Stargardt Disease

Clinical Characteristics
Ocular Features: 

Stargardt disease or fundus flavimaculatus is a progressive form of juvenile macular degeneration with considerable clinical and genetic heterogeneity.  It may be considered a syndromal cone-rod dystrophy because of overlapping clinical features such as loss of color vision and photophobia in some patients.  Adding to the confusion is the fact that mutations in at least 4 genes are responsible for similar clinical characteristics.  Due to the lack of diagnostic distinctions and the wide range of nonspecific clinical manifestations, Stargardt disease and fundus flavimaculatus are discussed here as a single entity.

Onset of vision loss is often noted late in the first decade of life usually with rapid progression.  However, some patients are asymptomatic until much later, even into the fifth decade.  There is evidence that patients with an early onset have a worse prognosis compared to those with a later onset.  Nevertheless, large series of patients contain at least 23% with 20/40 or better acuity, about 20% with 20/50 -20/100, 55% have 20/200-20/400, and a small number have vision less than 20/400. 

Some color discrimination is lost and photophobia may be a complaint.  Dark adaptation is prolonged but nightblindness does not usually occur and peripheral visual fields are normal.  The posterior pole characteristically has yellowish pisciform, round, and linear subretinal lipofuscin deposits which often extend to the equator.  These may be present before clinical symptoms are present.  Histopathology reveals accumulations of this material in RPE cells.  Atrophy of the RPE in the same region is often visible as well but these changes may be subtle initially.  Some patients have peripheral pigment clumping which may resemble the bone spicule configuration seen in retinitis pigmentosa.  However, retinal vessel caliber is normal in Stargardt disease.  Extensive macular disease can be associated with temporal pallor of the optic nerve.  The ERG shows reduced photopic responses with normal or near normal scotopic tracings.  Fluorescein angiography often reveals more extensive disease than seen on fundoscopy.  Window defects are common in the macula where the RPE is atrophied.  The flecks may be hypo- or hyperfluorescent.  Over 50% of patients have patches of angiographically dark choroid in the posterior pole which is thought to be secondary to transmission blockage by lipofuscin accumulations in the RPE. 

Systemic Features: 

None.

Genetics

This group of disorders may be caused by mutations in at least 4 genes.  These are: STGD1 (248200) caused by mutations in the ABCA4 gene located at 1p22.1, or in CNGB3 (262300) (8q21-q22) which also is mutant in achromatopsia 3 (ACHM3), STGD3 (605512) caused by mutations in the ELOVL4 gene at 6q14, and STGD4 (603786) caused by a mutation in PROM1 on chromosome 4p.  STGD4 and STGD3 disease have been found in pedigrees consistent with autosomal dominant inheritance but STGD1 disease seems to be inherited in an autosomal recessive pattern.

There is considerable diagnostic confusion regarding the clinical phenotypes and the classification of many patients.  In particular, areolar macular dystrophy, retinitis pigmentosa, juvenile macular degeneration, and cone dystrophies have been reported in association with several of these mutations and reports have also associated Stargardt disease with mutations in RDS.

A single family with a brother and sister with Stargardt disease and neurological malformations has been reported (612948).  Both had developmental delays associated with absence or hypoplasia of the corpus callosum, upslanted lid fissures, 'flared eyebrows', a broad nasal tip, a broad face with a pointed chin, and sensorineural hearing loss along with mild digital malformations.  Evidence of macular degeneration was seen at age 7 years and vision in both individuals was in the 20/100-20/200 range. No associated locus or mutation has been identified.

Genomics should help clarify the nosology especially among individuals reported to have areolar macular dystrophy, retinitis pigmentosa, juvenile macular degeneration, and cone dystrophies in association with several of these mutations.  Reports have also associated Stargardt disease with mutations in RDS.

Treatment
Treatment Options: 

There is no treatment for this disorder but low vision aids can be helpful especially in the early stages of the disease.

Isotretinoin has been shown to slow the accumulation of lipofuscin pigments in mice but its role in human Stargardt disease has not been reported.  Trials using stem cells are underway with encouraging early results.

References
Article Title: 

Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotype-phenotype correlations and unexpected diagnostic revisions

Zaneveld J, Siddiqui S, Li H, Wang X, Wang H, Wang K, Li H, Ren H, Lopez I, Dorfman A, Khan A, Wang F, Salvo J, Gelowani V, Li Y, Sui R, Koenekoop R, Chen R. Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotype-phenotype correlations and unexpected diagnostic revisions. Genet Med. 2014 Dec 4.  [Epub ahead of print].

PubMed ID: 
25474345

References

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PubMedID: 29068916

Tanna P, Strauss RW, Fujinami K, Michaelides M. Stargardt disease: clinical features, molecular genetics, animal models and therapeutic options. Br J Ophthalmol. 2016 Aug 4.  Review.

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Lambertus S, van Huet RA, Bax NM, Hoefsloot LH, Cremers FP, Boon CJ, Klevering BJ, Hoyng CB. Early-Onset Stargardt Disease: Phenotypic and Genotypic Characteristics. Ophthalmology. 2014 Oct 17.  [Epub ahead of print].

PubMedID: 25444351

Zaneveld J, Siddiqui S, Li H, Wang X, Wang H, Wang K, Li H, Ren H, Lopez I, Dorfman A, Khan A, Wang F, Salvo J, Gelowani V, Li Y, Sui R, Koenekoop R, Chen R. Comprehensive analysis of patients with Stargardt macular dystrophy reveals new genotype-phenotype correlations and unexpected diagnostic revisions. Genet Med. 2014 Dec 4.  [Epub ahead of print].

PubMedID: 25474345

Fujinami K, Zernant J, Chana RK, Wright GA, Tsunoda K, Ozawa Y, Tsubota K, Robson AG, Holder GE, Allikmets R, Michaelides M, Moore AT. Clinical and Molecular Characteristics of Childhood-Onset Stargardt Disease. Ophthalmology. 2014 Oct 10.  [Epub ahead of print].

PubMedID: 25312043

Heathfield L, Lacerda M, Nossek C, Roberts L, Ramesar RS. Stargardt disease: towards developing a model to predict phenotype. Eur J Hum Genet. 2013 May 22. [Epub ahead of print].

PubMedID: 23695285

Zahid S, Jayasundera T, Rhoades W, Branham K, Khan N, Niziol LM, Musch DC, Heckenlively JR. Clinical Phenotypes and Prognostic Full-Field Electroretinographic Findings in Stargardt Disease. Am J Ophthalmol. 2012 Dec 4. [Epub ahead of print] PubMed PMID: 23219216.

PubMedID: 23219216

Descartes M, Royal SA, Franklin J, Goodin K, Mancuso M, Mikhail FM, Holt L. A new syndrome with Stargardt macular degeneration, abnormalities of the corpus callosum, mental retardation, and dysmorphic features: a case report of two siblings. Clin Dysmorphol. 2009 Jul;18(3):178-80.

PubMedID: 19451813

Rotenstreich Y, Fishman GA, Anderson RJ. Visual acuity loss and clinical observations in a large series of patients with Stargardt disease. Ophthalmology. 2003 Jun;110(6):1151-8.

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Sparrow JR. Therapy for macular degeneration: insights from acne. Proc Natl Acad Sci U S A. 2003 Apr 15;100(8):4353-4.

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Weleber RG, Carr RE, Murphey WH, Sheffield VC, Stone EM. Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene. Arch Ophthalmol. 1993 Nov;111(11):1531-42.

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