Cary O Harding MD (Dr. Harding of Oregon Health & Science University received consulting fees and contracted research from BioMarin Pharmaceutical Inc.)
Barry Wolf MD PhD, editor. (Dr. Wolf of Ann & Robert H. Lurie Children's Hospital of Chicago has no relevant financial relationships to disclose.)
Originally released March 30, 1995; last updated January 25, 2015; expires January 25, 2018

This article includes discussion of phenylketonuria, atypical hyperphenylalaninemia, hyperphenylalaninemia, malignant hyperphenylalaninemia, and PKU. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.


In this article, the author 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 on 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.

Historical note and terminology

In 1934, Følling reported a compound in the urine of 2 developmentally disabled individuals that reacted with ferric chloride to produce a deep green color. He subsequently identified this compound as phenylpyruvic acid in the urine of 10 developmentally delayed individuals (Folling 1934). Penrose and Quastel named the disease "phenylketonuria” and first attempted dietary therapy (Penrose and Quastel 1937). The metabolic defect in phenylketonuria was determined to be impaired hydroxylation of phenylalanine to tyrosine (Jervis 1947), and the liver enzyme phenylalanine hydroxylase was ultimately shown to be deficient in individuals with phenylketonuria (Jervis 1953). With the development of a simple bacterial inhibition assay, known as the Guthrie test (Guthrie and Susi 1963), and along with the successful treatment by dietary restriction of phenylalanine using synthetic diets (Bickel et al 1953), neonatal screening and early treatment were introduced. Most neonatal screening programs have now discontinued the use of the Guthrie test to detect elevated phenylalanine concentrations in favor of the faster, more sensitive tandem mass spectrometry method that also detects several other amino acidopathies. The human gene encoding phenylalanine hydroxylase was cloned in 1983 (Woo et al 1983). Following the development of a relevant mouse model of phenylketonuria (McDonald et al 1990), the first successful liver-directed gene therapy for this disorder was reported (Fang et al 1994).

With the successful treatment of phenylketonuria, a group of individuals were identified who, despite dietary restriction of phenylalanine, had progressive neurologic disease and were designated as having "malignant phenylketonuria." These children patients were found to have a deficiency of 1 of the enzymes of tetrahydrobiopterin metabolism. Tetrahydrobiopterin is a necessary cofactor for phenylalanine hydroxylase, tyrosine-3-hydroxylase, and tryptophan-5-hydroxylase (the latter 2 are rate-limiting enzymes in the synthesis of catecholamines and serotonin, respectively), and all forms of nitric oxide synthase. In addition to being hyperphenylalaninemic, children with defects in the metabolism of tetrahydrobiopterin exhibit deficiency of biogenic amine neurotransmitters in the central nervous system. Treatment by dietary phenylalanine restriction alone is not successful, but must be combined with tetrahydrobiopterin replacement and administration of L-DOPA and 5-hydroxytryptophan to address the neurotransmitter deficiencies.

Nomenclature in this group of inborn errors of metabolism can be confusing because of the great phenotypic variability. "Classical phenylketonuria" usually refers to individuals with untreated plasma phenylalanine concentrations of greater than 1200 µmol/L (normal 40 to 83 µmol/L), phenylalanine metabolites in urine, and developmental delay, if untreated. "Hyperphenylalaninemia" usually refers to individuals with lower plasma concentration of phenylalanine, but sometimes is used to refer to individuals who may not need dietary therapy based on their untreated phenylalanine concentration. In the past, "atypical phenylketonuria" was used to refer to individuals with inherited tetrahydrobiopterin deficiency, but may also be used by some authors to refer to children with mild hyperphenylalaninemia due to phenylalanine hydroxylase deficiency. In this review, tetrahydrobiopterin deficiency will be called "biopterin-deficient hyperphenylalaninemia," "phenylketonuria” will refer to hyperphenylalaninemia requiring treatment (untreated plasma concentrations greater than or equal to 360 µmol/L), and "hyperphenylalaninemia" will refer to untreated concentrations that do not require treatment (less than 360 µmol/L).

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