Methylmalonic acid (MMA)

Methylmalonic acid (MMA) is looked at when assessing B12 status at cell level. Even when the B12 level in the blood is still unremarkable, a raised MMA value can show that too little B12 is effective in the cells; raised values do, however, also occur with reduced kidney function. MMA rises when B12 is missing as a cofactor of methylmalonyl-CoA mutase. Measured in the organic acids (urine).

What methylmalonic acid shows

Propionyl-CoA is formed in the breakdown of the amino acids valine, isoleucine, methionine and threonine, of odd-chain fatty acids and of the side chain of cholesterol. With the help of biotin it is converted into methylmalonyl-CoA, and methylmalonyl-CoA mutase converts this into succinyl-CoA, which enters the citric acid cycle. The mutase needs vitamin B12 in the form of adenosylcobalamin for this – alongside methionine synthase it is the only B12-dependent enzyme in humans. If this step stalls, more methylmalonic acid is formed from methylmalonyl-CoA; it enters the blood and is excreted via the kidneys. The value therefore shows whether B12 is actually effective in the mitochondria.

Low methylmalonic acid – what does it mean?

A low value is the normal case: methylmalonyl-CoA mutase has enough effective vitamin B12 and converts methylmalonyl-CoA promptly into succinyl-CoA, so that hardly any methylmalonic acid is left over. The breakdown pathway then also supplies succinyl-CoA for the citric acid cycle and for making haem.

High methylmalonic acid – what happens in the body?

When methylmalonic acid rises, the mutase is working more slowly, usually because too little effective B12 is reaching the cells – due to low intake, impaired absorption in the stomach or small intestine, or medications such as metformin and acid blockers. The build-up particularly affects the nerves: methylmalonyl-CoA and propionyl-CoA disrupt fatty acid synthesis in the myelin sheaths, unusual fatty acids are incorporated and the insulating layer of the nerves is weakened – tingling, numbness and unsteady gait may follow. At the same time, less succinyl-CoA is available for the citric acid cycle. Because methylmalonic acid is excreted via the kidneys, the value also rises with reduced kidney function; propionic acid-producing gut bacteria and, rarely, inherited disorders of the mutase also contribute to the value.

The interpretation is given in your report.