Artículo
The Genetic Landscape and Epidemiology of Phenylketonuria
Hillert, Alicia; Anikster, Yair; Belanger Quintana, Amaya; Burlina, Alberto; Burton, Barbara K.; Carducci, Carla; Chiesa, Ana Elena
; Christodoulou, John; Dordevic, Maja; Desviat, Lourdes R.; Eliyahu, Aviva; Evers, Roeland A.F.; Fajkusova, Lena; Feillet, Francois; Bonfim Freitas, Pedro E.; Gizewska, María; Gundorova, Polina; Karall, Daniela; Kneller, Katya; Kutsev, Sergey I.; Leuzzi, Vincenzo; Levy, Harvey L.; Lichter Koneck, Uta; Muntau, Ania C.; Namour, Fares; Oltarzewsk, Mariusz; Paras, Andrea; Perez, Belén; Polak, Emil; Polyakov, Alexander V.; Porta, Francesco; Rohrbach, Marianne; Scholl Bürgi, Sabine; Spécola, Norma; Stojiljkovic, Maja; Shen, Nan; Santana da Silva, Luiz C.; Skouma, Anastasia; van Spronsen, Francjan; Stoppioni, Vera; Thöny, Beat; Trefz, Friedrich K.; Vockley, Jerry; Yu, Youngguo; Zschocke, Johannes; Hoffmann, Georg F.; Garbade, Sven F.; Blau, Nenad
Fecha de publicación:
08/2020
Editorial:
Cell Press
Revista:
American Journal Of Human Genetics
ISSN:
0002-9297
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Palabras clave:
BH4
,
HYPERPHENYLALANINEMIA
,
PAH DEFICIENCY
,
PHENYLALANINE
,
PKU
,
TETRAHYDROBIOPTERIN
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Colecciones
Articulos(CEDIE)
Articulos de CENTRO DE INVESTIGACIONES ENDOCRINOLOGICAS "DR. CESAR BERGADA"
Articulos de CENTRO DE INVESTIGACIONES ENDOCRINOLOGICAS "DR. CESAR BERGADA"
Citación
Hillert, Alicia; Anikster, Yair; Belanger Quintana, Amaya; Burlina, Alberto; Burton, Barbara K.; et al.; The Genetic Landscape and Epidemiology of Phenylketonuria; Cell Press; American Journal Of Human Genetics; 107; 2; 8-2020; 234-250
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