Best Vitelliform Macular Dystrophy — BEST1 Mutation
medium
eye Ophthalmology
An 11-year-old boy presents with progressive difficulty reading the blackboard over the past year. Visual acuity is 6/9 OD and 6/12 OS. Dilated fundus examination reveals a striking bilateral, symmetric, round, well-circumscribed yellow-orange elevated lesion at the fovea with an egg-yolk appearance, approximately 1–2 disc diameters in size. OCT confirms hyperreflective subretinal material at the RPE–photoreceptor interface. The lesion marked **A** in the diagram shows this characteristic vitelliform deposit with an abnormal electrooculography Arden ratio of 1.3 (normal ≥1.85) and a normal full-field electroretinogram. Genetic testing confirms a heterozygous missense mutation in BEST1. Which of the following best describes the molecular basis of the pathology in this condition?
A. Mutation in PROM1 impairs ciliary disc formation and leads to early-onset photoreceptor apoptosis
B. Mutation in ABCA4 causes defective photoreceptor outer segment disc membrane turnover and retinoid accumulation
C. Loss of bestrophin-1 function impairs RPE phagocytosis of photoreceptor outer segments, leading to lipofuscin accumulation in the subretinal space
D. Defect in the PRPH2 gene disrupts photoreceptor disc morphogenesis and causes progressive photoreceptor degeneration
Explanation
Why "Loss of bestrophin-1 function impairs RPE phagocytosis of photoreceptor outer segments, leading to lipofuscin accumulation in the subretinal space" is right
Best vitelliform macular dystrophy (BVMD) is caused by mutations in BEST1 (VMD2), which encodes bestrophin-1, a calcium-activated chloride channel on the basolateral membrane of the retinal pigment epithelium. Loss of bestrophin function disrupts the RPE light-peak response and critically impairs phagocytosis of shed photoreceptor outer segments. This leads to accumulation of lipofuscin-rich material in the subretinal/sub-RPE space, producing the characteristic egg-yolk vitelliform lesion seen at the fovea in stage 1 disease. The abnormal EOG Arden ratio (<1.5) with a normal ERG is the pathognomonic diagnostic hallmark, reflecting generalized RPE dysfunction while photoreceptors remain intact. This is the molecular basis directly supported by Kanski, ISCEV EOG standards, and Boon's bestrophinopathy review.
Why each distractor is wrong
Mutation in ABCA4 causes defective photoreceptor outer segment disc membrane turnover and retinoid accumulation: This describes Stargardt disease (ABCA4-related), which presents with a beaten-bronze macula and pisciform yellow flecks, not a vitelliform egg-yolk lesion. ABCA4 mutations affect photoreceptor lipid transport, not RPE chloride channel function. The EOG is normal in Stargardt disease.
Defect in the PRPH2 gene disrupts photoreceptor disc morphogenesis and causes progressive photoreceptor degeneration: PRPH2 (RDS) mutations cause adult vitelliform macular dystrophy (AVMD) and pattern dystrophies, which present with smaller foveal deposits in patients aged 30–50 years with a normal EOG Arden ratio. PRPH2 encodes peripherin-2, a photoreceptor disc rim protein, not an RPE chloride channel.
Mutation in PROM1 impairs ciliary disc formation and leads to early-onset photoreceptor apoptosis: PROM1 mutations cause cone-rod dystrophy and retinitis pigmentosa variants, characterized by progressive photoreceptor loss with bone-spicule pigmentation and attenuated vessels—a pattern dystrophy phenotype (option B in the label key), not a vitelliform macular dystrophy.
High-YieldNEET PG
Best disease = BEST1 loss → RPE chloride channel dysfunction → impaired photoreceptor OS phagocytosis → lipofuscin accumulation → abnormal EOG with normal ERG.
Kanski Clinical Ophthalmology 9e Ch 14; Marmor EOG Standards ISCEV 2017; Boon Prog Retin Eye Res 2009 bestrophinopathies
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