Causes of and diagnostic approach to methylmalonic acidurias
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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.
KeywordsCobalamin Methylmalonic Complementation Group Methylmalonic Acid Methylmalonic Aciduria
- Baumgartner R (1983) Activity of the cobalamin-dependent methylmalonyl-CoA mutase. In: Hall CA, ed. The Cobalamins, Methods in Hematology, vol. 10, Edinburgh, New York: Churchill Livingston, 181–195.Google Scholar
- Coelho D, Suormala T, Stucki M, et al (2008) Gene identification for the cblD defect of vitamin B12 metabolism. N Engl J Med 358: 1454–1464.Google Scholar
- Fenton WA, Gravel RA, Rosenblatt DS (2001) Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 2165–2193.Google Scholar
- Rosenblatt DS, Fenton WA (2001) Inherited disorders of folate and cobalamin transport and metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc, eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 3897–3933.Google Scholar
- Yano S, Li L, Le TP, et al (2003) Infantile mitochondrial DNA depletion syndrome associated with methylmalonic aciduria and 3-methylcrotonyl-CoA and propionyl-CoA carboxylase deficiencies in two unrelated patients: a new phenotype ofmtDNA depletion syndrome. J Inherit Metab Dis 26: 481–488.CrossRefPubMedGoogle Scholar
- Zwicker T, Lindner M, Ibrahim HI, et al (2008) Diagnostic work-up and management of patients with isolated methylmalonic acidurias in European metabolic centres. J Inher Metab Dis. doi:10.1007/s10545-008-0804-2.