Sorsby's fundus dystrophy (SFD) is an autosomal dominant macular disorder with age of onset usually in the fourth decade. It is characterized by loss of central vision from subretinal neovascularization and atrophy of the ocular tissues (1). Generally, macular disciform degeneration develops in the fellow eye within 6 months to 6 years (2). Based on similar clinical and histopathological features, in particular at the level of Bruch's membrane, SFD is thought to provide a genetic model for the study of the more common macular degenerations (3-5). In this group, the age-related macular degeneration (AMD) has an estimated prevalence of almost 20% in the population over 65 years of age in developed countries (6), therefore constituting a major public health problem. The understanding of the molecular pathogenesis in these macular disorders will be crucial to facilitate the development of adequate therapeutic treatments. Recently, the SFD locus was mapped to chromosome 22ql 3-qter (7). The same region was shown to contain the gene encoding the tissue inhibitor of metalloproteinases-3 (TIMP3)(8). Subsequently, Tyrl68Cys and Serl81Cys mutations were identified in the TIMP3 gene in affected members of two unrelated SFD pedigrees, respectively (9). To further confirm TIMP3 as the SFD gene and to gain additional insights into the molecular mechanisms underlying the disease, we have now studied a large German-Czech family with an atypical form of SFD.

We have collected DNA samples from 12 affected and four unaffected members of the German-Czech SFD family. All affected individuals presented with clinical signs typical for Sorsby's fundus dystrophy (1). At the onset of the disease, a central subretinal neovascularisation occurred followed by extensive scarring. Corresponding to the morphological changes a central scotoma was found. However, in contrast to previous descriptions (1, 10), symptoms were observed approximately 10-15 years earlier with a mean age of onset at 25 years and the disease progressed more rapidly with a second eye involvement within months. In the course of several years, the patients developed tapetal retinal dystrophy with intraretinal perivascular bone spicular pigment proliferation, attenuation of the intraretinal arteries and atrophy of the choriocapillaris. These changes were accompanied by loss of the peripheral visual field, decrease in dark adaptation and subnormal scotopic and photopic ERG (U. Schonherr, in preparation). To first test for genetic linkage between the early-onset SFD locus and the TIMP3 gene we genotyped all family members with microsatellite markers D22S275, D22S280 and D22S283