Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB)

Friederike Hörster; Matthias R Baumgartner; Caroline Viardot; Terttu Suormala; Peter Burgard; Brian Fowler; Georg F Hoffmann; Sven F Garbade; Stefan Kölker; E Regula Baumgartner

doi:10.1203/PDR.0b013e3180a0325f

Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB)

Pediatr Res. 2007 Aug;62(2):225-30. doi: 10.1203/PDR.0b013e3180a0325f.

Authors

Friederike Hörster¹, Matthias R Baumgartner, Caroline Viardot, Terttu Suormala, Peter Burgard, Brian Fowler, Georg F Hoffmann, Sven F Garbade, Stefan Kölker, E Regula Baumgartner

Affiliation

¹ Department of General Pediatrics, Division of Inborn Metabolic Diseases, University Children's Hospital, D-69120 Heidelberg, Germany. [email protected]

PMID: 17597648
DOI: 10.1203/PDR.0b013e3180a0325f

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.

Publication types

Comparative Study
Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Age of Onset
Alkyl and Aryl Transferases / genetics*
Alkyl and Aryl Transferases / metabolism
Amino Acid Metabolism, Inborn Errors / complications
Amino Acid Metabolism, Inborn Errors / drug therapy
Amino Acid Metabolism, Inborn Errors / enzymology
Amino Acid Metabolism, Inborn Errors / genetics*
Amino Acid Metabolism, Inborn Errors / mortality
Child
Cobamides / metabolism*
Disease Progression
Female
Follow-Up Studies
Gastrointestinal Diseases / etiology
Genetic Predisposition to Disease
Humans
Kaplan-Meier Estimate
Kidney Failure, Chronic / etiology
Male
Membrane Transport Proteins / genetics*
Membrane Transport Proteins / metabolism
Methylmalonic Acid / metabolism*
Methylmalonic Acid / urine
Methylmalonyl-CoA Mutase / genetics*
Methylmalonyl-CoA Mutase / metabolism
Mitochondrial Membrane Transport Proteins
Mitochondrial Proteins / genetics*
Mitochondrial Proteins / metabolism
Mutation*
Nervous System Diseases / etiology
Prognosis
Prospective Studies
Time Factors
Vitamin B 12 / therapeutic use
Vitamin B Complex / therapeutic use

Substances

Cobamides
MMAA protein, human
Membrane Transport Proteins
Mitochondrial Membrane Transport Proteins
Mitochondrial Proteins
Vitamin B Complex
Methylmalonic Acid
Alkyl and Aryl Transferases
cob(I)alamin adenosyltransferase
Methylmalonyl-CoA Mutase
cobamamide
Vitamin B 12