Genetic mutation diversity in patients with classical phenylketonuria

Phenylketonuria is caused by mutations in the phenylalanine hydroxylase gene that enable the synthesis of the enzyme phenylalanine hydroxylase (PAH) containing 452 amino acids. Phenylketonuria is autosomal recessive dissease. PAH gene is located on chromosome 12q22-q24.1 and currently defined mutations in this gene are; missense mutations, splice region mutations, nonsense mutations, and small deletions and insertions. Missense mutations were detected in more than 60% of phenylalanine hydroxylase alleles. Detection of these mutations is used for both diagnostic and genetic counseling, long-term treatment follow-up or clinical follow-up. Early-stage mutation analysis is a guide in evaluating clinical prognosis and in cases of controversy regarding treatment. Mutations differ according to ethnic characteristics. For example, a splice region mutation (IVS10-11G> A) in intron 10 accounts for 40% of all mutations seen in Turks. Six different mutations are responsible for two-thirds of the mutant chromosomes in the European population. More than 80% of phenylalanine hydroxylase mutations in Asian society constitute the other six mutations. The remaining disease-causing mutations alone are rare. Extensive mutation data have been published for most countries as a result of research conducted in recent years. Our aim is to determine the genetic mutation diversity of patients with classical phenylketonuria followed by the Pediatric Genetics Department at Dokuz Eylül Univefrsity. The results of 112 patients who were diagnosed at their admission to an external center or hospital and who were being followed up with the diagnosis of classical phenylketonuria were evaluated. Data of classical phenylketonuria patients; SPSS Version 20.0 for Windows program was used for statistical analysis in terms of admission age, gender, geographical distribution, kinship, median blood phenylalanine level, treatment type, sapropterin response, treatment compliance and genotype diversity. The data were analyzed with the chi-square test and Mann Whitney-U test, and Pearson correlation analysis was used to evaluate the correlation between independent parameters, p <0.05 was considered statistically significant. While a homozygous mutation was found in the phenylalanine hydroxylase gene in 66 (58,9%) of 112 patients whose mutation analysis was performed, a combined heterozygous mutation was found in 44 (39,2%) cases. In 2 (1,7%) cases, no mutation was detected in phenylalanine hydroxylase gene analysis. As a result of the phenylalanine hydroxylase gene mutation analysis, 35 different alleles were detected. Three of these were mutations that were not previously described in the literature. The most common 3 mutations in our patients were c.1066-11G> A (37,3%), c.782G> A (10,9%), and c.441 + 5G> T (5,5%). 49 different genotypes were detected in 112 classical phenylketonuria patients. The most common was IVS10-11G> A / IVS10-11G> A (31,8%) genotype, the second most common being c.782G> A / c. Genotype 782G> A (9%) and IVS4 + 5G> T / IVS4 + 5G> T (4,5%) genotype were observed in the third order. Keywords: classical phenylketonuria, genotype, phenotype, treatment, follow-up