Phenylketonuria: a 21st century perspective


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.

Key Points

  • Phenylketonuria was the first successfully treated inborn error of metabolism, and with treatment, prevention from mental retardation became possible

  • Essentially, phenylketonuria is now a biochemical rather than a clinical diagnosis, which is largely based on high blood phenylalanine concentrations or phenylalanine to tyrosine ratio found at neonatal screening

  • Conventional treatment for phenylketonuria consists of dietary restriction of phenylalanine, which necessitates a stringent restriction of natural protein with supplementation of all amino acids apart from phenylalanine

  • Problems in the outcome of phenylketonuria are almost completely restricted to the brain, which suggests that the blood–brain barrier is of major importance in the pathophysiology of phenylketonuria

  • Notwithstanding the enormous improvement of neurocognitive outcome on dietary treatment, intelligence quotient and neuropsychological tests show deficits that necessitate improvements in diagnosis and new treatment strategies

  • New therapeutic modalities, including large neutral amino acids and tetrahydrobiopterin, may in part replace dietary restriction, while phenylalanine ammonia lyase, chaperone treatment and gene therapy are in development

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Figure 1: The metabolism of phenylalanine.


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The author declares associations with the following companies: Merck Serono (Consultant, Speakers Bureau, Grant/research support), Nutricia (Consultant, Speakers Bureau, Grant/research support).

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van Spronsen, F. Phenylketonuria: a 21st century perspective. Nat Rev Endocrinol 6, 509–514 (2010).

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