Methylmalonic acid (MMA) is a naturally occurring organic acid produced as a byproduct of protein and fat metabolism. Normally, MMA is quickly converted into a different compound and used for energy. Measuring MMA levels in the blood or urine is an established practice because an elevated concentration acts as a precise biomarker for a breakdown in metabolic processes. High levels of MMA, known as methylmalonic aciduria or acidemia, signal that the body is struggling to process certain nutrients effectively. This serious elevation requires medical investigation to determine the underlying cause and prevent potential health complications.
The Biological Role of Methylmalonic Acid and Vitamin B12
MMA is intrinsically linked to a specific step in the body’s energy production cycle. MMA exists as methylmalonyl-CoA, which must be converted into succinyl-CoA for the process to continue efficiently. This reaction allows the body to break down specific amino acids, such as valine and methionine, along with odd-chain fatty acids.
The enzyme responsible for catalyzing this transformation is methylmalonyl-CoA mutase. This enzyme requires an essential helper molecule: the active form of Vitamin B12 (cobalamin). If the body lacks sufficient active B12, or if the enzyme itself is impaired, the metabolic pathway becomes blocked. This obstruction causes methylmalonyl-CoA to back up, leading to the accumulation and measurable elevation of MMA in the bloodstream and urine.
Recognizing the Symptoms of Elevated MMA
Symptoms associated with elevated MMA vary significantly based on the severity of the condition and the patient’s age.
Symptoms in Infants
In infants, the onset is often rapid and severe, typically presenting within the first few days or weeks of life. These babies may experience a sudden metabolic crisis characterized by excessive vomiting, profound lethargy, and an inability to feed properly. The accumulation of the acid can rapidly lead to metabolic acidosis, overwhelming the body’s buffering capacity. Neurological signs include hypotonia (poor muscle tone), seizures, and progression to coma. If left untreated, this acute presentation can result in permanent neurological damage.
Symptoms in Adults
Adults with elevated MMA often experience a more subtle, slower progression of symptoms that primarily affect the nervous system and blood production. Neurological manifestations include peripheral neuropathy, presenting as numbness or tingling in the hands and feet. Patients may also develop gait abnormalities, experiencing difficulty with balance and walking due to spinal cord damage. Psychiatric and cognitive changes are common, including confusion, memory loss, and a decline in mental function. The buildup of MMA interferes with blood cell formation, frequently leading to megaloblastic anemia. This condition involves the production of abnormally large, immature red blood cells, resulting in fatigue, pallor, and general weakness.
Two Primary Causes of High MMA Levels
The reason for MMA elevation determines the required course of action and falls into two distinct categories: inherited metabolic disorder or acquired nutrient deficiency.
Methylmalonic Acidemia (MMAemia)
The first cause is Methylmalonic Acidemia (MMAemia), a group of rare, inherited metabolic disorders often passed down in an autosomal recessive pattern. This condition results from a genetic defect that causes the body to produce a faulty or insufficient amount of the methylmalonyl-CoA mutase enzyme. Because the enzyme itself is the source of the problem, the body cannot process the MMA precursor regardless of B12 availability. This genetic condition is typically severe and is often detected shortly after birth through mandatory newborn screening programs. Lifelong medical management is necessary to prevent the toxic buildup of MMA.
Vitamin B12 (Cobalamin) Deficiency
The second, and far more common, cause is Vitamin B12 (Cobalamin) Deficiency, which is an acquired condition. In this scenario, the body has a normal enzyme but lacks the necessary B12 cofactor required to activate it. Without adequate B12, the enzyme cannot perform its conversion function, resulting in the same chemical backlog and elevation of MMA. This deficiency typically affects adults and can be caused by insufficient dietary intake, such as in strict vegan diets, or more commonly, by malabsorption issues. Frequent culprits include pernicious anemia, where the body cannot absorb B12 from the gut, or certain gastrointestinal surgeries.
Diagnosis and Management Approaches
Diagnosing elevated MMA begins with a simple blood or urine test to measure the acid concentration, often performed alongside a test for Vitamin B12. MMA is considered a sensitive early marker for B12 deficiency because its levels can rise even before B12 levels drop into the deficient range. If tests confirm a high MMA level, further investigation is needed to differentiate between the two primary causes.
Management for B12 Deficiency
The management approach is entirely dependent on the identified cause. For Vitamin B12 deficiency, treatment is straightforward and highly effective, involving regular B12 supplementation. This is usually administered through injections or high-dose oral therapy, which often rapidly corrects the MMA level.
Management for MMAemia
Patients diagnosed with inherited Methylmalonic Acidemia face a more complex, lifelong regimen. This includes a tightly controlled, protein-restricted diet to limit the intake of precursor amino acids. In some genetic forms, high-dose Vitamin B12 injections may still be administered, along with supplements like carnitine, to support metabolic pathways and minimize the toxic accumulation of MMA.