MOLECULAR-BASIS FOR THE PHENOTYPICAL DIVERSITY OF PHENYLKETONURIA ANDRELATED HYPERPHENYLALANINAEMIAS

Phenylketonuria (PKU; McKusick 261600) is a monogenic autosomal recess ive defect of hepatic phenylalanine hydroxylase (PAH, EC 1.14.16.1; L- phenylalanine, tetrahydropteridine: oxygen oxidoreductase) that untrea ted causes mental retardation (Scriver et al 1989; Guttler and Lou 199 0). Neonatal screening has revealed that PAH deficiency is phenotypica lly heterogeneous with severe, moderate and mild PKU phenotypes, and n on-PKU hyperphenylalaninaemia (HPA, McKusick 261600) not needing thera py (Guttler 1980). Different mutations in the gene coding for PAH caus e a spectrum of in vitro enzyme activities (from 0% to 50% of normal) which correlates with the different phenotypes observed (Okano et al 1 991). The purpose of this report is to correlate mutation genotypes to biochemical and metabolic phenotypes in PAH-deficient patients rangin g from severe classic PKU to the nearly normal non-PKU HPA phenotype.