Abstract
Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine metabolism, in which especially high phenylalanine concentrations cause brain dysfunction. If untreated, this brain dysfunction results in severe intellectual disability, epilepsy, and behavioural problems. We aimed to investigate demographic, clinical, biochemical, and molecular genetic data in patients with phenylalanine metabolism disorder. This study included 99 predominantly Turkish patients diagnosed with phenylalanine metabolism disorder, primarily referred through newborn screening programs. These patients were evaluated at a single center over a 9-year period, from 2013 to 2021. Demographic, clinical, molecular and laboratory data were collected retrospectively. Among the 99 patients, 93 (93.9%) had hyperphenylalaninemia-phenylketonuria, 2 (2.0%) had tetrahydrobiopterin metabolism disorders [one due to 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency and the other due to dihydropteridine reductase (DHPR) deficiency], 3 (3.0%) had maternal PKU syndrome (one of whom also had mild phenylketonuria), and 1 (1.0%) had transient hyperphenylalaninemia. The majority of patients belonged to the mild hyperphenylalaninemia-not requiring treatment group. A total of 33 different alleles and 40 genotypes (59.6% compound heterozygous) were identified in the PAH gene, with missense variants accounting for the largest proportion (72.7%). The most frequent PAH gene variants were c.898G > T p.(Ala300Ser) (14.9%), c.1066-11G > A (8.5%), and c.1208C > T p.(Ala403Val) (8.5%), while the most common genotypes were c.898G > T p.(Ala300Ser)/c.898G > T p.(Ala300Ser) (6.4%) and c.898G > T p.(Ala300Ser) /c.1066-11G > A (6.4%), respectively. Among patients with mild hyperphenylalaninemia-not requiring treatment, the predominant genotypes were c.898G > T p.(Ala300Ser)/c.898G > T p.(Ala300Ser) (11.1%), c.898G > T p.(Ala300Ser)/c.1066-11G > A (11.1%), and c.1208C > T p.(Ala403Val)/c.1208C > T p.(Ala403Val) (7.4%), whereas c.842C > T p.(Pro281Leu)/c.842C > T p.(Pro281Leu) (33.3%) was frequently observed in classic PKU patients. The national newborn screening program has significantly improved the prognosis and quality of life for patients through early diagnosis and timely treatment. While the prevalence of hyperphenylalaninemia-phenylketonuria remains high in Turkey, the higher frequency of the hyperphenylalaninemia-not requiring treatment group, compared to European and Asian countries, is considered a favorable outcome. Additionally, the PAH genotype is identified as the primary determinant of the PKU phenotype.