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Causes of and diagnostic approach to methylmalonic acidurias

Fowler, B. and Leonard, J. V. and Baumgartner, M. R.. (2008) Causes of and diagnostic approach to methylmalonic acidurias. Journal of inherited metabolic disease, Vol. 31, no. 3. pp. 350-360.

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Official URL: http://edoc.unibas.ch/dok/A5253370

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Abstract

Several mutant genetic classes that cause isolated methylmalonic acidurias (MMAuria) are known based on biochemical, enzymatic and genetic complementation analysis. The mut(0) 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-[(57)Co] 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.
Faculties and Departments:03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Ehemalige Einheiten Pädiatrie (UKBB) > Labor (Fowler)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Ehemalige Einheiten Pädiatrie (UKBB) > Labor (Fowler)
03 Faculty of Medicine > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Pädiatrie (Frey)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Kinder- und Jugendheilkunde (Klinik) > Kinder- und Jugendheilkunde (UKBB) > Pädiatrie (Frey)
UniBasel Contributors:Fowler, Brian
Item Type:Article, refereed
Article Subtype:Book Review
Bibsysno:Link to catalogue
Publisher:Kluwer
ISSN:0141-8955
Note:Publication type according to Uni Basel Research Database: Journal item
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Last Modified:20 Jun 2014 07:55
Deposited On:22 Mar 2012 13:59

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