Methylmalonic Acid

The importance of maintaining adequate cellular levels of vitamin B12 is well known and early detection of deficiency is essential to prevent irreversible neurological damage which can also occur in the absence of relatively easy to diagnose - anaemia. Unfortunately an accurate diagnosis of vitamin B12 deficiency is still problematic. The timely detection, and correction, of vitamin B12 deficiency prevents macrocytic anaemia, elevated homocysteine (possible thrombotic risk factor), potentially irreversible peripheral neuropathy, memory loss and other cognitive deficits. Metabolic markers of status include circulatory levels of homocysteine and methylmalonic acid (MMA). Unfortunately, the utility of an elevated plasma homocysteine concentration to indicate impaired methionine synthase function as a consequence of poor vitamin B12 availability (specifically the methyl-cobalamin form) has a co-dependency on the optimal supply of 5-methyltetrahydrofolate. MMA does not share this limitation and its measurement is considered as the gold standard and the most representative marker of metabolic vitamin B12 insufficiency. Vitamin B12 (specifically the adenosyl-cobalamin form) is a cofactor for the methylmalonyl-CoA mutase catalysed conversion of methylmalonyl-CoA to succinyl-CoA. MMA is a by-product of this pathway with no known biological function. In vitamin B12 insufficiency excess of methylmalonyl-CoA is hydrolysed to MMA causing the circulatory concentration of MMA to increase.