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      • Abstract: found
      • Article: found

      Alagille Syndrome Associated with Myelinated Retinal Nerve Fibers


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          Purpose: Alagille syndrome is frequently associated with optic disc anomalies. This is the first report of a patient with Alagille syndrome and myelinated retinal nerve fibers. Methods: A 5-year-old female patient was referred to the Centre for Ophthalmology before a liver transplantation. Ocular examinations including slit lamp examination and funduscopy as well as anterior segment and fundus images were performed. Results: We observed myelinated retinal nerve fibers in both eyes of a 5-year-old female patient with Alagille syndrome. Conclusions: A broad spectrum of ocular anomalies is associated with Alagille syndrome. To our knowledge, this is the first reported case of myelinated retinal nerve fibers in a patient with Alagille syndrome.

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          Most cited references8

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          Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1.

          Alagille syndrome is an autosomal dominant disorder characterized by abnormal development of liver, heart, skeleton, eye, face and, less frequently, kidney. Analyses of many patients with cytogenetic deletions or rearrangements have mapped the gene to chromosome 20p12, although deletions are found in a relatively small proportion of patients (< 7%). We have mapped the human Jagged1 gene (JAG1), encoding a ligand for the developmentally important Notch transmembrane receptor, to the Alagille syndrome critical region within 20p12. The Notch intercellular signalling pathway has been shown to mediate cell fate decisions during development in invertebrates and vertebrates. We demonstrate four distinct coding mutations in JAG1 from four Alagille syndrome families, providing evidence that it is the causal gene for Alagille syndrome. All four mutations lie within conserved regions of the gene and cause translational frameshifts, resulting in gross alterations of the protein product Patients with cytogenetically detectable deletions including JAG1 have Alagille syndrome, supporting the hypothesis that haploinsufficiency for this gene is one of the mechanisms causing the Alagille syndrome phenotype.
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            NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway.

            Alagille syndrome (AGS) is caused by mutations in the gene for the Notch signaling pathway ligand Jagged1 (JAG1), which are found in 94% of patients. To identify the cause of disease in patients without JAG1 mutations, we screened 11 JAG1 mutation-negative probands with AGS for alterations in the gene for the Notch2 receptor (NOTCH2). We found NOTCH2 mutations segregating in two families and identified five affected individuals. Renal manifestations, a minor feature in AGS, were present in all the affected individuals. This demonstrates that AGS is a heterogeneous disorder and implicates NOTCH2 mutations in human disease.
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              Jagged1 (JAG1) mutations in Alagille syndrome: increasing the mutation detection rate.

              Alagille syndrome (AGS) is caused by heterozygous mutations in JAG1, and mutations have been previously reported in about 70% of patients who meet clinical diagnostic criteria. We studied a cohort of 247 clinically well-defined patients, and using an aggressive and sequential screening approach we identified JAG1 mutations in 94% of individuals. Mutations were found in 232 out of 247 patients studied and 83 of the mutations were novel. This increase in the mutation rate was accomplished by combining rigorous clinical phenotyping, with a combination of mutation detection techniques, including fluorescence in situ hybridization (FISH), genomic and cDNA sequencing, and quantitative PCR. This higher rate of mutation identification has implications for clinical practice, facilitating genetic counseling, prenatal diagnosis, and evaluation of living-related liver transplant donors. Our results suggest that more aggressive screening may similarly increase the rate of mutation detection in other dominant and recessive disorders.

                Author and article information

                S. Karger AG
                August 2009
                01 July 2009
                : 223
                : 5
                : 348-350
                aCentre for Ophthalmology and bClinics for Dermatology, University Hospital Tübingen, and cUniversity Children’s Hospital Tübingen, Tübingen, Germany
                226259 Ophthalmologica 2009;223:348–350
                © 2009 S. Karger AG, Basel

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                : 21 August 2008
                : 11 December 2008
                Page count
                Figures: 2, References: 10, Pages: 3
                Case Report

                Vision sciences,Ophthalmology & Optometry,Pathology
                Optic disc anomaly,Alagille syndrome,Myelinated retinal nerve fibers,Posterior embryotoxon


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