THE INFLUENCE OF MUTATIONS ON ENZYME-ACTIVITY AND PHENYLALANINE TOLERANCE IN PHENYLALANINE-HYDROXYLASE DEFICIENCY

The phenylalanine hydroxylase (PAH) deficiency trait is heterogeneous with a continuum of metabolic phenotypes ranging from classical phenyl ketonuria (PKU) to mild hyperphenylalaninaemia (MHP). More than 200 mu tations in the PAH gene are associated with PAH deficiency. From theor etical considerations or in vitro expression studies each mutation has a particular influence on enzyme activity, which explains the variati on in dietary tolerance for phenylalanine (Phe). This paper gives a su mmary of the effect of each type of mutation on PAH activity and illus trates how the combination of mutations (the genotype) is associated w ith the Phe tolerance (the metabolic phenotype). Mutations within a po pulation generally include a few prevalent mutations and a high number of rare mutations. The particular distribution of mutations implies t hat many PAH-deficient patients carry the same mutation combination, e nabling the establishment of genotype-phenotype correlations by compar ing clinical parameters in patients with identical genotypes. Because certain mutations always cause MHP irrespective of the mutation on the second allele, mutation typing of hyperphenylalaninaemic neonates wil l differentiate between PKU and MHP. In addition, genotyping will prov ide a tool for precise diagnosis of the metabolic phenotype of the neo nate with PKU and thereby permit earlier implementation of dietary the rapy better tailored to each individual patient.