ABERRANT PHENYLALANINE METABOLISM IN PHENYLKETONURIA HETEROZYGOTES

The wide variation in phenylalanine hydroxylating capacity observed am ong patients with phenylketonuria (PKU) is primarily due to allelic he terogeneity at the phenylalanine hydroxylase (PAH) locus. In this stud y, we examined phenylalanine metabolism after an oral phenylalanine lo ad in 148 carriers of known PAH gene mutations. As a group, heterozygo tes formed less tyrosine than normozygotes (p < 0.001), and there was a tendency that carriers of a severe PAH mutation formed less tyrosine than carriers of a mild mutation. Nevertheless, the interindividual v ariation was extensive, and we identified a group of individuals who f ormed no or very little tyrosine after the phenylalanine load. This ty rosine response was accompanied by a decreased ability to eliminate th e phenylalanine test dose but did not correlate with the intrinsic sev erity of the mutant PAH allele. Examination of the entire coding regio n of the PAH gene revealed no additional sequence alterations in these subjects. Our data suggest that a subset of PKU heterozygotes have re duced phenylalanine hydroxylating: capacity approaching or equalling t he levels observed in genetic compounds with non-PKU mild hyperphenyla laninaemia (MHP). Awareness of this phenotypic overlap between PKU car riers and genetic compounds with two mutant alleles may be useful for clinicians and paediatricians involved in diagnosis and genetic counse lling.