Abstract: 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 BH4 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. BH4 responsiveness was evaluated using a 6R-BH4 loading test.
We assessed genotype?phenotype associations and genotype?BH4 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.1066-11G4A (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-BH4 loading test: 102 were responders (87, carried either one or two BH4-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 BH4 responsiveness, which is relevant for
patient management, treatment and follow-up.
