The spectrum of mutations identified in Cypriot patients with phenylalanine hydroxylase deficiency detected through neonatal screening

Clin Biochem. 2012 May;45(7-8):588-92. doi: 10.1016/j.clinbiochem.2012.01.026. Epub 2012 Feb 4.


Objectives: The purpose of this study was to identify the mutations responsible for phenylalanine hydroxylase deficiency in Cypriot patients detected through neonatal screening.

Design and methods: Analysis of the PAH gene was performed by direct sequencing of the patients' genomic DNA, MLPA analysis and real-time PCR.

Results: Among 22 independent alleles thirteen previously described mutations were detected (detection rate 100%), all in compound heterozygosity: p.Arg395Gly (18.2%), c.168+5G>C (13.6%), p.EX3del (9%), c.1066-11G>A (9%), p.Ala403Val (9%), p.Glu178Gly (9%), p.Ser70Pro (4.5%), p.Arg241His (4.5%), p.Phe55fs (4.5%), p.Arg158Gln (4.5%), p.Asp222Gly (4.5%), p.Ala300Ser (4.5%), p.Pro225Thr (4.5%). Of the ten different genotypes, three have been previously reported to be associated with a mild clinical phenotype and to respond to tetrahydrobiopterin (BH₄) administration.

Conclusions: Marked genetic heterogeneity was found in Cypriot patients with hyperphenylalaninemia with two mutations accounting for 32% of the alleles. Most of the mutations detected have been found in other European and Mediterranean populations.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Biopterin / administration & dosage
  • Biopterin / analogs & derivatives
  • Cyprus / epidemiology
  • DNA Mutational Analysis
  • Genetic Heterogeneity
  • Heterozygote
  • Humans
  • Infant, Newborn
  • Mutation Rate
  • Mutation, Missense
  • Neonatal Screening / methods*
  • Phenylalanine Hydroxylase / deficiency
  • Phenylalanine Hydroxylase / genetics*
  • Phenylketonurias / diagnosis
  • Phenylketonurias / epidemiology
  • Phenylketonurias / genetics*


  • Biopterin
  • Phenylalanine Hydroxylase
  • sapropterin