Stargardt disease

Stargardt disease is the most common inherited . It is characterised by progressive macular atrophy, often accompanied by yellow-white retinal flecks at the level of the retinal pigment epithelium. Peripapillary sparing is a characteristic, although not invariable, finding. Symptoms most commonly begin in childhood or adolescence, but onset may range from early childhood to late adulthood. Affected individuals typically present with bilateral progressive impairment of central visual acuity.

Based on full-field electroretinography, three functional groups are recognised: disease confined to the macula, additional generalised cone dysfunction, and combined cone and rod dysfunction. Severity and rate of progression vary considerably. Late-onset disease with foveal sparing may retain central visual acuity for an extended period and can be mistaken for age-related macular degeneration.

The prevalence of Stargardt disease remains uncertain. While earlier estimates ranged from 1 in 8,000 to 1 in 10,000, a nationwide Dutch population study estimated a prevalence of approximately 1 in 22,000 individuals.

Biallelic germline pathogenic variants in ABCA4 are the predominant cause of Stargardt disease. ABCA4 encodes a photoreceptor-specific transporter involved in the clearance of retinoid intermediates generated during the visual cycle. Loss of function leads to the accumulation of toxic bisretinoids and lipofuscin within the retinal pigment epithelium, followed by progressive photoreceptor degeneration. Other genes are associated with Stargardt-like macular dystrophies or related macular and cone disorders that may enter the differential diagnosis. Representative examples include ELOVL4, PROM1 and PRPH2.

The most common form of Stargardt disease is ABCA4-associated and inherited in an autosomal recessive manner. The parents of an affected individual are typically unaffected carriers, and the recurrence risk for siblings is 25%. Less common Stargardt-like dystrophies associated with ELOVL4, PROM1 or PRPH2 generally follow an autosomal dominant inheritance pattern.

Stargardt disease is suspected based on characteristic findings on fundus examination and multimodal retinal imaging. Fundus autofluorescence and optical coherence tomography are used to assess the distribution and extent of retinal pigment epithelial and outer retinal abnormalities, while fluorescein angiography may show characteristic masking of the background choroidal fluorescence, known as a dark choroid. Full-field electroretinography assesses generalised cone and rod involvement and supports functional classification of disease severity. Molecular genetic testing can confirm the diagnosis, although causative variants are not identified in every individual with a clinically consistent phenotype.

• Molecular genetic testing can establish the underlying genetic diagnosis, confirm the clinical suspicion, enable predictive testing of at-risk family members and provide information relevant to family planning.
• The identified entity supports condition-specific monitoring and management decisions; therapeutic options are evaluated individually by the treating physicians.

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