Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]-1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066-11G>A (IVS10-11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066-11G>A];[1066-11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome.
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http://dx.doi.org/10.1016/j.ajhg.2020.06.006 | DOI Listing |
Postgrad Med
December 2024
Division of Pediatric Metabolism, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey.
Background: It has been reported that phenylalanine (Phe)-restricted diets may have negative effects on bone health in patients with classical phenylketonuria (cPKU). We aimed to evaluate bone mineral density (BMD) in adults with cPKU and determine the risk factors associated with low BMD.
Methods: Eighty adult patients with cPKU were examined, including 41 women and 39 men.
J Anxiety Disord
December 2024
School of Psychological and Cognitive Sciences and Beijing Key Laboratory of Behavior and Mental Health, Peking University, China; Institute for Artificial Intelligence, Peking University, China; State Key Laboratory of General Artificial Intelligence, Beijing Institute for General Artificial Intelligence, Beijing, China. Electronic address:
Social anxiety disorder (SAD) is a prevalent anxiety disorder marked by strong fear and avoidance of social scenarios. Early detection of SAD lays the foundation for the introduction of early interventions. However, due to the nature of social avoidance in social anxiety, the screening is challenging in the clinical setting.
View Article and Find Full Text PDFJ Neurol
December 2024
Service de Médecine Interne, Centre de Référence Des Maladies Héréditaires du Métabolisme, UMR INSERM 1253 « iBraiN », Université de Tours, CHU de Tours, Tours, France.
Background And Objective: Adult patients with early-treated phenylketonuria (AwET-PKU) may present some subtle neurocognitive deficits. The aim of the study was to investigate 1) neurocognitive functions in a large group of AwET-PKU 2) the influence of plasma phenylalanine (Phe).
Methods: Participants: 187 AwET-PKU (classic PKU [cPKU] 81%, mild PKU [mPKU] 14%, and mild persistent hyperphenylalaninemia [MPH] 5%).
Chem Sci
December 2024
LOB, CNRS, INSERM, École Polytechnique, Institut Polytechnique de Paris 91120 Palaiseau France
Photoreduction of oxidized flavins has a functional role in photocatalytic and photoreceptor flavoproteins. In flavoproteins without light-dependent physiological functions, ultrafast, reversible flavin photoreduction is supposedly photoprotective by nature, and holds potential for nonnatural photocatalytic applications. In this work, we combine protein mutagenesis, ultrafast spectroscopy, molecular dynamics simulations and quantum mechanics calculations to investigate the nonfunctional flavin photoreduction in a flavoenzyme, lysine-specific demethylase 1 (LSD1) which is pivotal in DNA transcription.
View Article and Find Full Text PDFJ Inherit Metab Dis
January 2025
Department of Diabetes, Endocrinology, Nutritional Medicine and Metabolism, Inselspital, Bern University Hospital and University of Bern, Bern, Switzerland.
Alterations in brain structure are frequently observed in adults with early-treated phenylketonuria (PKU) compared to healthy controls, with cerebral white matter (WM) being particularly affected. The extent to which temporary elevation of phenylalanine (Phe) levels impacts WM remains unclear. We conducted a double-blind, randomised, placebo-controlled crossover trial to investigate the effects of a 4-week high Phe exposure on cerebral WM and its relationship to cognitive performance and metabolic parameters in adults with PKU.
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