Molecular epidemiology of phenylalanine hydroxylase deficiency in Southern Italy: a 96% detection rate with ten novel mutations

Ann Hum Genet. 2007 Mar;71(Pt 2):185-93. doi: 10.1111/j.1469-1809.2006.00328.x. Epub 2006 Nov 10.

Abstract

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 (BH4)-responsive mutation, and are thus candidates for a customized therapeutic approach.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • DNA Mutational Analysis
  • Exons
  • Female
  • Genotype
  • Humans
  • Infant, Newborn
  • Introns
  • Italy / epidemiology
  • Male
  • Molecular Epidemiology
  • Mutation*
  • Neonatal Screening
  • Phenotype
  • Phenylalanine Hydroxylase / genetics*
  • Phenylketonurias / epidemiology
  • Phenylketonurias / genetics*
  • Promoter Regions, Genetic

Substances

  • Phenylalanine Hydroxylase