Mutational spectrum of phenylalanine hydroxylase deficiency in the population resident in Catalonia: genotype-phenotype correlation

Hyperphenylalaninemia (HPA) is a group of diseases characterized by the per sistent elevation of phenylalanine levels in tissues and biological fluids. It is an autosomal recessive disorder affecting 1 in 10,000 individuals in Caucasian populations and about 1 in 6,600 in Catalonia. We report the mut ational spectrum of phenylalanine hydroxylase deficiency in the population living in Catalonia and the genotype-phenotype correlation. The molecular s tudy was performed in 383 samples corresponding to 115 patients from 99 unr elated families and 268 relatives. We have characterized 90% of the mutant alleles; there were 57 different mutations, 49 of which have previously bee n described, 8 being novel mutations and two being large deletions. The 57 mutations detected corresponded to: five nonsense, seven frameshift, and ei ght splice defects, the remainder being missense mutations. These mutations cause 72 different genotypes in the 83 families characterized, confirming the mutational heterogeneity of phenylketonuria (PKU) in the Mediterranean population. according to our biochemical classification, our HPA population is composed of 40 PKU (35%), 36 variant PKU (31%), and 39 non-PKU HPA (34% ). Mutations such as IVS10, A403 V, and E390G correlated as expected with t he phenotype and the predicted residual activity in vitro. However, in four cases (165 T, V388 M, R261Q, and Y414 C), the observed metabolic phenotype was not consistent with the predicted genotypic effect. The identification of the mutations in the PAH gene and the genotype-phenotype correlation sh ould facilitate the evaluation of metabolic phenotypes, diagnosis, implemen tation of optimal dietary therapy, and determination of prognosis in the pa tients and genetic counselling for the patient's relatives.