A 35-year-old man from rural India presents with progressive night blindness since age 16, followed by development of distal weakness and areflexia over the past 5 years. Audiometry reveals bilateral high-frequency sensorineural hearing loss as shown by the pattern marked **A** in the diagram. Plasma phytanic acid is markedly elevated at 280 µmol/L (normal

Question

A 35-year-old man from rural India presents with progressive night blindness since age 16, followed by development of distal weakness and areflexia over the past 5 years. Audiometry reveals bilateral high-frequency sensorineural hearing loss as shown by the pattern marked **A** in the diagram. Plasma phytanic acid is markedly elevated at 280 µmol/L (normal <30). Which of the following enzyme deficiencies best explains the pathophysiology of this patient's presentation?

Accepted Answer

A. Phytanoyl-CoA hydroxylase (PHYH). ## Why Phytanoyl-CoA hydroxylase (PHYH) is right

Classical adult Refsum disease is caused by deficiency of phytanoyl-CoA hydroxylase (PHYH), the first enzyme of the peroxisomal α-oxidation pathway. Phytanic acid is a branched-chain (3-methyl) fatty acid derived exclusively from dietary sources (ruminant fats, dairy, certain fish) that cannot undergo conventional β-oxidation because the β-carbon is blocked. Loss of PHYH activity results in systemic accumulation of phytanic acid, which is incorporated into membrane lipids and disrupts myelin and photoreceptor function. The clinical tetrad comprises retinitis pigmentosa with night blindness, chronic polyneuropathy with areflexia, cerebellar ataxia, and elevated CSF protein. Bilateral progressive sensorineural hearing loss with high-frequency predominance (as marked **A**) occurs in approximately 50% of patients and is one of the cardinal features. The markedly elevated plasma phytanic acid (>200 µmol/L) with normal pristanic acid and very-long-chain fatty acids confirms the diagnosis of Refsum disease due to PHYH deficiency (Harrison 21e Ch 433; Cummings Otolaryngology 7e).

## Why each distractor is wrong

- **Acyl-CoA dehydrogenase (ACAD)**: ACAD catalyzes the first step of β-oxidation and is involved in the metabolism of straight-chain fatty acids. Deficiency causes various fatty acid oxidation disorders (e.g., MCAD deficiency) with hypoketotic hypoglycemia and encephalopathy, not the classic Refsum tetrad with retinitis pigmentosa and high-frequency SNHL.

- **Carnitine palmitoyltransferase I (CPT-I)**: CPT-I is required for transport of long-chain fatty acids into mitochondria for β-oxidation. Deficiency causes hypoketotic hypoglycemia and hepatomegaly, not the peroxisomal disorder with phytanic acid accumulation characteristic of Refsum disease.

- **Peroxisomal 3-ketoacyl-CoA thiolase (PKAT)**: PKAT is involved in the final steps of peroxisomal β-oxidation. Deficiency causes Zellweger spectrum disorders with severe neonatal presentation, developmental delay, and seizures—not the late-onset adult form of Refsum disease with selective accumulation of phytanic acid.

**High-Yield:** Refsum disease = PHYH deficiency → phytanic acid accumulation → retinitis pigmentosa + polyneuropathy + ataxia + high-frequency SNHL + elevated CSF protein; treat with dietary phytanic acid restriction.

[cite: Harrison 21e Ch 433; Cummings Otolaryngology 7e]

Answer

B. Carnitine palmitoyltransferase I (CPT-I)

Answer

C. Peroxisomal 3-ketoacyl-CoA thiolase (PKAT)

Answer

D. Acyl-CoA dehydrogenase (ACAD)

Explanation

Why Phytanoyl-CoA hydroxylase (PHYH) is right

Why each distractor is wrong

Practice similar questions