Stargardt disease (STGD) is a representative autosomal recessive macular dystrophy, characterized by atrophic lesions 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 gene mutations shows a wide variety of phenotypes.
In 1909, German ophthalmologist Karl Stargardt first reported it as familial macular degeneration in 7 cases. 1) In 1962, Franceschetti independently described cases with yellowish-white flecks as “Fundus Flavimaculatus,” 1) and in 1976, Fishman established the Stage I–IV classification. 3) In 1997, Allikmets et al. cloned the causative gene ABCA4, 4) and currently both are often considered as the same disease spectrum, ABCA4-associated retinopathy. 1)
The prevalence is estimated at 1:8,000–10,000, making it the most common hereditary macular disease. 1) The carrier frequency of pathogenic ABCA4 variants is about 1/20, and over 1,200 pathogenic mutations have been reported. 1) Age of onset ranges from childhood to the 30s, but adult-onset cases also exist. Earlier onset is associated with faster progression and worse prognosis. 5)
Although once considered separate diseases, they are now understood to be a single disease spectrum primarily caused by ABCA4 gene mutations. 1) There are differences in the distribution of flecks and age of onset, but the genetic background is common. Stargardt disease features macular lesions prominently, 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):
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 shows RP-like appearance with bone-spicule pigmentation, optic disc pallor, and vascular attenuation. 1)
Bull’s eye maculopathy is seen in about 20% of ABCA4-related retinopathy, but it is also observed in other diseases such as chloroquine/hydroxychloroquine retinopathy, cone dystrophy, and PRPH2-related pattern dystrophy. It is not a finding specific to Stargardt disease; comprehensive evaluation including fluorescein angiography and FAF, as well as genetic testing, is necessary.
| Type | Gene | Inheritance Pattern | Characteristics |
|---|---|---|---|
| STGD1 | ABCA4 | Autosomal recessive | Majority of patients. Over 1,200 pathogenic mutations known1) |
| STGD3 | ELOVL4 | Autosomal dominant | Fatty acid metabolism abnormality. Pathologically different 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 probability of a child developing the disease in each pregnancy is 25%. The carrier frequency of ABCA4 pathogenic variants in the general population, including Japanese, is as high as about 1 in 20, so many people are unaware they are carriers. It is recommended to consider genetic counseling and genetic testing of family members. 1)
Diagnosis relies on a combination of clinical findings (diagnostic triad), multimodal imaging, and genetic testing. With clinical diagnosis alone, 10–15% of cases may be phenocopies (similar phenotypes) caused by genetic mutations other than ABCA4. 1)
Fluorescein Angiography (FA)
Dark choroid: A phenomenon in which choroidal fluorescence is blocked in the early phase of fluorescein angiography. It is observed in about 62% of ABCA4 mutation cases. 1) This is a relatively specific key finding for Stargardt disease. It occurs because lipofuscin in the RPE blocks background fluorescence. It is not seen in all cases.
Fluorescence pattern of flecks: Fresh flecks show hyperfluorescence, while old flecks show hypofluorescence. 1)
Fundus Autofluorescence (FAF)
Atrophic areas: Show hypoautofluorescence due to loss of RPE cells. Useful for monitoring progression of atrophy. 1)
Flecks: Show hyperautofluorescence due to lipofuscin accumulation. Can be applied even in children where FA is difficult to perform.
Quantitative autofluorescence (qAF): Promising as an objective indicator for disease progression assessment. 9)
OCT
Outer segment/ellipsoid zone (EZ band): Loss of the EZ band in the fovea correlates with visual prognosis. 1)
RPE changes: Visualizes irregularity and atrophy of the RPE layer. Useful for diagnosis in children where FA is difficult.
ELM (external limiting membrane): 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 affected areas. In late stages, it shows marked reduction (RP-like pattern).
Genetic testing: Comprehensive genetic screening (WES, 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 Disease | Key Points for Differentiation |
|---|---|
| PRPH2-related pattern dystrophy | Autosomal dominant. Can mimic the triad findings. Note incomplete penetrance. 1) |
| Retinitis pigmentosa (RP) | Late-stage STGD1 may 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. Abnormal EOG. |
| Hydroxychloroquine retinopathy | Presents with bull’s eye appearance. Important to check medication history. |
| Psychogenic visual loss | Easily misdiagnosed in early cases with minimal fundus findings. |
There is no curative treatment; the mainstay of treatment is to slow progression and preserve visual function.
Avoidance of Light Exposure
Blocking UV and bright light: 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 excessive intake of vitamin A supplements and cod liver oil should be avoided.
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 enlarged 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)
Pharmacological therapy: ALK-001 (deuterated vitamin A), emixustat, etc.
In autosomal recessive inheritance, the probability that a child will be affected by carrier parents is 25% for each pregnancy. Carrier screening within families based on genetic test results is possible, and genetic diagnosis is also important for determining future eligibility for gene therapy. 1)
Several clinical trials of gene therapy targeting ABCA4 are underway, 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 lumen of the disc membrane to the cytoplasmic side, preventing the 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 and form A2E (N-retinylidene-N-retinylethanolamine). 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 most of the 9 cases showed a trend toward visual function improvement compared to the fellow eye.13) However, since ABCA4 is mainly 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)
