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.