Autosomal recessive phenylketonuria (PKU) is the most common genetic disorder of amino acid metabolism (prevalence 1:7,500-8,500). Due to a defect in phenylalanine hydroxylase (PAH), the amino acid phenylalanine can no longer be sufficiently metabolized to tyrosine. This leads to an unphysiological accumulation of phenylalanine, which, if left untreated, results in pronounced brain damage and consequent severe psychomotor retardation. The molecular cause is found in pathogenic variants in the PAH gene, which codes for phenylalanine hydroxylase. A large number of variants have been described that lead either to reduced enzyme activity or to complete failure of the enzyme. This also explains the existing genotype-phenotype correlation. The combination of two "mild variants" or a "mild" with a "severe variant" usually leads to mild hyperphenylalaninemia or mild phenylketonuria, respectively. The combination of two "severe variants" predominantly leads to classic phenylketonuria. However, this genotype-phenotype correlation is not always present, and variants have been described that can lead to different phenotypes in homozygous form.
Therapy of PKU is via a strict low phenylalanine diet. Another treatment option is the administration of tetrahydrobiopterin (BH4), a cofactor of phenylalanine hydroxylase. In pharmacological doses, tetrahydrobiopterin is able to stabilize the structure of misfolded phenylalanine hydroxylase (molecular chaperone) and increase its enzyme activity. A large proportion of patients benefit from BH4 therapy. There are also genotype-phenotype correlations in the efficacy of BH4 therapy, which in many cases allow the response to therapy to be estimated in advance.
Diagnosis of phenylketonuria is part of newborn screening. In the case of abnormal findings, the diagnosis can be confirmed by molecular genetics. With timely initiation of therapy and adherence to the necessary dietary measures, the disease is readily treatable.
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