Methylmalonic Acid

Methylmalonic acid (MMA) levels are commonly used to evaluate for vitamin B-12 deficiency. The normal value for MMA is < 3.6 μmol/mmol creatinine. ^[1]

Methylmalonic acid (MMA) levels are increased in association with the following:

• Vitamin B-12 deficiency

• Methylmalonic acidemia in children

• Cobalamin genetic defects and pregnancy

• Pernicious anemia

• Renal insufficiency

• Elderly (5%-15%)

Specimen: Blood

Container: Tiger-, lavender-, or green-top tube

All samples must be sent in a sealed, leak-proof container marked with a biohazard sticker to comply with Occupational Safety and Health Administration (OSHA) safety standards.

Description

Cobalamin plays a vital role in DNA synthesis and neuropsychological function. Its deficiency may lead to a wide spectrum of hematologic and neuropsychiatric disorders that can often be reversed by early diagnosis and prompt therapy. ^[2] According to the Framingham Offspring Study, vitamin B-12 deficiency may be more common than was previously believed. Vitamin B-12 deficiency is thought to be related to improper absorption rather than a decreased amount of dietary vitamin B-12, as many persons who consume large amounts of the vitamin still have a deficiency. ^[3]

Methylmalonic acid (MMA) is an intermediate in the propionate pathway. Deficiency of methylmalonyl CoA mutase, an enzyme responsible for conversion of methylmalonic CoA to succinyl CoA, results in methylmalonic aciduria, which has a poor outcome if it remains untreated. The classic presentation includes neonatal metabolic acidosis and an increased serum ammonia level.

Vitamin B-12 deficiency results in megaloblastic anemia, pancytopenia, peripheral neuropathy, dementia, depression, psychosis, subacute combined degeneration of cord, and, possibly, a heightened risk for vascular diseases such as myocardial infarction and strokes. ^[2]

The reference range of vitamin B-12 is typically wide. The lower end of the normal level is associated with clinical diseases due to vitamin B-12 deficiency. Therefore, upon clinical suspicion of vitamin B-12 deficiency in the setting of low normal laboratory values, MMA and homocysteine testing should be performed, since these tests are considered to be more sensitive metabolic markers of vitamin B-12 status. Both of these markers are elevated in vitamin B-12 deficiency. As homocysteine may be affected by other factors, such as renal failure, folate deficiency, tobacco, and alcohol abuse, it is less specific than MMA for identifying vitamin B-12 deficiency.

Indications/Applications

MMA testing is indicated for the following:

• Evaluation of methylmalonic academia in children

• Evaluation of megaloblastic anemia, as serum MMA is more sensitive than vitamin B-12 in vitamin B-12–deficiency states

Considerations

Although MMA is a more sensitive and specific marker of vitamin B-12 status, its assay is expensive and requires specialized instrumentation and is therefore unavailable in most clinical laboratories. Age and nutritional status should be considered in the assessment of serum MMA. ^[4]

It is unclear why increased serum MMA levels are more common (5%-15%) in elderly persons with low or normal serum vitamin B-12 levels. Pernicious anemia has been confirmed in only a few of such persons.

Vitamin B-12 deficiency can be excluded by a normal MMA level in persons with lymphoid disorders who have low unexplained vitamin B-12. In persons with HIV infection, who typically have low levels of vitamin B-12–binding proteins, the vitamin B-12 level may be low, but, again, the MMA level is normal in this scenario.

When the MMA level is mildly increased (0.4-2 µmol/L), vitamin B-12 supplementation has no significant effect on hemoglobin; mean corpuscular volume (MCV); or anemic (hematological), neurological, or gastroenterological symptoms, at least in the short term, despite normalization of the MMA level.

The urine MMA level (reference interval: 0-3.6 mmol/mol creatinine) is helpful not only in monitoring patients with methylmalonic aciduria but also in evaluating vitamin B-12 status. ^[5]

Because most patients with folate deficiency have normal MMA levels, and the remainder have only mild elevations, vitamin B-12 deficiency can be differentiated from folate deficiency with the combined use of homocysteine and MMA levels. When the patient receives replacement with the deficient vitamin, the abnormal metabolites normalize. A positive response to vitamin B-12 replacement, evidenced by decreasing levels of homocysteine and MMA, is proof of vitamin B-12 deficiency. Conversely, folate treatment in a patient with folate deficiency results in a fall in the isolated homocysteine level.

As several non–vitamin deficiency–related variables (eg, age, mild renal dysfunction) can falsely raise serum homocysteine and MMA levels, evidence of vitamin deficiency requires clear-cut demonstration of a decrease in metabolite levels after treatment with a specific vitamin. ^{[6, 7]}