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By Cary O Harding MD

Phenylketonuria (PKU) is also known as or subsumes Hyperphenylalaninemia. -ed.

In this clinical article, Dr. Cary O Harding reviews the history of the discovery of phenylketonuria, one of the oldest known inborn errors of metabolism, and reviews the development of dietary treatment and neonatal screening for this disorder. The pathophysiologic mechanisms that are thought to cause central nervous system damage are discussed. The development of novel therapeutic approaches, including enzyme substitution therapy, is changing the future of phenylketonuria treatment.

Key Points

  • Phenylketonuria is caused by deficient activity of phenylalanine hydroxylase, an enzyme in the intermediary metabolism of the amino acid, phenylalanine, and is one of the most common inborn errors of metabolism.
  • Phenylketonuria is inherited as an autosomal recessive disorder.
  • Neonatal screening for phenylketonuria allows for the early detection and treatment of infants with the disorder.
  • Dietary therapy of phenylketonuria is based upon restriction of dietary phenylalanine intake and largely prevents the major manifestations of the disorder, including profound developmental disability and seizures, but there are difficulties with lifelong adherence to the diet that may lead to cognitive impairment, particularly problems with executive functioning.
  • Novel therapeutic approaches for phenylketonuria include large neutral amino acid supplementation to block phenylalanine uptake into brain, sapropterin dihydrochloride treatment of a subset of patients who are responsive to the drug, and enzyme substitution therapy with polyethylene glycol-conjugated phenylalanine ammonia lyase.