Maple syrup urine disease (MSUD) is caused by deficiency of the branched-chain alpha-keto acid dehydrogenase (BCKAD) complex. The neurological damage in MSUD is primarily due to:

• A Hypoglycaemia from impaired gluconeogenesis due to deficient branched-chain amino acid catabolism
• B Deficiency of succinyl-CoA causing impaired haem synthesis and anaemia
• C Accumulation of leucine (and its keto-acid, alpha-ketoisocaproate) which inhibits brain protein synthesis and myelination ✓
• D Accumulation of propionyl-CoA causing organic acidaemia and impaired mitochondrial function

Explanation

BCKAD deficiency causes accumulation of leucine, isoleucine, valine and their branched-chain alpha-keto acids (BCKA). Of these, leucine is the primary neurotoxin — it competes with other neutral amino acids for the LAT-1 transporter at the blood-brain barrier (reducing tyrosine, tryptophan, phenylalanine entry for neurotransmitter synthesis) and its keto-acid alpha-ketoisocaproate inhibits pyruvate dehydrogenase and directly impairs myelination and brain development. The classic maple syrup odour comes from sotolone (a BCKA metabolite).

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

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Written and medically reviewed by the StethoPrep medical team.