MMA - Kresser Institute Membership Site

Marker Name: Methylmalonic acid (MMA)

REFERENCE RANGES FOR SERUM MMA:

Laboratory reference range: 0–378 nmol/L

Functional reference range: < 300 nmol/L

DESCRIPTION:

Methylmalonic acid is a small molecule formed from the catabolism of the amino acids isoleucine, methionine, threonine, and valine, as well as cholesterol and odd-chain fatty acids.^1,2 Beyond its role as an intermediate in these metabolic reactions, methylmalonic acid is not known to play a direct role in cellular or tissue function. Nevertheless, excessive levels of methylmalonic acid may cause a metabolic acidosis, ketosis, and hyperammonemia.^2,3

Methylmalonic acid is a key component of the methylmalonyl-CoA pathway.² Through this pathway, isoleucine, methionine, threonine, valine, thymidine, uracil, cholesterol, and odd-chain fatty acids are catabolized to form succinyl-CoA for use in the citric acid cycle. The isomerization of methylmalonyl-CoA to succinyl-CoA requires the vitamin B12-dependent enzyme methylmalonyl-CoA mutase. Thus, elevations in circulating methylmalonic acid are usually either due to mutations in this enzyme or a lack of the cofactor, vitamin B12.²

Since mutations in methylmalonyl-CoA mutase are rare (roughly one in 48,000) and come to clinical attention in the neonatal period, accumulations of methylmalonic acid in adults usually reflect vitamin B12 deficiency.⁴ In fact, methylmalonic acid is an extremely sensitive indicator of vitamin B12 deficiency and is considered the gold standard for confirmation of this diagnosis.⁵

An elevated plasma methylmalonic acid level is called methylmalonic acidemia. Methylmalonic acidemia is an umbrella term that is applied to a number of inherited errors of methylmalonic acid metabolism, but it also may be applied to transient elevations in plasma methylmalonic acid.² While genetic causes of methylmalonic acidemia result in large increases in plasma methylmalonic acid, the most common cause of elevated methylmalonic acid in plasma is vitamin B12 deficiency. Methylmalonic acid levels may also increase during pregnancy, renal insufficiency, and in a portion of otherwise healthy elderly individuals.^3,6

A low plasma methylmalonic acid does not appear to reflect any clinical disease or disorder. In fact, clinical laboratories may not include lower boundaries for normal serum methylmalonic acid ranges.³

Methylmalonic acid is commonly measured during investigation of suspected vitamin B12 or folate deficiency. Therefore, plasma methylmalonic acid may be measured with vitamin B12, folate, and homocysteine.⁷ In vitamin B12 deficiency, both serum homocysteine and methylmalonic acid levels will be elevated, but methylmalonic acid levels will be normal in folate deficiency.⁷

PATHOLOGICAL/CONVENTIONAL RANGE INDICATIONS:

High in:^2,6,8

Normal pregnancy
Vitamin B12 deficiency
Pernicious anemia
End-stage renal disease
Genetic disorders impairing methylmalonic acid metabolism

Low in:³

Not clinically relevant

FUNCTIONAL RANGE INDICATIONS:

High in:

Functional B12 deficiency
Pregnancy

Low in:

Not clinically relevant

References: