Autosomal dominant hemorrhagic macular dystrophy not associated with the TIMP3 gene

Objective: To describe the ophthalmic and genetic findings of a large kindr ed (UM:H389) With autosomal dominant hemorrhagic macular dystrophy. Methods: The disease state of family members was documented by dilated fund us examination, electroretinography, color vision tests, fluorescein angiog raphy, measurement of visual fields, biomicroscopy, gonioscopy, and intraoc ular pressure measurement. Linkage and haplotype analyses were carried out with markers flanking the Sorsby fundus dystrophy TIMP3 (tissue inhibitor o f metalloproteinase 3) gene locus, and mutation analysis was carried out by screening exon 5 of the TIMP3 gene. Results: This 4-generation pedigree with autosomal dominant hemorrhagic mac ular degeneration has visual symptoms beginning in the sixth decade of life . Several family members developed choroidal neovascular membrane formation in the macula of both eyes. The phenotype overlaps that of Sorsby fundus d ystrophy. Some of the affected members have unusual zonularlike radial stri ations on the anterior lens capsule surface, and glaucoma or ocular hyperte nsion has developed in 2 of them. Involvement of the TIMP3 gene was exclude d by linkage, haplotype, and mutation analyses. Conclusions: The phenotype of this family with autosomal dominant macular d ystrophy overlaps that of Sorsby fundus dystrophy. Exclusion of the TIMP3 g ene in this family indicates genetic heterogeneity for hemorrhagic macular dystrophy, Anterior segment anomalies may occur with this condition, but co segregation has not yet been established. Clinical Relevance: This study broadens the spectrum of hemorrhagic macular dystrophy by identifying a family in which the TIMP3 gene is not involved. Once the gene is cloned, we are eager to learn whether this gene may be in volved in age-related macular degeneration.