Phenylketonuria (PKU) is an autosomal recessive condition caused by a disorder of phenylalanine metabolism. This is usually due to defect in phenylalanine hydroxylase, an enzyme which converts phenylalanine to tyrosine. In a small number of cases the underlying defect is a deficiency of the tetrahydrobiopterin-deficient cofactor, e.g. secondary to defective dihydrobiopterin reductase. High levels of phenylalanine lead to problems such as learning difficulties and seizures. The gene for phenylalanine hydroxylase is located on chromosome 12. The incidence of PKU is around 1 in 10,000 live births.

Phenylalanine embryopathy— ↑ phenylalanine levels in pregnant patients with untreated phenylketonuria (PKU) can cause fetal growth restriction, microcephaly, intellectual disability, congenital heart defects. Can be prevented with dietary measures.

Features

• usually presents by 6 months e.g. with developmental delay
• child classically has fair hair and blue eyes
• learning difficulties, microcephaly
• seizures, typically infantile spasms
• eczema, hypopigmented skin
• 'musty' odour to urine and sweat*
  • Disorder of aromatic amino acid metabolism → musty body odor
  • due to phenyl ketones—phenylacetate, phenyl-lactate, and phenylpyruvate.

Diagnosis

• Guthrie test: the 'heel-prick' test done at 5-9 days of life - also looks for other biochemical disorders such as hypothyroidism
• hyperphenylalaninaemia
• phenylpyruvic acid in urine

Management

• ↓ phenylalanine and ↑ tyrosine in diet (eg, soy products, chicken, fish, milk), tetrahydrobiopterin supplementation
  • poor evidence base to suggest strict diet prevents learning disabilities
• Patients with PKU must avoid the artificial sweetener aspartame, which is converted to phenylalanine.
• dietary restrictions are however important during pregnancy as genetically normal fetuses may be affected by high maternal phenylalanine levels