A newborn screening test reveals elevated phenylalanine at 72 hours of life. Plasma phenylalanine is 22 mg/dL. The child appears normal clinically. If untreated, which of the following best describes the mechanism by which phenylketonuria (PKU) causes intellectual disability?
- A Phenylalanine excess competes with large neutral amino acids (LNAAs) at the blood-brain barrier transporter, reducing brain levels of tyrosine, tryptophan, and other LNAAs critical for neurotransmitter synthesis ✓
- B Direct neuronal toxicity from excessive dopamine and serotonin accumulation
- C Phenylketones inhibit myelin synthesis directly by blocking ceramide galactosyltransferase
- D Excess phenylalanine directly inhibits glutamate decarboxylase, reducing GABA production
Explanation
In PKU, hyperphenylalaninemia causes intellectual disability through competitive inhibition at the large neutral amino acid (LNAA) transporter at the blood-brain barrier. Phenylalanine, present in excess, outcompetes other LNAAs (tyrosine, tryptophan, leucine, isoleucine, valine, threonine) for entry into the brain. This depletion reduces synthesis of dopamine (from tyrosine), serotonin (from tryptophan), and other neurotransmitters, and impairs myelin formation. Phenylalanine itself may also directly inhibit enzymes such as pyruvate kinase and glutamate dehydrogenase. The LNAA competition mechanism is the most well-established explanation and forms the basis for LNAA supplementation as adjunct therapy.
Reference: Ghai Essential Pediatrics, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.