Genotypes of 2579 patients with phenylketonuria reveal a high rate of BH4 non-responders in Russia

PLoS One. 2019 Jan 22;14(1):e0211048. doi: 10.1371/journal.pone.0211048. eCollection 2019.


Phenylalanine hydroxylase (PAH) deficiency is responsible for most cases of phenylketonuria (PKU). Furthermore, numerous studies on BH4-sensitive PAH deficiency have been conducted. To date, BH4, a cofactor of PAH, has not been used to treat PKU in Russia.Genotype data of patients with PKU can be used to predict their sensitivity to BH4 therapy. A cohort of 2579 patients with PKU from Russia was analyzed for 25 common PAH gene mutations using custom allele-specific multiplex ligation-dependent probe amplification-based technology. A mutation detection rate of 84.1% chromosomes was accomplished. Both pathogenic alleles were identified in 73.1% of patients. The most frequent pathogenic variants were p.Arg408Trp (50.9%), p.Arg261Gln (5.3%), p.Pro281Leu (3.5%), IVS12+1G>A (3.1%), IVS10-11G>A (2.6%), and p.Arg158Leu (2.4%). The exact boundaries of a PAH exon 5 deletion were defined as EX5del4154ins268 (c.442-2913_509+1173del4154ins268). Severe phenotypes prevailed in the cohort, and classical PKU was observed in 71.8% cases. Due to the genotype-based prediction, 55.9% of the probands were non-responders to the BH4-treatment, and 20.2% were potential responders. Analysis of genotype data is useful to predict BH4 response in PKU patients. The high rate of non-responders among Russian patients was due to the high allele frequency of severe PAH mutations.

Publication types

  • Multicenter Study

MeSH terms

  • Alleles*
  • Cohort Studies
  • Drug Resistance / genetics*
  • Exons
  • Female
  • Gene Frequency*
  • Genotype*
  • Humans
  • Male
  • Mutation*
  • Phenylalanine Hydroxylase / genetics*
  • Phenylketonurias / drug therapy
  • Phenylketonurias / epidemiology
  • Phenylketonurias / genetics*
  • Russia / epidemiology


  • Phenylalanine Hydroxylase

Grant support

The authors received no specific funding for this work.