title: Mutations in ALDH6A1 encoding methylmalonate semialdehyde dehydrogenase are associated with dysmyelination and transient methylmalonic aciduria.
abstract: BACKGROUND
  Methylmalonate semialdehyde dehydrogenase (MMSDH) deficiency is a rare autosomal recessive disorder with varied metabolite abnormalities, including accumulation of 3-hydroxyisobutyric, 3-hydroxypropionic, 3-aminoisobutyric and methylmalonic acids, as well as β-alanine. Existing reports describe a highly variable clinical and biochemical phenotype, which can make diagnosis a challenge. To date, only three reported cases have been confirmed at the molecular level, through identification of homozygous mutations in ALDH6A1, the gene encoding MMSDH. Confirmation by enzyme assay has until now not been possible, due to the extreme instability of the enzyme substrate.
  
  
  RESULTS
  We report a child with severe developmental delays, abnormal myelination on brain MRI, and transient/variable elevations in lactate, methylmalonic acid, 3-hydroxyisobutyric and 3-aminoisobutyric acids. Compound heterozygous mutations were identified by exome sequencing and confirmed by Sanger sequencing within exon 6 (c.514 T > C; p. Tyr172His) and exon 12 (c.1603C > T; p. Arg535Cys) of ALDH6A1. The resulting amino acid changes, both occurring in residues conserved among mammals, are predicted to be damaging at the protein level. Subsequent MMSDH enzyme assay demonstrated reduced activity in patient fibroblasts, measuring 2.5 standard deviations below the mean.
  
  
  CONCLUSIONS
  We present the fourth reported case of MMSDH deficiency with confirmation at the molecular level, and expand on what is already an extremely variable clinical and biochemical phenotype. Furthermore, this is the first report to demonstrate a corresponding reduction in MMSDH enzyme activity. This report illustrates the emerging utilization of whole exome sequencing and variant data filtering using clinical data as an early tool in the diagnosis of rare and variable conditions.
authors.forename: Julien L
authors.initials: JL
authors.lastname: Marcadier
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Smith
authors.forename: Daniela
authors.initials: D
authors.lastname: Pohl
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Osama Y
authors.initials: OY
authors.lastname: Al-Dirbashi
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Sacha
authors.initials: S
authors.lastname: Ferdinandusse
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Dennis E
authors.initials: DE
authors.lastname: Bulman
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.forename: Pranesh
authors.initials: P
authors.lastname: Chakraborty
authors.forename: Michael T
authors.initials: MT
authors.lastname: Geraghty
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000201:enzymology* / Q000235:genetics; D002675:Child, Preschool; D059472:Exome / Q000235:genetics; D005260:Female; D006801:Humans; D050646:Methylmalonate-Semialdehyde Dehydrogenase (Acylating) / Q000172:deficiency* / Q000235:genetics*; D008764:Methylmalonic Acid / Q000378:metabolism; D009154:Mutation; D011686:Purine-Pyrimidine Metabolism, Inborn Errors / Q000175:diagnosis* / Q000201:enzymology / Q000235:genetics
chemical_list: D008764:Methylmalonic Acid; D050646:Methylmalonate-Semialdehyde Dehydrogenase (Acylating)