Molecular epidemiology, genotype–phenotype correlation and BH 4 responsiveness in Spanish patients with phenylketonuria

Phenylketonuria (PKU), the most common inborn error of amino acid metabolism, is caused by mutations in the phenylalanine-4-hydroxylase ( PAH ) gene. This study aimed to assess the genotype–phenotype correlation in the PKU Spanish population and the usefulness in establishing genotype-based predictions of BH 4 responsiveness in our population. It involved the molecular characterization of 411 Spanish PKU patients: mild hyperphenylalaninemia non-treated (mild HPA-NT) (34%), mild HPA (8.8%), mild-moderate (20.7%) and classic (36.5%) PKU. BH 4 responsiveness was evaluated using a 6R-BH 4 loading test. We assessed genotype–phenotype associations and genotype–BH 4 responsiveness in our population according to literature and classification of the mutations. The mutational spectrum analysis showed 116 distinct mutations, most missense (70.7%) and located in the catalytic domain (62.9%). The most prevalent mutations were c.1066-11G>A (9.7%), p.Val388Met (6.6%) and p.Arg261Gln (6.3%). Three novel mutations (c.61-13del9, p.Ile283Val and p.Gly148Val) were reported. Although good genotype–phenotype correlation was observed, there was no exact correlation for some genotypes. Among the patients monitored for the 6R-BH 4 loading test: 102 were responders (87, carried either one or two BH 4 -responsive alleles) and 194 non-responders (50, had two non-responsive mutations). More discrepancies were observed in non-responders. Our data reveal a great genetic heterogeneity in our population. Genotype is quite a good predictor of phenotype and BH 4 responsiveness, which is relevant for patient management, treatment and follow-up.