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Genotype-phenotype correlations and BH4 estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil

2019Journal article Open access
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dc.contributor.authorVieira Neto, Eduardo
dc.contributor.authorLaranjeira, F.
dc.contributor.authorQuelhas, D.
dc.contributor.authorRibeiro, I.
dc.contributor.authorSeabra, A.
dc.contributor.authorMineiro, N.
dc.contributor.authorCarvalho, L.
dc.contributor.authorLacerda, L.
dc.contributor.authorRibeiro, M.
dc.date.accessioned2020-05-27T15:29:57Z
dc.date.available2020-05-27T15:29:57Z
dc.date.issued2019
dc.description.abstractBackground: Genetic heterogeneity and compound heterozygosis give rise to a continuous spectrum of phenylalanine hydroxylase deficiency and metabolic phenotypes in phenylketonuria (PKU). The most used parameters for evaluating phenotype in PKU are pretreatment phenylalanine (Phe) levels, tolerance for dietary Phe, and Phe overloading test. Phenotype can vary from a "classic" (severe) form to mild hyperphenylalaninemia, which does not require dietary treatment. A subset of patients is responsive to treatment by the cofactor tetrahydrobiopterin (BH4 ). Genotypes of PKU patients from Rio de Janeiro, Brazil, were compared to predicted and observed phenotypes. Genotype-based estimations of responsiveness to BH4 were also conducted. Methods: Phenotype was defined by pretreatment Phe levels. A standard prediction system based on arbitrary assigned values was employed to measure genotype-phenotype concordance. Patients were also estimated as BH4 -responders according to the responsiveness previously reported for their mutations and genotypes. Results: A 48.3% concordance rate between genotype-predicted and observed phenotypes was found. When the predicted phenotypes included those reported at the BIOPKU database, the concordance rate reached 77%. A total of 18 genotypes from 30 patients (29.4%) were estimated as of potential or probable BH4 responsiveness. Inconsistencies were observed in genotypic combinations including the common "moderate" mutations p.R261Q, p.V388M, and p.I65T and the mild mutations p.L48S, p.R68S, and p.L249F. Conclusion: The high discordance rate between genotype-predicted and observed metabolic phenotypes in this study seems to be due partially to the high frequency of the so-called "moderate" common mutations, p.R261Q, p.V388M, and p.I65T, which are reported to be associated to erratic or more severe than expected metabolic phenotypes. Although our results of BH4 estimated responsiveness must be regarded as tentative, it should be emphasized that genotyping and genotype-phenotype association studies are important in selecting patients to be offered a BH4 overload test, especially in low-resource settings like Brazil.pt_PT
dc.description.sponsorshipDr. Vieira Neto reports two public grants from Coordination for the Improvement of Higher Level Personnel (Capes) of the Ministry of Education, Brazil, and private grants from FBM Pharmaceutical Industry Ltd., Anápolis, Goiás, Brazil, and from Danone Ltd., São Paulo, Brazil, during the conduct of the study.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationVieira Neto E, Laranjeira F, Quelhas D, et al. Genotype-phenotype correlations and BH4 estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazil. Mol Genet Genomic Med. 2019;7(5):e610. doi:10.1002/mgg3.610pt_PT
dc.identifier.doi10.1002/mgg3.610pt_PT
dc.identifier.issn2324-9269
dc.identifier.urihttp://hdl.handle.net/10400.16/2406
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherWiley Open Accesspt_PT
dc.relation.publisherversionhttps://onlinelibrary.wiley.com/doi/epdf/10.1002/mgg3.610pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/pt_PT
dc.subjectBrazilpt_PT
dc.subjectgenetic association studiespt_PT
dc.subjectgenotypept_PT
dc.subjecthyperphenylalaninemiapt_PT
dc.subjectphenotypept_PT
dc.subjectphenylalanine hydroxylasept_PT
dc.subjectphenylketonuriapt_PT
dc.titleGenotype-phenotype correlations and BH4 estimated responsiveness in patients with phenylketonuria from Rio de Janeiro, Southeast Brazilpt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.conferencePlaceUnited States of Americapt_PT
oaire.citation.issue5pt_PT
oaire.citation.startPagee610pt_PT
oaire.citation.titleMolecular genetics & genomic medicinept_PT
oaire.citation.volume7pt_PT
person.familyNameVieira Neto
person.givenNameEduardo
person.identifier.orcid0000-0002-0247-837X
person.identifier.ridC-5193-2014
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication84791826-4b88-4a7b-9cb0-f383075a4725
relation.isAuthorOfPublication.latestForDiscovery84791826-4b88-4a7b-9cb0-f383075a4725

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