Phenylketonuria (PKU) is the most frequent inborn error of amino acid metabolism and is characterized by mental disability from mild to severe in untreated patients.
The prevalence shows considerable geographic variation. It is estimated at 1/10.000 live births in Europe, with a higher rate in countries like Ireland or Italy. The prevalence is particularly high in Turkey with 1/4.000 live births. PKU is very rare in Finnish, African and Japanese populations.
PKU is caused by a wide range of mutations in the PAH (12q22-q24.2) encoding phenylalanine hydroxylase gene. The frequency of mutation varies among different ethnic groups. Low levels or lack of phenylalanine hydroxylase underlie the clinical manifestations, as a result of toxic accumulation of phenylalanine in the blood and brain.
Transmission is autosomal recessive. Genetic counselling to affected families must be provided.
Generally, the disorder is diagnosed through neonatal screening programs. In the absence of a neonatal diagnosis, symptoms appear during the first months of life, and can be from very mild to severe, and include gradual developmental delay, growth retardation, microcephaly, seizures, tremors, eczema and vomiting. Untreated patients later develop intellectual disabilities, behavioural disorders (hyperactivity) and motor disorders.
The most common form of the disease is the classical PKU, characterized by severe symptoms. It has also been reported a mild form. It has been described that a subset of patients with milder phenotypes match tetrahydrobiopterin (BH4) hydroxylation cofactor phenylalanine (BH4 sensitive HPA).
The mainstay of treatment is a diet low in phenylalanine and a mixture of amino acids. However there is no consensus on the level of phenylalanine above which treatment should be initiated and recommendations vary between countries. The prognosis of these patients is variable.