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

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.

Maple syrup urine disease: Characteristics of diagnosis and treatment in 45 patients in Chile

“…In terms of genetic variants detected, the proportion of patients with biallelic variants in BCKDHB is much larger than the reported in the Mennonite population (Strauss et al, 2020). Malaysian, Egyptian and Brazilian populations also show a predominance of biallelic variants in BCKDHB, being associated with 45-55% MSUD cases (Ali & Ngu, 2018;Khalifa et al, 2020;Margutti et al, 2020). Nevertheless, our population shows an even higher frequency of these variants.…”

“…This variant has a Spanish origin but with a low reported frequency in that population (Rodríguez-Pombo, Navarrete, Merinero, G omez-Puertas, & Ugarte, 2006). In Brazil, the allelic frequency of the same variant was almost 10-fold lower (0.05) than in our cohort, and the p.Pro200Ter in BCKDHB was also less frequent in that population (0.12 in Brazil, 0.17 in Chile) (Margutti et al, 2020). Although it was not possible to identify other Latin American cohorts genetically tested, we can infer that the genetic architecture of Chilean MSUD cohort differs widely from other studied populations.…”

The clinico‐radiological findings of MSUD in a group of Egyptian children: Contribution to early diagnosis and outcome

“…This study cohort included 21 MSUD patients (classic subtype). Other studies included nearly similar numbers of children with MSUD (classic subtype) ranging from 6 to 37 children (Cheng et al, 2017;Lee et al, 2008;Margutti et al, 2020;Yunus et al, 2012) (Strauss et al, 2020). In this study, the mean age of onset of symptoms to appear was mean 8.3 ± 6.9 days (range: 3-75 days).…”

“…This study cohort included 21 MSUD patients (classic subtype). Other studies included nearly similar numbers of children with MSUD (classic subtype) ranging from 6 to 37 children (Cheng et al, 2017 ; Lee et al, 2008 ; Margutti et al, 2020 ; Yunus et al, 2012 ). The largest study for MUSD children was the one done by Strauss et al who reported 184 MSUD children {including 176 children (95.7%) having the classic subtype} (Strauss et al, 2020 ).…”

“…In other studies, there was variable delay (ranging from 3 to 12 months) in confirming the diagnosis of MSUD either by MS/MS or by genetic studies. The need for a rapid diagnostic test or implementation of MSUD newborn screening program to help pre‐symptomatic diagnosis was mandatory to avoid that delay (Cheng et al, 2017 ; Lee et al, 2008 ; Margutti et al, 2020 ; Strauss et al, 2020 ; Yunus et al, 2012 ). This time lag between age of symptoms and confirming the diagnosis of MSUD; allows MRI brain to be a great diagnostic tool that saves time and gives chance to start early a specific management for these children which may improves their outcome.…”