. 2020 Nov 1;15(1):309.

doi: 10.1186/s13023-020-01590-7.

Maple syrup urine disease in Brazilian patients: variants and clinical phenotype heterogeneity

Ana Vitoria Barban Margutti¹, Wilson Araújo Silva Jr^{2

3

4}, Daniel Fantozzi Garcia^{2

3}, Greice Andreotti de Molfetta^{2

3

4}, Adriana Aparecida Marques³, Tatiana Amorim^{5

6}, Vânia Mesquita Gadelha Prazeres⁷, Raquel Tavares Boy da Silva⁸, Irene Kazue Miura⁹, João Seda Neto⁹, Emerson de Santana Santos¹⁰, Mara Lúcia Schmitz Ferreira Santos¹¹, Charles Marques Lourenço¹², Tássia Tonon¹³, Fernanda Sperb-Ludwig^{14

15}, Carolina Fischinger Moura de Souza¹⁶, Ida Vanessa Döederlein Schwartz¹⁶, José Simon Camelo Jr¹⁷

Affiliations

¹ Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Bandeirantes Av., 3900 - HC Criança - off D506, Ribeirão Prêto, SP, 14049-900, Brazil.
² Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
³ National Institute of Science and Technology in Stem Cell, and Cell Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto, SP, Brazil.
⁴ Center for Medical Genomics at Clinics Hospital of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
⁵ Associação de Pais e Amigos dos Excepcionais of Salvador, Salvador, BA, Brazil.
⁶ Department of Life Sciences, Bahia State University, Salvador, BA, Brazil.
⁷ Federal University of Amazonas, Manaus, AM, Brazil.
⁸ Department of Pediatrics, Medical Sciences School, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil.
⁹ Sírio-Libanês Hospital, São Paulo, SP, Brazil.
¹⁰ Department of Medicine, Federal University of Sergipe, São Cristóvão, SE, Brazil.
¹¹ Pequeno Príncipe Hospital, Curitiba, PR, Brazil.
¹² Medical School, Estácio University Center of Ribeirão Preto, Ribeirão Preto, SP, Brazil.
¹³ Posgraduate Programme in Medicine - Medical Sciences, Federal University of Rio Grande Do Sul, Porto Alegre, RS, Brazil.
¹⁴ Department of Genetics, Federal University of Rio Grande Do Sul, Porto Alegre, RS, Brazil.
¹⁵ BRAIN Laboratory (Basic Research and Advanced Investigations in Neurosciences), Clinics Hospital of Porto Alegre, Porto Alegre, RS, Brazil.
¹⁶ Medical Genetics Service, Clinics Hospital of Porto Alegre, Department of Genetics, Federal University of Rio Grande Do Sul, Porto Alegre, RS, Brazil.
¹⁷ Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Bandeirantes Av., 3900 - HC Criança - off D506, Ribeirão Prêto, SP, 14049-900, Brazil. jscamelo@fmrp.usp.br.

PMID: 33131499
PMCID: PMC7603684
DOI: 10.1186/s13023-020-01590-7

Maple syrup urine disease in Brazilian patients: variants and clinical phenotype heterogeneity

Ana Vitoria Barban Margutti et al. Orphanet J Rare Dis. 2020.

. 2020 Nov 1;15(1):309.

doi: 10.1186/s13023-020-01590-7.

Authors

Affiliations

¹ Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Bandeirantes Av., 3900 - HC Criança - off D506, Ribeirão Prêto, SP, 14049-900, Brazil.
² Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
³ National Institute of Science and Technology in Stem Cell, and Cell Therapy, Regional Blood Center of Ribeirão Preto, Ribeirão Preto, SP, Brazil.
⁴ Center for Medical Genomics at Clinics Hospital of the Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil.
⁵ Associação de Pais e Amigos dos Excepcionais of Salvador, Salvador, BA, Brazil.
⁶ Department of Life Sciences, Bahia State University, Salvador, BA, Brazil.
⁷ Federal University of Amazonas, Manaus, AM, Brazil.
⁸ Department of Pediatrics, Medical Sciences School, Rio de Janeiro State University, Rio de Janeiro, RJ, Brazil.
⁹ Sírio-Libanês Hospital, São Paulo, SP, Brazil.
¹⁰ Department of Medicine, Federal University of Sergipe, São Cristóvão, SE, Brazil.
¹¹ Pequeno Príncipe Hospital, Curitiba, PR, Brazil.
¹² Medical School, Estácio University Center of Ribeirão Preto, Ribeirão Preto, SP, Brazil.
¹³ Posgraduate Programme in Medicine - Medical Sciences, Federal University of Rio Grande Do Sul, Porto Alegre, RS, Brazil.
¹⁴ Department of Genetics, Federal University of Rio Grande Do Sul, Porto Alegre, RS, Brazil.
¹⁵ BRAIN Laboratory (Basic Research and Advanced Investigations in Neurosciences), Clinics Hospital of Porto Alegre, Porto Alegre, RS, Brazil.
¹⁶ Medical Genetics Service, Clinics Hospital of Porto Alegre, Department of Genetics, Federal University of Rio Grande Do Sul, Porto Alegre, RS, Brazil.
¹⁷ Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, Bandeirantes Av., 3900 - HC Criança - off D506, Ribeirão Prêto, SP, 14049-900, Brazil. jscamelo@fmrp.usp.br.

PMID: 33131499
PMCID: PMC7603684
DOI: 10.1186/s13023-020-01590-7

Abstract

Background: Maple syrup urine disease (MSUD) is an autosomal recessive inherited metabolic disease caused by deficient activity of the branched-chain α-keto acid dehydrogenase (BCKD) enzymatic complex. BCKD is a mitochondrial complex encoded by BCKDHA, BCKDHB, DBT, and DLD genes. MSUD is predominantly caused by Variants in BCKDHA, BCKDHB, and DBT genes encoding the E1α, E1β, and E2 subunits of BCKD complex, respectively. The aim of this study was to characterize the genetic basis of MSUD by identifying the point variants in BCKDHA, BCKDHB, and DBT genes in a cohort of Brazilian MSUD patients and to describe their phenotypic heterogeneity. It is a descriptive cross-sectional study with 21 MSUD patients involving molecular genotyping by Sanger sequencing.

Results: Eight new variants predicted as pathogenic were found between 30 variants (damaging and non-damaging) identified in the 21 patients analyzed: one in the BCKDHA gene (p.Tyr120Ter); five in the BCKDHB gene (p.Gly131Val, p.Glu146Glnfs * 13, p.Phe149Cysfs * 9, p.Cys207Phe, and p.Lys211Asn); and two in the DBT gene (p.Glu148Ter and p.Glu417Val). Seventeen pathogenic variants were previously described and five variants showed no pathogenicity according to in silico analysis.

Conclusion: Given that most of the patients received late diagnoses, the study results do not allow us to state that the molecular features of MSUD variant phenotypes are predictive of clinical severity.

Keywords: Branched-chain amino acids; Inborn errors of metabolism; Isoleucine; Leucine; Maple syrup urine disease; Valine.

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Conflict of interest statement

The authors declare that they have no competing interests.

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References

1. Chuang DT, Shih VE, et al. Maple syrup urine disease. In: Scriver CR, et al., editors. The metabolic and molecular bases of inherited diseases. 8. New York: McGraw-Hill; 2001. pp. 1971–2005.
1. Strauss KA, Carsona VJ, Soltys K, Young ME, Bowser LE, Puffenberger EG, Brigatti KW, Williams KB, Robinson DL, Hendrickson C, Beiler K, Morton DH. Branched-chain α-ketoacid dehydrogenase deficiency (maple syrup urine disease): Treatment, biomarkers, and outcomes. Mol Genet Metab. 2020;129:193–206. doi: 10.1016/j.ymgme.2020.01.006. - DOI - PubMed
1. Barschak AG, et al. Oxidative stress in plasma from maple syrup urine disease patients during treatment. Metab Brain Dis. 2008;23(1):711–780. doi: 10.1007/s11011-007-9077-y. - DOI - PubMed
1. Barschak AG, et al. Maple syrup urine disease in treated patients: biochemical and oxidative stress profiles. Clin Biochem. 2008;41(4–5):317–324. doi: 10.1016/j.clinbiochem.2007.11.015. - DOI - PubMed
1. Fisher CR, Fisher CW, Chuang DT, Cox RP. Occurrence of a Tyr393Asn (Y393N) mutation in the E1 alpha gene of the branched-chain alpha-keto acid dehydrogenase complex in maple syrup urine disease patients from a Mennonite population. Am J Hum Genet. 1991;49(2):429–434. - PMC - PubMed

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Maple syrup urine disease in Brazilian patients: variants and clinical phenotype heterogeneity

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Maple syrup urine disease in Brazilian patients: variants and clinical phenotype heterogeneity

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