A newborn is detected on NBS (newborn screening) to have phenylketonuria (PKU). Plasma phenylalanine is 22 mg/dL. The parents ask about the mechanism of intellectual disability if the condition is untreated. The PRIMARY mechanism is:

• A Phenylalanine excess directly denatures synaptic proteins causing apoptosis
• B Excess phenylpyruvate formed from phenylalanine transamination directly inhibits mitochondrial electron transport chain
• C Tyrosine deficiency alone causes insufficient dopamine synthesis, producing intellectual disability
• D Elevated phenylalanine competes with large neutral amino acids at the blood-brain barrier transporter (LAT1), depriving the brain of tyrosine, tryptophan, and other essential amino acids for neurotransmitter synthesis and myelin formation ✓

Explanation

In untreated PKU, excess phenylalanine competes with other large neutral amino acids (tyrosine, tryptophan, isoleucine, leucine, valine, histidine) for the LAT1 transporter across the blood-brain barrier. This competitive inhibition deprives the developing brain of amino acids needed for neurotransmitter synthesis (serotonin from tryptophan, dopamine/noradrenaline from tyrosine) and myelin protein production. The result is global neurodevelopmental impairment. This is the primary mechanism — not direct phenylalanine toxicity or mitochondrial inhibition alone, though phenylketone metabolites may also be toxic.

Reference: Ghai Essential Pediatrics, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.