The classical disease is due to a deficiency in the enzyme phenylalanine hydroxylase (PAH); the disease is transmitted as an autosomal recessive disorder.  There are, however, other forms of the disease that are non-responsive to dietary therapy, and these forms are due to defects in enzymes related to the biosynthesis of the cofactor tetrahydrobiopterin, a required cofactor for the hydroxylation of phenylalanine and other aromatic amino acids.

        Genetic analysis, using recombinant DNA techniques, has established that the genetic locus for PKU is on chromosome 12.  The structural gene codes for a (mature) protein of 452 amino acids.  SDS gel electrophoresis of purified enzyme shows two 50-kDa bands.  The native enzyme is found in a polymeric form, but it is not clear if the subunits are identical or not.

        The PAH gene contains 13 exons of various sizes, spread over approximately 90 kilobases of DNA.  DNA analysis has shown that the classical form of the disease is due not to deletion of the entire gene for PAH, but is instead due to mutations within the gene's sequence leading to amino acid substitutions or a premature stop codon.  Numerous haplotypes at the PAH locus have been identified by restriction fragment length polymorphism analysis.  About three fourths of the patients of European ancestry with classical PKU are genetic compounds, with different mutations in each of their two copies of the PAH gene.

        Defects in the enzymatic activity of three other enzymes can result in elevated serum levels of phenylalanine.  These latter enzymes are involved in the metabolism of the biopterin cofactor used in the hydroxylation.  Specifically, tetrahydrobiopterin (BH4) is used in the hydroxylation of phenylalanine; this cofactor is co-oxidized to dihydrobiopterin (BH2) which must then be regenerated to the BH4 form for continued enzymatic activity.  A deficiency in the activity of guanosine triphosphate cyclohydrolase I or pyruvoyl tetrahydropterin synthase can reduce or block the synthesis of tetrahydrobiopterin.  A third enzyme defect, in the enzyme dihydropteridine reductase, can block the regeneration of BH4 from BH2.  Approximately 1% to 3% of the patients presenting with hyperphenylalaninemia have a deficiency in BH4 metabolism, which may be mis-diagnosed instead as classical PKU, that is, as a deficiency in PAH activity.  Patients with defects in biopterin metabolism will likely have a distinctive urinary pterin profile that can be used to deduce the specific defect.

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