A 2-year-old child with intellectual disability, fair skin, and a musty odor has plasma phenylalanine of 2000 μmol/L (normal <120). Phenylalanine hydroxylase activity is absent. What is the biochemical mechanism underlying the neurological damage in classic PKU?

• A Deficiency of tyrosine causes impaired catecholamine and melanin synthesis with secondary neurotoxicity
• B Phenylpyruvate directly inhibits pyruvate dehydrogenase in brain neurons
• C Excess phenylalanine competes with large neutral amino acids at the blood-brain barrier transporter, starving the brain of tryptophan, tyrosine, and other LNAAs ✓
• D Elevated phenylalanine activates NMDA receptors causing excitotoxic neuronal death

Explanation

In PKU, excessive phenylalanine competes with other large neutral amino acids (LNAAs) including tyrosine, tryptophan, and branched-chain amino acids at the LAT1 transporter on the blood-brain barrier. This competition reduces brain uptake of neurotransmitter precursors (tryptophan → serotonin; tyrosine → dopamine), causing profound neurotransmitter deficits and impaired myelination. Phenylpyruvate and phenylacetate also contribute by inhibiting certain metabolic enzymes, but the LNAA competition model is the primary accepted mechanism for cognitive impairment.

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

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Written and medically reviewed by the StethoPrep medical team.