Methylmalonic acid (MMA) is an organic acid produced in the body during the normal process of breaking down proteins and fats for energy. It is a metabolic byproduct that exists in very small concentrations when the body is functioning optimally. When a medical professional orders an MMA test, they are looking for elevated levels in the blood or urine, which signals a potential metabolic problem. The measurement of MMA is particularly valuable because its accumulation can indicate a functional deficiency that might not be immediately apparent through other standard blood tests.
The Role of Methylmalonic Acid in Metabolism
MMA results from the breakdown of specific amino acids (valine, methionine, threonine, and isoleucine) and odd-chain fatty acids. This process creates an intermediate compound called methylmalonyl-Coenzyme A (methylmalonyl-CoA). To clear this intermediate and generate energy, methylmalonyl-CoA must be converted into succinyl-Coenzyme A, which enters the citric acid cycle.
This conversion requires the enzyme methylmalonyl-CoA mutase, which cannot function without the active form of Vitamin B12, adenosylcobalamin. If functional B12 is insufficient, the conversion process slows or stops, causing methylmalonyl-CoA to build up. The excess is then hydrolyzed into the methylmalonic acid measured in the bloodstream, reflecting an impairment in this B12-dependent metabolic step.
Elevated MMA: The Direct Link to Vitamin B12 Deficiency
The most common and significant reason for an elevated methylmalonic acid level is a functional deficiency of Vitamin B12 (cobalamin). Because the body cannot synthesize B12, it must be obtained through the diet, primarily from animal products or fortified foods. A lack of B12 impairs the activity of methylmalonyl-CoA mutase, leading to the accumulation of MMA. This makes MMA a highly specific and early indicator of poor B12 status at the cellular level, often rising before serum B12 levels drop below the typical deficiency range.
Causes of B12 Deficiency
B12 deficiency often stems from malabsorption, where the body struggles to extract the vitamin from food.
- Pernicious anemia, an autoimmune condition that prevents the production of intrinsic factor necessary for B12 absorption.
- Reduced stomach acid due to age or long-term use of medications like proton pump inhibitors.
- Gastrointestinal changes following procedures like bariatric surgery, which reduce the area available for B12 absorption.
- Dietary factors, such as strict vegan or vegetarian diets without adequate supplementation.
The consequence of this metabolic failure extends beyond the MMA buildup, leading to serious health issues. B12 deficiency can result in megaloblastic anemia, a condition characterized by abnormally large red blood cells. More concerning are the neurological complications, which can include peripheral neuropathy (numbness and tingling in the hands and feet), cognitive impairment, depression, and memory issues. These neurological symptoms can sometimes occur even before anemia is present, underscoring the importance of early detection.
Non-Nutritional Factors Leading to High MMA
While B12 deficiency is the primary cause, elevated MMA does not always point to a nutritional problem. Impaired kidney function, or renal insufficiency, is a common non-nutritional cause of high MMA levels. The kidneys are responsible for filtering and excreting methylmalonic acid from the bloodstream. When kidney function declines, MMA is not cleared efficiently and accumulates in the blood, leading to a false elevation even if the individual has sufficient B12.
Other Non-Nutritional Causes
Other factors can contribute to mild MMA elevation, including bacterial overgrowth in the small intestine. Certain gut bacteria can produce methylmalonic acid, which then enters the bloodstream and increases the measured level. Impaired thyroid function has also been associated with high MMA levels.
A much rarer cause is methylmalonic acidemia, a group of inherited metabolic disorders. This genetic condition is typically diagnosed in infancy through newborn screening. It involves a defect in the gene that codes for the methylmalonyl-CoA mutase enzyme or a defect in B12 metabolism. This genetic error causes a toxic accumulation of MMA regardless of dietary B12 intake and requires specialized medical management.
Interpreting Results and Treatment Options
A physician will interpret an elevated MMA result by considering it alongside a patient’s symptoms and other blood tests. The measurement is often paired with a homocysteine test, as homocysteine levels also rise in B12 deficiency. If both MMA and homocysteine are elevated, it strongly indicates a functional B12 deficiency. MMA is considered more specific to B12 status because homocysteine can also be elevated in folate deficiency, whereas MMA is not affected by folate levels.
If the diagnosis of B12 deficiency is confirmed, treatment focuses on replenishing the body’s store of cobalamin. The specific treatment method depends on the cause of the deficiency. For cases stemming from poor diet or where intestinal absorption is mostly intact, high-dose oral B12 supplementation is often effective. If the elevated MMA is due to a severe malabsorption issue, such as pernicious anemia, treatment involves intramuscular injections of B12, which bypass the need for intestinal absorption. Treatment must be monitored with follow-up blood tests to confirm that MMA levels return to the normal range.