Methylmalonic acidemia (MMA):Enzymatic studies in 5 non-related patients

Abstract

MMA may be caused by at least three different enzyme defects: l)Defect of methylmalonyl-CoA(MMCoA)mutase-apoenzyme; 2)Defective metabolism or transport of the coenzyme of MMCoA mutase, 5'-deoxyadenosylcobalamin(dA-B_l2), or of its precursor, vitamin B₁₂; 3) Deficiency of MMCoA racemase. -We have studied methylmalonate metabolism in leucocytes and cultured skin fibroblasts of 5 p. with MMA (1 p.B₁₂-responsive, 4 p. clinically non-responsive). Intact fibroblasts of all 5 p. failed to metabolize 2-methyl-¹⁴C-malonate (MM-¹⁴C)to ¹⁴CO₂, whether or not vitamin B₁₂ or dA-B₁₂ (10⁻⁵M) were added; whereas in intact leucocytes of the 3 p. so far investigated, ¹⁴CO₂ formation from MM-¹⁴C was always present and similar to controls. Disrupted fibroblasts were studied using a specific enzyme assay with propionyl-CoA and NaH¹⁴CO₃ as substrates. Methylmalonate metabolism was absent or severely impaired in all p. as revealed by methylmalonate accumulation and succinate formation. While addition of vitamin B₁₂ (10⁻¹¹ to 10⁻⁵M) had no effect in any of the p., addition of dA-B₁₂ (10⁻⁷ to 10⁻⁵M) did not enhance succinate formation in 2 p., but fully restored enzyme activity in 2 other p. These data suggest a defective metabolism rather than a defective transport mechanism of the B₁₂-coenzyme in the latter 2 p.

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