Phenylketonuria (PKU) is a well-characterized, treatable, biochemical disorder which results in dietary intolerance to the essential amino acid phenylalanine. It is the most common inborn error of amino acid metabolism in the Caucasian population with an average incidence of 1 in 10,000. Classic PKU is caused by complete or near-complete deficiency of phenylalanine hydroxylase activity secondary to mutations in the PAH gene. The primary route for phenylalanine metabolism is hydroxylation of phenylalanine to tyrosine catalyzed by phenylalanine hydroxylase; consequently a deficiency of this enzyme leads to an elevation of the plasma phenylalanine (phe) concentration (~ 1000 ?mol/L). Without dietary restriction of phenylalanine, children with classic PKU will develop severe and irreversible mental retardation. Other clinical features evident in untreated children can include microcephaly, epilepsy, behavioral problems, eczema, hypopigmentation, decreased myelin formation and musty urine odor.
Patients with hyperphenylalaninemia due to tetrahydrobiopterin (BH4) deficiency will not be expected to have disease causing mutations in PAH. BH4 deficiency is due to defects in the enzymes involved in the synthesis or regeneration of tetrahydrobiopterin (BH4), a cofactor for phenylalanine hydroxylase enzyme. BH4 deficient hyperphenylalaninemia is a genetically heterogeneous group of disorders caused by mutations in genes (GCH1, PTS, QDPR, PCBD) of the BH4 pathway.