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The Genetic Landscape and Epidemiology of Phenylketonuria
A. Hillert, Y. Anikster, A. Belanger-Quintana, A. Burlina, BK. Burton, C. Carducci, AE. Chiesa, J. Christodoulou, M. Đorđević, LR. Desviat, A. Eliyahu, RAF. Evers, L. Fajkusova, F. Feillet, PE. Bonfim-Freitas, M. Giżewska, P. Gundorova, D....
Language English Country United States
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
Grant support
L60 MD003721
NIMHD NIH HHS - United States
R01 DK117916
NIDDK NIH HHS - United States
R01 NR016991
NINR NIH HHS - United States
NLK
Cell Press Free Archives
from 1997-01-01 to 6 months ago
Free Medical Journals
from 1949 to 6 months ago
PubMed Central
from 1949 to 6 months ago
Europe PubMed Central
from 1949 to 6 months ago
Open Access Digital Library
from 2005-01-01
- MeSH
- Alleles MeSH
- Biopterins analogs & derivatives genetics MeSH
- Phenotype MeSH
- Phenylalanine blood MeSH
- Phenylalanine Hydroxylase genetics MeSH
- Phenylketonurias blood epidemiology genetics MeSH
- Gene Frequency genetics MeSH
- Genetic Predisposition to Disease genetics MeSH
- Genetic Association Studies methods MeSH
- Genotype MeSH
- Homozygote MeSH
- Humans MeSH
- Mutation genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Geographicals
- Europe MeSH
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.
Ann and Robert H Lurie Children's Hospital of Chicago Chicago IL 60611 USA
Centre of Molecular Biology and Gene Therapy University Hospital Brno 62500 Brno Czech Republic
Department of Experimental Medicine Sapienza University of Rome 00185 Rome Italy
Department of Human Neuroscience Sapienza University of Rome 00185 Rome Italy
Department of Pediatrics AOU Citta' della Salute e della Scienza di Torino 10126 Torino Italy
Department of Screening and Metabolic Diagnostics Institute of Mother and Child 01 211 Warsaw Poland
Division of Metabolism University Children's Hospital 8032 Zürich Switzerland
Fundación de Endocrinología Infantil C1425 Buenos Aires Argentina
Institute of Child Health 11526 Athens Greece
Institute of Human Genetics Medical University Innsbruck 6020 Innsbruck Austria
Institute of Molecular Genetics and Genetic Engineering University of Belgrade 11000 Belgrade Serbia
Institute of Mother and Child Healthcare Dr Vukan Čupić 11000 Belgrade Serbia
Research Centre for Medical Genetics 115522 Moscow Russia
Unidad de Enfermedades Metabolicas Servicio de Pediatria Hospital Ramon y Cajal 28034 Madrid Spain
Unidad de Metabolismo Hospital de Niños Sor Ludovica de La Plata 1904 Buenos Aires Argentina
University Children's Hospital University Medical Center Hamburg Eppendorf 20246 Hamburg Germany
UPMC Children's Hospital of Pittsburgh Pittsburgh PA 15224 USA
References provided by Crossref.org
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- $a 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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