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      Clinical Polymorphism of Stargardt Disease in a Large Consanguineous Tunisian Family; Implications for Nosology

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          Abstract

          Purpose

          To describe the polymorphic expression of Stargardt disease in a large Tunisian family with clinical intra- and interfamilial variation of the condition.

          Methods

          Twelve subjects from two related families with autosomal recessive Stargardt disease were enrolled. A detailed clinical examination including visual acuity and visual field measurement, fundus photography, fluorescein angiography, electroretinography (ERG) and color vision testing was performed for all subjects.

          Results

          The youngest child from family A manifested typical Stargardt disease while her two brothers presented with Stargardt disease-fundus flavimaculatus (STGD-FFM) and her two sisters demonstrated a peculiar phenotype overlapping Stargardt disease and cone-rod dystrophy; their phenotypic manifestation corresponded well with ERG groups I, II and III, respectively. This uncommon occurrence of an age-related decline in ERG amplitude and worsening of fundus changes is suggestive of a grading pattern in Stargardt disease. Their two cousins in family B, displayed the STGD-FFM phenotype. Despite clinically similar STGD-FFM patterns in both families, age of onset and progression of the phenotype in family B differed from family A.

          Conclusion

          This is the first report on phenotypic variation of Stargardt disease in a large Tunisian family. Regarding phenotype and severity of visual symptoms, family A demonstrated Stargardt disease at various stages of progression. In addition, STGD-FFM appeared to be an independent clinical entity in family B. These findings imply that further parameters are required to classify Stargardt’s disease.

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          Most cited references35

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          Standard for clinical electroretinography (2004 update).

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            Genotype/Phenotype analysis of a photoreceptor-specific ATP-binding cassette transporter gene, ABCR, in Stargardt disease.

            Mutation scanning and direct DNA sequencing of all 50 exons of ABCR were completed for 150 families segregating recessive Stargardt disease (STGD1). ABCR variations were identified in 173 (57%) disease chromosomes, the majority of which represent missense amino acid substitutions. These ABCR variants were not found in 220 unaffected control individuals (440 chromosomes) but do cosegregate with the disease in these families with STGD1, and many occur in conserved functional domains. Missense amino acid substitutions located in the amino terminal one-third of the protein appear to be associated with earlier onset of the disease and may represent misfolding alleles. The two most common mutant alleles, G1961E and A1038V, each identified in 16 of 173 disease chromosomes, composed 18.5% of mutations identified. G1961E has been associated previously, at a statistically significant level in the heterozygous state, with age-related macular degeneration (AMD). Clinical evaluation of these 150 families with STGD1 revealed a high frequency of AMD in first- and second-degree relatives. These findings support the hypothesis that compound heterozygous ABCR mutations are responsible for STGD1 and that some heterozygous ABCR mutations may enhance susceptibility to AMD.
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              The 2588G-->C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease.

              In 40 western European patients with Stargardt disease (STGD), we found 19 novel mutations in the retina-specific ATP-binding cassette transporter (ABCR) gene, illustrating STGD's high allelic heterogeneity. One mutation, 2588G-->C, identified in 15 (37.5%) patients, shows linkage disequilibrium with a rare polymorphism (2828G-->A) in exon 19, suggesting a founder effect. The guanine at position 2588 is part of the 3' splice site of exon 17. Analysis of the lymphoblastoid cell mRNA of two STGD patients with the 2588G-->C mutation shows that the resulting mutant ABCR proteins either lack Gly863 or contain the missense mutation Gly863Ala. We hypothesize that the 2588G-->C alteration is a mild mutation that causes STGD only in combination with a severe ABCR mutation. This is supported in that the accompanying ABCR mutations in at least five of eight STGD patients are null (severe) and that a combination of two mild mutations has not been observed among 68 STGD patients. The 2588G-->C mutation is present in 1 of every 35 western Europeans, a rate higher than that of the most frequent severe autosomal recessive mutation, the cystic fibrosis conductance regulator gene mutation DeltaPhe508. Given an STGD incidence of 1/10,000, homozygosity for the 2588G-->C mutation or compound heterozygosity for this and other mild ABCR mutations probably does not result in an STGD phenotype.
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                Author and article information

                Journal
                J Ophthalmic Vis Res
                J Ophthalmic Vis Res
                JOVR
                Journal of Ophthalmic & Vision Research
                Ophthalmic Research Center
                2008-2010
                2008-322X
                October 2013
                : 8
                : 4
                : 341-350
                Affiliations
                [1 ]Department of Ophthalmology, Hedi Rais Institute of Ophthalmology, Tunis, Tunisia
                [2 ]Ocular Genetics Research Unit (UR17/04), Hedi Rais Institute of Ophthalmology, Tunis, Tunisia
                [3 ]Molecular Investigation of Genetic Orphan Diseases Unit, Institut Pasteur, Tunis, Tunisia
                Author notes
                Leila El Matri, MD. Hedi Rais Institute of Ophthalmology, Boulevard 9 Avril 1006 Bab Saadoun, Tunis , Tunisia; Tel: +216 71 573604, Fax: +216 71 575956; e-mail: L eila.elmatri@ 123456rns.tn
                Article
                JOVR-08-341
                3957041
                24653822
                22dff9ce-e817-4661-bf45-8b232407eb90
                © 2013 Ophthalmic Research Center, Shahid Beheshti University of Medical Sciences

                This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License which allows users to read, copy, distribute and make derivative works for non-commercial purposes from the material, as long as the author of the original work is cited properly.

                History
                : 24 July 2012
                : 20 July 2013
                Categories
                Original Article

                Ophthalmology & Optometry
                stargardt disease,fundus flavimaculatus,intrafamilial,interfamilial,progression,classification,prognosis

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