Phenylketonuria: a 21st century perspective

Nat Rev Endocrinol. 2010 Sep;6(9):509-14. doi: 10.1038/nrendo.2010.125.


Phenylketonuria is the most prevalent inherited defect in amino acid metabolism. Owing to mutations in the gene encoding the enzyme phenylalanine hydroxylase, the essential amino acid phenylalanine cannot be hydroxylated to tyrosine and blood and tissue concentrations of phenylalanine increase. Untreated, phenylketonuria causes severe mental retardation, epilepsy and behavioral problems. The combined effect of neonatal screening and treatment has, however, meant that phenylketonuria is now a biochemical rather than a clinical diagnosis. Treatment consists of stringent dietary restriction of natural protein intake and supplementation of amino acids other than phenylalanine by a chemically manufactured protein substitute. Although clinical outcome on a phenylalanine-restricted diet is good, neuropsychological deficits are now known to exist in dietary-treated patients with phenylketonuria, and quality of life, nutritional condition and psychosocial outcome could probably also be improved. The need for new therapeutic approaches is being met by supplementation with tetrahydrobiopterin or large neutral amino acids, whilst development of the use of phenylalanine ammonia lyase, and, in the longer term, gene therapy and chaperone treatment holds promise. This Review provides an overview of the history of phenylketonuria, the challenges of treatment today and the treatment possibilities in the near future.

Publication types

  • Historical Article
  • Review

MeSH terms

  • Diet Therapy / methods
  • Endocrinology / history
  • Endocrinology / methods
  • Endocrinology / trends*
  • History, 21st Century
  • Humans
  • Infant, Newborn
  • Models, Biological
  • Neonatal Screening
  • Phenylketonurias / diagnosis
  • Phenylketonurias / etiology*
  • Phenylketonurias / therapy*
  • Practice Guidelines as Topic
  • Treatment Outcome