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

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

Polina Gundorova  1 , Anna A Stepanova  1 , Irina A Kuznetsova  1 , Sergey I Kutsev  2 , Aleksander V Polyakov  1
Affiliations
Multicenter Study

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

Polina Gundorova et al. PLoS One. .

Abstract

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Genotype-phenotype correlations in patients from Russia with phenylketonuria (N = 1243).
The genotype groups are marked with different shades of grey. Phenylketonuria was classified as stated in the Materials and Methods.
Fig 2
Fig 2. Clinical features of patients with at least one mild mutation in the PAH gene (N = 271).
Groups of patients heterozygous or homozygous for p.Arg261Gln pathogenic variant were identified separately. Phenylketonuria was classified as stated in the Materials and Methods.
See this image and copyright information in PMC

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