturation in humans. Several studies have investigated the associations between retinal oxygen saturation and retinal diseases. In the present systematic review, we examine whether there are associations between...

  20. Dorzolamide increases retinal oxygen tension after branch retinal vein occlusion

    DEFF Research Database (Denmark)

    Noergaard, Michael Hove; Bach-Holm, Daniella; Scherfig, Erik;

    2008-01-01

    To study the effect of dorzolamide on the preretinal oxygen tension (RPO(2)) in retinal areas affected by experimental branch retinal vein occlusion (BRVO) in pigs.......To study the effect of dorzolamide on the preretinal oxygen tension (RPO(2)) in retinal areas affected by experimental branch retinal vein occlusion (BRVO) in pigs....

  1. 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…

  2. The heat-shock response co-inducer arimoclomol protects against retinal degeneration in rhodopsin retinitis pigmentosa

    Science.gov (United States)

    Parfitt, D A; Aguila, M; McCulley, C H; Bevilacqua, D; Mendes, H F; Athanasiou, D; Novoselov, S S; Kanuga, N; Munro, P M; Coffey, P J; Kalmar, B; Greensmith, L; Cheetham, M E

    2014-01-01

    Retinitis pigmentosa (RP) is a group of inherited diseases that cause blindness due to the progressive death of rod and cone photoreceptors in the retina. There are currently no effective treatments for RP. Inherited mutations in rhodopsin, the light-sensing protein of rod photoreceptor cells, are the most common cause of autosomal-dominant RP. The majority of mutations in rhodopsin, including the common P23H substitution, lead to protein misfolding, which is a feature in many neurodegenerative disorders. Previous studies have shown that upregulating molecular chaperone expression can delay disease progression in models of neurodegeneration. Here, we have explored the potential of the heat-shock protein co-inducer arimoclomol to ameliorate rhodopsin RP. In a cell model of P23H rod opsin RP, arimoclomol reduced P23H rod opsin aggregation and improved viability of mutant rhodopsin-expressing cells. In P23H rhodopsin transgenic rat models, pharmacological potentiation of the stress response with arimoclomol improved electroretinogram responses and prolonged photoreceptor survival, as assessed by measuring outer nuclear layer thickness in the retina. Furthermore, treated animal retinae showed improved photoreceptor outer segment structure and reduced rhodopsin aggregation compared with vehicle-treated controls. The heat-shock response (HSR) was activated in P23H retinae, and this was enhanced with arimoclomol treatment. Furthermore, the unfolded protein response (UPR), which is induced in P23H transgenic rats, was also enhanced in the retinae of arimoclomol-treated animals, suggesting that arimoclomol can potentiate the UPR as well as the HSR. These data suggest that pharmacological enhancement of cellular stress responses may be a potential treatment for rhodopsin RP and that arimoclomol could benefit diseases where ER stress is a factor. PMID:24853414

  3. ER stress in retinal degeneration in S334ter Rho rats.

    Directory of Open Access Journals (Sweden)

    Vishal M Shinde

    Full Text Available The S334ter rhodopsin (Rho rat (line 4 bears the rhodopsin gene with an early termination codon at residue 334 that is a model for several such mutations found in human patients with autosomal dominant retinitis pigmentosa (ADRP. The Unfolded Protein Response (UPR is implicated in the pathophysiology of several retinal disorders including ADRP in P23H Rho rats. The aim of this study was to examine the onset of UPR gene expression in S334ter Rho retinas to determine if UPR is activated in ADRP animal models and to investigate how the activation of UPR molecules leads to the final demise of S334ter Rho photoreceptors. RT-PCR was performed to evaluate the gene expression profiles for the P10, P12, P15, and P21 stages of the development and progression of ADRP in S334ter Rho photoreceptors. We determined that during the P12-P15 period, ER stress-related genes are strongly upregulated in transgenic retinas, resulting in the activation of the UPR that was confirmed using western blot analysis and RT-PCR. The activation of UPR was associated with the increased expression of JNK, Bik, Bim, Bid, Noxa, and Puma genes and cleavage of caspase-12 that together with activated calpains presumably compromise the integrity of the mitochondrial MPTP, leading to the release of pro-apoptotic AIF1 into the cytosol of S334ter Rho photoreceptor cells. Therefore, two major cross-talking pathways, the UPR and mitochondrial MPTP occur in S334ter-4 Rho retina concomitantly and eventually promote the death of the photoreceptor cells.

  4. Terapia gênica em distrofias hereditárias de retina Gene therapy for inherited retinal dystrophies

    Directory of Open Access Journals (Sweden)

    Monique Côco

    2009-08-01

    Full Text Available As distrofias hereditárias de retina abrangem um amplo número de doenças caracterizadas por lenta e progressiva degeneração da retina. São o resultado de mutações em genes expressos em fotorreceptores e no epitélio pigmentado da retina. A herança pode ser autossômica dominante, autossômica recessiva, ligada ao X recessiva, digênica ou herança mitocondrial. Atualmente não há tratamento para essas doenças e os pacientes convivem com a perda progressiva da visão. O aconselhamento genético e o suporte para reabilitação têm indicação nestes casos. Pesquisas envolvendo a base molecular e genética dessas doenças está continuamente em expansão e ampliam as perspectivas para novas formas de tratamento. Dessa forma, a terapia gênica, que consiste na inserção de material genético exógeno em células de um indivíduo com finalidade terapêutica, tem sido a principal forma de tratamento para as distrofias hereditárias de retina. O olho é um órgão peculiar para a terapia gênica, pois é anatomicamente dividido em compartimentos, imunologicamente privilegiado e com meios transparentes. A maioria das doenças oculares tem defeitos em genes conhecidos. Além disso, há modelo animal bem caracterizado para algumas condições. Propostas para pesquisa clínica em terapia gênica nas degenerações retinianas hereditárias com defeito no gene RPE65, recentemente tiveram aprovação ética e os resultados preliminares obtidos trouxeram grandes expectativas na melhora da qualidade de vida dos pacientes.The inherited retinal dystrophies comprise a large number of disorders characterized by a slow and progressive retinal degeneration. They are the result of mutations in genes that express in either the photoreceptor cells or the retinal pigment epithelium. The mode of inheritance can be autosomal dominant, autosomal recessive, X linked recessive, digenic or mitochondrial DNA inherited. At the moment, there is no treatment for these

  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. Progressive outer retinal necrosis-like retinitis in immunocompetent hosts.

    Science.gov (United States)

    Chawla, Rohan; Tripathy, Koushik; Gogia, Varun; Venkatesh, Pradeep

    2016-08-10

    We describe two young immunocompetent women presenting with bilateral retinitis with outer retinal necrosis involving posterior pole with centrifugal spread and multifocal lesions simulating progressive outer retinal necrosis (PORN) like retinitis. Serology was negative for HIV and CD4 counts were normal; however, both women were on oral steroids at presentation for suspected autoimmune chorioretinitis. The retinitis in both eyes responded well to oral valaciclovir therapy. However, the eye with the more fulminant involvement developed retinal detachment with a loss of vision. Retinal atrophy was seen in the less involved eye with preservation of vision. Through these cases, we aim to describe a unique evolution of PORN-like retinitis in immunocompetent women, which was probably aggravated by a short-term immunosuppression secondary to oral steroids.

  7. Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration.

    Science.gov (United States)

    Yang, Zhenglin; Alvarez, Bernardo V; Chakarova, Christina; Jiang, Li; Karan, Goutam; Frederick, Jeanne M; Zhao, Yu; Sauvé, Yves; Li, Xi; Zrenner, Eberhart; Wissinger, Bernd; Hollander, Anneke I Den; Katz, Bradley; Baehr, Wolfgang; Cremers, Frans P; Casey, Joseph R; Bhattacharya, Shomi S; Zhang, Kang

    2005-01-15

    Retina and retinal pigment epithelium (RPE) belong to the metabolically most active tissues in the human body. Efficient removal of acid load from retina and RPE is a critical function mediated by the choriocapillaris. However, the mechanism by which pH homeostasis is maintained is largely unknown. Here, we show that a functional complex of carbonic anhydrase 4 (CA4) and Na+/bicarbonate co-transporter 1 (NBC1) is specifically expressed in the choriocapillaris and that missense mutations in CA4 linked to autosomal dominant rod-cone dystrophy disrupt NBC1-mediated HCO3- transport. Our results identify a novel pathogenic pathway in which a defect in a functional complex involved in maintaining pH balances, but not expressed in retina or RPE, leads to photoreceptor degeneration. The importance of a functional CA4 for survival of photoreceptors implies that CA inhibitors, which are widely used as medications, particularly in the treatment of glaucoma, may have long-term adverse effects on vision.

  8. Evidence for a major retinitis pigmentosa locus on 19q13.4 (RP11), and association with a unique bimodal expressivity phenotype

    Energy Technology Data Exchange (ETDEWEB)

    Al-Maghtheh, M.; Vithana, E.; Tarttelin, E.; Evans, K. [Moorfields Eye Hospital, London (United Kingdom)] [and others

    1996-10-01

    Retinitis pigmentosa (RP) is the name given to a heterogeneous group of retinal degenerations mapping to at least 16 loci. The autosomal dominant form (adRP), accounting for {approximately}25% of cases, can be caused by mutations in two genes, rhodopsin and peripherin/RDS, and by at least six other loci identified by linkage analysis. The RP11 locus for adRP has previously been mapped to chromosome 19q13.4 in a large English family. This linkage has been independently confirmed in a Japanese family, and we now report three additional unrelated linked U.K. families, suggesting that this is a major locus for RP. Linkage analysis in the U.K. families refines the RP11 interval to 5 cM between markers D19S180 and AFMc001yb1. All linked families exhibit incomplete penetrance; some obligate gene carriers remain asymptomatic throughout their lives, whereas symptomatic individuals experience night blindness and visual field loss in their teens and are generally registered as blind by their 30s. This {open_quotes}bimodal expressivity{close_quotes} contrasts with the variable-expressivity RP mapping to chromosome 7p (RP9) in another family, which has implications for diagnosis and counseling of RP11 families. These results may also imply that a proportion of sporadic RP, previously assumed to be recessive, might result from mutations at this locus. 27 refs., 3 figs., 1 tab.

  9. Additivity dominance

    Directory of Open Access Journals (Sweden)

    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.

  10. XLPRA: A canine retinal degeneration inherited as an X-linked trait

    Energy Technology Data Exchange (ETDEWEB)

    Acland, G.M.; Blanton, S.H.; Hershfield, B.; Aguirre, G.D.

    1994-08-01

    Breeding studies are reported of a previously undescribed hereditary retinal degeneration identified in the Siberian Husky breed of dog. This disorder clinically resembles the previously reported autosomal recessive canine hereditary retinal degenerations collectively termed progressive retinal atrophy (PRA). However, the pedigree of the propositus, a male Siberian Husky, exhibited an X-linked pattern of transmission. This dog was outcrossed to three phenotypically normal female laboratory Beagles and two of their F1 daughters were bred to a phenotypically normal male Beagle, producing affected males in the F2 generation. Subsequent inbreedings produced further affected males and affected females as well. X-linked transmission was established by exclusion of alternative modes of inheritance and, consequently, the disease has been termed X-linked progressive retinal atrophy (XLPRA). This is the first reported X-linked retinal degeneration in an animal. Because of the many similarities of PRA in dogs to retinitis pigmentosa (RP) in humans, this new disease may not only represent the first animal model of X-linked RP (XLRP) but may well be a true homolog of one of the XLRP loci (RP2, RP3, RP6). It is the first retinal degeneration in dogs that can be assigned to an identified canine chromosome, and the first for which linkage mapping offers a realistic approach to proceed by positional cloning towards identifying the responsible gene. 58 refs., 1 fig., 3 tabs.

  11. 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 ...

  12. Bioelectronic retinal prosthesis

    Science.gov (United States)

    Weiland, James D.

    2016-05-01

    Retinal prosthesis have been translated to clinical use over the past two decades. Currently, two devices have regulatory approval for the treatment of retinitis pigmentosa and one device is in clinical trials for treatment of age-related macular degeneration. These devices provide partial sight restoration and patients use this improved vision in their everyday lives to navigate and to detect large objects. However, significant vision restoration will require both better technology and improved understanding of the interaction between electrical stimulation and the retina. In particular, current retinal prostheses do not provide peripheral visions due to technical and surgical limitations, thus limiting the effectiveness of the treatment. This paper reviews recent results from human implant patients and presents technical approaches for peripheral vision.

  13. Probabilistic retinal vessel segmentation

    Science.gov (United States)

    Wu, Chang-Hua; Agam, Gady

    2007-03-01

    Optic fundus assessment is widely used for diagnosing vascular and non-vascular pathology. Inspection of the retinal vasculature may reveal hypertension, diabetes, arteriosclerosis, cardiovascular disease and stroke. Due to various imaging conditions retinal images may be degraded. Consequently, the enhancement of such images and vessels in them is an important task with direct clinical applications. We propose a novel technique for vessel enhancement in retinal images that is capable of enhancing vessel junctions in addition to linear vessel segments. This is an extension of vessel filters we have previously developed for vessel enhancement in thoracic CT scans. The proposed approach is based on probabilistic models which can discern vessels and junctions. Evaluation shows the proposed filter is better than several known techniques and is comparable to the state of the art when evaluated on a standard dataset. A ridge-based vessel tracking process is applied on the enhanced image to demonstrate the effectiveness of the enhancement filter.

  14. Retinal Detachment in Preeclampsia

    Directory of Open Access Journals (Sweden)

    Prado Renata Silva do

    2002-01-01

    Full Text Available Preeclampsia is an obstetric disease of unknown cause that affects approximately 5% of pregnant women. The visual system may be affected with variable intensity, being the retinal detachment a rare complication. The retinal detachment in preeclampsia is usually bilateral and serous, and its pathogenesis is related to the choroidal ischemia secondary to an intense arteriolar vasospasm. The majority of patients have complete recovery of vision with clinical management, and surgery is unnecessary. This is a case report of a 27 year old patient who developed the severe form of preeclampsia on her first pregnancy. She had progressive blurred vision, until she could see only shadows. Ophthalmic examination diagnosed spread and bilateral retinal detachment. With blood pressure control at postpartum, the patient had her retina reattached, and recovery of vision.

  15. Retinal flow cytometer.

    Science.gov (United States)

    Alt, C; Veilleux, I; Lee, H; Pitsillides, C M; Côté, D; Lin, C P

    2007-12-01

    The in vivo flow cytometer is an instrument capable of continuous, real-time monitoring of fluorescently labeled cells in the circulation without the need to draw blood samples. However, the original system probes a single vessel in the mouse ear; the small sample volume limits the sensitivity of the technique. We describe an in vivo retinal flow cytometer that simultaneously probes five artery-vein pairs in the mouse eye by circularly scanning a small laser spot rapidly around the optic nerve head. We demonstrate that the retinal flow cytometer detects about five times more cells per minute than the original in vivo flow cytometer does in the ear.

  16. Retinal locus for scanning text.

    Science.gov (United States)

    Timberlake, George T; Sharma, Manoj K; Grose, Susan A; Maino, Joseph H

    2006-01-01

    A method of mapping the retinal location of text during reading is described in which text position is plotted cumulatively on scanning laser ophthalmoscope retinal images. Retinal locations that contain text most often are the brightest in the cumulative plot, and locations that contain text least often are the darkest. In this way, the retinal area that most often contains text is determined. Text maps were plotted for eight control subjects without vision loss and eight subjects with central scotomas from macular degeneration. Control subjects' text maps showed that the fovea contained text most often. Text maps of five of the subjects with scotomas showed that they used the same peripheral retinal area to scan text and fixate. Text maps of the other three subjects with scotomas showed that they used separate areas to scan text and fixate. Retinal text maps may help evaluate rehabilitative strategies for training individuals with central scotomas to use a particular retinal area to scan text.

  17. Learning about Retinitis Pigmentosa

    Science.gov (United States)

    ... that detect light). Photoreceptor cells capture and process light helping us to see. As these cells breakdown and die, patients experience progressive vision loss. The most common feature of all forms of RP is a ... cells that detect dim light) and cones (retinal cells that detect light and ...

  18. Retinal vein occlusion

    Science.gov (United States)

    ... decrease the risk of retinal vein occlusion. These measures include: Eating a low-fat diet Getting regular exercise Maintaining an ideal weight Not smoking Aspirin or other blood thinners may help prevent blockages in the other eye. Controlling diabetes may ...

  19. Nanomaterials and Retinal Toxicity

    Science.gov (United States)

    The neuroretina should be considered as a potential site of nanomaterial toxicity. Engineered nanomaterials may reach the retina through three potential routes of exposure including; intra­ vitreal injection of therapeutics; blood-borne delivery in the retinal vasculature an...

  20. Duration of rhegmatogenous retinal detachment predicts recovery of retinal sensitivity

    Directory of Open Access Journals (Sweden)

    Rose Rose

    2016-02-01

    Full Text Available The decision to treat a disease is often based on the presence or absence of symptoms, one prototype case being rhegmatogenous retinal detachment. Detachment of the neural retina from the pigment epithelium is a major cause of anatomical and functional dysfunction of the retina, where retinal recovery is inversely related to duration of detachment. The purpose of retinal reattachment is to effect recovery of the photoreceptors and pigment epithelium from degeneration. The aim of this study was to determine the critical duration of rhegmatogenous retinal detachment resulting in optimal retinal recovery after reattachment. A prospective study was conducted at a private hospital in Yogyakarta. Thirty five eyes were involved in this study. Three months after reattachment, central retinal recovery was measured by means of a Goldmann manual kinetic perimeter. The results showed that retinal recovery developed three months after surgery if the onset of rhegmatogenous retinal detachment was less than 28 days before surgery. The results were not significant if the onset of rhegmatogenous retinal detachment was more than 35 days. Although the Goldmann manual kinetic perimeter can efficiently detect central retinal sensitivity, it should be supported by more sensitive tools to evaluate the anatomy and function of the retina.

  1. Peripapillary retinal thermal coagulation following electrical injury

    Directory of Open Access Journals (Sweden)

    Manjari Tandon

    2013-01-01

    Full Text Available In this study, we have presented the case report of a 20 year old boy who suffered an electric injury shock, following which he showed peripapillary retinal opacification and increased retinal thickening that subsequently progressed to retinal atrophy. The fluorescein angiogram revealed normal retinal circulation, thus indicating thermal damage to retina without any compromise to retinal circulation.

  2. Ablation of C/EBP homologous protein does not protect T17M RHO mice from retinal degeneration.

    Directory of Open Access Journals (Sweden)

    Sonali Nashine

    Full Text Available Despite the proposed link between ablation of the CHOP protein and delay of the onset of ER stress-mediated disorders including diabetes, Alzheimer Disease, and cardiac hypertrophy, the role of CHOP protein in photoreceptor cell death associated with Autosomal Dominant Retinitis Pigmentosa (ADRP has not been investigated. T17M RHO transgenic mice carry a mutated human rhodopsin transgene, the expression of which in retina leads to protein misfolding, activation of UPR and progressive retinal degeneration. The purpose of this study is to investigate the role of CHOP protein in T17M RHO retina. Wild-type, CHOP-/-, T17M RHO and T17M RHO CHOP-/-mice were used in the study. Evaluation of the impact of CHOP ablation was performed using electroretinography (ERG, spectral-domain optical coherence tomography (SD-OCT, quantitative Real-Time PCR (qRT-PCR and western blot analysis. Dark-adapted ERG analysis demonstrated that by 1 month, the T17M RHO CHOP-/- mice had a 70% reduction of the a-wave amplitude compared to the T17M RHO mice. The loss of function in T17M RHO CHOP-/- photoreceptors was associated with a 22-24% decline in the thickness of the outer nuclear layer. These mice had significant reduction in the expression of transcription factors, Crx and Nrl, and also in mouse Rho, and human RHO. The reduction was associated with an 8-fold elevation of the UPR marker, p-eIf2α protein and 30% down-regulation of sXbp1 protein. In addition, the histone deacetylase 1 (Hdac1 protein was 2-fold elevated in the T17M RHO CHOP-/- retina. The ablation of CHOP led to a reduction in the expression of photoreceptor-specific transcriptional factors, and both endogenous and exogenous RHO mRNA. Thus, despite its role in promoting apoptosis, CHOP protects rod photoreceptors carrying an ADRP mutation.

  3. HOXA2 haploinsufficiency in dominant bilateral microtia and hearing loss.

    Science.gov (United States)

    Brown, Kerry K; Viana, Lucas M; Helwig, Cecilia C; Artunduaga, Maria A; Quintanilla-Dieck, Lourdes; Jarrin, Patricia; Osorno, Gabriel; McDonough, Barbara; DePalma, Steven R; Eavey, Roland D; Seidman, Jonathan G; Seidman, Christine E

    2013-10-01

    Microtia is a rare, congenital malformation of the external ear that in some cases has a genetic etiology. We ascertained a three-generation family with bilateral microtia and hearing loss segregating as an autosomal dominant trait. Exome sequencing of affected family members detected only seven shared, rare, heterozygous, nonsynonymous variants, including one protein truncating variant, a HOXA2 nonsense change (c.703C>T, p.Q235*). The HOXA2 variant was segregated with microtia and hearing loss in the family and was not seen in 6,500 individuals sequenced by the NHLBI Exome Sequencing Project or in 218 control individuals sequenced in this study. HOXA2 has been shown to be critical for outer and middle ear development through mouse models and has previously been associated with autosomal recessive bilateral microtia. Our data extend these conclusions and define HOXA2 haploinsufficiency as the first genetic cause for autosomal-dominant nonsyndromic microtia.

  4. 一个X-连锁视网膜色素变性中国家系的RPGR基因的新突变%A novel RPGR gene mutation in a Chinese family with X-linked dominant retinitis pigmentosa

    Institute of Scientific and Technical Information of China (English)

    李杨; 董冰; 胡爱莲; 崔彤彤; 郑远远

    2005-01-01

    目的对中国人X-连锁视网膜色素变性一家系进行分子遗传学检测,报告RPGR基因突变.方法首先对该家系X染色体进行致病基因的连锁分析,然后用单链构象多态性技术和直接DNA测序方法进行基因突变分析. 结果连锁分析在多态性微卫星遗传标记DXS8012和DXS8025产生正的Lod值分别为2.41(Zmax=2.40, θ=0) 和1.26.进一步单倍型分析确定该家系致病基因位于Xp21.1, 与 RP3连锁.用RPGR基因突变分析,在外显子ORF15+483_484发现GA缺失,引起阅读框架的改变,该基因缺失突变在家系中共分离.结论报告了中国人X-连锁视网膜色素变性RPGR基因外显子ORF15+483_484的GA缺失突变,丰富了中国人RPGR基因突变谱,为今后研究X-连锁视网膜色素变性的基因奠定基础.%Objective To report a novel mutation in RPGR gene in a Chinese family with X-linked dominant retinitis pigmentosa(XLRP). Methods Genetic linkage analysis was performed on the known genetic loci for XLRP with a panel of polymorphic markers, then the mutations were identified by single-strand conformation polymorphism(SSCP) and direct sequencing. Results Significant two-point Lod score was generated using marker DXS8025 (Zmax=2.4,θ=0). The disease gene locus was confined to Xp21.1 with further analysis of genetic linkage and haplotype. Mutations screening of RPGR gene in this family revealed a GA deletion at ORF15 +483_484 which caused the open reading frameshift. This novel mutation co-segregated with the affected members of the pedigree, but it was not present in the unaffected relatives. Conclusion The above finding expands the spectrum of RPGR mutations causing XLRP in Chinese family and is useful for further genetic consultation and genetic diagnosis.

  5. Domination, Eternal Domination, and Clique Covering

    Directory of Open Access Journals (Sweden)

    Klostermeyer William F.

    2015-05-01

    Full Text Available Eternal and m-eternal domination are concerned with using mobile guards to protect a graph against infinite sequences of attacks at vertices. Eternal domination allows one guard to move per attack, whereas more than one guard may move per attack in the m-eternal domination model. Inequality chains consisting of the domination, eternal domination, m-eternal domination, independence, and clique covering numbers of graph are explored in this paper.

  6. Retinitis pigmentosa caused by mutations in the ciliary MAK gene is relatively mild and is not associated with apparent extra-ocular features

    NARCIS (Netherlands)

    Huet, R.A.C. van; Siemiatkowska, A.M.; Ozgul, R.K.; Yucel, D.; Hoyng, C.B.; Banin, E.; Blumenfeld, A.; Rotenstreich, Y.; Riemslag, F.C.; Hollander, A.I. den; Theelen, T.; Collin, R.W.J.; Born, L.I. van den; Klevering, B.J.

    2015-01-01

    PURPOSE: Defects in MAK, encoding a protein localized to the photoreceptor connecting cilium, have recently been associated with autosomal recessive retinitis pigmentosa (RP). The aim of this study is to describe our detailed clinical observations in patients with MAK-associated RP, including an ass

  7. Retinal flow cytometer

    OpenAIRE

    Alt, C.; Veilleux, I.; H. Lee; Pitsillides, C. M.; Côté, D.; Lin, C.P.

    2007-01-01

    The in vivo flow cytometer is an instrument capable of continuous, real-time monitoring of fluorescently labeled cells in the circulation without the need to draw blood samples. However, the original system probes a single vessel in the mouse ear; the small sample volume limits the sensitivity of the technique. We describe an in vivo retinal flow cytometer that simultaneously probes five artery–vein pairs in the mouse eye by circularly scanning a small laser spot rapidly around the optic nerv...

  8. Inherited Retinal Degenerative Disease Registry

    Science.gov (United States)

    2016-03-21

    Eye Diseases Hereditary; Retinal Disease; Achromatopsia; Bardet-Biedl Syndrome; Bassen-Kornzweig Syndrome; Batten Disease; Best Disease; Choroidal Dystrophy; Choroideremia; Cone Dystrophy; Cone-Rod Dystrophy; Congenital Stationary Night Blindness; Enhanced S-Cone Syndrome; Fundus Albipunctatus; Goldmann-Favre Syndrome; Gyrate Atrophy; Juvenile Macular Degeneration; Kearns-Sayre Syndrome; Leber Congenital Amaurosis; Refsum Syndrome; Retinitis Pigmentosa; Retinitis Punctata Albescens; Retinoschisis; Rod-Cone Dystrophy; Rod Dystrophy; Rod Monochromacy; Stargardt Disease; Usher Syndrome

  9. RP1L1 variants are associated with a spectrum of inherited retinal diseases including retinitis pigmentosa and occult macular dystrophy.

    Science.gov (United States)

    Davidson, Alice E; Sergouniotis, Panagiotis I; Mackay, Donna S; Wright, Genevieve A; Waseem, Naushin H; Michaelides, Michel; Holder, Graham E; Robson, Anthony G; Moore, Anthony T; Plagnol, Vincent; Webster, Andrew R

    2013-03-01

    In one consanguineous family with retinitis pigmentosa (RP), a condition characterized by progressive visual loss due to retinal degeneration, homozygosity mapping, and candidate gene sequencing suggested a novel locus. Exome sequencing identified a homozygous frameshifting mutation, c.601delG, p.Lys203Argfs*28, in RP1L1 encoding RP 1-like1, a photoreceptor-specific protein. A screen of a further 285 unrelated individuals with autosomal recessive RP identified an additional proband, homozygous for a missense variant, c.1637G>C, p.Ser546Thr, in RP1L1. A distinct retinal disorder, occult macular dystrophy (OCMD) solely affects the central retinal cone photoreceptors and has previously been reported to be associated with variants in the same gene. The association between mutations in RP1L1 and the disorder OCMD was explored by screening a cohort of 28 unrelated individuals with the condition; 10 were found to harbor rare (minor allele frequency ≤0.5% in the 1,000 genomes dataset) heterozygous RP1L1 missense variants. Analysis of family members revealed many unaffected relatives harboring the same variant. Linkage analysis excluded the possibility of a recessive mode of inheritance, and sequencing of RP1, a photoreceptor protein that interacts with RP1L1, excluded a digenic mechanism involving this gene. These findings imply an important and diverse role for RP1L1 in human retinal physiology and disease.

  10. Mutation rate analysis at 19 autosomal microsatellites.

    Science.gov (United States)

    Qian, Xiao-Qin; Yin, Cai-Yong; Ji, Qiang; Li, Kai; Fan, Han-Ting; Yu, Yan-Fang; Bu, Fan-Li; Hu, Ling-Li; Wang, Jian-Wen; Mu, Hao-Fang; Haigh, Steven; Chen, Feng

    2015-07-01

    Previous studies have demonstrated that a large sample size is needed to reliably estimate population- and locus-specific microsatellite mutation rates. Therefore, we conducted a long-term collaboration study and performed a comprehensive analysis on the mutation characteristics of 19 autosomal short tandem repeat (STR) loci. The STR loci located on 15 of 22 autosomal chromosomes were analyzed in a total of 21,106 samples (11,468 parent-child meioses) in a Chinese population. This provided 217,892 allele transfers at 19 STR loci. An overall mutation rate of 1.20 × 10(-3) (95% CI, 1.06-1.36 × 10(-3) ) was observed in the populations across 18 of 19 STR loci, except for the TH01 locus with no mutation found. Most STR mutations (97.7%) were single-step mutations, and only a few mutations (2.30%) comprised two and multiple steps. Interestingly, approximately 93% of mutation events occur in the male germline. The mutation ratios increased with the paternal age at child birth (r = 0.99, ptesting, kinship analysis, and population genetics.

  11. Retinal Thickening and Photoreceptor Loss in HIV Eyes without Retinitis.

    Directory of Open Access Journals (Sweden)

    Cheryl A Arcinue

    Full Text Available To determine the presence of structural changes in HIV retinae (i.e., photoreceptor density and retinal thickness in the macula compared with age-matched HIV-negative controls.Cohort of patients with known HIV under CART (combination Antiretroviral Therapy treatment were examined with a flood-illuminated retinal AO camera to assess the cone photoreceptor mosaic and spectral-domain optical coherence tomography (SD-OCT to assess retinal layers and retinal thickness.Twenty-four eyes of 12 patients (n = 6 HIV-positive and 6 HIV-negative were imaged with the adaptive optics camera. In each of the regions of interest studied (nasal, temporal, superior, inferior, the HIV group had significantly less mean cone photoreceptor density compared with age-matched controls (difference range, 4,308-6,872 cones/mm2. A different subset of forty eyes of 20 patients (n = 10 HIV-positive and 10 HIV-negative was included in the retinal thickness measurements and retinal layer segmentation with the SD-OCT. We observed significant thickening in HIV positive eyes in the total retinal thickness at the foveal center, and in each of the three horizontal B-scans (through the macular center, superior, and inferior to the fovea. We also noted that the inner retina (combined thickness from ILM through RNFL to GCL layer was also significantly thickened in all the different locations scanned compared with HIV-negative controls.Our present study shows that the cone photoreceptor density is significantly reduced in HIV retinae compared with age-matched controls. HIV retinae also have increased macular retinal thickness that may be caused by inner retinal edema secondary to retinovascular disease in HIV. The interaction of photoreceptors with the aging RPE, as well as possible low-grade ocular inflammation causing diffuse inner retinal edema, may be the key to the progressive vision changes in HIV-positive patients without overt retinitis.

  12. A novel frameshift mutation in KCNQ4 in a family with autosomal recessive non-syndromic hearing loss.

    Science.gov (United States)

    Wasano, Koichiro; Mutai, Hideki; Obuchi, Chie; Masuda, Sawako; Matsunaga, Tatsuo

    2015-08-01

    Mutation of KCNQ4 has been reported to cause autosomal dominant non-syndromic hearing loss (DFNA2A) that usually presents as progressive hearing loss starting from mild to moderate hearing loss during childhood. Here, we identified a novel KCNQ4 mutation, c.1044_1051del8, in a family with autosomal recessive non-syndromic hearing loss. The proband was homozygous for the mutation and was born to consanguineous parents; she showed severe hearing loss that was either congenital or of early childhood onset. The proband had a sister who was heterozygous for the mutation but showed normal hearing. The mutation caused a frameshift that eliminated most of the cytoplasmic C-terminus, including the A-domain, which has an important role for protein tetramerization, and the B-segment, which is a binding site for calmodulin (CaM) that regulates channel function via Ca ions. The fact that the heterozygote had normal hearing indicates that sufficient tetramerization and CaM binding sites were present to preserve a normal phenotype even when only half the proteins contained an A-domain and B-segment. On the other hand, the severe hearing loss in the homozygote suggests that complete loss of the A-domain and B-segment in the protein caused loss of function due to the failure of tetramer formation and CaM binding. This family suggests that some KCNQ4 mutations can cause autosomal recessive hearing loss with more severe phenotype in addition to autosomal dominant hearing loss with milder phenotype. This genotype-phenotype correlation is analogous to that in KCNQ1 which causes autosomal dominant hereditary long QT syndrome 1 with milder phenotype and the autosomal recessive Jervell and Lange-Nielsen syndrome 1 with more severe phenotype due to deletion of the cytoplasmic C-terminus of the potassium channel.

  13. [Application of retinal oximeter in ophthalmology].

    Science.gov (United States)

    Li, Jing; Ma, Jianmin; Wang, Ningli

    2015-11-01

    Retinal oximeter is a new machine which has been used in the diagnose, treatment and research of several ophthalmic diseases for recent years. It allows ophthalmologists to gain retinal oxygen saturation directly. Therefore, retinal oximeter might be useful for ophthalmologists to understand ophthalmic diseases more deeper and clarify the impact of ischemia on retinal function. It has been reported in the literatures that retinal oximeter has potentially useful diagnostic and therapeutic indications in various eye diseases such as diabetic retinopathy, central retinal vein and artery occlusion, retinitis pigmentosa, glaucomatous optic neuropathy, et al. In this thesis, the application of retinal oximeter in ophthalmology is reviewed.

  14. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism.

    Science.gov (United States)

    Grønskov, Karen; Dooley, Christopher M; Østergaard, Elsebet; Kelsh, Robert N; Hansen, Lars; Levesque, Mitchell P; Vilhelmsen, Kaj; Møllgård, Kjeld; Stemple, Derek L; Rosenberg, Thomas

    2013-03-07

    Autosomal-recessive albinism is a hypopigmentation disorder with a broad phenotypic range. A substantial fraction of individuals with albinism remain genetically unresolved, and it has been hypothesized that more genes are to be identified. By using homozygosity mapping of an inbred Faroese family, we identified a 3.5 Mb homozygous region (10q22.2-q22.3) on chromosome 10. The region contains five protein-coding genes, and sequencing of one of these, C10orf11, revealed a nonsense mutation that segregated with the disease and showed a recessive inheritance pattern. Investigation of additional albinism-affected individuals from the Faroe Islands revealed that five out of eight unrelated affected persons had the nonsense mutation in C10orf11. Screening of a cohort of autosomal-recessive-albinism-affected individuals residing in Denmark showed a homozygous 1 bp duplication in C10orf11 in an individual originating from Lithuania. Immunohistochemistry showed localization of C10orf11 in melanoblasts and melanocytes in human fetal tissue, but no localization was seen in retinal pigment epithelial cells. Knockdown of the zebrafish (Danio rerio) homolog with the use of morpholinos resulted in substantially decreased pigmentation and a reduction of the apparent number of pigmented melanocytes. The morphant phenotype was rescued by wild-type C10orf11, but not by mutant C10orf11. In conclusion, we have identified a melanocyte-differentiation gene, C10orf11, which when mutated causes autosomal-recessive albinism in humans.

  15. Dominant optic atrophy

    Directory of Open Access Journals (Sweden)

    Lenaers Guy

    2012-07-01

    Full Text Available Abstract Definition of the disease Dominant Optic Atrophy (DOA is a neuro-ophthalmic condition characterized by a bilateral degeneration of the optic nerves, causing insidious visual loss, typically starting during the first decade of life. The disease affects primary the retinal ganglion cells (RGC and their axons forming the optic nerve, which transfer the visual information from the photoreceptors to the lateral geniculus in the brain. Epidemiology The prevalence of the disease varies from 1/10000 in Denmark due to a founder effect, to 1/30000 in the rest of the world. Clinical description DOA patients usually suffer of moderate visual loss, associated with central or paracentral visual field deficits and color vision defects. The severity of the disease is highly variable, the visual acuity ranging from normal to legal blindness. The ophthalmic examination discloses on fundoscopy isolated optic disc pallor or atrophy, related to the RGC death. About 20% of DOA patients harbour extraocular multi-systemic features, including neurosensory hearing loss, or less commonly chronic progressive external ophthalmoplegia, myopathy, peripheral neuropathy, multiple sclerosis-like illness, spastic paraplegia or cataracts. Aetiology Two genes (OPA1, OPA3 encoding inner mitochondrial membrane proteins and three loci (OPA4, OPA5, OPA8 are currently known for DOA. Additional loci and genes (OPA2, OPA6 and OPA7 are responsible for X-linked or recessive optic atrophy. All OPA genes yet identified encode mitochondrial proteins embedded in the inner membrane and ubiquitously expressed, as are the proteins mutated in the Leber Hereditary Optic Neuropathy. OPA1 mutations affect mitochondrial fusion, energy metabolism, control of apoptosis, calcium clearance and maintenance of mitochondrial genome integrity. OPA3 mutations only affect the energy metabolism and the control of apoptosis. Diagnosis Patients are usually diagnosed during their early childhood, because of

  16. Perceptual Fading without Retinal Adaptation

    Science.gov (United States)

    Hsieh, Po-Jang; Colas, Jaron T.

    2012-01-01

    A retinally stabilized object readily undergoes perceptual fading and disappears from consciousness. This startling phenomenon is commonly believed to arise from local bottom-up sensory adaptation to edge information that occurs early in the visual pathway, such as in the lateral geniculate nucleus of the thalamus or retinal ganglion cells. Here…

  17. Retinal detachment surgery without cryotherapy.

    OpenAIRE

    Chignell, A H; Markham, R H

    1981-01-01

    A series of cases of retinal detachment treated without the application of cryotherapy at the time of surgery has been studied. The omission of cryotherapy while not interfering with retinal reattachment, carries the risk of redetachment at a later date. Macular pucker may still occur in spite of the absence of cryotherapy.

  18. A New Therapeutic Strategy for Autosomal Dominant Polycystic Kidney Disease: Activation of AMP Kinase by Metformin

    Science.gov (United States)

    2013-07-01

    inhibitors). Cells were homogenized in a tight-fitting Dounce homogenizer, chilled on ice for 10 min, and then rotated for 15 min. Nonidet P - 40 was added to...cells counted from each of n=6 mice) in comparison to 10.6±3.6% s.e.m. (450 cells counted from each of n=4 mice) in metformin-treated mice ( p ɘ.0074...situ. AMPK activation levels were assessed by staining sections with an antibody directed against p -AMPK. We find that treatment with 375 mg/kg

  19. Analysis of autosomal dominant spinocerebellar ataxia type 1 in an extended family of central India

    Directory of Open Access Journals (Sweden)

    Shashikant Sharma

    2012-01-01

    Full Text Available Background: Spinocerebeller ataxia type 1 (SCA1 is a specific type of ataxia among a group of inherited diseases of the central nervous system. In SCA1, genetic defects lead to impairment of specific nerve fibers carrying messages to and from the brain, resulting in the degeneration of the cerebellum, the coordination center of the brain. We investigated 24 members of an extended family in Gwalior city, India, some of which were earlier clinically diagnosed to be suffering from yet unconfirmed type of SCA neurodegenerative disorder. Materials and Methods: All the family members from each age group were screened clinically and the characteristics of those resembling with ataxia were recorded for diagnosis by MRI. The confirmed patients of the family were genetically tested by PCR based molecular testing to identify the type of SCA (i.e., SCA 1, 2, 3, 4, 6 or 7. Family tree of the disease inheritance was constructed by pedigree based method. Result and Conclusion: We found the clinical (symptoms and MRI and genetic (Pedigree and PCR results to be correlated. The PCR result revealed the disease to be of SCA 1 type being inherited in the family.

  20. The autosomal dominant spinocerebellar ataxias: emerging mechanistic themes suggest pervasive Purkinje cell vulnerability.

    Science.gov (United States)

    Hekman, Katherine E; Gomez, Christopher M

    2015-05-01

    The spinocerebellar ataxias are a genetically heterogeneous group of disorders with clinically overlapping phenotypes arising from Purkinje cell degeneration, cerebellar atrophy and varying degrees of degeneration of other grey matter regions. For 22 of the 32 subtypes, a genetic cause has been identified. While recurring themes are emerging, there is no clear correlation between the clinical phenotype or penetrance, the type of genetic defect or the category of the disease mechanism, or the neuronal types involved beyond Purkinje cells. These phenomena suggest that cerebellar Purkinje cells may be a uniquely vulnerable neuronal cell type, more susceptible to a wider variety of genetic/cellular insults than most other neuron types.

  1. LMNA-Associated Cardiocutaneous Progeria: a Novel Autosomal Dominant Premature Aging Syndrome with Late Onset

    Science.gov (United States)

    Kane, Megan S.; Lindsay, Mark E.; Judge, Daniel P.; Barrowman, Jemima; Rhys, Colette Ap; Simonson, Lisa; Dietz, Harry C.; Michaelis, Susan

    2013-01-01

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a well-characterized premature aging disorder caused by mutations in LMNA, the gene encoding the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. Emerging evidence indicates that LMNA-linked progerias can be grouped into two classes: 1) the processing-deficient, early onset “typical” progerias (e.g. HGPS), and 2) the processing-proficient “atypical” progeria syndromes (APS) that are later in onset. Here we describe a novel progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that causes LCPS is a heterozygous missense mutation resulting in an amino acid substitution (D300G) in the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors (FTIs), as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease. PMID:23666920

  2. Potential Deleterious Effects of Vasopressin in Chronic Kidney Disease and Particularly Autosomal Dominant Polycystic Kidney Disease

    NARCIS (Netherlands)

    Meijer, E.; Boertien, W. E.; Zietse, R.; Gansevoort, R. T.

    2011-01-01

    The antidiuretic hormone vasopressin is crucial for regulating free water clearance in normal physiology. However, it has also been hypothesized that vasopressin has deleterious effects on the kidney. Vasopressin is elevated in animals and patients with chronic kidney disease. Suppression of vasopre

  3. Asymmetric dimethylarginine and lipid peroxidation products in early autosomal dominant polycystic kidney disease

    DEFF Research Database (Denmark)

    Wang, Dan; Strandgaard, S.; Borresen, M.L.

    2008-01-01

    of nitric oxide synthase and the lipid peroxidation product 13-hydroxyoctadecadienoic acid (HODE) as a marker of oxidative stress in patients with early ADPKD. Study Design: Cross-sectional study. Setting & Participants: Patients with early ADPKD (n = 27) and age-matched volunteers (n = 30) from a single...... academic medical center. Factor: Patients with ADPKD versus controls. Outcomes & Measurement: Plasma (P) levels, urinary (U) excretion, and urinary clearance (C) of ADMA and HODE. Because of multiple comparisons, P for significance is considered less than 0.0167. Results: Patients with ADPKD had......-sectional nature of study, and limited number of markers of oxidative stress. Conclusions: P-ADMA and P-HODE levels are increased in patients with early ADPKD. Increased P-ADMA level is related to decreased CADMA and is accompanied by oxidative stress. Am J Kidney Dis 51:184-191. (c) 2008 by the National Kidney...

  4. Ultrabiomicroscopic-Histopathologic Correlations in Individuals with Autosomal Dominant Congenital Microcoria: Three-Generation Family Report

    Directory of Open Access Journals (Sweden)

    Arturo Ramirez-Miranda

    2011-05-01

    Full Text Available Background: Congenital microcoria (CMC is due to a maldevelopment of the dilator pupillae muscle of the iris, with a pupil diameter of less than 2 mm. It is associated with juvenile open angle glaucoma and myopia. We report on a three-generation Mexican-Mestizo family with CMC. The eldest member’s iris biopsy proved muscle anomalies. Further, we analyzed novel ultrasound biomicroscopy findings in the family members who did not require surgery. Patients and Methods: A 62-year-old woman, her 41-year-old son and her 9-year-old grandson affected with microcoria since birth, documented by clinical examination and ultrasound biomicroscopy. The eldest member underwent phacoemulsification, and a biopsy of the iris and the anterior capsule of the lens was taken. Results: Ultrasound biomicroscopy confirmed the CMC diagnosis showing iris thinning and a pupil diameter of less than 2 mm. Histopathology of the iris showed a significant reduction of smooth muscle cells, but no alterations of the anterior lens capsule. Discussion: Although CMC is a rare disorder, which is due to a maldevelopment of the dilator pupillae muscle of the iris, it could be associated with juvenile open angle glaucoma and myopia; therefore, precise diagnosis is required. Ultrasound biomicroscopy could be a great option to confirm the disorder.

  5. Morphologic,mechanical and functional sonographic parameters of arteries in autosomal dominant polycystic kidney disease

    Institute of Scientific and Technical Information of China (English)

    戎殳

    2006-01-01

    Objective To investigate whether the risk factors of cardiovascular disease exist in early stage of ADPKD patients with normal renal function. Methods Morphologic , mechanical and functional sonographic parameters of arteries were examined by high-frequency ultrasonography in 32 hypertensive and 28 normotensive ADPKD patients with preserved renal function, 25 patients with es-

  6. Bilineal inheritance of type 1 autosomal dominant polycystic kidney disease (ADPKD) and recurrent fetal loss.

    Science.gov (United States)

    Peces, Ramón; Peces, Carlos; Coto, Eliecer; Selgas, Rafael

    2008-10-01

    We report for the first time a family with type 1 ADPKD in which the marriage between affected non-consanguinous individuals resulted in two live-born heterozygous offspring and two fetuses lost in mid-pregnancy. Given a 25% chance for mutant compound heterozygosity in the offspring of this family, our findings suggest that compound heterozygosity of PKD1 mutations in humans may be embryonically lethal.

  7. A novel frameshift mutation in FGF14 causes an autosomal dominant episodic ataxia.

    Science.gov (United States)

    Choquet, Karine; La Piana, Roberta; Brais, Bernard

    2015-07-01

    Episodic ataxias (EAs) are a heterogeneous group of neurological disorders characterized by recurrent attacks of ataxia. Mutations in KCNA1 and CACNA1A account for the majority of EA cases worldwide. We recruited a two-generation family affected with EA of unknown subtype and performed whole-exome sequencing on two affected members. This revealed a novel heterozygous mutation c.211_212insA (p.I71NfsX27) leading to a premature stop codon in FGF14. Mutations in FGF14 are known to cause spinocerebellar ataxia type 27 (SCA27). Sanger sequencing confirmed segregation within the family. Our findings expand the phenotypic spectrum of SCA27 by underlining the possible episodic nature of this ataxia.

  8. 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...

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

    NARCIS (Netherlands)

    Burrage, L.C.; Charng, W.L.; Eldomery, M.K.; Willer, J.R.; Davis, E.E.; Lugtenberg, D.; Zhu, W.; Leduc, M.S.; Akdemir, Z.C.; Azamian, M.; Zapata, G.; Hernandez, P.P.; Schoots, J.; Munnik, S.A. de; Roepman, R.; Pearring, J.N.; Jhangiani, S.; Katsanis, N.; Vissers, L.E.L.M.; Brunner, H.G.; Beaudet, A.L.; Rosenfeld, J.A.; Muzny, D.M.; Gibbs, R.A.; Eng, C.M.; Xia, F.; Lalani, S.R.; Lupski, J.R.; Bongers, E.M.H.F.; Yang, Y

    2015-01-01

    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

  10. A New Therapeutic Strategy for Autosomal Dominant Polycystic Kidney Disease: Activation of AMP Kinase by Metformin

    Science.gov (United States)

    2012-07-01

    magnitude, [32]), indicating that urine succinate levels could be a potential biomarker for detecting diabetic nephropathy early on in the disease progression...a drug in wide clinical use for both non-insulin dependent diabetes mellitus and Polycystic Ovary Syndrome, stimulates AMPK (10, 11). We therefore...regimens can produce AMPK activation in wild type mice. In addition, we will determine whether activation of AMPK by metformin treatment exhibits any

  11. LMNA-associated cardiocutaneous progeria: an inherited autosomal dominant premature aging syndrome with late onset.

    Science.gov (United States)

    Kane, Megan S; Lindsay, Mark E; Judge, Daniel P; Barrowman, Jemima; Ap Rhys, Colette; Simonson, Lisa; Dietz, Harry C; Michaelis, Susan

    2013-07-01

    Hutchinson-Gilford Progeria Syndrome (HGPS) is a premature aging disorder caused by mutations in LMNA, which encodes the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. LMNA-linked progerias can be grouped into two classes: (1) the processing-deficient, early onset "typical" progerias (e.g., HGPS), and (2) the processing-proficient "atypical" progeria syndromes (APS) that are later in onset. Here we describe a previously unrecognized progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that caused LCPS in this family is a heterozygous c.899A>G (p.D300G) mutation predicted to alter the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors, as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease.

  12. The role of the IRE1/Xbp1 pathway in a Drosophila model for autosomal dominant

    OpenAIRE

    Costa, Rita Esperto, 1987-

    2011-01-01

    Tese de mestrado. Biologia (Biologia Molecular e genética). Universidade de Lisboa, Faculdade de Ciências, 2011 Neurodegenerative disorders are a major medical problem for society. Growing evidence indicates that endoplasmic reticulum (ER) stress is an important common pathological event in a variety of neurodegenerative diseases. The unfolded protein response (UPR) is triggered by the accumulation of misfolded proteins provoked by ER stress conditions, to restore homeostasis. We are parti...

  13. Seasonal palmar keratoderma in erythropoietic protoporphyria indicates autosomal recessive inheritance.

    Science.gov (United States)

    Holme, S Alexander; Whatley, Sharon D; Roberts, Andrew G; Anstey, Alexander V; Elder, George H; Ead, Russell D; Stewart, M Felicity; Farr, Peter M; Lewis, Helen M; Davies, Nicholas; White, Marion I; Ackroyd, R Simon; Badminton, Michael N

    2009-03-01

    Erythropoietic protoporphyria (EPP) is an inherited disorder that results from partial deficiency of ferrochelatase (FECH). It is characterized clinically by acute photosensitivity and, in 2% of patients, liver disease. Inheritance is usually autosomal dominant with low penetrance but is recessive in about 4% of families. A cross-sectional study of 223 patients with EPP in the United Kingdom identified six individuals with palmar keratoderma. We now show that these and three additional patients, from six families, have an inherited subtype of EPP which is characterized by seasonal palmar keratoderma, relatively low erythrocyte protoporphyrin concentrations, and recessive inheritance. No patient had evidence of liver dysfunction; four patients had neurological abnormalities. Patients were hetero- or homoallelic for nine different FECH mutations; four of which were previously unreported. Prokaryotic expression predicted that FECH activities were 2.7-25% (mean 10.6%) of normal. Neither mutation type nor FECH activity provided an explanation for the unusual phenotype. Our findings show that palmar keratoderma is a clinical indicator of recessive EPP, identify a phenotype that occurs in 38% of reported families with recessive EPP that to our knowledge is previously unreported, and suggest that patients with this phenotype may carry a lower risk of liver disease than other patients with recessive EPP.

  14. Acute retinal necrosis

    Directory of Open Access Journals (Sweden)

    Hugo Hernán Ocampo

    2009-12-01

    Full Text Available Purpose: Clinical features in a case of acute retinal necrosis are described as well as its diagnostic approach and response to early treatment. Methods: This is a descriptive and retrospective study case report of a 26 year old male patient who arrived to the emergency room with a three day history of sudden visual loss in the right eye (RE. At initial evaluation a visual acuity of hand movements in the RE, 20/15 in the left eye (LE and a right relative afferent pupillary defect were found. Fundoscopy revealed profuse soft exudates and hemorrhages involving posterior pole, inferior hemiretina and superotemporal periphery. Infectious workup and fluoresceinic angiography were made and positive serologies for herpes virus types 1 and 2, without HIV, were found. A diagnosis of acute retinal necrosis was made and treatment with intravenous valgancyclovir for two weeks and intra-vitreous triamcinolone for severe vasculitis, was given. Then a 3 months treatment with oral antiviral agents was prescribed. Results: Patient’s evolution showed improvement with treatment and at two and a half months of follow up, visual acuity was 20/50 in the right eye, normal slit lamp examination, tonometry of 12 mm Hg and fundoscopy improved when compared to initial pictures.Conclusions: A high index of suspicion is needed for diagnosing ARN taking into account clinical findings. Prompt intravenous and intra-vitreous treatments are needed to achieve good clinical and functional outcomes and to avoid central nervous system complications.

  15. Expression of PRPF31 and TFPT: regulation in health and retinal disease.

    Science.gov (United States)

    Rose, Anna M; Shah, Amna Z; Waseem, Naushin H; Chakarova, Christina F; Alfano, Giovanna; Coussa, Razek G; Ajlan, Radwan; Koenekoop, Robert K; Bhattacharya, Shomi S

    2012-09-15

    PRPF31, a gene located at chromosome 19q13.4, encodes the ubiquitous splicing factor PRPF31. The gene lies in a head-to-head arrangement with TFPT, a poorly characterized gene with a role in cellular apoptosis. Mutations in PRPF31 have been implicated in autosomal dominant retinitis pigmentosa (adRP), a frequent and important cause of blindness worldwide. Disease associated with PRPF31 mutations is unusual, in that there is often non-penetrance of the disease phenotype in affected families, caused by differential expression of PRPF31. This study aimed to characterize the basic promoter elements of PRPF31 and TFPT. Luciferase reporter constructs were made, using genomic DNA from an asymptomatic individual with a heterozygous deletion of the entire putative promoter region. Fragments were tested by the dual-luciferase reporter assay in HeLa and RPE-1 cell lines. A comparison was made between the promoter regions of symptomatic and asymptomatic mutation-carrying individuals. A patient (CAN493) with adRP was identified, harbouring a regulatory region mutation; both alleles were assayed by the dual-luciferase reporter assay. Luciferase assays led to the identification of core promoters for both PRPF31 and TFPT; despite their shared gene architecture, the two genes appear to be controlled by slightly different regulatory regions. One functional polymorphism was identified in the PRPF31 promoter that increased transcriptional activation. The change was not, however, consistent with the observed symptomatic-asymptomatic phenotypes in a family affected by PRPF31-adRP. Analysis of the mutant promoter fragment from CAN493 showed a >50% reduction in promoter activity, suggesting a disease mechanism of functional haploinsufficiency-the first report of this disease mechanism in adRP.

  16. Treatment of Laser-Induced Retinal Injuries

    Science.gov (United States)

    1989-06-29

    Distribution List (enclosed) bI’TF rruIoN STATEMEN A Approved for publi reljaso Disatbunon Unlimited TREATMENT OF LASER-INDUCED RETINAL INJURIES FINAL...suprathreshold retinal laser lesions II. Subthreshold retinal laser lesions III. Effect of steroid treatment on laser-induced retinal injury Discussion and...In the present study we investigated the effect of corticosteroid treatment of argon laser-induced retinal injury on vitreal accumulation of both

  17. A novel form of progressive retinal atrophy in Swedish vallhund dogs.

    Directory of Open Access Journals (Sweden)

    Ann E Cooper

    Full Text Available Inherited retinal degenerations, such as retinitis pigmentosa (RP and age-related macular degeneration (AMD, represent leading causes of incurable blindness in humans. This is also true in dogs, where the term progressive retinal atrophy (PRA is used to describe inherited photoreceptor degeneration resulting in progressive vision loss. Because of the similarities in ocular anatomy, including the presence of a cone photoreceptor-rich central retinal region, and the close genotype-phenotype correlation, canine models contribute significantly to the understanding of retinal disease mechanisms and the development of new therapies. The screening of the pure-bred dog population for new forms of PRA represents an important strategy to establish new large animal models. By examining 324 dogs of the Swedish vallhund breed in seven countries and across three continents, we were able to describe a new and unique form of PRA characterized by the multifocal appearance of red and brown discoloration of the tapetal fundus followed over time by thinning of the retina. We propose three stages of the disease based on the appearance of the ocular fundus and associated visual deficits. Electroretinography revealed a gradual loss of both rod and cone photoreceptor-mediated function in Stages 2 and 3 of the disease. In the few dogs that suffered from pronounced vision loss, night-blindness occurred first in late Stage 2, followed by decreased day-vision in Stage 3. Histologic examinations confirmed the loss of photoreceptor cells at Stage 3, which was associated with the accumulation of autofluorescent material in the adjacent retinal pigment epithelium. Pedigree analysis was suggestive of an autosomal-recessive mode of inheritance. Mutations in six known canine retinal degeneration genes as well as hypovitaminosis E were excluded as causes of the disease. The observed variability in the age of disease onset and rate of progression suggest the presence of genetic and

  18. Retinal Microvascular Abnormalities in Neurofibromatosis Type 1 Associated with Congenital Retinal Macrovessels

    Science.gov (United States)

    Makino, Shinji; Endoh, Katsuhisa; Tampo, Hironobu

    2013-01-01

    Here, we report a case of retinal microvascular abnormalities in a patient with neurofibromatosis type 1 (NF1) associated with congenital retinal macrovessels. An abnormal retinal macrovessel, crossing the macula horizontally, was detected in the right eye. Additionally, retinal microvascular abnormalities were detected. Eight years after the initial visit, the retinal microvascular abnormalities were noted to have changed substantially. We speculate that retinal microvascular abnormalities in NF1 may change dynamically over the years. PMID:23781366

  19. Retinal Microvascular Abnormalities in Neurofibromatosis Type 1 Associated with Congenital Retinal Macrovessels

    Directory of Open Access Journals (Sweden)

    Shinji Makino

    2013-01-01

    Full Text Available Here, we report a case of retinal microvascular abnormalities in a patient with neurofibromatosis type 1 (NF1 associated with congenital retinal macrovessels. An abnormal retinal macrovessel, crossing the macula horizontally, was detected in the right eye. Additionally, retinal microvascular abnormalities were detected. Eight years after the initial visit, the retinal microvascular abnormalities were noted to have changed substantially. We speculate that retinal microvascular abnormalities in NF1 may change dynamically over the years.

  20. Autosomal recessive transmission of MYBPC3 mutation results in malignant phenotype of hypertrophic cardiomyopathy.

    Directory of Open Access Journals (Sweden)

    Yilu Wang

    Full Text Available BACKGROUND: Hypertrophic cardiomyopathy (HCM due to mutations in genes encoding sarcomere proteins is most commonly inherited as an autosomal dominant trait. Since nearly 50% of HCM cases occur in the absence of a family history, a recessive inheritance pattern may be involved. METHODS: A pedigree was identified with suspected autosomal recessive transmission of HCM. Twenty-six HCM-related genes were comprehensively screened for mutations in the proband with targeted second generation sequencing, and the identified mutation was confirmed with bi-directional Sanger sequencing in all family members and 376 healthy controls. RESULTS: A novel missense mutation (c.1469G>T, p.Gly490Val in exon 17 of MYBPC3 was identified. Two siblings with HCM were homozygous for this mutation, whereas other family members were either heterozygous or wild type. Clinical evaluation showed that both homozygotes manifested a typical HCM presentation, but none of others, including 5 adult heterozygous mutation carriers up to 71 years of age, had any clinical evidence of HCM. CONCLUSIONS: Our data identified a MYBPC3 mutation in HCM, which appeared autosomal recessively inherited in this family. The absence of a family history of clinical HCM may be due to not only a de novo mutation, but also recessive mutations that failed to produce a clinical phenotype in heterozygous family members. Therefore, consideration of recessive mutations leading to HCM is essential for risk stratification and genetic counseling.

  1. [Retinal vasculitis in lupic disease].

    Science.gov (United States)

    Brissaud, P; Laroche, L; Krulik, M; Prier, A M; Saraux, H; Canuel, C; Debray, J

    1985-01-01

    Three cases of retinal vasculitis in SLE-type diseases are reported. The first was central retinal vein occlusion occurring during clinical remission of SLE in a 55 year old black female. Prednisone maintenance therapy was unchanged and visual loss rapidly regressed with heparin therapy. The second case was a 33 year old black female in whom SLE was discovered following relapsing bilateral optic neuritis. A progressive visual improvement was obtained with high dose of prednisone (1 mg/kg/day). The third cas was a 17 year old white girl with retinal vasculitis. She had an unclassified connective tissue disease inaugurated by optic neuritis at the age of 10. High dose prednisone (1 mg/kg/day) was effective on the visual loss. Retinal vasculitis lesions in SLE and their therapy are reviewed.

  2. AUTOMATIC RETINAL VESSEL TORTUOSITY MEASUREMENT

    Directory of Open Access Journals (Sweden)

    Nidhal Khdhair El Abbadi

    2013-01-01

    Full Text Available Retinal vascular vessels have the role to indicate the retinal diseases and for systematic diseases when there are any abnormalities in retinal vascular pattern. A characteristic of the vascular pattern that is appreciated by clinicians is vascular tortuosity, i.e., how curved or kinked a blood vessel, either vein or artery, appears along its course. In this study we suggest a novel mask filter to track the blood vessel along its course and measuring the blood vessels tortuosity over the entire human retinal vessel network in fundus eye image, by using the arc to chord ratio. The suggested algorithm tested with straight and curve hand drawing lines and gives high accurate results.

  3. Midlife diagnosis of Refsum Disease in siblings with Retinitis Pigmentosa – the footprint is the clue: a case report

    Directory of Open Access Journals (Sweden)

    Jayaram Hari

    2008-03-01

    Full Text Available Abstract Introduction Refsum disease is a potentially lethal and disabling condition associated with retinitis pigmentosa in which early treatment can prevent some of the systemic manifestations. Case presentation We present the cases of two brothers with a diagnosis of retinitis pigmentosa from childhood in whom Refsum disease was subsequently diagnosed midlife, after routine enquiry into hand and feet abnormalities. Subsequent treatment through dietary modification stabilised visual impairment and has prevented development of neurological complications to date. Conclusion It is therefore important to consider the diagnosis of Refsum disease in any patient with autosomal recessive or simplex retinitis pigmentosa, and to enquire about the presence of "unusual" feet or hands in such patients.

  4. Filling in the retinal image

    Science.gov (United States)

    Larimer, James; Piantanida, Thomas

    1990-01-01

    The optics of the eye form an image on a surface at the back of the eyeball called the retina. The retina contains the photoreceptors that sample the image and convert it into a neural signal. The spacing of the photoreceptors in the retina is not uniform and varies with retinal locus. The central retinal field, called the macula, is densely packed with photoreceptors. The packing density falls off rapidly as a function of retinal eccentricity with respect to the macular region and there are regions in which there are no photoreceptors at all. The retinal regions without photoreceptors are called blind spots or scotomas. The neural transformations which convert retinal image signals into percepts fills in the gaps and regularizes the inhomogeneities of the retinal photoreceptor sampling mosaic. The filling-in mechamism plays an important role in understanding visual performance. The filling-in mechanism is not well understood. A systematic collaborative research program at the Ames Research Center and SRI in Menlo Park, California, was designed to explore this mechanism. It was shown that the perceived fields which are in fact different from the image on the retina due to filling-in, control some aspects of performance and not others. Researchers have linked these mechanisms to putative mechanisms of color coding and color constancy.

  5. Retinal implants: a systematic review.

    Science.gov (United States)

    Chuang, Alice T; Margo, Curtis E; Greenberg, Paul B

    2014-07-01

    Retinal implants present an innovative way of restoring sight in degenerative retinal diseases. Previous reviews of research progress were written by groups developing their own devices. This systematic review objectively compares selected models by examining publications describing five representative retinal prostheses: Argus II, Boston Retinal Implant Project, Epi-Ret 3, Intelligent Medical Implants (IMI) and Alpha-IMS (Retina Implant AG). Publications were analysed using three criteria for interim success: clinical availability, vision restoration potential and long-term biocompatibility. Clinical availability: Argus II is the only device with FDA approval. Argus II and Alpha-IMS have both received the European CE Marking. All others are in clinical trials, except the Boston Retinal Implant, which is in animal studies. Vision restoration: resolution theoretically correlates with electrode number. Among devices with external cameras, the Boston Retinal Implant leads with 100 electrodes, followed by Argus II with 60 electrodes and visual acuity of 20/1262. Instead of an external camera, Alpha-IMS uses a photodiode system dependent on natural eye movements and can deliver visual acuity up to 20/546. Long-term compatibility: IMI offers iterative learning; Epi-Ret 3 is a fully intraocular device; Alpha-IMS uses intraocular photosensitive elements. Merging the results of these three criteria, Alpha-IMS is the most likely to achieve long-term success decades later, beyond current clinical availability.

  6. Retinal prosthesis for the blind.

    Science.gov (United States)

    Margalit, Eyal; Maia, Mauricio; Weiland, James D; Greenberg, Robert J; Fujii, Gildo Y; Torres, Gustavo; Piyathaisere, Duke V; O'Hearn, Thomas M; Liu, Wentai; Lazzi, Gianluca; Dagnelie, Gislin; Scribner, Dean A; de Juan, Eugene; Humayun, Mark S

    2002-01-01

    Most of current concepts for a visual prosthesis are based on neuronal electrical stimulation at different locations along the visual pathways within the central nervous system. The different designs of visual prostheses are named according to their locations (i.e., cortical, optic nerve, subretinal, and epiretinal). Visual loss caused by outer retinal degeneration in diseases such as retinitis pigmentosa or age-related macular degeneration can be reversed by electrical stimulation of the retina or the optic nerve (retinal or optic nerve prostheses, respectively). On the other hand, visual loss caused by inner or whole thickness retinal diseases, eye loss, optic nerve diseases (tumors, ischemia, inflammatory processes etc.), or diseases of the central nervous system (not including diseases of the primary and secondary visual cortices) can be reversed by a cortical visual prosthesis. The intent of this article is to provide an overview of current and future concepts of retinal and optic nerve prostheses. This article will begin with general considerations that are related to all or most of visual prostheses and then concentrate on the retinal and optic nerve designs. The authors believe that the field has grown beyond the scope of a single article so cortical prostheses will be described only because of their direct effect on the concept and technical development of the other prostheses, and this will be done in a more general and historic perspective.

  7. Autosomal recessive cerebellar ataxias : the current state of affairs

    NARCIS (Netherlands)

    Vermeer, S.; van de Warrenburg, B. P. C.; Willemsen, M. A. A. P.; Cluitmans, M.; Scheffer, H.; Kremer, B. P.; Knoers, N. V. A. M.

    2011-01-01

    Among the hereditary ataxias, autosomal recessive cerebellar ataxias (ARCAs) encompass a diverse group of rare neurodegenerative disorders in which a cerebellar syndrome is the key clinical feature. The clinical overlap between the different cerebellar ataxias, the occasional atypical phenotypes, an

  8. Meiotic behaviour of evolutionary sex-autosome translocations in Bovidae.

    Science.gov (United States)

    Vozdova, Miluse; Ruiz-Herrera, Aurora; Fernandez, Jonathan; Cernohorska, Halina; Frohlich, Jan; Sebestova, Hana; Kubickova, Svatava; Rubes, Jiri

    2016-09-01

    The recurrent occurrence of sex-autosome translocations during mammalian evolution suggests common mechanisms enabling a precise control of meiotic synapsis, recombination and inactivation of sex chromosomes. We used immunofluorescence and FISH to study the meiotic behaviour of sex chromosomes in six species of Bovidae with evolutionary sex-autosome translocations (Tragelaphus strepsiceros, Taurotragus oryx, Tragelaphus imberbis, Tragelaphus spekii, Gazella leptoceros and Nanger dama ruficollis). The autosomal regions of fused sex chromosomes showed normal synapsis with their homologous counterparts. Synapsis in the pseudoautosomal region (PAR) leads to the formation of characteristic bivalent (in T. imberbis and T. spekii with X;BTA13/Y;BTA13), trivalent (in T. strepsiceros and T. oryx with X/Y;BTA13 and G. leptoceros with X;BTA5/Y) and quadrivalent (in N. dama ruficollis with X;BTA5/Y;BTA16) structures at pachynema. However, when compared with other mammals, the number of pachynema lacking MLH1 foci in the PAR was relatively high, especially in T. imberbis and T. spekii, species with both sex chromosomes involved in sex autosome translocations. Meiotic transcriptional inactivation of the sex-autosome translocations assessed by γH2AX staining was restricted to their gonosomal regions. Despite intraspecies differences, the evolutionary fixation of sex-autosome translocations among bovids appears to involve general mechanisms ensuring sex chromosome pairing, synapsis, recombination and inactivation.

  9. Retinal vascular oximetry during ranibizumab treatment of central retinal vein occlusion

    DEFF Research Database (Denmark)

    Traustason, Sindri; la Cour, Morten; Larsen, Michael

    2014-01-01

    PURPOSE: To investigate the effect of intravitreal injections of the vascular endothelial growth factor inhibitor ranibizumab on retinal oxygenation in patients with central retinal vein occlusion (CRVO). METHODS: Retinal oxygen saturation in patients with CRVO was analysed using the Oxymap Retin...

  10. Genome-wide association and linkage analyses localize a progressive retinal atrophy locus in Persian cats.

    Science.gov (United States)

    Alhaddad, Hasan; Gandolfi, Barbara; Grahn, Robert A; Rah, Hyung-Chul; Peterson, Carlyn B; Maggs, David J; Good, Kathryn L; Pedersen, Niels C; Lyons, Leslie A

    2014-08-01

    Hereditary eye diseases of animals serve as excellent models of human ocular disorders and assist in the development of gene and drug therapies for inherited forms of blindness. Several primary hereditary eye conditions affecting various ocular tissues and having different rates of progression have been documented in domestic cats. Gene therapy for canine retinopathies has been successful, thus the cat could be a gene therapy candidate for other forms of retinal degenerations. The current study investigates a hereditary, autosomal recessive, retinal degeneration specific to Persian cats. A multi-generational pedigree segregating for this progressive retinal atrophy was genotyped using a 63 K SNP array and analyzed via genome-wide linkage and association methods. A multi-point parametric linkage analysis localized the blindness phenotype to a ~1.75 Mb region with significant LOD scores (Z ≈ 14, θ = 0.00) on cat chromosome E1. Genome-wide TDT, sib-TDT, and case-control analyses also consistently supported significant association within the same region on chromosome E1, which is homologous to human chromosome 17. Using haplotype analysis, a ~1.3 Mb region was identified as highly associated for progressive retinal atrophy in Persian cats. Several candidate genes within the region are reasonable candidates as a potential causative gene and should be considered for molecular analyses.

  11. Dominant inheritance of overo spotting in paint horses.

    Science.gov (United States)

    Bowling, A T

    1994-01-01

    Analysis of selected studbook records of the American Paint Horse Association, consisting of 687 foals sired by 13 overo stallions from non-overo mares, supports the inheritance of overo spotting as an autosomal dominant gene. More than one gene may control patterns registered as overo. Additional studies are necessary to explain the sporadic occurrence of overo spotting from nonspotted quarter horse parents and to confirm the inheritance of overo spotting in other breeds.

  12. [Congenital retinal folds in different clinical cases].

    Science.gov (United States)

    Munteanu, M

    2005-01-01

    We present 12 clinical cases of congenital retinal folds with different etiologies: posterior primitive vitreous persistency and hyperplasia (7 cases),retinocytoma (1 case). retinopathy of prematurity (1 case), astrocytoma of the retina (1 case), retinal vasculitis (1 case), Goldmann-Favre syndrome (1 case). Etiopathogenic and nosological aspects are discussed; the congenital retinal folds are interpreted as a symptom in a context of a congenital or acquired vitreo-retinal pathology.

  13. Choroidal melanoma clinically simulating a retinal angioma

    Energy Technology Data Exchange (ETDEWEB)

    Shields, J.A.; Joffe, L.; Guibor, P.

    1978-01-01

    An amelanotic fundus lesion in a 35-year-old man was associated with a dilated retinal vessel, thus suggesting the diagnosis of retinal angioma. Fluorescein angiography and B-scan ultrasonography were not diagnostic, but a radioactive phosphorus uptake test suggested the lesion was malignant. The enucleated globe showed a malignant choroidal melanoma drained by a large retinal vein.

  14. Choroidal melanoma clinically simulating a retinal angioma.

    Science.gov (United States)

    Shields, J A; Joffe, L; Guibor, P

    1978-01-01

    An amelanotic fundus lesion in a 35-year-old man was associated with a dilated retinal vessel, thus suggesting the diagnosis of retinal angioma. Fluorescein angiography and B-scan ultrasonography were not diagnostic, but a radioactive phosphorus uptake test suggested the lesion was malignant. The enucleated globe showed a malignant choroidal melanoma drained by a large retinal vein.

  15. Exploring the retinal connectome

    Science.gov (United States)

    Anderson, James R.; Jones, Bryan W.; Watt, Carl B.; Shaw, Margaret V.; Yang, Jia-Hui; DeMill, David; Lauritzen, James S.; Lin, Yanhua; Rapp, Kevin D.; Mastronarde, David; Koshevoy, Pavel; Grimm, Bradley; Tasdizen, Tolga; Whitaker, Ross

    2011-01-01

    Purpose A connectome is a comprehensive description of synaptic connectivity for a neural domain. Our goal was to produce a connectome data set for the inner plexiform layer of the mammalian retina. This paper describes our first retinal connectome, validates the method, and provides key initial findings. Methods We acquired and assembled a 16.5 terabyte connectome data set RC1 for the rabbit retina at ≈2 nm resolution using automated transmission electron microscope imaging, automated mosaicking, and automated volume registration. RC1 represents a column of tissue 0.25 mm in diameter, spanning the inner nuclear, inner plexiform, and ganglion cell layers. To enhance ultrastructural tracing, we included molecular markers for 4-aminobutyrate (GABA), glutamate, glycine, taurine, glutamine, and the in vivo activity marker, 1-amino-4-guanidobutane. This enabled us to distinguish GABAergic and glycinergic amacrine cells; to identify ON bipolar cells coupled to glycinergic cells; and to discriminate different kinds of bipolar, amacrine, and ganglion cells based on their molecular signatures and activity. The data set was explored and annotated with Viking, our multiuser navigation tool. Annotations were exported to additional applications to render cells, visualize network graphs, and query the database. Results Exploration of RC1 showed that the 2 nm resolution readily recapitulated well known connections and revealed several new features of retinal organization: (1) The well known AII amacrine cell pathway displayed more complexity than previously reported, with no less than 17 distinct signaling modes, including ribbon synapse inputs from OFF bipolar cells, wide-field ON cone bipolar cells and rod bipolar cells, and extensive input from cone-pathway amacrine cells. (2) The axons of most cone bipolar cells formed a distinct signal integration compartment, with ON cone bipolar cell axonal synapses targeting diverse cell types. Both ON and OFF bipolar cells receive

  16. Topics on domination

    CERN Document Server

    Hedetniemi, ST

    1991-01-01

    The contributions in this volume are divided into three sections: theoretical, new models and algorithmic. The first section focuses on properties of the standard domination number &ggr;(G), the second section is concerned with new variations on the domination theme, and the third is primarily concerned with finding classes of graphs for which the domination number (and several other domination-related parameters) can be computed in polynomial time.

  17. Dominating Sets and Domination Polynomials of Paths

    Directory of Open Access Journals (Sweden)

    Saeid Alikhani

    2009-01-01

    Full Text Available Let G=(V,E be a simple graph. A set S⊆V is a dominating set of G, if every vertex in V\\S is adjacent to at least one vertex in S. Let 𝒫ni be the family of all dominating sets of a path Pn with cardinality i, and let d(Pn,j=|𝒫nj|. In this paper, we construct 𝒫ni, and obtain a recursive formula for d(Pn,i. Using this recursive formula, we consider the polynomial D(Pn,x=∑i=⌈n/3⌉nd(Pn,ixi, which we call domination polynomial of paths and obtain some properties of this polynomial.

  18. Total well dominated trees

    DEFF Research Database (Denmark)

    Finbow, Arthur; Frendrup, Allan; Vestergaard, Preben D.

    cardinality then G is a total well dominated graph. In this paper we study composition and decomposition of total well dominated trees. By a reversible process we prove that any total well dominated tree can both be reduced to and constructed from a family of three small trees....

  19. Dominance in domestic dogs

    NARCIS (Netherlands)

    Borg, Van Der J.A.M.; Schilder, M.B.H.; Vinke, C.M.; Vries, De Han; Petit, Odile

    2015-01-01

    A dominance hierarchy is an important feature of the social organisation of group living animals. Although formal and/or agonistic dominance has been found in captive wolves and free-ranging dogs, applicability of the dominance concept in domestic dogs is highly debated, and quantitative data are

  20. [Study on preferred retinal locus].

    Science.gov (United States)

    Dai, Bing-Fa; Hu, Jian-Min; Xu, Duan-Lian

    2012-03-01

    Preferred retinal locus (PRL) is always found in the age-related macular degeneration and other macular damages in patients with low vision, and it is a very important anatomic position in patients with central vision impairment to achieve the rehabilitation. In recent years, the training of preferred retinal locus (PRL) has become a research hotspot of low vision rehabilitation, it can clearly improve functional vision and quality of life. The authors reviewed relevant literatures, and summarized the definition, position, characteristics, training and clinical implications of the PRL.

  1. Angiographic results of retinal-retinal anastomosis and retinal-choroidal anastomosis after treatments in eyes with retinal angiomatous proliferation

    Directory of Open Access Journals (Sweden)

    Saito M

    2012-08-01

    Full Text Available Masaaki Saito,1 Tomohiro Iida,1,2 Mariko Kano,1 Kanako Itagaki11Department of Ophthalmology, Fukushima Medical University School of Medicine, Fukushima, 2Department of Ophthalmology, Tokyo Women's Medical University School of Medicine, Tokyo, JapanBackground: The purpose of this study was to evaluate the angiographic results of retinal-retinal anastomosis (RRA and retinal-choroidal anastomosis (RCA for eyes with retinal angiomatous proliferation (RAP after treatment with intravitreal bevacizumab injections as monotherapy or intravitreal bevacizumab combined with photodynamic therapy.Methods: In this interventional, consecutive case series, we retrospectively reviewed five naïve eyes from four patients (mean age 80 years treated with three consecutive monthly intravitreal bevacizumab (1.25 mg/0.05 mL injections as initial treatment, and followed up for at least 3 months. In cases with over 3 months of follow-up and having recurrence of RAP or leakage by fluorescein angiography, retreatment was performed with a single intravitreal bevacizumab injection and photodynamic therapy.Results: Indocyanine green angiography showed RRA in three eyes with subretinal neovascularization and RCA in two eyes with choroidal neovascularization at baseline. At 3 months after baseline (month 3, neither the RRA nor RCA was occluded in any eye on indocyanine green angiography. Retreatment with intravitreal bevacizumab plus photodynamic therapy was performed in three eyes at months 3 (persistent leakage on fluorescein angiography, 6, and 7 (recurrence of RAP lesion, which achieved obvious occlusion of the RRA and RCA. Mean best-corrected visual acuity improved from 0.13 to 0.21 at month 3 (P = 0.066. No complications or systemic adverse events were noted.Conclusion: Although intravitreal bevacizumab for RAP was effective in improving visual acuity during short-term follow-up, intravitreal bevacizumab could not achieve complete occlusion of RRA and RCA, which could

  2. Spectrophotometric retinal oximetry in pigs

    DEFF Research Database (Denmark)

    Traustason, Sindri; Kiilgaard, Jens Folke; Karlsson, Robert;

    2013-01-01

    , Reykjavik, Iceland). The device simultaneously acquires images at two wavelengths (570 nm and 600 nm) and specialized software automatically detects retinal blood vessels. In three pigs, invasive pO2-measurements were performed after the initial non-invasive measurements. RESULTS: Comparison of femoral...... arterial oxygen saturation and the optical density ratio over retinal arteries revealed an approximately linear relationship (R(2) = 0.74, p = 3.4 x 10(-9)). In order to test the validity of applying the arterial calibration to veins, we compared non-invasive oximetry measurements to invasive pO2...

  3. Autosomal Recessive Polycystic Kidney Disease: Antenatal Diagnosis and Histopathological Correlation

    Directory of Open Access Journals (Sweden)

    Dayananda Kumar Rajanna

    2013-01-01

    Full Text Available Autosomal recessive polycystic kidney disease (ARPKD is one of the most common inheritable disease manifesting in infancy and childhood with a frequency of 1:6,000 to 1:55,000 births. The patient in her second trimester presented with a history of amenorrhea. Ultrasound examination revealed bilateral, enlarged, hyperechogenic kidneys, placentomegaly, and severe oligohydramnios. The pregnancy was terminated. An autopsy was performed on the fetus. Both the kidneys were found to be enlarged and the cut surface showed numerous cysts. The liver sections showed changes due to fibrosis. The final diagnosis of autosomal recessive polycystic kidney disease was made based on these findings. In this article, we correlate the ante-natal ultrasound and histopathological findings in autosomal recessive polycystic kidney disease.

  4. [Progress of research in retinal image registration].

    Science.gov (United States)

    Yu, Lun; Wei, Lifang; Pan, Lin

    2011-10-01

    The retinal image registration has important applications in the processes of auxiliary diagnosis and treatment for a variety of diseases. The retinal image registration can be used to measure the disease process and the therapeutic effect. A variety of retinal image registration techniques have been studied extensively in recent years. However, there are still many problems existing and there are numerous research possibilities. Based on extensive investigation of existing literatures, the present paper analyzes the feature of retinal image and current challenges of retinal image registration, and reviews the transformation models of the retinal image registration technology and the main research algorithms in current retinal image registration, and analyzes the advantages and disadvantages of various types of algorithms. Some research challenges and future developing trends are also discussed.

  5. Retinal imaging and image analysis

    NARCIS (Netherlands)

    Abramoff, M.D.; Garvin, Mona K.; Sonka, Milan

    2010-01-01

    Many important eye diseases as well as systemic diseases manifest themselves in the retina. While a number of other anatomical structures contribute to the process of vision, this review focuses on retinal imaging and image analysis. Following a brief overview of the most prevalent causes of blindne

  6. Differential modulation of retinal degeneration by Ccl2 and Cx3cr1 chemokine signalling.

    Science.gov (United States)

    Luhmann, Ulrich F O; Lange, Clemens A; Robbie, Scott; Munro, Peter M G; Cowing, Jill A; Armer, Hannah E J; Luong, Vy; Carvalho, Livia S; MacLaren, Robert E; Fitzke, Frederick W; Bainbridge, James W B; Ali, Robin R

    2012-01-01

    Microglia and macrophages are recruited to sites of retinal degeneration where local cytokines and chemokines determine protective or neurotoxic microglia responses. Defining the role of Ccl2-Ccr2 and Cx3cl1-Cx3cr1 signalling for retinal pathology is of particular interest because of its potential role in age-related macular degeneration (AMD). Ccl2, Ccr2, and Cx3cr1 signalling defects impair macrophage trafficking, but have, in several conflicting studies, been reported to show different degrees of age-related retinal degeneration. Ccl2/Cx3cr1 double knockout (CCDKO) mice show an early onset retinal degeneration and have been suggested as a model for AMD. In order to understand phenotypic discrepancies in different chemokine knockout lines and to study how defects in Ccl2 and/or Cx3cr1 signalling contribute to the described early onset retinal degeneration, we defined primary and secondary pathological events in CCDKO mice. To control for genetic background variability, we compared the original phenotype with that of single Ccl2, Cx3cr1 and Ccl2/Cx3cr1 double knockout mice obtained from backcrosses of CCDKO with C57Bl/6 mice. We found that the primary pathological event in CCDKO mice develops in the inferior outer nuclear layer independently of light around postnatal day P14. RPE and vascular lesions develop secondarily with increasing penetrance with age and are clinically similar to retinal telangiectasia not to choroidal neovascularisation. Furthermore, we provide evidence that a third autosomal recessive gene causes the degeneration in CCDKO mice and in all affected re-derived lines and subsequently demonstrated co-segregation of the naturally occurring RD8 mutation in the Crb1 gene. By comparing CCDKO mice with re-derived CCl2(-/-)/Crb1(Rd8/RD8), Cx3cr1(-/-)/Crb1(Rd8/RD8) and CCl2(-/-)/Cx3cr1(-/-)/Crb1(Rd8/RD8) mice, we observed a differential modulation of the retinal phenotype by genetic background and both chemokine signalling pathways. These findings

  7. Retinal detachment in a patient with extensive myelinated retinal nerve fibers.

    Science.gov (United States)

    Chen, Muh-Shy; Ho, Tzyy-Chang; Chang, Ching-Chung; Hou, Ping-Kang

    2007-01-01

    We report extensive myelinated retinal nerve fibers in a 42-year-old patient with retinal detachment. Fundus examination revealed a horseshoe-shaped tear near the temporal edge. Pars plana vitrectomy was performed and firm vitreo-retinal adhesion was noticed in the area of extensive myelinated retinal nerve fibers. Following vitrectomy with silicone oil tamponade, the retina was reattached successfully. In conclusion, retinal detachment may develop in patients with extensive myelinated retinal nerve fibers. Vitrectomy may be performed to treat this condition.

  8. Heterochronic misexpression of Ascl1 in the Atoh7 retinal cell lineage blocks cell cycle exit.

    Science.gov (United States)

    Hufnagel, Robert B; Riesenberg, Amy N; Quinn, Malgorzata; Brzezinski, Joseph A; Glaser, Tom; Brown, Nadean L

    2013-05-01

    Retinal neurons and glia arise from a common progenitor pool in a temporal order, with retinal ganglion cells (RGCs) appearing first, and Müller glia last. The transcription factors Atoh7/Math5 and Ascl1/Mash1 represent divergent bHLH clades, and exhibit distinct spatial and temporal retinal expression patterns, with little overlap during early development. Here, we tested the ability of Ascl1 to change the fate of cells in the Atoh7 lineage when misexpressed from the Atoh7 locus, using an Ascl1-IRES-DsRed2 knock-in allele. In Atoh7(Ascl1KI/+) and Atoh7(Ascl1KI/Ascl1KI) embryos, ectopic Ascl1 delayed cell cycle exit and differentiation, even in cells coexpressing Atoh7. The heterozygous retinas recovered, and eventually produced a normal complement of RGCs, while homozygous substitution of Ascl1 for Atoh7 did not promote postnatal retinal fates precociously, nor rescue Atoh7 mutant phenotypes. However, our analyses revealed two unexpected findings. First, ectopic Ascl1 disrupted cell cycle progression within the marked Atoh7 lineage, but also nonautonomously in other retinal cells. Second, the size of the Atoh7 retinal lineage was unaffected, supporting the idea of a compensatory shift of the non-proliferative cohort to maintain lineage size. Overall, we conclude that Ascl1 acts dominantly to block cell cycle exit, but is incapable of redirecting the fates of early RPCs.

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

    Directory of Open Access Journals (Sweden)

    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.

  10. Prenatal detection of rare chromosomal autosomal abnormalities in Europe

    NARCIS (Netherlands)

    Baena, N; De Vigan, C; Cariati, E; Clementi, M; Stoll, C; Caballin, MR; Guitart, M

    2003-01-01

    The aim of the present study was to evaluate the prenatal detection of rare chromosomal autosomal abnormalities by ultrasound (US) examination. Data were obtained from 19 congenital malformation registries from 11 European countries, between 01/07/96 and 31/12/98. A total of 664,340 births were cove

  11. Cytomegalovirus retinitis associated with acquired immunodeficiency syndrome

    Institute of Scientific and Technical Information of China (English)

    GENG Shuang; YE Jun-jie; ZHAO Jia-liang; LI Tai-sheng; HAN Yang

    2011-01-01

    Background Cytomegalovirus (CMV) retinitis is the most severe intraocular complication that results in total retinal destruction and loss of visual acuity in patients with acquired immunodeficiency syndrome (AIDS). This study aimed to investigate the fundus characteristics, systemic manifestations and therapeutic outcomes of CMV retinitis associated with AIDS.Methods It was a retrospective case series. CMV retinitis was present in 39 eyes (25 patients). Best corrected visual acuities, anterior segment, fundus features, fundus fluorescence angiography (FFA) and CD4+ T-lymphocyte counts of the patients with CMV retinitis associated with AIDS were analyzed. Intravitreal injections of ganciclovir (400 μg) were performed in 4 eyes (2 patients).Results Retinal vasculitis, dense, full-thickness, yellow-white lesions along vascular distribution with irregular granules at the border, and hemorrhage on the retinal surface were present in 28 eyes. The vitreous was clear or mildly opaque.Late stage of the retinopathy was demonstrated in 8 eyes characterized as atrophic retina, sclerotic and attenuated vessels, retinal pigment epithelium (RPE) atrophy, and optic nerve atrophy. Retinal detachment was found in 3 eyes. The average CD4+ T-lymphocyte count in peripheral blood of the patients with CMV retinitis was (30.6±25.3) ×106/L (range,(0-85) × 106/L). After intravitreal injections of ganciclovir, visual acuity was improved and fundus lesions regressed.Conclusions CMV retinitis is the most severe and the most common intraocular complication in patients with AIDS. For the patients with yellow-white retinal lesions, hemorrhage and retinal vasculitis without clear cause, human immunodeficiency virus (HIV) serology should be performed. Routine eye examination is also indicated in HIV positive patients.

  12. [Vitreo-retinal surgery for complicated retinal detachment].

    Science.gov (United States)

    Wang, J Z

    1993-07-01

    93 eyes (93 patients) of complicated retinal detachment were treated with vitreo-retinal surgery. Among the series, 75 eyes were rhegmatogenous with PVR C3-D3 in 66 eyes (88.0%), while the remaining 18 eyes were traction induced. None of the cases had giant tears or complicating diabetes. On discharge from the hospital, the operation was effective in 62 cases (66.7%), in whom the retina was totally reattached or only a small amount of subretinal fluid remained. In a group of 40 eyes where the inert gas SF6 was used, the operation was effective in 30 cases (75.0%). 41 cases were followed up postoperatively for over 3 months, averaging 13.7 months, to find the operative results stable in 33 eyes (80.5%), with the visual acuity improved in 22 cases (66.7%), unchanged in 9 cases (27.3%), and decreased in 2 cases (6.0%). The operative procedures, the peeling of pre-retinal membrane, the effect of PVR severity on the operative results, and the promotion of operative efficacy by application of wide encircling buckle and inert gas tamponade were discussed.

  13. Advances in Retinal Stem Cell Biology

    Directory of Open Access Journals (Sweden)

    Andrea S Viczian

    2013-01-01

    Full Text Available Tremendous progress has been made in recent years to generate retinal cells from pluripotent cell sources. These advances provide hope for those suffering from blindness due to lost retinal cells. Understanding the intrinsic genetic network in model organisms, like fly and frog, has led to a better understanding of the extrinsic signaling pathways necessary for retinal progenitor cell formation in mouse and human cell cultures. This review focuses on the culture methods used by different groups, which has culminated in the generation of laminated retinal tissue from both embryonic and induced pluripotent cells. The review also briefly describes advances made in transplantation studies using donor retinal progenitor and cultured retinal cells.

  14. Automatic Vessel Segmentation on Retinal Images

    Institute of Scientific and Technical Information of China (English)

    Chun-Yuan Yu; Chia-Jen Chang; Yen-Ju Yao; Shyr-Shen Yu

    2014-01-01

    Several features of retinal vessels can be used to monitor the progression of diseases. Changes in vascular structures, for example, vessel caliber, branching angle, and tortuosity, are portents of many diseases such as diabetic retinopathy and arterial hyper-tension. This paper proposes an automatic retinal vessel segmentation method based on morphological closing and multi-scale line detection. First, an illumination correction is performed on the green band retinal image. Next, the morphological closing and subtraction processing are applied to obtain the crude retinal vessel image. Then, the multi-scale line detection is used to fine the vessel image. Finally, the binary vasculature is extracted by the Otsu algorithm. In this paper, for improving the drawbacks of multi-scale line detection, only the line detectors at 4 scales are used. The experimental results show that the accuracy is 0.939 for DRIVE (digital retinal images for vessel extraction) retinal database, which is much better than other methods.

  15. A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy.

    NARCIS (Netherlands)

    Weterman, M.A.J.; Sorrentino, V.; Kasher, P.R.; Jakobs, M.E.; Engelen, B.G.M. van; Fluiter, K.; Wissel, M.B. de; Sizarov, A.; Nurnberg, G.; Nurnberg, P.; Zelcer, N.; Schelhaas, H.J.; Baas, F.

    2012-01-01

    Despite the high number of genes identified in hereditary polyneuropathies/Charcot-Marie-Tooth (CMT) disease, the genetic defect in many families is still unknown. Here we report the identification of a new gene for autosomal dominant axonal neuropathy in a large three-generation family. Linkage ana

  16. Dominant inherited distal spinal muscular atrophy with atrophic and hypertrophic calves

    NARCIS (Netherlands)

    Groen, R J; Sie, O G; van Weerden, T W

    1993-01-01

    The clinical, electrophysiological, radiological and morphological data of 3 members of a family with autosomal dominant distal spinal muscular atrophy (DSMA) are reported. One patient has the clinical picture of peroneal muscular atrophy with atrophic calves. His father and sister suffer from cramp

  17. Retinal Cell Degeneration in Animal Models

    OpenAIRE

    Masayuki Niwa; Hitomi Aoki; Akihiro Hirata; Hiroyuki Tomita; Green, Paul G.; Akira Hara

    2016-01-01

    The aim of this review is to provide an overview of various retinal cell degeneration models in animal induced by chemicals (N-methyl-d-aspartate- and CoCl2-induced), autoimmune (experimental autoimmune encephalomyelitis), mechanical stress (optic nerve crush-induced, light-induced) and ischemia (transient retinal ischemia-induced). The target regions, pathology and proposed mechanism of each model are described in a comparative fashion. Animal models of retinal cell degeneration provide insi...

  18. Genetics Home Reference: autosomal recessive spastic ataxia of Charlevoix-Saguenay

    Science.gov (United States)

    ... Genetics Home Health Conditions ARSACS autosomal recessive spastic ataxia of Charlevoix-Saguenay Enable Javascript to view the ... Open All Close All Description Autosomal recessive spastic ataxia of Charlevoix-Saguenay , more commonly known as ARSACS , ...

  19. Intrinsically photosensitive retinal ganglion cells

    Institute of Scientific and Technical Information of China (English)

    Gary; E.PICKARD; Patricia; J.SOLLARS

    2010-01-01

    A new mammalian photoreceptor was recently discovered to reside in the ganglion cell layer of the inner retina.These intrinsically photosensitive retinal ganglion cells(ipRGCs) express a photopigment,melanopsin,that confers upon them the ability to respond to light in the absence of all rod and cone photoreceptor input.Although relatively few in number,ipRGCs extend their dendrites across large expanses of the retina making them ideally suited to function as irradiance detectors to assess changes in ambient light levels.Phototransduction in ipRGCs appears to be mediated by transient receptor potential channels more closely resembling the phototransduction cascade of invertebrate rather than vertebrate photoreceptors.ipRGCs convey irradiance information centrally via the optic nerve to influence several functions.ipRGCs are the primary retinal input to the hypothalamic suprachiasmatic nucleus(SCN),a circadian oscillator and biological clock,and this input entrains the SCN to the day/night cycle.ipRGCs contribute irradiance signals that regulate pupil size and they also provide signals that interface with the autonomic nervous system to regulate rhythmic gene activity in major organs of the body.ipRGCs also provide excitatory drive to dopaminergic amacrine cells in the retina,providing a novel basis for the restructuring of retinal circuits by light.Here we review the ground-breaking discoveries,current progress and directions for future investigation.

  20. Retinal occlusive vasculer disorder and rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Huseyin Ortak

    2013-03-01

    Full Text Available Rheumatoid arthritis is a systemic inflammatory disease that affected older women with many ocular manifestations. Also, these systemic diseases can cause retinal vein occlusion and arterial occlusion that lead to serious and permanent visual loss. Rheumatoid arthritis's the most common manifestation is that retinal vasculitis and retinal vascular complications are associated with this complication. In this review, retinal vascular occlusive diseases are presented to associated with rheumatoid arthritis in literature. Rheumatoid arthritis and its complications have been outlined and was made to create a new perspective. [J Contemp Med 2013; 3(1.000: 71-73