MUTATIONS IN THE PHENYLALANINE-HYDROXYLASE GENE - GENETIC-DETERMINANTS FOR THE PHENOTYPIC VARIABILITY OF HYPERPHENYLALANINEMIA

Phenylalanine hydroxylase (PAH) deficiency is a heterogeneous disease at the phenotype level. The spectrum of clinical and metabolic phenoty pes spans from the potential pathogenic disease classical phenylketonu ria (PKU) to the benign condition non-PKU hyperphenylalaninemia (non-P KU 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 out come. Complete genotype determination in a large number of patients wi th PAH-deficient hyperphenylalaninemia demonstrates that clinical hete rogeneity can be explained by a multiplicity of mutations in the PAH g ene. Some combinations of mutations are associated with phenylalanine levels fluctuating around the border between PKU and non-PKU HPA. Howe ver, certain mutations seem always to cause non-PKU HPA irrespective o f 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 hyp erphenylalaninemia can be used for rapid and highly efficient differen tial diagnosis of PAH deficiency, and for predicting the severity of t he disease. These possibilities may facilitate and optimize the manage ment of hyperphenylalaninemia and thereby improve prognosis.