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

Ana Vitoria Barban Margutti,Mara Lúcia Schmitz Ferreira Santos,Raquel Tavares Boy Da Silva,Fernanda Sperb-Ludwig,Ida Vanessa Döederlein Schwartz,José Simon Camelo,Carolina Fischinger Moura De Souza,Greice Andreotti De Molfetta,Adriana Aparecida Marques,João Seda Neto,Charles Marques Lourenço,Vânia Mesquita Gadelha Prazeres,Irene Kazue Miura,Emerson De Santana Santos,Daniel Fantozzi Garcia,Wilson Araújo Silva,Tatiana Amorim,Tássia Tonon

doi:10.1186/s13023-020-01590-7

Abstract

BackgroundMaple 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.ResultsEight 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.ConclusionGiven 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.

Highlights

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
Eight new variants predicted as pathogenic were found between 30 variants identified in the 21 patients analyzed: one in the Branched chain keto acid dehydrogenase E1 (BCKDHA) gene, five in the Branched chain keto acid dehydrogenase E1 (BCKDHB) gene and two in the Dihydrolipoamide branched chain transacylase E2 (DBT) gene
Another seventeen pathogenic variants found in Brazilian patients have been reported in the literature: five in the BCKDHA gene, eleven in the BCKDHB gene, and one in the DBT gene

Summary

Introduction

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. Maple syrup urine disease (MSUD) (OMIM #24860), known as leucinosis, is an inborn error of metabolism (IEM) caused by the deficiency of thiaminedependent branched-chain α-ketoacid dehydrogenase (BCKD), composed of the subunits E1α, E1β, E2, and E3. This particular enzymatic deficiency is found in the several tissues, resulting in elevated blood plasma. Another two different genes were more recently described how members of the BCKD complex in MSUD: BCKDK gene (MIM # 614923) and PPM1K gene (MIM # 615135); defects of PPM1K may account for a subset of human MSUD; inactivating variants of BCKDK in humans are associated with BCAA deficiency, MSUD, autism, epilepsy, and intellectual disability [10]

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