{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T11:19:37Z","timestamp":1783595977184,"version":"3.55.0"},"reference-count":49,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003593","name":"CNPq","doi-asserted-by":"crossref","award":["CNPq"],"award-info":[{"award-number":["CNPq"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"crossref"}]},{"name":"FIPE-HCPA","award":["2021-0397"],"award-info":[{"award-number":["2021-0397"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Orphanet J Rare Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Phenylketonuria (PKU), one of the most common inherited metabolic disorders, is caused by biallelic loss-of-function variants in the\n                    <jats:italic>phenylalanine hydroxylase<\/jats:italic>\n                    (\n                    <jats:italic>PAH<\/jats:italic>\n                    ) gene. More than 1000 pathogenic variants have been described in this gene. Although genotype-phenotype correlations are imperfect,\n                    <jats:italic>PAH<\/jats:italic>\n                    genotypes can influence treatment decision-making. To better characterize the genetic landscape of PKU in Brazil, we compiled a dataset of\n                    <jats:italic>PAH<\/jats:italic>\n                    genotypes from 742 patients by combining data from the literature (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009486), public databases (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009117), and direct physician reports (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009139). Most patients were classified as having classical PKU (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009455\/742; 61.3%). The most prevalent variants were c.1162G\u2009&gt;\u2009A (16.6%), c.1066-11G\u2009&gt;\u2009A (13.9%), and c.782G\u2009&gt;\u2009A (11.8%), which are also the predominant ones in Portugal, Spain, and Latin America. This study confirms the allelic heterogeneity of PKU in the Brazilian population and provide relevant insights to support public health policies for this disorder.\n                  <\/jats:p>","DOI":"10.1186\/s13023-026-04435-x","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:32:11Z","timestamp":1783593131000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic landscape of phenylketonuria in Brazil"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3685-1451","authenticated-orcid":false,"given":"Rafael Hencke","family":"Tresbach","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9334-140X","authenticated-orcid":false,"given":"Jo\u00e3o Braga","family":"de Abreu Neto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2460-7064","authenticated-orcid":false,"given":"Fernanda","family":"Sperb-Ludwig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6489-4002","authenticated-orcid":false,"given":"Marta Wey","family":"Vieira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roseli Divino","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2118-7727","authenticated-orcid":false,"given":"Pedro Eduardo Bonfim","family":"Freitas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1017-6221","authenticated-orcid":false,"given":"Luiz Carlos Santana","family":"da Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7232-9882","authenticated-orcid":false,"given":"Louise Lapagesse","family":"de Camargo Pinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1624-7572","authenticated-orcid":false,"given":"Marcial Francis","family":"Galera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4049-4645","authenticated-orcid":false,"given":"Keyla Christy Christine Mendes Samp","family":"Cunha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cezar Antonio Abreu","family":"de Souza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0912-3782","authenticated-orcid":false,"given":"Jos\u00e9 N\u00e9lio","family":"Janu\u00e1rio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0497-5262","authenticated-orcid":false,"given":"Marcos Jos\u00e9 Burle","family":"Aguiar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina Soledad","family":"Heredia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1061-2059","authenticated-orcid":false,"given":"Maria Teresa Alves","family":"da Silva Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1865-1333","authenticated-orcid":false,"given":"Monique Oliveira","family":"Poubel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1979-5769","authenticated-orcid":false,"given":"Fran\u00e7ois","family":"Maillot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7933-6687","authenticated-orcid":false,"given":"Ida Vanessa Doederlein","family":"Schwartz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"4435_CR1","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.ajhg.2017.01.002","volume":"100","author":"Y Anikster","year":"2017","unstructured":"Anikster Y, Haack TB, Vilboux T, Pode-Shakked B, Th\u00f6ny B, Shen N, et al. Biallelic Mutations in DNAJC12 Cause Hyperphenylalaninemia, Dystonia, and Intellectual Disability. Am J Hum Genet. 2017;100:257\u201366. https:\/\/doi.org\/10.1016\/j.ajhg.2017.01.002.","journal-title":"Am J Hum Genet"},{"key":"4435_CR2","doi-asserted-by":"publisher","first-page":"662","DOI":"10.1126\/science.aba4991","volume":"373","author":"Y Li","year":"2021","unstructured":"Li Y, Tan Z, Zhang Y, Zhang Z, Hu Q, Liang K, et al. A noncoding RNA modulator potentiates phenylalanine metabolism in mice. Science. 2021;373:662\u201373. https:\/\/doi.org\/10.1126\/science.aba4991.","journal-title":"Science"},{"key":"4435_CR3","doi-asserted-by":"publisher","DOI":"10.1002\/cpbi.5","author":"G Stelzer","year":"2016","unstructured":"Stelzer G, Rosen N, Plaschkes I, Zimmerman S, Twik M, Fishilevich S, et al. Curr Protocols Bioinf. 2016;54(130). https:\/\/doi.org\/10.1002\/cpbi.5. The GeneCards Suite: From Gene Data Mining to Disease Genome Sequence Analyses."},{"key":"4435_CR4","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-017-1779-6","author":"PD Stenson","year":"2017","unstructured":"Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, et al. Hum Genet Springer Berlin Heidelberg. 2017;136:665\u201377. https:\/\/doi.org\/10.1007\/s00439-017-1779-6. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies."},{"key":"4435_CR5","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41572-021-00267-0","volume":"7","author":"FJ van Spronsen","year":"2021","unstructured":"van Spronsen FJ, Blau N, Harding C, Burlina A, Longo N, Bosch AM, Phenylketonuria. Nat Reviews Disease Primers. 2021;7:1\u201319. https:\/\/doi.org\/10.1038\/s41572-021-00267-0.","journal-title":"Nat Reviews Disease Primers"},{"key":"4435_CR6","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1016\/j.ajhg.2020.06.006","volume":"107","author":"A Hillert","year":"2020","unstructured":"Hillert A, Anikster Y, Belanger-Quintana A, Burlina A, Burton BK, Carducci C, et al. The Genetic Landscape and Epidemiology of Phenylketonuria. Am J Hum Genet. 2020;107:234\u201350. https:\/\/doi.org\/10.1016\/j.ajhg.2020.06.006.","journal-title":"Am J Hum Genet"},{"key":"4435_CR7","doi-asserted-by":"publisher","first-page":"466","DOI":"10.1007\/s10545-007-0669-9","volume":"30","author":"GJC Borrajo","year":"2007","unstructured":"Borrajo GJC. Newborn screening in Latin America at the beginning of the 21st century. J Inher Metab Disea. 2007;30:466\u201381. https:\/\/doi.org\/10.1007\/s10545-007-0669-9.","journal-title":"J Inher Metab Disea"},{"key":"4435_CR8","doi-asserted-by":"publisher","first-page":"101026","DOI":"10.1016\/j.ymgmr.2023.101026","volume":"38","author":"A Chiesa","year":"2024","unstructured":"Chiesa A, Sp\u00e9cola N, Poubel M, Vela-Amieva M, Jurecki E, Vilela DR, et al. Adherence to PKU guidelines among patients with phenylketonuria: A cross-sectional national multicenter survey-based study in Argentina, Brazil, and Mexico. Mol Genet Metabolism Rep. 2024;38:101026. https:\/\/doi.org\/10.1016\/j.ymgmr.2023.101026.","journal-title":"Mol Genet Metabolism Rep"},{"key":"4435_CR9","doi-asserted-by":"publisher","first-page":"e6709","DOI":"10.1590\/1414-431X20176709","volume":"51","author":"E Vieira Neto","year":"2018","unstructured":"Vieira Neto E, Maia Filho HS, Monteiro CB, Carvalho LM, Tonon T, Vanz AP, et al. Quality of life and adherence to treatment in early-treated Brazilian phenylketonuria pediatric patients. Braz J Med Biol Res. 2018;51:e6709. https:\/\/doi.org\/10.1590\/1414-431X20176709.","journal-title":"Braz J Med Biol Res"},{"key":"4435_CR10","doi-asserted-by":"publisher","DOI":"10.1007\/s12687-024-00762-3","author":"CFM De Souza","year":"2025","unstructured":"De Souza CFM, Tonon T, Silva TO, Bachega TASS. Newborn screening in Brazil: realities and challenges. J Community Genet [Internet]. 2025. https:\/\/doi.org\/10.1007\/s12687-024-00762-3. [cited 2025 Jan 15].","journal-title":"J Community Genet [Internet]"},{"key":"4435_CR11","doi-asserted-by":"publisher","first-page":"101134","DOI":"10.1016\/j.lana.2025.101134","volume":"47","author":"PR Vargas","year":"2025","unstructured":"Vargas PR, Poubel M, Martins B, Velez P, Vilela D, Mesojedovas D, et al. Patient journey and disease burden characterization of the population with phenylketonuria (PKU) in Brazil: a retrospective analysis through data reported in the public health system administrative database (DATASUS). Lancet Reg Health - Americas. 2025;47:101134. https:\/\/doi.org\/10.1016\/j.lana.2025.101134.","journal-title":"Lancet Reg Health - Americas"},{"key":"4435_CR12","unstructured":"BRASIL. Minist\u00e9rio da Sa\u00fade. Secretaria de Aten\u00e7\u00e3o Especializada \u00e0 Sa\u00fade. Painel Programa Nacional de Triagem Neonatal (PNTN) - Cobertura Percentual de 2012 a 2024 [Internet]. Portal Gov.br. Triagem Neonatal; 2025 [cited 2026 May 15]. https:\/\/www.gov.br\/saude\/pt-br\/composicao\/saes\/triagem-neonatal\/painel. Accessed 15 May 2026."},{"key":"4435_CR13","doi-asserted-by":"publisher","first-page":"580","DOI":"10.1038\/s41436-018-0081-x","volume":"21","author":"SF Garbade","year":"2019","unstructured":"Garbade SF, Shen N, Himmelreich N, Haas D, Trefz FK, Hoffmann GF, et al. Allelic phenotype values: a model for genotype-based phenotype prediction in phenylketonuria. Genet Med Springer US. 2019;21:580\u201390. https:\/\/doi.org\/10.1038\/s41436-018-0081-x.","journal-title":"Genet Med Springer US"},{"key":"4435_CR14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S2213-8587(16)30320-5","volume":"8587","author":"FJ van Spronsen","year":"2017","unstructured":"van Spronsen FJ, van Wegberg AM, Ahring K, B\u00e9langer-Quintana A, Blau N, Bosch AM, et al. Key European guidelines for the diagnosis and management of patients with phenylketonuria. Lancet Diabetes Endocrinol. 2017;8587:1\u201314. https:\/\/doi.org\/10.1016\/S2213-8587(16)30320-5.","journal-title":"Lancet Diabetes Endocrinol"},{"key":"4435_CR15","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","volume":"581","author":"KJ Karczewski","year":"2020","unstructured":"Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alf\u00f6ldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434\u201343. https:\/\/doi.org\/10.1038\/s41586-020-2308-7.","journal-title":"Nature"},{"key":"4435_CR16","doi-asserted-by":"publisher","first-page":"1004","DOI":"10.1038\/s41467-022-28648-3","volume":"13","author":"MS Naslavsky","year":"2022","unstructured":"Naslavsky MS, Scliar MO, Yamamoto GL, Wang JYT, Zverinova S, Karp T, et al. Whole-genome sequencing of 1,171 elderly admixed individuals from Brazil. Nat Commun. 2022;13:1004. https:\/\/doi.org\/10.1038\/s41467-022-28648-3.","journal-title":"Nat Commun"},{"key":"4435_CR17","unstructured":"BRASIL. Instituto Brasileiro de Geografia e Estat\u00edstica (IBGE). Resolu\u00e7\u00e3o no 1, de 27 de agosto de 2025. Divulga as estimativas de popula\u00e7\u00e3o para Estados e Munic\u00edpios com data de refer\u00eancia em 1o de julho de 2025 [Internet]. Di\u00e1rio Oficial da Uni\u00e3o Aug 28, 2025 p. 53. https:\/\/ftp.ibge.gov.br\/Estimativas_de_Populacao\/Estimativas_2025\/estimativa_dou_2025.pdf. Accessed 15 May 2026."},{"key":"4435_CR18","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1186\/s13073-024-01421-5","volume":"16","author":"RK Hart","year":"2024","unstructured":"Hart RK, Fokkema IFAC, DiStefano M, Hastings R, Laros JFJ, Taylor R, et al. HGVS Nomenclature 2024: improvements to community engagement, usability, and computability. Genome Med. 2024;16:149. https:\/\/doi.org\/10.1186\/s13073-024-01421-5.","journal-title":"Genome Med"},{"key":"4435_CR19","doi-asserted-by":"crossref","unstructured":"Acosta AX, Silva WA, Carvalho TM, Gomes M, Zago MA. Mutations of the phenylalanine hydroxylase (PAH) gene in Brazilian patients with phenylketonuria. Human Mutation. Springer International Publishing; 2001","DOI":"10.1002\/1098-1004(200102)17:2<122::AID-HUMU4>3.0.CO;2-C"},{"key":"4435_CR20","doi-asserted-by":"publisher","unstructured":"Acosta AX. An\u00e1lise molecular do gene da fenilalanina hidroxilase em pacientes com fenilceton\u00faria [Thesis] [Doutorado Direto em Cl\u00ednica M\u00e9dica]. [Ribeir\u00e3o Preto]: Universidade de S\u00e3o Paulo; 2001. https:\/\/doi.org\/10.11606\/T.17.2001.tde-18032024-125357","DOI":"10.11606\/T.17.2001.tde-18032024-125357"},{"key":"4435_CR21","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1590\/S0004-282X2007000200003","volume":"65","author":"CE Steiner","year":"2007","unstructured":"Steiner CE, Acosta AX, Guerreiro MM, Marques-de-Faria AP. Genotype and natural history in unrelated individual with phenylketonuria and autistic behavior. Arq Neuro-Psiquiatr. 2007;65:202\u20135. https:\/\/doi.org\/10.1590\/S0004-282X2007000200003.","journal-title":"Arq Neuro-Psiquiatr"},{"key":"4435_CR22","unstructured":"Santos LL dos. Frequ\u00eancia das muta\u00e7\u00f5es I65T, Y414C, R252W e R261Q em indiv\u00edduos com fenilceton\u00faria do estado de Minas Gerais. [Thesis]: UNIVERSIDADE FEDERAL DE MINAS GERAIS; 2004."},{"key":"4435_CR23","unstructured":"Magalh\u00e3es, M de C. Frequencia das muta\u00e7\u00f5es v388m, r408w, ivs10nt11 e ivs12nt1 em indiv\u00edduos com fenilceton\u00faria do estado de minas gerais.[Thesis] UNIVERSIDADE FEDERAL DE MINAS GERAIS (UFMG). 2003"},{"key":"4435_CR24","unstructured":"Santos LL dos, Magalh\u00e3es MDC, Reis ADO, Starling ALP, Janu\u00e1rio JN, Fonseca CG da, et al. Frequencies of phenylalanine hydroxylase mutations I65T, R252W, R261Q, R261X, IVS10nt11, V388M, R408W, Y414C, and IVS12nt1 in Minas Gerais, Brazil. Genetics and molecular research\u202f: GMR. 2006;5:16\u201323."},{"key":"4435_CR25","doi-asserted-by":"publisher","first-page":"1","DOI":"10.4238\/vol9-1gmr670","volume":"9","author":"LL Santos","year":"2010","unstructured":"Santos LL, Fonseca CG, Starling ALP, Janu\u00e1rio JN, Aguiar MJB, Peixoto MGCD, et al. Variations in genotype-phenotype correlations in phenylketonuria patients. Genet Mol Res. 2010;9:1\u20138. https:\/\/doi.org\/10.4238\/vol9-1gmr670.","journal-title":"Genet Mol Res"},{"key":"4435_CR26","unstructured":"Santos, LL dos. AS BASES MOLECULARES DA FENILCETON\u00daRIA NO ESTADO DE MINAS GERAIS. [Thesis] UNIVERSIDADE FEDERAL DE MINAS GERAIS; 2007."},{"key":"4435_CR27","doi-asserted-by":"publisher","unstructured":"Louren\u00e7o Pollice E. Caracteriza\u00e7\u00e3o molecular da fenilcetonuria em pacientes da regi\u00e3o de Campinas [Internet] [Doutor em Ci\u00eancias M\u00e9dicas]. [Campinas, SP]: Universidade Estadual de Campinas; 2008 [cited 2025 Apr 25]. https:\/\/doi.org\/10.47749\/T\/UNICAMP.2008.431843","DOI":"10.47749\/T\/UNICAMP.2008.431843"},{"key":"4435_CR28","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/mgg3.610","volume":"7","author":"E Vieira Neto","year":"2019","unstructured":"Vieira Neto E, Laranjeira F, Quelhas D, Ribeiro I, Seabra A, Mineiro N, et al. Genotype-phenotype correlations and BH 4 estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil. Mol Genet Genomic Med. 2019;7:1\u201316. https:\/\/doi.org\/10.1002\/mgg3.610.","journal-title":"Mol Genet Genomic Med"},{"key":"4435_CR29","unstructured":"Vieira Neto E. Fenilceton\u00faria no Rio de Janeiro: perfil mutacional e desfechos do tratamento precoce. [Thesis]: UNIVERSIDADE FEDERAL DO RIO DE JANEIRO; 2018."},{"key":"4435_CR30","doi-asserted-by":"publisher","unstructured":"Vieira Neto E, Laranjeira F, Quelhas D, Ribeiro I, Seabra A, Mineiro N, et al. Mutation analysis of the PAH gene in phenylketonuria patients from Rio de Janeiro, Southeast Brazil. Molecular Genetics and Genomic Medicine. 2018;6:575\u201391. https:\/\/doi.org\/10.1002\/mgg3.408.","DOI":"10.1002\/mgg3.408"},{"key":"4435_CR31","unstructured":"Amorim Boa Sorte TRS. Estudo de bases moleculares de Fenilceton\u00faria no Nordeste do Brasil [Internet] [Thesis]. 2010 [cited 2025 Apr 25]. https:\/\/www.arca.fiocruz.br\/handle\/icict\/4310. Accessed 25 Apr 2025."},{"key":"4435_CR32","unstructured":"Santana Santos E de, Rocha MAA, Costa D, Amorim T, Acosta AX. Caracteriza\u00e7\u00e3o gen\u00e9tico-cl\u00ednica de pacientes com fenilceton\u00faria no Estado de Alagoas. Sci Med. 2012;22:64\u201370."},{"key":"4435_CR33","unstructured":"Silva CAN. Caracteriza\u00e7\u00e3o cl\u00ednica e molecular de pacientes com fenilceton\u00faria no Estado da Bahia [Internet]. 2018 [cited 2025 Apr 25]. https:\/\/www.arca.fiocruz.br\/handle\/icict\/30493. Accessed 25 Apr 2025."},{"key":"4435_CR34","unstructured":"Bonfim-Freitas PE. Identifica\u00e7\u00e3o e caracteriza\u00e7\u00e3o molecular de muta\u00e7\u00f5es causadoras de fenilceton\u00faria em pacientes do estado do Par\u00e1. [Thesis]: UNIVERSIDADE FEDERAL DO PAR\u00c1; 2006."},{"key":"4435_CR35","doi-asserted-by":"publisher","first-page":"e2224","DOI":"10.1002\/mgg3.2224","volume":"11","author":"PE Bonfim-Freitas","year":"2023","unstructured":"Bonfim-Freitas PE, Andrade RS, Ribeiro\u2010dos\u2010Santos \u00c2K, Silva LCS. Molecular characterization of phenylketonuria patients from the North Region of Brazil: State of Par\u00e1. Molec Gen Gen Med. 2023;11:e2224. https:\/\/doi.org\/10.1002\/mgg3.2224.","journal-title":"Molec Gen Gen Med"},{"key":"4435_CR36","unstructured":"Costa RD. Estudo das muta\u00e7\u00f5es IVS10NT-11G>A, V388M, R261Q, R261X, R252W E R408W no gene da fenilalanina hidroxilase em pacientes com fenilceton\u00faria do estado de Mato Grosso. [Thesis] Universidade Federal de Mato Grosso; 2017."},{"key":"4435_CR37","doi-asserted-by":"publisher","unstructured":"Costa RD, Galera BB, Rezende BC, Ven\u00e2ncio AC, Galera MF. Identification of mutations in the PAH gene in PKU patients in the state of Mato Grosso. Revista Paulista de Pediatria. 2020;38. https:\/\/doi.org\/10.1590\/1984-0462\/2020\/38\/2018351.","DOI":"10.1590\/1984-0462\/2020\/38\/2018351"},{"key":"4435_CR38","unstructured":"Santana Da Silva LC. Identifica\u00e7\u00e3o e caracteriza\u00e7\u00e3o molecular de muta\u00e7\u00f5es e polimorfismos no gene da fenilalanina hidroxilase em fenilceton\u00faricos do sul do pa\u00eds. 2000 [Thesis] UNIVERSIDADE FEDERAL DO RIO GRANDE DO SUL."},{"key":"4435_CR39","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1016\/S1096-7192(03)00032-5","volume":"79","author":"LC Santana Da Silva","year":"2003","unstructured":"Santana Da Silva LC, Santos Carvalho T, Britto Da Silva F, Morari L, Aguirres Fachel \u00c2, Pires R, et al. Molecular characterization of phenylketonuria in South Brazil. Mol Genet Metab. 2003;79:17\u201324. https:\/\/doi.org\/10.1016\/S1096-7192(03)00032-5.","journal-title":"Mol Genet Metab"},{"key":"4435_CR40","doi-asserted-by":"publisher","first-page":"20","DOI":"10.3390\/genes12010020","volume":"12","author":"RH Tresbach","year":"2020","unstructured":"Tresbach RH, Sperb-Ludwig F, Ligabue-Braun R, Tonon T, de Oliveira Cardoso MT, Heredia RS, et al. Phenylketonuria Diagnosis by Massive Parallel Sequencing and Genotype-Phenotype Association in Brazilian Patients. Genes. 2020;12:20. https:\/\/doi.org\/10.3390\/genes12010020.","journal-title":"Genes"},{"key":"4435_CR41","unstructured":"Tresbach RH. An\u00e1lise do gen\u00f3tipo e fen\u00f3tipo em pacientes brasileiros com hiperfenilalaninemias e doen\u00e7a da urina do xarope do bordo. [Thesis] Universidade Federal do Rio Grande do Sul. 2021."},{"key":"4435_CR42","doi-asserted-by":"publisher","first-page":"541","DOI":"10.3390\/children12050541","volume":"12","author":"AJ Nunes","year":"2025","unstructured":"Nunes AJ, Franceschetto BF, Da Gama L, Poloni S, Refosco LF, Tonon T, et al. The Influence of Phenylalanine Fluctuations and Intake on a 24\u00a0h Sapropterin Responsiveness Test in Patients with Phenylketonuria. Children. 2025;12:541. https:\/\/doi.org\/10.3390\/children12050541.","journal-title":"Children"},{"key":"4435_CR44","doi-asserted-by":"publisher","first-page":"495","DOI":"10.1590\/1678-4685-gmb-2018-0076","volume":"42","author":"AM de Souza","year":"2019","unstructured":"de Souza AM, Resende SS, de Sousa TN, de Brito CFA. A systematic scoping review of the genetic ancestry of the brazilian population. Genet Mol Biology. 2019;42:495\u2013508. https:\/\/doi.org\/10.1590\/1678-4685-gmb-2018-0076.","journal-title":"Genet Mol Biology"},{"key":"4435_CR45","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/mgg3.1559","volume":"9","author":"F Ferreira","year":"2021","unstructured":"Ferreira F, Azevedo L, Neiva R, Sousa C, Fonseca H, Marc\u00e3o A, et al. Phenylketonuria in Portugal: Genotype\u2013phenotype correlations using molecular, biochemical, and haplotypic analyses. Mol Genet Genomic Med. 2021;9:1\u201312. https:\/\/doi.org\/10.1002\/mgg3.1559.","journal-title":"Mol Genet Genomic Med"},{"key":"4435_CR46","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1186\/s12887-024-05140-z","volume":"24","author":"AS Aguirre","year":"2024","unstructured":"Aguirre AS, Haro E, Campod\u00f3nico A, Arias-Almeida B, Mendoza A, Pozo-Palacios J, et al. Expanding diversity within phenylketonuria in ecuadorian patients: genetic analysis and literature review of newborn screenings. BMC Pediatr. 2024;24:739. https:\/\/doi.org\/10.1186\/s12887-024-05140-z.","journal-title":"BMC Pediatr"},{"key":"4435_CR47","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.ymgme.2011.08.017","volume":"104","author":"N Blau","year":"2011","unstructured":"Blau N, Hennermann JB, Langenbeck U, Lichter-Konecki U. Diagnosis, classification, and genetics of phenylketonuria and tetrahydrobiopterin (BH4) deficiencies. Mol Genet Metab. 2011;104:2\u20139. https:\/\/doi.org\/10.1016\/j.ymgme.2011.08.017.","journal-title":"Mol Genet Metab"},{"key":"4435_CR48","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1002\/humu.22320","volume":"34","author":"C Heintz","year":"2013","unstructured":"Heintz C, Cotton RGH, Blau N. Tetrahydrobiopterin, its Mode of Action on Phenylalanine Hydroxylase, and Importance of Genotypes for Pharmacological Therapy of Phenylketonuria. Hum Mutat. 2013;34:927\u201336. https:\/\/doi.org\/10.1002\/humu.22320.","journal-title":"Hum Mutat"},{"key":"4435_CR49","unstructured":"Sacramento AP, Almeida AO, Portugal CM, Losco LN, de Souza AB, Galv\u00e3o L et al. Coordena\u00e7\u00e3o de incorpora\u00e7\u00e3o de tecnologias \u2013 CITEC\/CGGTS\/DGITIS\/SCTIE\/MS. Report No: 253."},{"key":"4435_CR50","unstructured":"IBGE IB de G e E. Censo Demogr\u00e1fico 2022 [Internet]. 2022. https:\/\/www.ibge.gov.br\/estatisticas\/sociais\/populacao\/22827-censo-demografico-2022.html?edicao=35938"}],"container-title":["Orphanet Journal of Rare Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04435-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13023-026-04435-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13023-026-04435-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:32:24Z","timestamp":1783593144000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s13023-026-04435-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["4435"],"URL":"https:\/\/doi.org\/10.1186\/s13023-026-04435-x","relation":{"references":[{"id-type":"doi","id":"10.1002\/cpbi.5","asserted-by":"subject"},{"id-type":"doi","id":"10.1007\/s00439-017-1779-6","asserted-by":"subject"}]},"ISSN":["1750-1172"],"issn-type":[{"value":"1750-1172","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]},"assertion":[{"value":"19 January 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 May 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"All included participants, whose data were not obtained from the literature, signed an informed consent form before participating in this study.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"241"}}