The data, published online in the journal Cell Reports, demonstrate that intravenous administration of an mRNA therapeutic encoding for human methylmalonyl-CoA
mutase, the enzyme most frequently mutated in MMA, enabled liver expression of MUT in MMA mouse models, leading to a significant reduction in methylmalonic acid, a substantial improvement in weight gain, and the complete survival of the full cohort of treated mice versus control group.
Deficiency of AdoCbl results in decreased MMCoA mutase activity, accumulation of methylmalonyl-CoA
, and subsequent production of methylmalonic acid.
The other Cbl-dependent reaction is the conversion of methylmalonyl-CoA
MMA is a compound that can build up in the bloodstream if there isn't enough vitamin B12 in the body for an enzyme, methylmalonyl-CoA
mutase, to function properly.
This vitamin exerts its physiological action through two enzymatic pathways: the first acts as a co-factor for the methionine synthase enzyme that converts homocysteine into methionine and the second acts upon L-methylmalonyl Coenzyme A (CoA) mutase enzyme to convert methylmalonyl-CoA
organic acidurias such as glutaryl-CoA dehydrogenase, 3-hydroxy-3-methylglutaryl-CoA lyase, [beta]-ketothiolase, Propionyl-CoA carboxylase, Methylmalonyl-CoA
mutase, and Isovaleryl-CoA dehydrogenase) (Vreken et al.
D-methylmalonyl CoA is isomerized to L-methylmalonyl CoA via methylmalonyl-CoA
Methylmalonic Acidemias [Adenosylcobalamin Synthesis Defects (CblA and CblB) and Methylmalonyl-CoA
Mutase Deficiencies (mut- and mut+)]--An enzymatic defect in the oxidation of amino acids is the cause of these conditions, with an incidence of 1 in 50,000 to 1 in 100,000 live births.
Samples obtained from the original NBS specimens of confirmed cases with [beta]-cystathionine synthase deficiency (n = 4), propionyl-CoA carboxylase deficiency (n = 2), methylmalonyl-CoA
mutase deficiency (n = 4), Cbl C deficiency (n = 7), various remethylation disorders [methylenetetrahydrofolate reductase (MTHFR), n = 3; Cbl G, n = 3; Cbl D variant 1, n = 1], and maternal vitamin [B.
12] is an essential cofactor for L-methylmalonyl-CoA
mutase, which converts methylmalonyl-CoA
to succinyl-CoA (1).
Normally propionyl-CoA is metabolized to methylmalonyl-CoA
by the action of propionyl-CoA carboxylase (PCC), but if the metabolite is in excess the propionyl species is released from the mitochondrion after conversion by carnitine palmitoyl transferase II to the corresponding acylcarnitine (Fig.
Classical MMA results from deficiency of methylmalonyl-CoA
mutase, a cobalamin- (vitamin [B.