Maple syrup urine disease (MSUD) results from deficiency of the branched-chain alpha-ketoacid dehydrogenase complex. Which specific biochemical mechanism leads to the neurological crisis if not treated promptly?
- A Accumulation of valine inhibits succinate dehydrogenase in the TCA cycle
- B Isoleucine accumulation directly inhibits synaptic vesicle release
- C Accumulation of leucine and its ketoacid (alpha-ketoisocaproate) causes competitive inhibition of large neutral amino acid transport across the blood-brain barrier, starving the brain of essential amino acids and disrupting myelin synthesis ✓
- D The elevated branched-chain amino acids promote mTOR hyperactivation and autophagy suppression
Explanation
In MSUD, leucine, isoleucine, and valine (and their alpha-ketoacids) accumulate because the mitochondrial BCKDH complex cannot decarboxylate them. Leucine (and alpha-ketoisocaproate) is particularly neurotoxic. Large neutral amino acids (LNAAs — leucine, phenylalanine, tyrosine, tryptophan) compete for the same BBB transporter (LAT1). Massively elevated leucine outcompetes other LNAAs, depleting brain levels of serotonin/dopamine precursors (tryptophan, tyrosine) and reducing protein synthesis needed for myelination. Treatment includes restriction of BCAAs plus supplementation of isoleucine and valine to compete with leucine.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.