This is a global, multi-center, non-interventional study for patients with confirmed diagnosis of MMA due to
methylmalonyl-CoA mutase deficiency or PA.
This reaction requires the involvement of three enzymes: propionyl-CoA-carboxylase, methylmalonyl-CoA-racemase and
methylmalonyl-CoA mutase (Voet et al., 2008).
Keywords: Methylmalonic aciduria,
Methylmalonyl-CoA mutase deficiency, Cobalamin related remethylation disorders, Vitamin B 12 deficiency, Pakistan.
Several enzymes are involved in the incorporation of these substrates in the gluconeogenesis pathway [3]: lactate dehydrogenase (LDH) for lactate; glycerol kinase (GK) and glycerol-3-phosphate dehydrogenase (GPD) for glycerol; and acyl-CoA synthetase short-chain family member 3 (ACSS3), propionyl-CoA carboxylase (PCC),
methylmalonyl-CoA epimerase (MCEE), and
methylmalonyl-CoA mutase (MUT) for propionate.
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.
Vitamin [B.sub.12] [cobalamin (Cbl)] plays an essential role both in the conversion of
methylmalonyl-CoA to succinyl-CoA and in the synthesis of methionine (Met) from homocysteine (Hcy) (Fig.
The other Cbl-dependent reaction is the conversion of
methylmalonyl-CoA to succinyl-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 into succinyl-CoA4.
MMA can build up in the bloodstreamif there is not enough vitamin [B.sub.12] in the body for an enzyme (
methylmalonyl-CoA mutase) to function properly.
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., 1999).
D-methylmalonyl CoA is isomerized to L-methylmalonyl CoA via
methylmalonyl-CoA racemase.
