Spectrum of PAH gene mutations and genotype-phenotype correlation in patients with phenylalanine hydroxylase deficiency from Turkey

Cinar M., Yildirim G. K., KOCAGİL S., ÇİLİNGİR O.

JOURNAL OF PEDIATRIC ENDOCRINOLOGY & METABOLISM, vol.35, no.5, pp.639-647, 2022 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 35 Issue: 5
  • Publication Date: 2022
  • Doi Number: 10.1515/jpem-2022-0047
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, CAB Abstracts, EMBASE, MEDLINE
  • Page Numbers: pp.639-647
  • Keywords: genotype-phenotype correlation, hyperphenylalaninemia, phenylketonuria, PHENYLKETONURIA, TETRAHYDROBIOPTERIN, RESPONSIVENESS, EPIDEMIOLOGY
  • Eskisehir Osmangazi University Affiliated: Yes


Objectives The aim of our study was to define the genotype-phenotype correlations of mutations in the PAH gene among the Turkey's Central Anatolian region. Methods Demographic characteristics of 108 patients with hyperphenylalaninemia (HPA) and 94 patients whose diagnosis was confirmed by PAH gene analysis (Sanger DNA Sequence Analysis and Next-Generation Sequencing) were determined retrospectively. Blood phenylalanine levels were analyzed using the high-performance liquid chromatography method. Results Mild HPA-not-requiring-treatment (NT) was found in 50.9% of the patients, and a classical phenylketonuria (PKU) phenotype was found in 25.9%. Forty-seven types of variants were identified. The predominant variants were p.Ala403Val (9.9%), p.Ala300Ser (9.4%), and c.1066-11G>A (splicing) (9.4%). Missense mutations accounted for 68% of mutations and attenuated the clinical impact; splice variations were found in 14.8% of cases with severe features. The p.Thr380Met allele was specific to the mild HPA-NT group. The c.1066-11G>A (splicing) allele was associated with classical PKU, whereas the p.Arg408Trp allele was linked to severe symptoms. Three variations of unknown clinical significance were discovered: c.706+4A>T (splicing), c.843-5T>C (splicing), and p.Thr323=. Of these variants, the patient who was homozygous for the c.843-5T>C (splicing) allele related to the classical PKU phenotype. 70% of the patients who underwent tetrahydrobiopterin (BH4) test were responsive. Phenotypes that responded to BH4 treatment were mostly mild phenotypes. Conclusions The PAH genotype is the main factor that determines the phenotype of PKU. Establishing the relationship between the identified genetic mutations and phenotypic characteristics will provide very important data for each patient in terms of the specific management style.