Maple syrup urine disease in Brazilian patients: variants and clinical phenotype heterogeneity.
Branched-chain amino acids
Inborn errors of metabolism
Isoleucine
Leucine
Maple syrup urine disease
Valine
Journal
Orphanet journal of rare diseases
ISSN: 1750-1172
Titre abrégé: Orphanet J Rare Dis
Pays: England
ID NLM: 101266602
Informations de publication
Date de publication:
01 11 2020
01 11 2020
Historique:
received:
18
11
2019
accepted:
15
10
2020
entrez:
2
11
2020
pubmed:
3
11
2020
medline:
22
6
2021
Statut:
epublish
Résumé
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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 33131499
doi: 10.1186/s13023-020-01590-7
pii: 10.1186/s13023-020-01590-7
pmc: PMC7603684
doi:
Substances chimiques
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
EC 1.2.4.4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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