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Causes of and diagnostic approach to methylmalonic acidurias

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Journal of Inherited Metabolic Disease

Summary

Several mutant genetic classes that cause isolated methylmalonic acidurias (MMAuria) are known based on biochemical, enzymatic and genetic complementation analysis. The mut0 and mut− defects result from deficiency of MMCoA mutase apoenzyme which requires adenosyl-cobalamin (Ado-Cbl) as coenzyme. The cblA, cblB and the variant 2 form of cblD complementation groups are linked to processes unique to Ado-Cbl synthesis. The cblC, cblD and cblF complementation groups are associated with defective methyl-cobalamin synthesis as well. Mutations in the genes associated with most of these defects have been described. Recently a few patients have been described with mild MMAuria associated with mutations of the MMCoA epimerase gene or with neurological symptoms due to SUCL mutations. A comprehensive diagnostic approach involves investigations at the level of metabolites, genetic complementation analysis and enzymatic studies, and finally mutation analysis. MMA levels in urine range from 10–20 mmol/mol creatinine in mild disturbances of MMA metabolism to over 20000 mmol/mol creatinine in severe MMCoA mutase deficiency, but show considerable overlap and are of limited value for differential diagnosis. The underlying defect in isolated MMAuria can be characterized in cultured skin fibroblasts using several assays, e.g. conversion of propionate to succinate, specific activity of MMCoA, cobalamin adenosyltransferase assay, cellular uptake of CN-[57Co] cobalamin and its conversion to cobalamin coenzymes and complementation analysis. The reliable characterization of patients with isolated MMAuria pinpoints the correct gene for mutation analysis. Reliable classification of these patients is essential for ongoing and future prospective studies on treatment and outcome.

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Authors and Affiliations

  1. Metabolic Unit, University Children’s Hospital, Roemergasse 8, Basel, CH-4058, Switzerland

    B. Fowler

  2. Institute of Child Health, London, UK

    J. V. Leonard

  3. Division of Metabolism and Molecular Pediatrics, University Children’s Hospital, Zürich, Switzerland

    M. R. Baumgartner

Authors
  1. B. Fowler
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  2. J. V. Leonard
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  3. M. R. Baumgartner
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Correspondence to B. Fowler.

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Communicating editor: Marinus Duran

Competing interests: None declared

References to electronic databases: Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency, mut0 and mut− defects: OMIM 251000. cblA: OMIM 251100. cblB: OMIM 251110. cblD: OMIM 277410. Cobalamin adenosyltransferase: EC 2.5.1.17. MMCoA mutase: EC 5.4.99.2.

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Fowler, B., Leonard, J.V. & Baumgartner, M.R. Causes of and diagnostic approach to methylmalonic acidurias. J Inherit Metab Dis 31, 350–360 (2008). https://doi.org/10.1007/s10545-008-0839-4

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  • DOI: https://doi.org/10.1007/s10545-008-0839-4

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