A 7-year-old with untreated PKU has intellectual disability. Which mechanism best explains how elevated phenylalanine causes brain damage?

• A Phenylalanine inhibits mitochondrial complex I
• B Phenylalanine directly destroys myelin sheaths
• C Phenylalanine causes cerebral vasospasm and infarction
• D Phenylalanine competitively inhibits tyrosine hydroxylase and tryptophan hydroxylase, impairing neurotransmitter synthesis ✓

Explanation

Phenylalanine competes with tyrosine and tryptophan for tyrosine hydroxylase and tryptophan hydroxylase, reducing synthesis of dopamine, norepinephrine, and serotonin. It also inhibits pyruvate kinase and hexokinase in brain. This neurotransmitter disruption, combined with impaired LAT1 transport at the blood-brain barrier, underlies the intellectual disability. Direct myelin destruction is not the primary mechanism.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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