STARGARDT’S DISEASE (FUNDUS FLAVIMACULATUS)

Signs and Symptoms

Stargardt’s disease is the most common autosomal recessive macular dystrophy, and it is on the continuum of macular degeneration.1-11 It was first described in 1909 by Carl Stargardt as a flecked retina disease in which patients presented with a chief complaint of decreased visual acuity in the first or second decade of life.1-4,10,12 Today, many continue to refer to it as juvenile macular degeneration.1-5 The reported prevalence of the disease is one in 8,000-10,000.3

Dysfunction of the ABCA gene causes the pathologic accumulation of lipofuscin, which is toxic to the RPE and photoreceptors.1-3,12-18 Presenting symptoms, fundus appearance and progression of the disease are variable.1-7 The disease presents with bilateral atrophic changes in the central retina associated with the degeneration of both photoreceptors and underlying RPE cells.12 The presence of “fish-shaped” or pisciform yellow flecks extending from the macula is the hallmark characteristic, though not omnipresent.12 Stargardt’s disease has four classic fundus presentation patterns: (1) macular pigmentary changes without flecks; (2) macular pigmentary changes with perifoveal flecks; (3) macular pigmentary changes with diffuse flecks; and (4) diffuse flecks without any macular compromise.3,4 The most common symptom is diminished central visual acuity; however, myopic refractive error, mild photophobia, glare disability and color vision defects are also commonly encountered.5,6 While the onset of symptoms usually occurs in the first or second decade of life, a substantial number of patients remain asymptomatic until the fourth or fifth decade.1-6 Choroidal neovascularization has been noted as a late complication.3 The disease has been associated with the broader syndromes of retinitis pigmentosa and Laurence-Moon-Bardet-Biedl disease, as well as obesity, hypogenitalism, retardation, pigmentary retinopathy and polydactyly.3,17

Pathophysiology

Stargardt’s disease has an autosomal recessive transmission pattern, and affected individuals typically exhibit bilateral and symmetrical presentations.3,5,12 Stargardt’s disease is considered to be one of the macular dystrophies.10-16

Research has provided a three-step explanation of the pathophysiology of Stargardt’s disease. Initially, defective rim protein (a glycoprotein associated with the rim of the photoreceptor outer-segment), encoded by the ABCA4 gene, causes an accumulation of protonated N-retinylidene-PE in the rod outer segments; this ATP binding cassette transmembrane protein is involved in the transport of all-trans-retinal (atRAL) and lipofuscin. Dysfunction in this protein causes accumulation of lipofuscin, which is toxic to the RPE and photoreceptors. It also creates a distinct thickening of the external limiting membrane. A2-E, a byproduct of N-retinylidene-PE and an accumulation of vitamin A-derived lipofuscin fluorophores, then accumulates in the RPE cells and is also toxic. Photoreceptors eventually die secondary to loss of the RPE support function.1-3,5,10-18 Generically, Stargardt’s disease is the result of a faulty lipid transporter that facilitates the removal of potentially toxic retinal compounds from photoreceptors following photoexcitation.16-18 Many blinding diseases are associated with these same mutations, including cone-rod dystrophy, retinitis pigmentosa and increased susceptibility to age-related macular degeneration.13,14 Electrophysiologic testing has conclusively confirmed that the defect responsible for the disease’s physical and symptomatic expression is in the RPE.4

In the milder variant known as late-onset Stargardt’s disease, there is increased potential for maintaining visual acuity of 20/40 or better due to the disease’s characteristic foveal sparing.3,20,21 An autosomal dominant form of Stargardt’s disease, known in the literature as Stargardt-like dystrophy, has been identified.12 It is caused by mutations in a gene encoding for ELOVL4, an enzyme that catalyzes the elongation of very long-chain fatty acids in photoreceptors and other tissues.12

Management

Since the destruction of the RPE results in photoreceptor loss, progressively worsening visual consequences are inevitable.1-7 There exists no effective treatment. Stem cell therapy for ocular disease has made significant progress within the last decade.14 Stem and progenitor populations for many ocular cell types have been identified. As their behavior becomes understood, it may be possible to conceive potential clinical applications.14 The application of embryonic stem cell-based therapy is in clinical development for Stargardt’s disease and dry age-related macular degeneration.14 Until these approaches produce clinical results, vision care specialists should advise those at risk of the benefits of genetic counseling in hopes of creating better anticipation and understanding of the disease, its potential prognosis and its risks for inheritance.1-3,13 Patients should take advantage of programs which provide guidance from subspecialties such as low vision rehabilitation, psychology/psychiatry and work-related therapists.2,3,6

Ultra-high frequency and maximum depth OCT is a clinically useful tool for examining intraretinal and subretinal changes—photoreceptor and RPE atrophy in particular—making it a reasonable imaging system for this disease.10 Short-wavelength fundus autofluorescence (FAF) originates from lipofuscin in the RPE and near-infrared (NIR) autofluorescence originates from RPE melanin. Instruments capable of generating this imaging can gather detailed data in Stargardt’s disease patients.22

Clinical Pearls

Since the disease is capable of producing symptoms without signs in young patients, this entity deserves consideration and testing before a diagnosis of amblyopia is suggested.

Stargardt’s disease generally does not induce the production of choroidal neovascularization.

A genetic pedigree may be helpful in diagnosis and understanding the mode of transmission of Stargardt’s disease, as well as the potential for other associated syndromes.

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10. Klevering BJ, Deutman AF, Maugeri A, et al. The spectrum of retinal phenotypes caused by mutations in the ABCA4 gene. Graefes Arch Clin Exp Ophthalmol. 2005;243(2):90-100.

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12. Molday RS, Zhang K. Defective lipid transport and biosynthesis in recessive and dominant Stargardt macular degeneration. Prog Lipid Res. 2010;49(4):476-92.

13. Han Z, Conley SM, Naash MI. Gene therapy for Stargardt disease associated with ABCA4 gene. Adv Exp Med Biol. 2014;801(7):719-24.

14. Radu RA, Hu J, Yuan Q, et al. Complement system dysregulation and inflammation in the retinal pigment epithelium of a mouse model for Stargardt macular degeneration. J Biol Chem. 2011;286(21):18593-601.

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16. Eveleth DD. Cell-based therapies for ocular disease. J Ocul Pharmacol Ther. 2013;29(10):844-54.

17. Sahel JA, Marazova K, Audo I. Clinical characteristics and current therapies for inherited retinal degenerations. Cold Spring Harb Perspect Med. 2014;5(2):pii,a017111.

18. Lee W, Nõupuu K, Oll M, et al. The external limiting membrane in early-onset Stargardt disease. Invest Ophthalmol Vis Sci. 2014;55(10):6139-49.

19. Dystrophy. Merriam Webster Dictionary. www.merriam-webster.com/dictionary/dystrophy.

20. Westeneng-van Haaften SC, Boon CJ, Cremers FP, et al. Clinical and genetic characteristics of late-onset Stargardt’s disease. Ophthalmology. 2012;119(6):1199-210.

21. van Huet RA, Bax NM, Westeneng-Van Haaften SC, et al. Foveal sparing in Stargardt disease. Invest Ophthalmol Vis Sci. 2014;55(11):7467-78.

22. Duncker T, Marsiglia M, Lee W, et al. Correlations among near-infrared and short-wavelength autofluorescence and spectral-domain optical coherence tomography in recessive Stargardt disease. Invest Ophthalmol Vis Sci. 2014;55(12):8134-43.