In most instances macular dystrophy with flecks (Stargardt disease) shows an autosomal recessive pattern of inheritance; see 248200. Cibis et al. (1980) reported an extensive family with an apparently dominant form of macular dystrophy with flecks. Some patients ... In most instances macular dystrophy with flecks (Stargardt disease) shows an autosomal recessive pattern of inheritance; see 248200. Cibis et al. (1980) reported an extensive family with an apparently dominant form of macular dystrophy with flecks. Some patients had no flecks. The authors thought there was insufficient evidence to place the disorder in the category of 'cone dystrophy,' and stated that 'cone dystrophy is never associated with the fundus flavimaculatus flecks synonymous with Stargardt's disease.' The pedigree contained 34 affected individuals distributed in many sibships over 5 generations. No evidence of male-to-male transmission was observed, but there were 4 daughters of affected males who were said to be unaffected. Stone et al. (1994) described a large family with a macular dystrophy whose main clinical features were similar to those of Stargardt disease, but inherited in an autosomal dominant fashion. Affected persons had normal vision in early childhood but began to experience difficulty with central vision between 5 and 23 years of age. Fundus examination early in the disease course revealed flecks in the macula. Central atrophy developed later, with visual acuity decreasing to 20/200 or worse in all patients older than 31 years. Fluorescein angiography failed to show a silent or dark choroid. The ERG was near normal in younger affected individuals and was most notable for prolonged 'implicit times' in a 73-year-old patient. The progressive nature of the disorder in the family reported by Stone et al. (1994) was a clinical feature distinguishing it from the North Carolina form of macular dystrophy (MCDR1; 136550). Griesinger et al. (2000) reported a family with autosomal dominant macular dystrophy characterized by progressive retinal pigment epithelial atrophy in the macula without apparent peripheral involvement by ophthalmoscopy or functional studies. Acuity loss progressed with age and generally was worse in the older affected individuals. The rod and cone function remained normal or nearly normal in all tested affected members up to 61 years of age. The phenotype in this family was similar to Stargardt-like macular degeneration except that (1) color vision for all affected individuals but 1 was very good or normal and did not correlate with acuity loss, and (2) all affected fundi showed slight darkening of the fluorescein angiogram background, but none had the stark black 'dark choroid' observed in Stargardt disease.
In all affected members of 5 families with STGD3 or ADMD, including the family reported by Griesinger et al. (2000), Zhang et al. (2001) identified a 5-bp deletion in the ELOVL4 gene (605512.0001).
In all affected ... In all affected members of 5 families with STGD3 or ADMD, including the family reported by Griesinger et al. (2000), Zhang et al. (2001) identified a 5-bp deletion in the ELOVL4 gene (605512.0001). In all affected members of a family with a dominant Stargardt-like macular dystrophy, Bernstein et al. (2001) identified a complex mutation in the ELOVL4 gene in which two 1-bp deletions (605512.0002) separated by 4 nucleotides resulted in a frameshift and truncation of the ELOVL4 protein. The effect of this mutation was similar to that of the previously described 5-bp deletion. The authors concluded that the discovery of a second mutation in the ELOVL4 gene segregating with macular dystrophy confirms the role of this gene in a subset of dominant macular dystrophies with a wide range of clinical expression. They asserted that their work suggests a role for modifying genes and/or environmental factors in the macular dystrophy disease process. Maugeri et al. (2004) studied a European family with characteristic features of STGD3. A novel ELOVL4 tyr270-to ter (Y270X) mutation (605512.0004) was detected in affected individuals. Transfection studies indicated that, unlike wildtype ELOVL4, the mutated protein did not localize to the endoplasmic reticulum but rather appeared to be sequestered in an aggregate pattern in the cytoplasm.