Tetrahydrobiopterin responsiveness in Phenylalanine hydroxylase deficient patients from North-east of Iran: genotype-phenotype correlation, identification of a novel mutation and seven new responsive genotypes
Tetrahydrobiopterin responsiveness in Phenylalanine hydroxylase deficient patients from North-east of Iran: genotype-phenotype correlation, identification of a novel mutation and seven new responsive genotypes
Tayebeh Hamzehloei,1,*Faeze Khaghani,2Peyman Eshraghi,3
1. Dr Tayebeh Hamzehloei, Mashhad University of medical sciences, Genetics department, Mashhad-Iran. 2. Faeze Khaghani, Mashhad University of medical sciences, Genetics department, Mashhad-Iran. 3. Mashhad University of medical science, Pediatrics department. Mashhad-Iran.
Introduction: 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.
Methods: 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 24h and 48h 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.
Results: 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
Conclusion: 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.