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SC Khani, SJ Atkins, JE Young, E Reichel, R Ayyagari; Exclusion of the TIMP3 gene in a large Family with Late-Onset Sorsby-Like Macular Degeneration with Features Resembling Age-Related Macular Degeneration . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2825.
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Purpose: Age-related macular degeneration (AMD) is a complex heterogeneous disease of unknown etiology accounting for the majority of the cases of blindness among the elderly in the US. We have recently located a large three-generation pedigree with over 200 living members and a unique late-onset macular degeneration with prominent atrophic and exudative features closely resembling those found in AMD and a rare form of inherited maculopathy termed Sorsby fundus dystrophy (SFD). Our purpose is to better define the phenotype and the spectrum of clinical findings in this unique family, and to examine the possible role of TIMP3 gene mutations, which have been causally associated with SFD previously. Methods: Recruitment of family members for the study was carried out under an IRB-approved protocol after obtaining informed consent. Ophthalmologic data were obtained from history, fundus photography and in select cases from direct clinical examination, fluorescin angiography, visual field testing, and electroretinography. Blood samples were collected and processed to isolate the genomic DNA. Polymorphic microsatellite markers flanking the TIMP3 and other maculopathy candidate genes were tested for linkage to confirm or exclude the role of the maculopathy-associated candidate gene in causing the disease. Limited direct genomic sequence analysis of the exons and the flanking intron sequences of the TIMP3 gene was carried out to screen for mutations. Results: The macular degeneration appears to be inherited as an autosomal dominant trait in this family. Symptoms are first manifest in the fifth decade of life and include multiple relative central scotomas and variable and progressive reduction in acuity. All the affected individuals display characteristic atrophic macular changes with or without superimposed choroidal neovascularization. Linkage and haplotype analysis with microsatellite markers tightly linked to the TIMP3 gene and lack of mutations in the coding region of the TIMP3 gene excluded the SFD locus in our pedigree. Examination of other candidate maculopathy-associated loci is currently underway. Conclusion: The unique late-onset autosomal dominant macular degeneration studied in the large family above mimics AMD and SFD both in their atrophic and exudative forms. The disease is however not caused by mutations in the TIMP3 gene which are known to cause SFD in other families. Additional maculopathy associated loci are being tested for linkage.
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