Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Phenylketonuria (PKU) [E70.0], Hyperphenylalaninemia (HPA) [E70.1]

OMIM numbers: 261600, 612349 (PAH)

Dipl.-Biol. Wolfgang Rupprecht, Dipl.-Biol. Birgit Busse

Scientific Background

Phenylketonuria (PKU) is an autosomal recessive inherited metabolic disorder and with a prevalence of approx. 1 in 7,500-8,500 the most frequent genetic disorder of the amino acid metabolism. Due to a defect of phenylalanine hydroxylase (PAH), the amino acid phenylalanine can no longer be sufficiently metabolized into tyrosine. An unphysiological accumulation of phenylalanine occurs which, untreated, results in severe brain damage and therefore in severe psychomotor impairment. The molecular cause are mutations in the PAH gene, which encodes for phenylalanine hydroxylase. There are different mutations, that lead to either a reduced enzyme activity or to a complete malfunction of the enzyme, which explains the genotype-phenotype correlation. The combination of two “mild” mutations or a “mild” and a “severe” mutation usually leads to a mild hyperphenylalaninemia or mild phenylketonuria. The combination of two “severe” mutations predominantly leads to a classic phenylketonuria. The  genotype-phenotype correlation, however, is not always present and there are mutations that can lead to different phenotypes in homozygous form.

Treatment of PKU is usually a strict diet low in phenylalanine. Another possibilty is administering tetrahydrobiopterin (BH4), a cofactor of phenylalanine hydroxylase. In pharmacological doses, tetrahydrobiopterin can stabilize the structure of the misfolded phenylalanine hydroxylase (molecular chaperone) and increase its enzymatic activity. A large part of the patients benefit from a BH4 treatment. There are genotype-phenotype correlations regarding the effectiveness of a BH4 treatment as well, which allow predictions regarding the response to the treatment.