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A rare inborn error of amino acid metabolism characterized by elevated blood phenylalanine and low levels or absence of phenylalanine hydroxylase enzyme. If not detected early or left untreated, the disorder manifests with mild to severe mental disability.
ORPHA:716Classification level: Disorder
The prevalence of phenylketonuria (PKU) shows considerable geographic variation. It is estimated to be 1/10,000 live births in Europe with a higher rate in some countries (Ireland, Italy). Prevalence is particularly high in Turkey: 1/4,000 live births. PKU is far rarer in the Finnish, African and Japanese populations.
In the absence of neonatal diagnosis, symptoms develop within a few months of birth, may be very mild to severe and include gradual developmental delay, stunted growth, microcephaly, seizures, tremors, eczema, vomiting, and musty odor. Untreated patients subsequently develop intellectual disability, behavioral disorders (hyperactivity) and motor disorders. Patients often have fair coloring as a result of tyrosine deficiency. The most common form of the condition is known as classical phenylketonuria and is characterized by severe symptoms. A mild form has also been described (mild PKU), and an even milder form known as mild hyperphenylalaninemia (mild HPA or non-PKU HPA). A subset of patients with milder phenotypes has been found to be responsive to tetrahydrobiopterin (BH4), the cofactor of phenylalanine hydroxylase (BH4-responsive HPA).
PKU is caused by a wide range of variants in the PAH gene (12q22-q24.2) coding for phenylalanine hydroxylase. Non-PAH variants have been reported to cause a disorder known as hyperphenylalaninemia due to BH4 deficiency. Variant frequency varies among different ethnic groups. Lower levels or absence of the phenylalanine hydroxylase enzyme underlie the clinical manifestations, as a result of toxic accumulation of phenylalanine in the blood and brain.
The disorder is usually diagnosed through neonatal screening programs.
PKU should be distinguished from BH4 deficiency.
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them of the 25% risk of having an affected child at each pregnancy.
Management and treatment
The mainstay of treatment is a low-phenylalanine diet and amino acids mixture for the forms that require treatment. According to the European guidelines for the management of PKU, the recommended maintenance level is usually between 120 and 360 micromol/L in newborns, with treatment considered essential in older patients with levels above 600 micromol/L.
Prognosis is variable, but favorable if diagnosed early and treated properly.
- Guidance for genetic testing
- English (2011)
- Clinical genetics review
- English (2017)