Tetrahydrobiopterin responsiveness in Phenylalanine hydroxylase deficient patients from North-east of Iran: Genotype-phenotype correlation, identification of a novel mutation and 7 new responsive genotypes

Eur J Med Genet. 2022 Sep;65(9):104536. doi: 10.1016/j.ejmg.2022.104536. Epub 2022 Jun 8.


Phenylalanine hydroxylase enzyme defects result in a hereditary metabolic disorder called phenylketonuria. Sapropterin (tetrahydrobiopterin) is one of the treatment strategies for this disorder. Even though a correlation between genotype and BH4 responsiveness was established by earlier studies, a subset of mutations often presented inconsistent responses and/or phenotypes. Different genetic background is one of the potential reasons for this fact. In this study, the genotype of a total of 34 PAH deficient patients from Khorasan-Razavi providence in the north-east of Iran was obtained. Among this patients, 21 individuals took the 24 h and 48 h BH4 loading test and if the result was positive, their Phenylalanine tolerance was assessed. It is the first study of its type in patients from Iran to evaluate genotype role in predicting the most probable responsive individuals. The known pathogenic variant p.R169P and the novel variant p. Leu72_Asp75delinsTyr were first classified as responsive.Seven genotypes were reported as responsive for the first time. All patients carrying at least one pathogenic variant, which was previously reported as BH4 responsive, respond to BH4. Three patients with p.L48S, p.R261Q and p.A309V pathogenic variants were exceptions. There was no certain statistical correlation between genotype and response. Genotype and phenotype were significantly correlated and majority of patients with mild phenotype carried at least one non-null pathogenic variant. In Khorasan-Razavi province of Iran, patients with at least one non-null mutation are most probable to demonstrate mild phenotype and respond to BH4 phenotype.

Keywords: BH4 response; Genotype; Hyperphenylalanemia; Phenotype.

MeSH terms

  • Biopterins / analogs & derivatives
  • Genetic Association Studies
  • Genotype
  • Humans
  • Iran
  • Mutation
  • Phenylalanine Hydroxylase* / genetics
  • Phenylketonurias* / drug therapy
  • Phenylketonurias* / genetics


  • Biopterins
  • Phenylalanine Hydroxylase
  • sapropterin