Stargardt disease (STGD) is a representative autosomal recessive macular dystrophy, characterized by atrophy of the sensory retina and RPE in the macula, and multiple yellowish flecks scattered around the macula. The most important causative gene is ABCA4 (ATP-binding cassette transporter), and retinal degeneration due to ABCA4 mutations shows a wide range of phenotypes. It is now recognized that a broad disease spectrum exists from classic Stargardt disease (macular-limited type) to cone-rod dystrophy and retinitis pigmentosa-like phenotypes, all caused by mutations in the same gene.
In 1909, German ophthalmologist Karl Stargardt first reported 7 cases of familial macular degeneration. 1) In 1962, Franceschetti independently described cases with yellowish-white flecks in the fundus as “Fundus Flavimaculatus,” 1) and in 1976, Fishman established a classification from Stage I to IV. 3) In 1997, Allikmets et al. cloned the causative gene ABCA4, 4) and currently both conditions are often considered as the same disease spectrum under the term ABCA4-associated retinopathy. 1)
The prevalence is estimated at 1:8,000–10,000, making it the most common inherited macular disease. 1) The carrier frequency of pathogenic ABCA4 variants is approximately 1 in 20, and over 1,200 pathogenic mutations have been reported. 1) Age of onset is often from childhood to the 30s, but adult-onset cases also exist. Earlier onset is associated with faster progression and poorer prognosis. 5)
They were once considered separate diseases, but both are now understood to be part of the same disease spectrum primarily caused by ABCA4 gene mutations. 1) Although there are differences in the distribution of flecks and age of onset, the genetic background is shared. Stargardt disease features prominent macular lesions, while fundus flavimaculatus tends to have flecks widely distributed from the posterior pole to the periphery.
Diagnostic triad (the presence of the following three findings strongly suggests ABCA4-related retinopathy) 1):
Bull’s eye maculopathy is observed in approximately 20% of ABCA4-related retinopathy. 1) It occurs excessively in patients with the c.5882G>A mutation (p.Gly1961Glu) and precedes the diagnostic triad findings as a circular atrophy confined to the central macula, which can make early diagnosis difficult.
Fishman et al. classified the fundus findings of Stargardt disease into Stages I to IV. 3)
| Stage | Macular findings | Flecks |
|---|---|---|
| I | No to mild atrophy (beaten-bronze appearance) | Perimacular only |
| II | Macular atrophy present | Perimacular only |
| III | Macular atrophy present (progressive fleck resorption) | Macula + posterior pole |
| IV | Extensive choroidal atrophy (RP-like fundus) | Posterior pole to periphery |
In the advanced stage (Stage IV), the fundus exhibits a retinitis pigmentosa (RP)-like appearance with bone spicule pigmentation, optic disc pallor, and vascular attenuation. 1) On ERG, both cone and rod responses may be extinguished.
Bull’s eye maculopathy (target macula) is observed in approximately 20% of ABCA4-associated retinopathy, but it is also seen in other diseases such as chloroquine/hydroxychloroquine retinopathy, cone dystrophy, and PRPH2-associated pattern dystrophy. It is not a specific finding for Stargardt disease; comprehensive evaluation including fluorescein angiography, FAF, and genetic testing is necessary.
| Type | Gene | Inheritance | Characteristics |
|---|---|---|---|
| STGD1 | ABCA4 | Autosomal recessive | Majority of patients. Over 1,200 pathogenic mutations known1) |
| STGD3 | ELOVL4 | Autosomal dominant | Fatty acid metabolism abnormality. Clinically and pathophysiologically distinct from STGD11) |
| STGD4 | PROM1 | Autosomal dominant | Recessive type shows RP-like phenotype1) |
STGD1 (ABCA4 mutation) is an autosomal recessive disorder. If both parents are carriers, the chance of the child developing the disease in each pregnancy is 25%. The carrier frequency of ABCA4 pathogenic variants in the general population is about 1/20, so many people are unaware they are carriers. Genetic counseling and family genetic testing are recommended. 1)
Diagnosis relies on a combination of clinical findings (diagnostic triad), multimodal imaging, and genetic testing. Clinical diagnosis alone may miss 10–15% of cases due to phenocopies (similar phenotypes) caused by mutations in genes other than ABCA4. 1)
Fluorescein Angiography (FA)
Dark choroid: A phenomenon in which choroidal fluorescence is blocked in the early phase of angiography. It is observed in about 62% of ABCA4 mutation cases. 1) This is a relatively specific finding for Stargardt disease. It occurs because lipofuscin in the RPE blocks background fluorescence. Not all cases show this sign.
Fluorescence pattern of flecks: Fresh flecks appear hyperfluorescent, while old flecks appear hypofluorescent. 1)
Fundus Autofluorescence (FAF)
Atrophic areas: Show hypoautofluorescence due to loss of RPE cells. Useful for monitoring atrophy progression. 1)
Flecks: Show hyperautofluorescence due to lipofuscin accumulation. Applicable even in children where FA is difficult to perform.
Quantitative autofluorescence (qAF): A promising objective indicator for assessing disease progression. 9)
OCT
Ellipsoid zone (EZ): Loss of the EZ at the fovea correlates with visual prognosis. 1)
RPE changes: Irregularity and atrophy of the RPE layer can be visualized. Useful for diagnosis in children where FA is difficult.
External limiting membrane (ELM): Thickening of the ELM has been reported as an early change. 10)
ERG: In early stages, full-field ERG is often normal. Useful for estimating the extent of the lesion. In late stages, it shows marked reduction (RP-like).
Genetic testing: Comprehensive genetic screening (WES or panel testing) including ABCA4 is useful for definitive diagnosis, genetic counseling, and determining eligibility for future gene therapy. 1) It is necessary to exclude phenocopies (similar phenotypes caused by mutations in PRPH2, PROM1, CRX, RPE65, etc.).
| Differential Diagnosis | Key Points for Differentiation |
|---|---|
| PRPH2-associated pattern dystrophy | Autosomal dominant. Can mimic the three findings of the diagnostic triad. Note incomplete penetrance. 1) |
| Retinitis pigmentosa (RP) | Late-stage STGD1 can present with RP-like fundus. History of night blindness and visual field constriction are clues for differentiation. 1) |
| Age-related macular degeneration (AMD) | Clinically similar to late-onset STGD1. Note family history of AMD. 1) |
| Best disease | Characterized by vitelliform lesions. BEST1 gene mutation. Shows abnormal EOG. |
| Hydroxychloroquine retinopathy | Presents with bull’s eye maculopathy. Medication history is important. |
| Psychogenic visual loss | Easily misdiagnosed in early cases with minimal fundus findings. |
There is no curative treatment; the mainstay is slowing progression and preserving visual function.
Light Exposure Avoidance
UV and bright light blocking: Light exposure is thought to accelerate lipofuscin accumulation. Regular use of UV-blocking sunglasses is recommended. 1)
Vitamin A restriction: In ABCA4 mutations, the visual cycle is impaired, so avoid excessive intake of vitamin A supplements and cod liver oil.
Low Vision Care
Magnifiers and monoculars: To maximize remaining visual function.
Tinted glasses: Useful for reducing photophobia.
Learning support: For school-age children, use of large-print textbooks, seating arrangements, and tablet devices are important.
Social support: Obtaining a visual impairment certificate and coordination with employment support.
Investigational Treatments
Gene therapy: Clinical trials of ABCA4 gene replacement using AAV and dual AAV vectors, CRISPR/Cas9, and AON therapy are ongoing.
Stem cell therapy: Clinical research on transplantation of hESC-derived RPE cells. 13)
Pharmacotherapy: ALK-001 (deuterated vitamin A), emixustat hydrochloride, etc.
In autosomal recessive inheritance, the probability of an affected child being born to carrier parents is 25% for each pregnancy. Carrier screening within families based on genetic test results is possible, and genetic diagnosis is important for determining future eligibility for gene therapy. 1)
Multiple clinical trials of gene therapy targeting ABCA4 are ongoing, but as of 2026, it is not yet available as general medical practice. For details, refer to the section on latest research and future prospects. Those wishing to participate should contact a specialized facility.
The core pathology of Stargardt disease is impairment of the visual cycle and accumulation of lipofuscin.
ABCA4 protein is the only importer among mammalian ABC transporters localized to the disc membranes of photoreceptor outer segments, and functions as a flippase. 11) It transports N-retinylidene-phosphatidylethanolamine (NRPE) and phosphatidylethanolamine (PE) from the disc membrane lumen to the cytoplasmic side, preventing accumulation of all-trans-retinal. 11) ABCA4 is also expressed in the RPE, suggesting an additional role in the RPE. 1)
These impairments cause all-trans-retinal to dimerize, producing A2E (N-retinylidene-N-retinyl-ethanolamine). A2E accumulates in the lysosomes of RPE cells, forming lipofuscin and exerting cytotoxicity.
Ferroptosis is an iron-dependent regulated cell death caused by lipid peroxidation. Accumulation of A2E increases oxidative stress in RPE cells, which is thought to induce ferroptosis.2) Ferroptosis inhibitors are being studied as a new therapeutic target for Stargardt disease.
Zampatti et al. (2023) identified for the first time worldwide compound heterozygous mutations in RDH8 in Stargardt disease patients without ABCA4 mutations. 2) This discovery highlights the importance of RDH8 in the second step of the visual cycle (reduction of all-trans-retinal) and proposed the ferroptosis pathway and TLR3 activation as new therapeutic targets. 2)
In a Phase I/II trial of human ESC-derived RPE cell transplantation, safety was confirmed, and the majority of 9 cases showed a trend toward visual function improvement compared to the contralateral eye. 13) However, since ABCA4 is primarily expressed in photoreceptors, RPE cell replacement alone may have limited long-term efficacy, and combined RPE + photoreceptor sheet transplantation is being considered as a future direction. 1)
