Methylmalonic Acid 

Methylmalonic Acid 

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Methylmalonic acid (MMA) levels are commonly used to evaluate for vitamin B-12 deficiency.

The reference range of MMA is 0-0.4 µmol/L (0-4.7 µg/dL).

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.

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. [1] 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. [2]

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. [1]

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.

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

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. [3]

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. [4]

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. [5, 6]

Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician. Mar 1 2003;67(5):979-986.:

McBride J. B12 Deficiency May Be More Widespread Than Thought. 2000;. Available at Accessed: April26, 2012.

Williamson MA, Snyder LM, Wallach JB. Wallach’s interpretation of diagnostic tests. th ed. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins Health; 2011.:

Monsen AL, Refsum H, Markestad T, Ueland PM. Cobalamin status and its biochemical markers methylmalonic acid and homocysteine in different age groups from 4 days to 19 years. Clin Chem. Dec 2003;49(12):2067-2075:

AC A. Megaloblastic anemias. In: Hoffman R BJE, Shattil SJ,, ed. Hematology: Basic Principles and Practice. 4th ed. Philadelphia: Elsevier Churchill Livingstone; 2005:519:

Antony AC. Prevalence of cobalamin (vitamin B-12) and folate deficiency in India–audi alteram partem. The American journal of clinical nutrition. Aug 2001;74(2):157-159.

Bishnu Prasad Devkota, MD, MHI, FRCS(Edin), FRCS(Glasg), FACP Professor of Medicine, St Louis University School of Medicine

Bishnu Prasad Devkota, MD, MHI, FRCS(Edin), FRCS(Glasg), FACP is a member of the following medical societies: American College of Physicians, American Medical Informatics Association, Royal College of Physicians and Surgeons of Glasgow, Healthcare Information and Management Systems Society, Royal College of Surgeons of Edinburgh

Disclosure: Nothing to disclose.

Eric B Staros, MD Associate Professor of Pathology, St Louis University School of Medicine; Director of Clinical Laboratories, Director of Cytopathology, Department of Pathology, St Louis University Hospital

Eric B Staros, MD is a member of the following medical societies: American Medical Association, American Society for Clinical Pathology, College of American Pathologists, Association for Molecular Pathology

Disclosure: Nothing to disclose.

Methylmalonic Acid 

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