Methylmalonic acid (MMA) is a small organic acid produced naturally within the body as a byproduct of normal metabolic processes. While it is not obtained directly from the diet, MMA is formed during the breakdown of certain amino acids and fats. Measurement of MMA levels is most commonly used in medicine to detect a deficiency of vitamin B12, a condition that typically causes MMA levels to rise significantly. However, a result showing lower-than-expected MMA levels is a less common finding. This finding usually points toward decreased production or increased clearance of the compound rather than a specific disease state.
The Metabolic Function of Methylmalonic Acid
Methylmalonic acid is integral to the body’s energy production pathway, specifically within the mitochondria of cells. It is part of the final metabolic route for breaking down four amino acids—isoleucine, valine, threonine, and methionine—as well as odd-chain fatty acids. This complex process begins with these substances being converted into propionyl-Coenzyme A (propionyl-CoA).
Propionyl-CoA is then converted into L-methylmalonyl-CoA, which is the direct precursor to MMA. The crucial step in this pathway is the conversion of L-methylmalonyl-CoA into succinyl-Coenzyme A (succinyl-CoA), a molecule that directly enters the Krebs cycle for energy generation. This final step is catalyzed by the enzyme methylmalonyl-CoA mutase (MCM).
The MCM enzyme requires adenosylcobalamin, one of the active forms of vitamin B12, to function properly. When there is a lack of functional B12, this conversion process stalls, causing L-methylmalonyl-CoA to accumulate. The accumulated compound is then converted to methylmalonic acid, which is why elevated MMA is a sensitive indicator of B12 deficiency.
Specific Medical Causes of Decreased MMA
Since MMA levels are normally kept low by efficient metabolism, a measured decrease below the standard reference range is an unusual occurrence. This warrants investigation into the mechanisms of its production and clearance. One physiological cause relates directly to the availability of precursor molecules.
A severely restricted protein intake, often seen in cases of extreme malnutrition or highly specialized therapeutic diets, can limit the supply of the amino acids isoleucine, valine, threonine, and methionine. This deficiency of precursor amino acids leads to a decrease in the body’s ability to form propionyl-CoA, thereby reducing the total amount of MMA produced.
In rare instances, patients with specific inborn errors of metabolism affecting the upstream propionate pathway may exhibit an unusual metabolic diversion. For example, a disorder causing propionyl-CoA to be shunted preferentially into an alternative metabolic route could reduce the pool of methylmalonyl-CoA available for conversion into MMA.
Another mechanism for low measured MMA involves increased renal clearance, which is the rate at which the kidneys filter and excrete the substance from the blood. While kidney impairment typically causes MMA to build up, conditions that increase the glomerular filtration rate (GFR), such as high fluid volume states or certain kidney disorders causing polyuria, can enhance the excretion of organic acids. This accelerated removal can lead to lower concentrations of MMA in the plasma, even if the rate of production is normal.
A low MMA reading can also be an artifact of sample handling or a side effect of medication. Certain broad-spectrum antibiotics, such as metronidazole, can suppress the gut bacteria that contribute significantly to the propionate pool. These bacteria produce propionic acid, which is converted to propionyl-CoA, a key precursor to MMA. The suppression of this microbial source reduces the overall flux of the metabolic pathway, resulting in a drug-induced reduction in MMA levels.
Testing Methods and Clinical Interpretation
Methylmalonic acid levels are typically measured using either blood plasma (serum) or urine samples. Serum MMA testing is often preferred for diagnosing functional vitamin B12 deficiency, while urine MMA is sometimes used for monitoring rare inherited metabolic disorders. Laboratories establish reference ranges, and a result falling below the lower limit of this range is considered low.
The clinical approach to interpreting a low MMA result is generally non-concerning, as this finding is not associated with any known pathology requiring specific treatment. Unlike elevated MMA, which signals a metabolic block or deficiency, a low result is usually interpreted as efficient metabolism or a low rate of precursor availability.
Clinicians will first rule out technical or pre-analytical errors, such as a sample being drawn soon after the patient began a low-protein diet or while they were taking certain medications. The primary purpose of the MMA test is to identify elevated levels. In most cases, a low MMA reading simply confirms that the metabolic pathway is functioning effectively with minimal accumulation of the intermediate acid.