Phenylalanine hydroxylase deficiency, so phenylalanine accumulates and tyrosine becomes essential
Expansion
Defect: phenylalanine hydroxylase, which normally converts phenylalanine to tyrosine, using the cofactor tetrahydrobiopterin. Autosomal recessive.
Consequences
- Phenylalanine accumulates and is diverted to phenylketones (phenylpyruvate, phenylacetate), giving the characteristic musty or mousy odour
- Tyrosine becomes essential, so melanin, thyroxine, dopamine, noradrenaline and adrenaline synthesis are all impaired
- Untreated: severe intellectual disability, seizures, microcephaly, eczema, and fair skin and hair with blue eyes
Detected on newborn screening (the blood spot at day 5), which must be taken after feeding has begun so that phenylalanine has been ingested.
Treatment: lifelong phenylalanine-restricted diet with tyrosine supplementation. Aspartame must be avoided, since it is hydrolysed to phenylalanine.
Maternal PKU is a distinct hazard: high maternal phenylalanine is teratogenic to a heterozygous fetus, causing microcephaly and congenital heart disease, so strict dietary control is needed before conception.
A minority have defects in tetrahydrobiopterin synthesis rather than the enzyme, and these do not respond to dietary restriction alone.