MSUD (maple syrup urine disease) involves defective branched-chain alpha-keto acid dehydrogenase complex (BCKDH). Accumulation of which metabolites causes the characteristic neurotoxicity?

• A Accumulated propionyl-CoA from isoleucine and valine catabolism, inhibiting the TCA cycle and causing organic acidemia
• B Elevated alloisoleucine only, a stereoisomeric by-product with specific neurotoxic properties
• C Accumulated branched-chain amino acids (leucine, isoleucine, valine) and their alpha-ketoacid derivatives, with leucine being the most neurotoxic ✓
• D Elevated acetyl-CoA from leucine catabolism, causing excessive ketogenesis and ketoacidosis as the primary toxic mechanism

Explanation

BCKDH catalyses the oxidative decarboxylation of branched-chain alpha-keto acids (derived from transamination of leucine → alpha-ketoisocaproate, isoleucine → alpha-keto-beta-methylvalerate, valine → alpha-ketoisovalerate). Deficiency causes accumulation of all three BCAAs and their keto acids in blood, urine, and CSF. Leucine (and its keto acid alpha-ketoisocaproate) is the most neurotoxic, impairs protein synthesis in the brain, and inhibits transport of other amino acids across the BBB. Alloisoleucine is a pathognomonic marker of MSUD but is not the primary neurotoxin. Treatment involves BCAA-restricted diet and liver transplantation.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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