A 14-year-old boy presents with progressive bilateral central vision loss over the past 2 years, now measuring 20/100 in each eye. Fundoscopy reveals a beaten-bronze macular appearance with characteristic yellow-white pisciform flecks in the posterior pole. Fundus autofluorescence shows hyperautofluorescent flecks with central hypoautofluorescence and a hyperautofluorescent ring at the disease frontier. The structure marked **B** in the diagram represents the most likely diagnosis. Which of the following genetic mutations is responsible for the photoreceptor and RPE degeneration seen in this condition?
A. ELOVL4 gene mutation affecting very long-chain fatty acid synthesis in the photoreceptor
B. ABCA4 gene mutation encoding a retina-specific ATP-binding cassette transporter that flips N-retinylidene-phosphatidylethanolamine across photoreceptor outer segment disc membranes
RPE65 gene mutation impairing the visual cycle and retinoid metabolism
C.
D. PROM1 gene mutation disrupting photoreceptor disc morphogenesis
Explanation
Why ABCA4 gene mutation is correct
The structure marked B is Stargardt disease, which is caused by autosomal recessive mutations in the ABCA4 gene (1p22.1). This gene encodes a retina-specific ATP-binding cassette transporter responsible for flipping N-retinylidene-phosphatidylethanolamine across photoreceptor outer segment disc membranes. Dysfunction of this transporter leads to accumulation of toxic bisretinoid lipofuscin (A2E) in the RPE, causing progressive photoreceptor and RPE death. The clinical presentation—bilateral progressive central vision loss in a young patient with beaten-bronze maculopathy, pisciform flecks, and characteristic fundus autofluorescence pattern—is pathognomonic for ABCA4-related Stargardt disease, the most common form of inherited juvenile macular dystrophy (AAO BCSC Section 12: Retina).
Why each distractor is wrong
ELOVL4 gene mutation: While ELOVL4 mutations can cause rare autosomal dominant variants of Stargardt-like disease, they are not the primary cause of classic Stargardt disease. ELOVL4 affects very long-chain fatty acid synthesis, not the retinoid transport mechanism central to typical Stargardt pathophysiology.
PROM1 gene mutation: PROM1 mutations are another rare autosomal dominant cause of Stargardt-like maculopathy, but they disrupt photoreceptor disc morphogenesis rather than the lipofuscin accumulation pathway. They account for a tiny fraction of cases compared to ABCA4.
RPE65 gene mutation: RPE65 mutations cause Leber congenital amaurosis (LCA) and early-onset retinal dystrophy through impaired visual cycle function and retinoid metabolism. This presents with nyctalopia and more severe early vision loss, not the progressive central vision loss pattern of Stargardt disease.
