Elsevier

Survey of Ophthalmology

Volume 46, Issue 2, September–October 2001, Pages 149-163
Survey of Ophthalmology

Current research
Autosomal Dominant Stargardt-Like Macular Dystrophy

https://doi.org/10.1016/S0039-6257(01)00251-XGet rights and content

Abstract

Autosomal dominant Stargardt-like macular dystrophy is one of the early onset macular dystrophies. It is characterized clinically in its early stages by visual loss and by the presence of atrophic macular changes with or without the presence of yellowish flecks. It is an important retinal dystrophy to study, not only because it has implications in the care and treatment of patients with the condition, but because it also provides important information regarding retinal function. Review of the literature suggests that many of the reported families are linked to chromosome 6q. Genetic and genealogical evidence suggests that these families have descended from a common ancestor or founder. The recent identification of a disease-causing gene that is involved in fatty acid metabolism may have implications in the study of the more common age-related macular degeneration. We review the recent clinical, genetic, and genealogical aspects of autosomal dominant Stargardt-like macular dystrophy.

Section snippets

Clinical Presentation

Visual loss is the most common presenting clinical symptom in patients with autosomal dominant Stargardt-like macular dystrophy.12 In our experience, this change often occurs in the first or second decade of life. It may precede retinal changes and is often associated with subtle retinal pigment epithelial abnormalities.12 There is often pallor of the temporal optic nerve head, which may precede retinal findings as well.12 These early findings are later followed by an atrophic macular

Summary of Families with Autosomal Dominant Stargardt-Like Macular Dystrophy

We found reports for 12 families with features consistent with autosomal dominant Stargardt-like macular dystrophy characterized by 1) early onset visual loss, 2) atrophic macular changes with or without the presence or flecks, 3) relatively good functional vision, 4) minimal color vision defects, and 5) the absence of significant ERG changes. One such family was initially reported by Klein and Krill in 1967,23 and a pedigree for this family was subsequently published by Krill in 1977 (4

Evidence for a Founder Effect in Autosomal Dominant Stargardt-Like Macular Dystrophy and a Single Larger Family Linked to Chromosome 6

Linkage to chromosome 6 and determination of the disease-associated haplotype have been reported in these 12 families with the exception of Families 1, 3, 4, and 6.10, 66 In addition, six of the remaining families (Families 2, 5, 7, 8, 10, and 11) have been joined together through extensive genealogical and molecular genetic investigations10, 12 to identify a founder effect and demonstrate a common ancestor, as described below.

Chromosome 6–Associated Retinopathies

Seven distinct hereditary retinal diseases have been linked to the long arm of chromosome 6q in the region of the autosomal dominant Stargardt-like macular dystrophy gene. Because of their proximity to each other, these conditions have been referred to as the chromosome 6q retinopathies. The genes for these seven disorders are all localized to within a maximum of 30 cM from each other. In addition to dominant Stargardt-like macular dystrophy, recessive retinitis pigmentosa families, a Leber

Cloning the Disease-Causing Gene

Efforts to clone the gene for autosomal dominant Stargardt-like macular dystrophy employed a positional-candidate gene approach.10, 11, 66 The localization of the gene was progressively refined using affected and unaffected individuals with meiotic recombinations (meiotic breakpoint mapping).10, 16, 26, 29, 53, 66, 67 The critical region based on recombination events in affected patients was ultimately reduced to a 1.2 cM interval with the centromeric border at approximately D6S1625.10, 16 The

Gene Properties

The ELOVL4 gene is expressed as a 2.9 kilobase messenger RNA in brain, retina, and testes by reverse transcription-polymerase chain reaction (RT-PCR) analysis.66 Hybridization of the ELOVL4 messenger RNA to rhesus monkey and mouse retina showed expression exclusively in rod and cone photoreceptors. The expression was primarily localized to the inner segments of the photoreceptors. The messenger RNA encodes a predicted protein (ELOVL4p) of 314 amino acids with homology to the GNS1/SUR4 family of

Implications for Other Retinal Disease Genes

The identification of the ELOVL4 gene in dominant Stargardt-like macular degeneration implicates fatty acid elongation in the pathogenesis of macular dystrophies and degenerations for the first time, as noted above. In addition to ELOVL4, three other proteins predicted from expressed and genomic sequence have been identified in mammalian systems. The two human genes were called ELOVL1 and ELOVL2 because of their homology to the SUR4 family of yeast elongation of very long chain fatty acid

Lipids and Macular Degeneration

Dietary lipids and lipid peroxidation have been implicated in retinal disorders. Long chain polyunsaturated fatty acids are abundant in the retina. The concentration of polyunsaturated lipids in rod outer segments combined with a geographic proximity to an arterial oxygen supply suggests an environment conducive to fatty acid peroxidation. For example, docosahexaenoic acid (DHA; 22:6n-3) accounts for 33% of the fatty acid content of photoreceptor outer segments40 and 16–22% of the fatty acids

Patient Management

The management of hereditary diseases can be separated into 1) treatment of affected patients, 2) genetic counseling, and 3) reducing the risk of transmitting the disease gene to offspring.

At this time no therapy of autosomal dominant Stargardt-like macular dystrophy can be recommended based on experimental evidence in humans. The accumulation of A2E (N-retinyl-N-retinylidene ethanolamine; a lipofusion component) in a transgenic mouse model homozygous for ABCR knockout (a recessive Stargardt

Summary

The identification of the autosomal dominant Stargardt-like macular dystrophy gene provides a basis for distinguishing this disorder from the recessive form and other early onset macular dystrophies that may show similar phenotypic features. It also provides a method to identify family members who are likely related, and it provides additional evidence for a founder effect in this condition. A study of the genes function and the development of suitable animal models will allow for new

Methods of Literature Search

The primary literature search was performed using PubMed (www.ncbi.nlm.nih.gov/PubMed) using the search terms Stargardt macular dystrophy and fatty acid elongation, and covering the years 1966 to the present. All languages were used. In addition, the authors used their own database of references. Additional citations were identified from the Pub Med screen and of the articles presently in the authors' possession.

Outline

I. Clinical presentation

II. Summary of families with autosomal dominant Stargardt-like macular dystrophy

III. Evidence for a founder effect in autosomal dominant stargardt-like macular dystrophy and a single larger family linked to chromosome 6

A. Founder effect in retinal diseases

B. Founder effect in autosomal dominant Stargardt-like macular dystrophy linked to chromosome 6

C. Single larger family linked to chromosome 6

IV. Chromosome 6–associated retinopathies

V. Cloning the disease-causing gene

Acknowledgements

Supported, in part, by the Henry and Corinne Bower Laboratory for Macular Degeneration, the Reuben and Molly Gordon Foundation, and the estates of Margaret Mercer, Elizabeth King, Harry B. Right, Dorothy Hartman, and Martha W.S. Rogers. Supported by NIH grant EY12699 (Drs. Edwards and Donoso), a Career development award from Research to Prevent Blindness (Dr. Edwards), the Foundation Fighting Blindness, the Schollmaier Foundation, the Anne Marie and Thomas B. Walker Jr. Fund for Age-related

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