The genetic landscape and epidemiology of phenylketonuria

• Verfasst von: Hillert, Alicia [VerfasserIn]
• Verfasst von: Thöny, Beat [VerfasserIn]
• Verfasst von: Trefz, Friedrich K. [VerfasserIn]
• Verfasst von: Hoffmann, Georg Friedrich [VerfasserIn]
• Verfasst von: Garbade, Sven [VerfasserIn]
• Verfasst von: Blau, Nenad [VerfasserIn]
• Titel: The genetic landscape and epidemiology of phenylketonuria
• Verf.angabe: Alicia Hillert, Yair Anikster, Amaya Belanger-Quintana, Alberto Burlina, Barbara K. Burton, Carla Carducci, Ana E. Chiesa, John Christodoulou, Maja Đorđević, Lourdes R. Desviat, Aviva Eliyahu, Roeland A. F. Evers, Lena Fajkusova, François Feillet, Pedro E. Bonfim-Freitas, Maria Giżewska, Polina Gundorova, Daniela Karall, Katya Kneller, Sergey I. Kutsev, Vincenzo Leuzzi, Harvey L. Levy, Uta Lichter-Konecki, Ania C. Muntau, Fares Namour, Mariusz Oltarzewski, Andrea Paras, Belen Perez, Emil Polak, Alexander V. Polyakov, Francesco Porta, Marianne Rohrbach, Sabine Scholl-Bürgi, Norma Spécola, Maja Stojiljković, Nan Shen, Luiz C. Santana-da Silva, Anastasia Skouma, Francjan van Spronsen, Vera Stoppioni, Beat Thöny, Friedrich K. Trefz, Jerry Vockley, Youngguo Yu, Johannes Zschocke, Georg F. Hoffmann, Sven F. Garbade, Nenad Blau
• E-Jahr: 2020
• Jahr: 14 July 2020
• Umfang: 17 S.
• Fussnoten: Gesehen am 20.10.2020 ; PDF ist kostenpflichtig
• Titel Quelle: Enthalten in: The American journal of human genetics
• Ort Quelle: New York, NY [u.a.] : Cell Press, 1949
• Jahr Quelle: 2020
• Band/Heft Quelle: 107(2020), 2, Seite 234-250
• ISSN Quelle: 1537-6605
• DOI: doi:10.1016/j.ajhg.2020.06.006
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: BH4
• Sach-SW: hyperphenylalaninemia
• Sach-SW: PAH deficiency
• Sach-SW: phenylalanine
• Sach-SW: PKU
• Sach-SW: tetrahydrobiopterin
• K10plus-PPN: 1736014587

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.