Stargardt Disease 3

A number sign (#) is used with this entry because of evidence that Stargardt disease-3 (STGD3) is caused by heterozygous mutation in the ELOVL4 gene (605512) on chromosome 6q14.

For a general phenotypic description and a discussion of genetic heterogeneity of Stargardt disease, see 248200.

Clinical Features

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 (ADMD) 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.

Mapping

Linkage studies by Stone et al. (1994) in an extensively affected family with an autosomal dominant form of Stargardt-like progressive macular dystrophy demonstrated that the disease-causing gene was located near the centromere on 6q; maximum lod = 5.50 at theta = 0.0 with marker D6S280. Multipoint analysis resulted in a peak lod score of 6.2 in the interval between markers D6S313 and D6S252 and excluded the interval containing the North Carolina macular dystrophy gene (MCDR1), which had been mapped to 6q14-q16.2. Presumably the disorder in the new family maps to the region 6cen-q14.

Zhang et al. (1994) studied a large Indiana family with Stargardt disease inherited as an autosomal dominant. Because of some similarities to Best disease (153700), which maps to 11q13, linkage studies were performed that excluded a location on that chromosome. Although Zhang et al. (1994) found linkage to chromosome 13q34 in this family, Zhang et al. (2001) reported additional clinical studies of children in this family who were initially too young to establish a diagnosis. Genetic linkage and haplotype analyses of these children placed the disease gene for the Stargardt-like phenotype in this family to the STGD3 locus on 6q14 (maximum lod of 9.66 at theta of 0.0 with D6S460), thus eliminating the previously suggested locus (STGD2) for an autosomal dominant Stargardt-like phenotype on 13q34.

Griesinger et al. (2000) performed haplotype analysis in a family with autosomal dominant macular dystrophy and localized the disease gene to an 8-cM region at 6q14, within the 18-cM interval of STGD3 but excluding the cone-rod dystrophy-7 (CORD7; 603649) and MCDR1 (136550) loci. The mapping interval overlapped with that of retinitis pigmentosa-25 (RP25; 602772). The authors concluded that the autosomal dominant macular dystrophy, STGD3, and RP25 loci may be allelic.

Donoso et al. (2001) characterized a disease-associated haplotype in 7 families with autosomal dominant Stargardt-like macular dystrophy and determined that the families shared a common ancestor. They examined 171 patients and genotyped 145 samples. They concluded that most reported cases of autosomal dominant Stargardt-like macular dystrophy in North America are part of a single larger family, consisting of 31 branches and 2,314 individuals, associated with a gene locus on chromosome 6q16. They refined the critical region for the gene to approximately 1,000 kb on chromosome 6q16 and eliminated part or all of 9 candidate disease-causing genes. They found that the DNA haplotype associated with disease was useful in excluding individuals with phenotypically similar retinal conditions.

Pathogenesis

In the large Utah family with STGD3 reported by Bernstein et al. (2001) to have a mutation in the ELOVL4 gene (605512.0002), Hubbard et al. (2006) found evidence that the phenotypic diversity of family members may be due to differences in dietary fat intake as reflected by adipose and red blood cell lipids.

Molecular Genetics

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 heterozygosity for 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 heterozygous 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.

Animal Model

Karan et al. (2005) generated transgenic mice expressing the 5-bp deletion mutant form of ELOVL4 (605512.0001). They found that the mutant ELOVL4 exerted a dominant effect on the accumulation of undigested phagosomes and lipofuscin by the retinal pigment epithelium (RPE), which was followed by RPE atrophy. Subsequently, photoreceptor degeneration occurred in the central retina in a pattern closely resembling that of human Stargardt-like macular dystrophy and age-related macular degeneration (see 153800). Karan et al. (2005) concluded that these ELOVL4 transgenic mice provide a good model for both STGD and dry ARMD.