Sorsby et al. (1949) described 5 families with a fundus dystrophy that occurred in several generations in a dominant pedigree pattern. It became manifest at about the age of 40 years, beginning as a central (macular) lesion showing ... Sorsby et al. (1949) described 5 families with a fundus dystrophy that occurred in several generations in a dominant pedigree pattern. It became manifest at about the age of 40 years, beginning as a central (macular) lesion showing edema, hemorrhage, and exudates. In the course of years, atrophy with pigmentation and extension peripherally occurred. The choroidal vessels became exposed and appeared somewhat sclerotic. Within about 35 years after onset the entire fundus was involved. The choroidal vessels disappeared by this stage and the terminal picture was one of extensive choroidal atrophy with pigmentation. Night blindness was not a feature at any stage. The authors considered the process to be primarily choroidal. Kalmus and Seedburgh (1976) established a genealogic link between one of the families originally reported from England by Sorsby et al. (1949) and one reported from Australia by Fraser and Wallace (1971). Sandvig (1955) described 13 cases of central choroidal degeneration in 4 generations of a family. Krill and Archer (1971) described mother and 3 children with diffuse total choroidal vascular atrophy. Forsius (1981), who referred to the condition as Sorsby hemorrhagic degeneration of the retina and choroid, described an instructive Finnish family with marriage of 2 affected persons whose 8 children were all affected. Bleeding occurred in the macula at about age 20 or 25 years, but the most severe case had onset at age 13 years. Drusen appeared in the midperiphery and the periphery became albinoid. Follow-up studies of the families initially characterized by Sorsby et al. (1949) emphasized the occurrence of interfamilial phenotypic variation and raised the possibility of genetic heterogeneity. In his original report, Sorsby et al. (1949) noticed bilateral macular 'hemorrhage and exudates developing into mineralized choroidal atrophy with massive pigment proliferation.' Affected members of one of his families, the Kempster family, reported progressive difficulties with night vision for as long as 25 years before loss of visual acuity (Capon et al., 1988), whereas the Carver family had difficulties in adapting to sudden changes in ambient light (Polkinghorne et al., 1989), and the affected members of the Ewbanks family were asymptomatic before loss of visual acuity (Hoskin et al., 1981). Affected individuals in the last family experienced a sudden decrease in central vision triggered by subretinal macular neovascularization. In contrast, 2 patients from the Kempster family showed atrophic macular disease without choroidal neovascularization, whereas Carver family patients predominantly demonstrated a slow progression of the disease associated with chorioretinal atrophy.
In 2 SFD pedigrees, Weber et al. (1994) studied TIMP3 as a candidate gene on the basis of its chromosomal location at 22q12.1-q13.2 and its pivotal physiologic role in extracellular matrix remodeling. They demonstrated point mutations in the ... In 2 SFD pedigrees, Weber et al. (1994) studied TIMP3 as a candidate gene on the basis of its chromosomal location at 22q12.1-q13.2 and its pivotal physiologic role in extracellular matrix remodeling. They demonstrated point mutations in the TIMP3 gene in affected members of both pedigrees. The mutations predicted disruption of the tertiary structure and thus the functional properties of the mature protein. The existence of an autosomal recessive form of Sorsby fundus dystrophy had been proposed. Felbor et al. (1997) examined the TIMP3 gene in a large, highly consanguineous Finnish family previously thought to have early-onset autosomal recessive SFD (Forsius et al., 1982). They identified a novel heterozygous gly166-to-cys mutation in the TIMP3 gene (188826.0004) in all affected individuals and provided strong evidence for autosomal dominant inheritance of the SFD phenotype in this family. These results, in conjunction with the critical review of reported cases, rendered the existence of a recessive mode of inheritance in SFD questionable. Considering all available data, they suggested that SFD is a genetically homogeneous, clinically variable, autosomal dominant disorder.