Mutations in the phenylalanine hydroxylase gene: genetic determinants for the phenotypic variability of hyperphenylalaninemia.

[classical phenylketonuria]

Phenylalanine hydroxylase (PAH ) deficiency is a heterogeneous disease at the phenotype level . The spectrum of clinical and metabolic phenotypes spans from the potential pathogenic disease classical phenylketonuria (PKU ) to the benign condition non-PKU hyperphenylalaninemia (non-PKU HPA ). This review provides an introduction to the clinical variants of PAH deficiency , and summarizes our attempts to define the disease at the molecular level and to relate mutation genotype to clinical outcome . Complete genotype determination in a large number of patients with PAH -deficient hyperphenylalaninemia demonstrates that clinical heterogeneity can be explained by a multiplicity of mutations in the PAH gene . Some combinations of mutations are associated with phenylalanine levels fluctuating around the border between PKU and non-PKU HPA . However , certain mutations seem always to cause non-PKU HPA irrespective of the mutation on the second allele and can , therefore , unambiguously be designated as being associated with the non-PKU HPA phenotype . Our results suggest that mutation analysis in newborns presenting with hyperphenylalaninemia can be used for rapid and highly efficient differential diagnosis of PAH deficiency , and for predicting the severity of the disease . These possibilities may facilitate and optimize the management of hyperphenylalaninemia and thereby improve prognosis .