Current researchAutosomal 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
References (67)
- et al.
Long-term follow-up of Stargardts disease and fundus flavimaculatus
Ophthalmology
(1998) - et al.
Prospective study of dietary fat and the risk of age-related macular degeneration
Am J Clin Nutr
(2001) - et al.
A novel locus for Leber congenital amaurosis maps to chromosome 6q
Am J Hum Genet
(2000) - et al.
Autosomal dominant Stargardt-like macular dystrophyI. Clinical characterization, longitudinal follow-up, and evidence for a common ancestry in families linked to chromosome 6q14
Am J Ophthalmol
(1999) - et al.
Clinical features of progressive bifocal chorioretinal atrophya retinal dystrophy linked to chromosome 6q
Ophthalmology
(1996) - et al.
Refinement of the locus for autosomal recessive Retinitis pigmentosa (RP25) linked to chromosome 6q in a family of Pakistani origin
Am J Hum Genet
(1999) - et al.
Genetic association of manganese superoxide dismutase with exudative age-related macular degeneration
Am J Ophthalmol
(2000) - et al.
Fundus flavimaculatus. Clinical, functional and histopathologic observations
Am J Ophthalmol
(1967) - et al.
A new locus for autosomal dominant stargardt-like disease maps to chromosome 4
Am J Hum Genet
(1999) - et al.
A new locus for dominant drusen and macular degeneration maps to chromosome 6q14
Am J Ophthalmol
(2000)
Dominant macular degenerations. The cone dystrophies
Am J Ophthalmol
Autosomal dominant Stargardt-like macular dystrophy segregating in a large Canadian family
Can J Ophthalmol
Autosomal-dominant fundus flavimaculatus. Clinicopathologic correlation
Ophthalmology
The 2588G to C mutation in the ABCR gene is a mild frequent founder mutation in the Western European population and allows the classification of ABCR mutations in patients with Stargardt disease
Am J Hum Genet
A major locus for autosomal recessive retinitis pigmentosa on 6q, determined by homozygosity mapping of chromosomal regions that contain gamma-aminobutyric acid-receptor clusters
Am J Hum Genet
Clinical spectrum of chromosome 6-linked autosomal dominant drusen and macular degeneration
Am J Ophthalmol
The ABCR gene in recessive and dominant Stargardt diseasesa genetic pathway in macular degeneration
Genomics
Stargardts disease and fundus flavimaculatusevaluation of morphologic progression and intrafamilial co-existence
Trans Am Ophthalmol Soc
A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy
Nat Genet
A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy
Nat Genet
Dominant inheritance of Stargardts disease
J Am Optom Assoc
Dominantly inherited macular dystrophy with flecks (Stargardt)
Arch Ophthalmol
Flecked retina disorders
Bull Soc Belge Ophthalmol
Autosomal dominant stargardt-like macular dystrophyfounder effect and reassessment of genetic heterogeneity
Arch Ophthalmol
Inherited macular dystrophiesa clinical overview
Aust NZ J Ophthalmol
Rod-cone dystrophy of the retina. Continuation of a family study described in 1923
Acta Ophthalmol (Copenh)
Autosomal dominant macular atrophy at 6q14 excludes CORD7 and MCDR1/PBCRA loci
Invest Ophthalmol Vis Sci
Retina-Vitreous-Macula
Identification of a consensus motif for retention of transmembrane proteins in the endoplasmic reticulum
EMBO J
Localization of the gene for progressive bifocal chorioretinal atrophy (PBCRA) to chromosome 6q
Hum Mol Genet
Clinical and genetic studies of an autosomal dominant cone-rod dystrophy with features of Stargardt disease
Ophthalmic Genet
Cited by (40)
Very long chain fatty acid-containing lipids: A decade of novel insights from the study of ELOVL4
2021, Journal of Lipid ResearchCitation Excerpt :It is also possible that mutations in ELOVL4 that significantly change the conformation of the protein structure and its active site may steer ELOVL4 substrate preference for either SFA or PUFA, hence the tissue-specific disorders caused by the different ELOVL4 mutations. A pathologic hallmark of STGD3 is the presence of lipid-containing residue lipofuscin in the RPE, RPE atrophy, and macular degeneration (10, 11, 66). VLC-PUFA are the main products of ELOVL4 in the retina and testes, whereas VLC-SFA are predominantly synthesized in the skin, brain, and Meibomian glands.
Differential composition of DHA and very-long-chain PUFAs in rod and cone photoreceptors
2018, Journal of Lipid ResearchEndoplasmic reticulum stress and the unfolded protein responses in retinal degeneration
2014, Experimental Eye ResearchCitation Excerpt :ER stress has also been linked to two not-so-commonly studied retinal degenerative diseases: Stargardt disease and Leber congenital amaurosis (LCA). Stargardt disease is an inherited macular degenerative disease that affects juveniles between the ages of six and twelve (reviewed in Shroyer et al., 1999; Donoso et al., 2001; Vasireddy et al., 2010). The symptoms of the disease are most similar to age-related macular degeneration, with rapid central vision loss, but the onset of the disease occurs much sooner in life.
Geographic chorioretinal atrophy in pseudoxanthoma elasticum
2013, American Journal of OphthalmologyCitation Excerpt :Within the next year, he developed subretinal hemorrhage and subretinal fibrosis from the laser scars that eventually extended into the area of atrophy. Geographic atrophy may be seen in several diseases, including age-related macular degeneration (AMD),11 maternally inherited diabetes and deafness,12 inherited pattern dystrophies,13 Stargardt macular dystrophy,14 central areolar dystrophy,15 extensive macular atrophy with pseudodrusen-like appearance,16 late-onset retinal macular degeneration,17 and a resolved vitelliform lesion associated with cuticular drusen.18 There are scattered reports describing geographic atrophy in pseudoxanthoma elasticum in the absence of CNV.7–10
Defective lipid transport and biosynthesis in recessive and dominant Stargardt macular degeneration
2010, Progress in Lipid ResearchRetinal very long-chain PUFAs: New insights from studies on ELOVL4 protein
2010, Journal of Lipid ResearchCitation Excerpt :Clinically, it is very similar to the more common autosomal recessive Stargardt's disease (STGD1) to the extent that fundus (the inner interior surface of the eye) examination alone is not enough to distinguish between the two disorders (153). Donoso et al. (153) reported that STGD3 patients have a milder phenotype of the disease, have relatively good visual function, and minimal color vision defects without significant abnormalities in their electro-occulogram or electroretinogram (ERG) (154). Similar to STGD1, the onset of loss of vision in patients ranges from 3 to 50 years with a mean age of 14 years, while on the average, Snellen acuity of 20/200 occurred at an average age of 22 years. (155).
- ☆
The authors have no commercial or proprietary interest in any product or concept discussed in this article.