Maple syrup urine disease (MSUD) is an intoxication-type inherited metabolic disorder in which hyperleucinemia leads to brain swelling and death without treatment. MSUD is caused by branched-chain alpha-ketoacid dehydrogenase deficiency due to biallelic loss of the protein products from the genes BCKDHA, BCKDHB, or DBT, while a distinct but related condition is caused by loss of DLD. In this case series, eleven individuals with MSUD caused by two pathogenic variants in DBT are presented. All eleven individuals have a deletion of exon 2 (delEx2, NM_001918.3:c.48_171del); six individuals are homozygous and five individuals are compound heterozygous with a novel missense variant (NM_001918.5:c.916 T > C [p.Ser306Pro]) confirmed to be in trans. Western Blot indicates decreased amount of protein product in delEx2;c.916 T > C liver cells and absence of protein product in delEx2 homozygous hepatocytes. Ultrahigh performance liquid chromatography–tandem mass spectrometry demonstrates an accumulation of branched-chain amino acids and alpha-ketoacids in explanted hepatocytes. Individuals with these variants have a neonatal-onset, non-thiamine-responsive, classical form of MSUD. Strikingly, the entire cohort is derived from families who immigrated to the Washington, DC, metro area from Honduras or El Salvador suggesting the possibility of a founder effect.
Bibliographical noteFunding Information:
The authors would like to express thanks to Jeanine Fogarty, Andrew Pryor, Christin Hamilton, Nathan Day, Diana Berry, Morgan Donovan, Crystal Passmore, and Christal Ralph for their technical assistance and to Carlos Ferreira for his support with the thiamine challenge. The authors also want to express gratitude to Dr. Marshall Summar and the Children's National Rare Disease Institute for all their help.
© 2022 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.
- branched-chain alpha-ketoacids
- maple syrup urine disease
PubMed: MeSH publication types
- Case Reports