title: Clinical and molecular heterogeneity in patients with the cblD inborn error of cobalamin metabolism.
abstract: OBJECTIVE
  To describe 3 patients with the cblD disorder, a rare inborn error of cobalamin metabolism caused by mutations in the MMADHC gene that can result in isolated homocystinuria, isolated methylmalonic aciduria, or combined homocystinuria and methylmalonic aciduria.
  
  
  METHODS
  Patient clinical records were reviewed. Biochemical and somatic cell genetic studies were performed on cultured fibroblasts. Sequence analysis of the MMADHC gene was performed on patient DNA.
  
  
  RESULTS
  Patient 1 presented with isolated methylmalonic aciduria, patient 3 with isolated homocystinuria, and patient 2 with combined methylmalonic aciduria and homocystinuria. Studies of cultured fibroblasts confirmed decreased synthesis of adenosylcobalamin in patient 1, decreased synthesis of methylcobalamin in patient 3, and decreased synthesis of both cobalamin derivatives in patient 2. The diagnosis of cblD was established in each patient by complementation analysis. Mutations in the MMADHC gene were identified in all patients.
  
  
  CONCLUSIONS
  The results emphasize the heterogeneous clinical, cellular and molecular phenotype of the cblD disorder. The results of molecular analysis of the MMADHC gene are consistent with the hypothesis that mutations affecting the N terminus of the MMADHC protein are associated with methylmalonic aciduria, and mutations affecting the C terminus are associated with homocystinuria.
authors.affiliation: Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada.
authors.forename: Isabelle R
authors.initials: IR
authors.lastname: Miousse
authors.forename: David
authors.initials: D
authors.lastname: Watkins
authors.forename: David
authors.initials: D
authors.lastname: Coelho
authors.forename: Tony
authors.initials: T
authors.lastname: Rupar
authors.forename: Eric A
authors.initials: EA
authors.lastname: Crombez
authors.forename: Eric
authors.initials: E
authors.lastname: Vilain
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Bernstein
authors.forename: Tina
authors.initials: T
authors.lastname: Cowan
authors.forename: Christopher
authors.initials: C
authors.lastname: Lee-Messer
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Enns
authors.forename: Brian
authors.initials: B
authors.lastname: Fowler
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenblatt
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D002478:Cells, Cultured; D003038:Cobamides / Q000172:deficiency*; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006712:Homocystinuria / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008764:Methylmalonic Acid / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics; D010641:Phenotype; D014806:Vitamin B 12 Deficiency / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology
chemical_list: D003038:Cobamides; D047908:Intracellular Signaling Peptides and Proteins; C527938:MMADHC protein, human; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D008764:Methylmalonic Acid