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.

Phenylketonuria (PKU) is an autosomal recessive inherited disorder of phenylalanine metabolism caused by deficiency of the enzyme phenylalanine hydroxylase that converts phenylalanine into tyrosine. Untreated, PKU results in elevated phenylalanine levels in blood and brain, which cause severe intellectual disability, epilepsy and behavioural problems. For this first revision of the European PKU Guidelines previous recommendations were re-evaluated and updated according to new research findings. Twenty-one professionals were divided across four working groups and supported by a coordinator and chair. In addition to an update of the previous 70 recommendations, 20 new topics were included, resulting in a total of 87 statements in this first revision of the guidelines. Research publications were reviewed up until September 2022. Evidence was graded as high, moderate, low, very low or expert opinion and the recommendations were graded conditional or strong according to GRADE methodology. All recommendations were discussed during 14 plenary online or in person meetings. Recommendations were accepted if more than 75 % of the professionals were in agreement. When recommendations were not amended, the text reported in the European guidelines of 2017 remains valid.

Phenylketonuria (PKU) is an autosomal recessive inherited disorder of phenylalanine metabolism resulting from a deficiency of phenylalanine hydroxylase. The aim of this study was to evaluate the dental status and periodontal health of PKU patients in Latvia. Forty-five PKU patients and age/sex-matched controls were recruited for this cross-sectional study. Their anamnestic data, periodontal health and dental status were assessed by one experienced dentist. Dental and periodontal clinical evaluation revealed that the median number of filled teeth was significantly smaller among PKU patients compared to the control group (p=0.021). PKU patients had a significantly larger median number of carious teeth than their healthy counterparts (p<0.001). Significant differences between the PKU and control groups were observed for several oral hygiene indices (p<0.001): Silness-Löe plaque index, OR=29.3 (95% CI: 3.7-232.4); CPITN index, OR=35.2 (95% CI: 4.5-278.3); Greene-Vermillion index, OR=10.2 (95% CI: 2.8-38.0); calculus removal necessity, OR=12.3 (95% CI: 3.3-45.4). Dental status and periodontal health of PKU patients was found to be significantly inferior compared to healthy controls. This is likely due to the regular consumption of PKU formula and the difficulties which mentally and/or physically disabled PKU patients experience with their oral hygiene. To prevent tooth decay and periodontal disease, PKU patients should visit a professional oral hygienist every three to six months. Furthermore, they should adopt the habit of rinsing their mouth with water immediately after consuming PKU formula to counteract the acidity in their oral cavity.

Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine metabolism, mostly caused by PAH gene variants. The aim of this study was to identify the frequency of PAH gene variants in Turkish population with PKU. In 433 patients with PKU, PAH gene was examined using next generation sequencing (NGS) method. IVS10- 11G>A, p.R261Q, p.A300S, p.A403V, and p.T380 variants, which are the most common variants in this study, constituted 45,9% of the variants in our study. Nine novel variants p.A34V, K73Qfs*4, R157H, R261S, p.T266I, p.S310P, T328A, p.F351I, and K363N were identified. This study determines the most common PAH variants in Turkey and shows that PKU can be screened before marriage with the screening kits. Identification of the PAH gene variant spectrum is important for early diagnosis, understanding molecular mechanisms, clinical follow-up, treatment, and genetic counseling. And the novel variants found this study are important for further studies.

Phenylketonuria (PKU) is an inherited autosomal recessive disorder of phenylalanine metabolism. It is mainly caused by a deficiency in phenylalanine hydroxylase (PAH) and frequently diagnosed with Sanger sequencing. To some extent, allelic dropout can explain the inconsistency in genotype and phenotype. Three families were evaluated through DNA sequence analysis, multiplex ligation-dependent probe amplification (MLPA) and prenatal diagnosis technologies. The possibility of inconsistency in phenotype and genotype with c.331C>T variant was analysed. Through pedigree analysis, three mothers carried a homozygous c.331C>T variant, which was a false-positive result. New primers were used, and this error was caused by allelic dropout. In this case, c.158G>A was likely a benign variant. Sequence variants in primer-binding regions could cause allelic dropout, creating unpredictable errors in genotyping. Our results emphasised the need for careful measures to treat genotype-phenotype inconsistencies.