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Methylmalonic Acid

The concentration of plasma methylmalonic acid (MMA) is elevated primarily in patients affected with methylmalonic acidemia and patients with a nutritional deficiency of cobalamin (vitamin B12) or folic acid. In adults, moderately time elevated values indicate a likely cobalamin deficiency.

In the elderly, cobalamin deficiency is often due to intestinal malabsorption, impaired digestion, or poor diet. Elderly patients may present with peripheral neuropathy, ataxia, loss of position and vibration senses, memory impairment, depression, and dementia in the absence of anemia.

Serum and urine concentrations of MMA are elevated in cobalamin deficiency, due to a decreased rate of metabolism. Patients with serum cobalamin values at the lower end of the normal range range may be truly cobalamin deficient. Measurement of the serum concentrations of MMA, along with homocysteine, appears to be more sensitive for the diagnosis of B12 deficiency than vitamin levels alone.

Other conditions such as renal insufficiency, hypovolemia, and bacterial overgrowth of the small intestine also contribute to the possible causes of mild methylmalonic acidemia and aciduria. Propionic acid generated by anaerobic gut flora may be a precursor of MMA in cobalamin-deficient patients.

In pediatric patients, markedly elevated MMA values usually indicate methylmalonic acidemia, which is caused by mutations in the gene coding for methylmalonyl coenzyme A mutase (MMACHC). Newborn screening identifies approximately 1 in 30,000 live births with a methylmalonic acidemia. The most frequent clinical manifestations are neonatal or infantile metabolic ketoacidosis, failure to thrive, and developmental delay. Depending on the mutation, patients may exhibit methylmalonic aciduria, homocystinuria, or both.

The most common disorder in this group is the cobalamin C type (cblC type), which results in both methylmalonic aciduria and homocystinuria.  It is most commonly caused by a 271dupA mutation in the MMACHC gene and inherited as an autosomal recessive disorder with a variable age of onset. In children, symptoms appear in the first several years of life and include failure to thrive, developmental delay, seizures, metabolic crisis, and hydrocephalus. Adults present with confusion or other changes in mental status, cognitive decline, and megaloblastic anemia.

Another early-onset mutation is R111X, which is common in the Cajun and French Canadian populations. R132X is a late-onset mutation that has been identified in individuals of Indian, Pakistani, and Middle Eastern ethnicity.

Many other mutations have been identified that lead to deficiencies of both

adenosylcobalamin and methylcobalamin. DNA sequencing is utilized to detect mutations in the MMACHC gene.

Specimen requirement for MMA quantitation is a green top (heparin) or purple top (EDTA) tube of blood. Reference range is 0 - 0.40 nmol/mL.

Specimen requirement for gene sequencing is a lavender top (EDTA) or yellow top (ACD) of blood.

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