Phenylketonuria (PKU)


Phenylketonuria (PKU) is one of the first characterised metabolic diseases. PKU is an autosomal recessive metabolic disorder resulting in increased phenylalanine concentrations. Without intervention, such as pharmaceutical or dietary restriction of phenylalanine, most children with PKU develop a profound and irreversible intellectual disability. In fact, this treatable condition is one of the leading causes of mental retardation. PKU can occur via two main mechanisms: classical and nonclassical. Classical PKU results from impaired activity of the liver enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine. In nonclassical PKU, there is an absence or deficiency of dihydropteridine reductase which impairs the regeneration of tetrahydrobiopterin, a necessary cofactor in the conversion of phenylalanine to tyrosine. The advent of neonatal screening for PKU has enabled the start of a low‐phenylalanine diet early in life and thus, the prevention of intellectual retardation associated with the disease. The mainstay of treatment is a phenylalanine‐restricted diet, but its application varies both internationally and nationally.

Key Concepts

  • Phenylketonuria (PKU) is a rare metabolic disorder, characterised by an impaired ability to metabolise the amino acid phenylalanine and resultant high circulating levels of phenylalanine.
  • Classical PKU (the most common form) is caused by mutations in the gene for phenylalanine hydroxylase (PAH).
  • Nonclassical PKU can be caused by defects in the synthesis or function of the cofactor for PAH (BH4).
  • If not treated shortly after birth, PKU can be destructive to the nervous system, causing intellectual disability.
  • The identification of PKU during routine newborn screening and management with a diet low in phenylalanine became standard practice in the early 1960s.
  • PKU is a disorder that has an unequal geographic and ethnic distribution.
  • Individuals on well‐controlled phenylalanine‐free diet may still develop cognitive symptoms.
  • Several new therapies have recently emerged that provide alternatives to the strict low‐phenylalanine diet. A description of these treatments (medical foods, BH4 administration, large neutral amino acid supplementation and enzymatic therapy) is covered herein.

Keywords: PKU; metabolic disorder; hyperphenylalaninaemia; phenylalanine hydroxylase; inborn errors of metabolism; autosomal recessive; intellectual disability

Figure 1. Phenylalanine metabolism. Phenylalanine hydroxylase (PAH) catalyses the conversion of phenylalanine to tyrosine. Deficiencies in the activity of this enzyme result in incomplete phenylalanine metabolism and build‐up of toxic waste products. BH4, tetrahydrobiopterin; q‐BH2, quinonoid dihydrobiopterin; GTP, guanosine triphosphate.
Figure 2. Summary of potential mechanisms of neurocognitive impairment by hyperphenylalaninaemia. Excess phenylalanine competes with LNAA entry into the brain through LAT1. Phe indicates phenylalanine; BBB, blood–brain barrier; LNAA, large neutral amino acids; LAT1, large neutral amino acid carrier; BH4, tetrahydrobiopterin; Tyr, tyrosine; Trp, tryptophan.
Figure 3. Potential therapeutic approaches for phenylketonuria. Baby image reproduced from Shutterstock and is licensed under the Shutterstock Royalty‐Free License Agreement.


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Further Reading

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Waisbren SE, Noel K, Fahrbach K, et al. (2007) Phenylalanine blood levels and clinical outcomes in phenylketonuria: a systematic literature review and meta‐analysis. Molecular Genetics and Metabolism 92 (1–2): 63–70.

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Gonzalez‐Lopez, Eugene, McFalls, Ashley J, and Vrana, Kent E(Nov 2016) Phenylketonuria (PKU). In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0002006.pub2]