Clinical meaning
Phenylketonuria (PKU) is an autosomal recessive inborn error of metabolism caused by deficiency of phenylalanine hydroxylase (PAH), the hepatic enzyme that converts phenylalanine (Phe) to tyrosine. Without functional PAH, phenylalanine accumulates in the blood and crosses the blood-brain barrier, where it competitively inhibits large neutral amino acid transport, disrupts neurotransmitter synthesis (dopamine, serotonin, norepinephrine), impairs myelin formation, and causes oxidative stress to neurons. In adults who discontinue dietary treatment, elevated phenylalanine causes executive dysfunction, anxiety, depression, tremor, and white matter changes on MRI. Maternal PKU syndrome occurs when women with PKU become pregnant without adequate phenylalanine control (Phe >6 mg/dL), causing microcephaly, congenital heart defects, intellectual disability, and intrauterine growth restriction in the non-PKU fetus due to teratogenic effects of elevated maternal Phe crossing the placenta.
Diagnosis & workup
Diagnostics & workup: - Quantitative plasma phenylalanine levels (target 120-360 micromol/L or 2-6 mg/dL for adults) - Plasma tyrosine levels (often low due to impaired conversion from phenylalanine) - Plasma amino acid profile to assess nutritional adequacy of medical food - BH4 loading test to determine sapropterin responsiveness (20 mg/kg oral challenge) - Neuropsychological testing for executive function, attention, and processing speed - Brain MRI for white matter changes in patients with chronically elevated Phe - Bone density screening (DXA scan) — PKU patients on restricted diets are at risk for osteopenia