A 35-year-old man of Chinese descent presents with progressive night blindness and paracentral scotomas over the past 3 years. Fundoscopy reveals numerous yellow-white refractile crystalline deposits in the posterior pole with progressive retinal pigment epithelium atrophy and visible large choroidal vessels. The condition marked **B** in the diagram is suspected. Which of the following genetic and metabolic abnormalities best explains the pathophysiology of this disorder?

Question

Accepted Answer

B. Mutation in CYP4V2 gene leading to defective polyunsaturated fatty acid omega-hydroxylation and lipid accumulation in the RPE and choroid. ## Why CYP4V2 mutation with defective PUFA omega-hydroxylation is correct

Bietti crystalline dystrophy (marked **B**) is definitively caused by mutations in the CYP4V2 gene (4q35.2), which encodes a cytochrome P450 family enzyme responsible for fatty acid omega-hydroxylation and lipid metabolism, particularly polyunsaturated fatty acid (n-3 PUFA) hydrolysis. Defective lipid metabolism leads to accumulation of cholesterol and cholesterol esters in the RPE, choroid, lymphocytes, and skin fibroblasts, manifesting as the pathognomonic yellow-white intraretinal crystalline deposits seen on examination. This metabolic defect, combined with the patient's East Asian ethnicity, night blindness, and characteristic fundoscopic findings, confirms the diagnosis. The condition is autosomal recessive, and genetic testing for CYP4V2 mutations is the gold standard for confirmation (Garcia-Garcia et al; OMIM #210370).

## Why each distractor is wrong

- **ABCA4 mutation**: This causes Stargardt disease and pattern dystrophies, characterized by lipofuscin accumulation and central vision loss, not the diffuse crystalline deposits and choroidal sclerosis seen in Bietti dystrophy.
- **PRPH2 mutation**: This causes pattern dystrophies and retinitis pigmentosa, affecting photoreceptor outer segment structure, not lipid metabolism or crystalline deposition.
- **BEST1 mutation**: This causes Best vitelliform macular dystrophy, characterized by vitelliform lesions and RPE dysfunction, not the diffuse crystalline deposits and progressive choroidal sclerosis of Bietti dystrophy.

**High-Yield:** Bietti crystalline dystrophy = CYP4V2 mutation → defective lipid metabolism → cholesterol crystal deposition in RPE/choroid + progressive night blindness + East Asian prevalence.

[cite: Garcia-Garcia GP et al, Bietti Crystalline Dystrophy review; OMIM #210370]

Answer

A. Mutation in BEST1 gene leading to bestrophin dysfunction and RPE tight junction compromise

Answer

C. Mutation in PRPH2 gene resulting in disrupted photoreceptor outer segment disc formation

Answer

D. Mutation in ABCA4 gene causing impaired retinoid transport and lipofuscin accumulation in photoreceptors

Explanation

Why CYP4V2 mutation with defective PUFA omega-hydroxylation is correct

Why each distractor is wrong

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