The Genetic Landscape and Epidemiology of Phenylketonuria.

Am J Hum Genet

Division of Child Neurology and Metabolic Medicine, Centre for Child and Adolescent Medicine, Clinic I, University Hospital Heidelberg, 69120 Heidelberg, Germany; Division of Metabolism, University Children's Hospital, 8032 Zürich, Switzerland. Electronic address:

Published: August 2020

AI Article Synopsis

  • Phenylketonuria (PKU) is an autosomal-recessive disorder caused by mutations in the PAH gene, with a global prevalence of about 1 in 23,930 live births, affecting approximately 450,000 individuals worldwide.
  • A study of 16,092 PKU patients across 51 countries found significant variations in disease severity, with 62% classified as classic PKU, 22% as mild PKU, and 16% as mild hyperphenylalaninemia; this also showed a geographic gradient in phenotype severity across Europe.
  • The research identified the most common PAH variants and allowed for genotype-to-phenotype prediction, enabling better tailoring of treatments based on individual patient genetics

Article Abstract

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://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413859PMC
http://dx.doi.org/10.1016/j.ajhg.2020.06.006DOI Listing

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