Molecular basis of non-PKU hyperphenylalaninaemia in Spain: prevalence of A403V, a mutation with high residual activity.

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Phenylketonuria (PKU ; McKusick 261600), caused by a deficiency of hepatic phenylalanine hydroxylase (PAH), is clinically very heterogeneous, ranging from classical PKU to non-PKU hyperphenylalaninaemia (non-PKU HPA), which is defined by blood phenylalanine concentrations below 600 μmol/L without dietary restriction. In Spain, the frequency of non-PKU HPA is 27%, and the rest of the patients belong to the mild (43%), classical (22%) and moderate (8%) PKU phenotypes (Martinez-Pardo et al 1994). Today, much is known about the molecular basis for the phenotypic diversity of PKU. More than 200 different mutations have been identified in the PAH gene and expression studies have served to correlate the residual activity of the mutant enzyme(s) with the biochemical phenotype. Non-PKU HPA can be the result of two mild mutations, but most of the cases result from a PKU mutation which causes complete loss of enzyme activity and results in the severe phenotype in homozygosity, and a mild mutation on the other allele (Avigad et al 1991 ; Economou-Petersen et al 1992 ; Guldberg et al 1994). In this study we have investigated 57 Spanish non-PKU HPA patients to determine the molecular basis of non-PKU HPA in Spain. A403V was the most frequent mutation found (14%) and was further analysed in COS cells to determine its in vitro residual activity.