Maple syrup urine disease (MSUD) presents in neonates with encephalopathy and sweet-smelling urine. The toxic accumulating metabolites are branched-chain alpha-keto acids from leucine, isoleucine, and valine. The primary neurotoxic mechanism is:
- A Branched-chain keto acids inhibit pyruvate dehydrogenase, causing lactic acidosis and energy failure
- B Excess leucine saturates mTOR pathway causing hyperactivation of protein synthesis and cerebral oedema
- C Valine keto acid accumulates and directly inhibits GABA-A receptors causing seizures
- D Alpha-ketoisocaproate (from leucine) and other BCKAs competitively inhibit neural amino acid transporters, depleting brain of glutamate, GABA, and aromatic amino acids needed for neurotransmitter synthesis; also directly inhibit mitochondrial function ✓
Explanation
In MSUD, deficiency of branched-chain alpha-keto acid dehydrogenase complex (BCKDH) causes accumulation of leucine, isoleucine, valine, and their corresponding alpha-keto acids. The primary mechanisms of neurotoxicity include: (1) alpha-ketoisocaproate from leucine inhibits dihydrolipoamide dehydrogenase (the E3 component shared with PDH and alpha-KG dehydrogenase), impairing oxidative phosphorylation and energy metabolism; (2) elevated leucine and BCKAs competitively inhibit the large neutral amino acid transporter (LAT1) at the blood-brain barrier, reducing brain uptake of tryptophan, phenylalanine, tyrosine (precursors of serotonin, dopamine, noradrenaline) causing neurotransmitter depletion; (3) osmotic cerebral oedema from amino acid accumulation. Direct GABA-A receptor inhibition by valine metabolites is not established.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.