title: Methylmalonic acidaemia: examination of genotype and biochemical data in 32 patients belonging to mut, cblA or cblB complementation group.
abstract: Methylmalonic acidaemia (MMA) is a genetic disorder caused by defects in methylmalonyl-CoA mutase or in any of the different proteins involved in the synthesis of adenosylcobalamin. The aim of this work was to examine the biochemical and clinical phenotype of 32 MMA patients according to their genotype, and to study the mutant mRNA stability by real-time PCR analysis. Using cellular and biochemical methods, we classified our patient cohort as having the MMA forms mut (n = 19), cblA (n = 9) and cblB (n = 4). All the mut (0) and some of the cblB patients had the most severe clinical and biochemical manifestations, displaying non-inducible propionate incorporation in the presence of hydroxocobalamin (OHCbl) in vitro and high plasma odd-numbered long-chain fatty acid (OLCFA) concentrations under dietary therapy. In contrast, mut (-) and cblA patients exhibited a milder phenotype with propionate incorporation enhanced by OHCbl and normal OLCFA levels under dietary therapy. No missense mutations identified in the MUT gene, including mut (0) and mut (-) changes, affected mRNA stability. A new sequence variation (c.562G>C) in the MMAA gene was identified. Most of the cblA patients carried premature termination codons (PTC) in both alleles. Interestingly, the transcripts containing the PTC mutations were insensitive to nonsense-mediated decay (NMD).
authors.affiliation: Centro de Diagnóstico de Enfermedades Moleculares, Centro de Biología Molecular, Facultad de Ciencias, Universidad Autónoma, CIBER de Enfermedades Raras, Madrid, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Merinero
authors.forename: B
authors.initials: B
authors.lastname: Pérez
authors.forename: C
authors.initials: C
authors.lastname: Pérez-Cerdá
authors.forename: A
authors.initials: A
authors.lastname: Rincón
authors.forename: L R
authors.initials: LR
authors.lastname: Desviat
authors.forename: M A
authors.initials: MA
authors.lastname: Martínez
authors.forename: P Ruiz
authors.initials: PR
authors.lastname: Sala
authors.forename: M J
authors.initials: MJ
authors.lastname: García
authors.forename: L
authors.initials: L
authors.lastname: Aldamiz-Echevarría
authors.forename: J
authors.initials: J
authors.lastname: Campos
authors.forename: V
authors.initials: V
authors.lastname: Cornejo
authors.forename: M
authors.initials: M
authors.lastname: Del Toro
authors.forename: A
authors.initials: A
authors.lastname: Mahfoud
authors.forename: M
authors.initials: M
authors.lastname: Martínez-Pardo
authors.forename: R
authors.initials: R
authors.lastname: Parini
authors.forename: C
authors.initials: C
authors.lastname: Pedrón
authors.forename: L
authors.initials: L
authors.lastname: Peña-Quintana
authors.forename: M
authors.initials: M
authors.lastname: Pérez
authors.forename: M
authors.initials: M
authors.lastname: Pourfarzam
authors.forename: M
authors.initials: M
authors.lastname: Ugarte
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000235:genetics*; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics*; D015415:Biomarkers / Q000032:analysis; D002460:Cell Line; D015331:Cohort Studies; D005816:Genetic Complementation Test; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D026901:Membrane Transport Proteins / Q000235:genetics*; D008764:Methylmalonic Acid / Q000097:blood*; D008765:Methylmalonyl-CoA Mutase / Q000145:classification / Q000235:genetics*; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics*; D009154:Mutation / Q000502:physiology; D014805:Vitamin B 12 / Q000235:genetics
chemical_list: D015415:Biomarkers; C497512:MMAA protein, human; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D008764:Methylmalonic Acid; D019883:Alkyl and Aryl Transferases; C019920:cob(I)alamin adenosyltransferase; D008765:Methylmalonyl-CoA Mutase; D014805:Vitamin B 12