title: Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB).
abstract: Isolated methylmalonic acidurias comprise a heterogeneous group of inborn errors of metabolism caused by defects of methylmalonyl-CoA mutase (MCM) (mut0, mut-) or deficient synthesis of its cofactor 5'-deoxyadenosylcobalamin (AdoCbl) (cblA, cblB). The aim of this study was to compare the long-term outcome in patients from these four enzymatic subgroups. Eighty-three patients with isolated methylmalonic acidurias (age 7-33 y) born between 1971 and 1997 were enzymatically characterized and prospectively followed to evaluate the long-term outcome (median follow-up period, 18 y). Patients with mut0 (n = 42), mut- (n = 10), cblA (n = 20), and cblB (n = 11) defects were included into the study. Thirty patients (37%) died, and 26 patients survived with a severe or moderate neurologic handicap (31%), whereas 27 patients (32%) remained neurologically uncompromised. Chronic renal failure (CRF) was found most frequently in mut0 (61%) and cblB patients (66%), and was predicted by the urinary excretion of methylmalonic acid (MMA) before CRF. Overall, patients with mut0 and cblB defects had an earlier onset of symptoms, a higher frequency of complications and deaths, and a more pronounced urinary excretion of MMA than those with mut- and cblA defects. In addition, long-term outcome was dependent on the age cohort and cobalamin responsiveness.
authors.affiliation: Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital, D-69120 Heidelberg, Germany. Friederike.Hoerster@med.uni-heidelberg.de
authors.forename: Friederike
authors.initials: F
authors.lastname: Hörster
authors.forename: Matthias R
authors.initials: MR
authors.lastname: Baumgartner
authors.forename: Caroline
authors.initials: C
authors.lastname: Viardot
authors.forename: Terttu
authors.initials: T
authors.lastname: Suormala
authors.forename: Peter
authors.initials: P
authors.lastname: Burgard
authors.forename: Brian
authors.initials: B
authors.lastname: Fowler
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.forename: Sven F
authors.initials: SF
authors.lastname: Garbade
authors.forename: Stefan
authors.initials: S
authors.lastname: Kölker
authors.forename: E Regula
authors.initials: ER
authors.lastname: Baumgartner
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D019883:Alkyl and Aryl Transferases / Q000235:genetics* / Q000378:metabolism; D000592:Amino Acid Metabolism, Inborn Errors / Q000150:complications / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000401:mortality; D002648:Child; D003038:Cobamides / Q000378:metabolism*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D005767:Gastrointestinal Diseases / Q000209:etiology; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000209:etiology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008764:Methylmalonic Acid / Q000378:metabolism* / Q000652:urine; D008765:Methylmalonyl-CoA Mutase / Q000235:genetics* / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009422:Nervous System Diseases / Q000209:etiology; D011379:Prognosis; D011446:Prospective Studies; D013997:Time Factors; D014805:Vitamin B 12 / Q000627:therapeutic use; D014803:Vitamin B Complex / Q000627:therapeutic use
chemical_list: D003038:Cobamides; C497512:MMAA protein, human; D026901:Membrane Transport Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D014803:Vitamin B Complex; D008764:Methylmalonic Acid; D019883:Alkyl and Aryl Transferases; C019920:cob(I)alamin adenosyltransferase; D008765:Methylmalonyl-CoA Mutase; C000913:cobamamide; D014805:Vitamin B 12