Molecular Epidemiology of Phenylalanine Hydroxylase Deficiency in Southern Italy: a 96% Detection Rate with Ten Novel Mutations

Summary Hyperphenylalaninemia (HPA) comprises a group of autosomal recessive disorders mainly caused by phenylalanine hydroxylase ( PAH ) gene mutations. We investigated PAH mutations in 126 HPA patients from Southern Italy who were identified in a neonatal screening program. The promoter, coding and exon‐flanking intronic sequences of the PAH gene were amplified and sequenced. Mutations were identified in 240/249 alleles (detection rate: 96.4%). We found 60 gene variants; the most frequent were p.R261Q (15.7% of alleles), p.A403V (11.6% of alleles) and c.1066‐11G > A (8.8% of alleles). The remaining mutations were rare, and ten are novel. This mutation epidemiology differs from that reported for Northern Italy and other European countries. We also identified several discordant genotype/phenotype correlations. About two‐thirds of all mild phenylketonuria patients showed at least one tetrahydrobiopterin (BH 4 )‐responsive mutation, and are thus candidates for a customized therapeutic approach.