Evidence of common ancestry for the maple syrup urine disease (MSUD) Y438N allele in non-Mennonite MSUD patients

Latisha D. Love-Gregory, Julia Grasela, Richard E. Hillman, Charlotte L. Phillips

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

Maple syrup urine disease (MSUD) is a rare (1/185,000) autosomal recessive inborn error of branched-chain amino acid metabolism characterized by increased plasma leucine, isoleucine, and valine levels. Though, genetically heterogeneous in the worldwide population, MSUD in Old Order Mennonites (1/150-176) is the result of a tyrosine to asparagine substitution (Y438N; previously Y393N) in the E1α subunit of the branched-chain α-keto acid dehydrogenase (BCKAD) complex. Due to endogamous practices, the presence of Y438N in all reported Mennonite MSUD patients has historically been attributed to a founder effect. However, we have also identified the Y438N defect in eight MSUD patients of non-Mennonite lineage. To evaluate the genetic origin of this defect in these non-Mennonite patients, we examined Mennonite MSUD families and non-Mennonite MSUD families using microsatellite markers located on chromosome 19q13.1-13.2 (location of E1α gene, BCKDHA). Haplotype analyses revealed a major and four minor haplotypes that cosegregate with the Y438N allele in the Old Order Mennonite MSUD patients and carrier relatives. Analyses of eight non-Mennonite MSUD patients reveal that three of the non-Mennonite MSUD patients shared common Mennonite Y438N haplotypes, strongly suggesting Mennonite ancestry. However, the remaining non-Mennonite patients carry Y438N haplotypes that are significantly different from the Mennonite Y438N haplotype, suggesting that the occurrence of the defect in these families is due to either pre-Mennonite or de novo events.

Original languageEnglish
Pages (from-to)79-90
Number of pages12
JournalMolecular genetics and metabolism
Volume75
Issue number1
DOIs
StatePublished - Jan 1 2002
Externally publishedYes

Keywords

  • Amino acidemias
  • Haplotypes
  • Maple syrup urine disease
  • Metabolic disorder

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