The Genetic Landscape and Epidemiology of Phenylketonuria

被引：181

作者：

Hillert, Alicia ^{[1
]}

Anikster, Yair ^{[2
]}

Belanger-Quintana, Amaya ^{[3
]}

Burlina, Alberto ^{[4
]}

Burton, Barbara K. ^{[5
]}

Carducci, Carla ^{[6
]}

Chiesa, Ana E. ^{[7
]}

Christodoulou, John ^{[8
,9
]}

Dordevic, Maja ^{[10
]}

Desviat, Lourdes R. ^{[11
]}

Eliyahu, Aviva ^{[2
]}

Evers, Roeland A. F. ^{[12
]}

Fajkusova, Lena ^{[13
]}

Feillet, Francois ^{[14
]}

Bonfim-Freitas, Pedro E. ^{[15
]}

Gizewska, Maria ^{[16
]}

Gundorova, Polina ^{[17
]}

Karall, Daniela ^{[18
]}

Kneller, Katya ^{[2
]}

Kutsev, Sergey, I ^{[17
]}

Leuzzi, Vincenzo ^{[19
]}

Levy, Harvey L. ^{[20
]}

Lichter-Konecki, Uta ^{[21
]}

Muntau, Ania C. ^{[22
]}

Namour, Fares ^{[14
]}

Oltarzewski, Mariusz ^{[23
]}

Paras, Andrea ^{[5
]}

Perez, Belen ^{[11
]}

Polak, Emil ^{[24
]}

Polyakov, Alexander, V ^{[17
]}

Porta, Francesco ^{[25
]}

Rohrbach, Marianne ^{[26
]}

Scholl-Burgi, Sabine ^{[18
]}

Specola, Norma ^{[27
]}

Stojiljkovic, Maja ^{[28
]}

Shen, Nan ^{[29
]}

Santana-da Silva, Luiz C. ^{[15
]}

Skouma, Anastasia ^{[30
]}

van Spronsen, Francjan ^{[12
]}

Stoppioni, Vera ^{[31
]}

Thony, Beat ^{[26
]}

Trefz, Friedrich K. ^{[1
]}

Vockley, Jerry ^{[21
]}

Yu, Youngguo ^{[32
]}

Zschocke, Johannes ^{[33
]}

Hoffmann, Georg F. ^{[1
]}

Garbade, Sven F. ^{[1
]}

Blau, Nenad ^{[1
,26
]}

机构：

[1] Univ Hosp Heidelberg, Ctr Child & Adolescent Med, Div Child Neurol & Metab Med, Clin 1, D-69120 Heidelberg, Germany

[2] Tel Aviv Univ, Edmond & Lily Safra Childrens Hosp, Sheba Med Ctr, Metab Dis Unit, IL-52621 Tel Aviv, Israel

[3] Hosp Ramon & Cajal, Serv Pediat, Unidad Enfermedades Metab, Madrid 28034, Spain

[4] Univ Hosp, Dept Womans & Childs Hlth, Div Inherited Metab Dis, I-35129 Padua, Italy

[5] Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA

[6] Sapienza Univ Rome, Dept Expt Med, I-00185 Rome, Italy

[7] Fdn Endocrinol Infantil FEI, C1425, Buenos Aires, DF, Argentina

[8] Univ Melbourne, Murdoch Childrens Res Inst, Melbourne, Vic 3052, Australia

[9] Univ Melbourne, Dept Pediat, Melbourne, Vic 3052, Australia

[10] Inst Mother & Child Healthcare Dr Vukan Cupic, Belgrade 11000, Serbia

[11] Univ Autonoma Madrid, Ctr Diagnost Enfermedades Mol, Ctr Biol Mol CSIC UAM, IdiPAz,CIBERER, Madrid 28049, Spain

[12] Univ Groningen, Univ Med Ctr Groningen, Beatrix Childrens Hosp, Sect Metab Dis, NL-9712 CP Groningen, Netherlands

[13] Univ Hosp Brno, Ctr Mol Biol & Gene Therapy, Brno 62500, Czech Republic

[14] Univ Hosp Nancy, Reference Ctr Inherited Metab Dis, F-54511 Vandoeuvre Les Nancy, France

[15] Fed Univ Para, Inst Biol Sci, Lab Inborn Errors Metab, BR-66075110 Belem, Para, Brazil

[16] Pomeranian Med Univ, Dept Pediat Endocrinol Diabetol Metab Dis & Cardi, PL-71252 Szczecin, Poland

[17] Res Ctr Med Genet, Moscow 115522, Russia

[18] Med Univ Innsbruck, Div Inherited Metab Disorders, Clin Pediat, A-6020 Innsbruck, Austria

[19] Sapienza Univ Rome, Dept Human Neurosci, I-00185 Rome, Italy

[20] Harvard Med Sch, Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA

[21] UPMC, Childrens Hosp Pittsburgh, Pittsburgh, PA 15224 USA

[22] Univ Med Ctr Hamburg Eppendorf, Univ Childrens Hosp, D-20246 Hamburg, Germany

[23] Inst Mother & Child Hlth, Dept Screening & Metab Diagnost, PL-01211 Warsaw, Poland

[24] Comenius Univ, Fac Nat Sci, Dept Mol Biol, Bratislava 84215 4, Slovakia

[25] AOU Citta Salute & Sci Torino, Dept Pediat, I-10126 Turin, Italy

[26] Univ Childrens Hosp, Div Metab, CH-8032 Zurich, Switzerland

[27] Hosp Ninos Sor Ludovica La Plata, Unidad Metab, RA-1904 Buenos Aires, DF, Argentina

[28] Univ Belgrade, Inst Mol Genet & Genet Engn, Belgrade 11000, Serbia

[29] Shanghai Jiao Tong Univ, Shanghai Childrens Med Ctr, Sch Med, Dept Infect Dis, Shanghai 2000025, Peoples R China

[30] Inst Child Hlth, Athens 11526, Greece

[31] Azienda Osped Osped Riuniti Marche Nord, Ctr Screening Neonatale Reg Marche, I-61032 Fano, Italy

[32] Shanghai Jiao Tong Univ, Xinhua Hosp, Shanghai Inst Pediat Res, Dept Pediat Endocrinol Genet,Sch Med, Shanghai 2000025, Peoples R China

[33] Med Univ Innsbruck, Inst Human Genet, A-6020 Innsbruck, Austria

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2020年 / 107卷 / 02期

关键词：

PHENYLALANINE-HYDROXYLASE DEFICIENCY; GENOTYPE-PHENOTYPE CORRELATIONS; MOLECULAR CHARACTERIZATION; PAH GENE; MUTATIONS; HYPERPHENYLALANINEMIA; DIAGNOSIS; PATIENT; ORIGINS; STATE;

D O I：

10.1016/j.ajhg.2020.06.006

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页码：234 / 250

页数：17

共 49 条

[1]

Bik-Multanowski M, 2013, ACTA BIOCHIM POL, V60, P613

[2] Alternative therapies to address the unmet medical needs of patients with phenylketonuria [J].

Blau, Nenad ;

Longo, Nicola .

EXPERT OPINION ON PHARMACOTHERAPY, 2015, 16 (06) :791-800

[3] Molecular genetics and diagnosis of phenylketonuria: state of the art [J].

Blau, Nenad ;

Shen, Nan ;

Carducci, Carla .

EXPERT REVIEW OF MOLECULAR DIAGNOSTICS, 2014, 14 (06) :655-671

[4] Phenylketonuria [J].

Blau, Nenad ;

van Spronsen, Francjan J. ;

Levy, Harvey L. .

LANCET, 2010, 376 (9750) :1417-1427

[5] Phenylketonuria Scientific Review Conference: State of the science and future research needs [J].

Camp, Kathryn M. ;

Parisi, Melissa A. ;

Acosta, Phyllis B. ;

Berry, Gerard. T. ;

Bilder, Deborah A. ;

Blau, Nenad ;

Bodamer, Olaf A. ;

Brosco, Jeffrey P. ;

Brown, Christine S. ;

Burlina, Alberto B. ;

Burton, Barbara K. ;

Chang, Christine S. ;

Coates, Paul M. ;

Cunningham, Amy C. ;

Dobrowolski, Steven F. ;

Ferguson, John H. ;

Franklin, Thomas D. ;

Frazier, Dianne M. ;

Grange, Dorothy K. ;

Greene, Carol L. ;

Groft, Stephen C. ;

Harding, Cary O. ;

Howell, R. Rodney ;

Huntington, Kathleen L. ;

Hyatt-Knorr, Henrietta D. ;

Jevaji, Indira P. ;

Levy, Harvey L. ;

Lichter-Konecki, Uta ;

Lindegren, Mary Lou ;

Lloyd-Puryear, Michele A. ;

Matalon, Kimberlee ;

MacDonald, Anita ;

McPheeters, Melissa L. ;

Mitchell, John J. ;

Mofidi, Shideh ;

Moseley, Kathryn D. ;

Mueller, Christine M. ;

Mulberg, Andrew E. ;

Nerurkar, Lata S. ;

Ogata, Beth N. ;

Pariser, Anne R. ;

Prasad, Suyash ;

Pridjian, Gabriella ;

Rasmussen, Sonja A. ;

Reddy, Uma M. ;

Rohr, Frances J. ;

Singh, Rani H. ;

Sirrs, Sandra M. ;

Stremer, Stephanie E. ;

Tagle, Danilo A. .

MOLECULAR GENETICS AND METABOLISM, 2014, 112 (02) :87-122

[6] Mapping the functional landscape of frequent phenylalanine hydroxylase (PAH) genotypes promotes personalised medicine in phenylketonuria [J].

Danecka, Marta K. ;

Woidy, Mathias ;

Zschocke, Johannes ;

Feillet, Francois ;

Muntau, Ania C. ;

Gersting, Soren W. .

JOURNAL OF MEDICAL GENETICS, 2015, 52 (03) :175-185

[7]

DESVIAT LR, 1995, AM J HUM GENET, V57, P337

[8]

EISENSMITH RC, 1992, AM J HUM GENET, V51, P1355

[9] The Prevalence of Phenylketonuria in Arab Countries, Turkey, and Iran: A Systematic Review [J].

El-Metwally, Ashraf ;

Al-Ahaidib, Lujane Yousef ;

Sunqurah, Alaa Ayman ;

Al-Surimi, Khaled ;

Househ, Mowafa ;

Alshehri, Ali ;

Da'ar, Omar B. ;

Razzak, Hira Abdul ;

AlOdaib, Ali Nasser .

BIOMED RESEARCH INTERNATIONAL, 2018, 2018

[10]

Ellingsen S, 1997, HUM MUTAT, V9, P88, DOI 10.1002/(SICI)1098-1004(1997)9:1<88::AID-HUMU21>3.3.CO

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