methylmalonic acid

What is methylmalonic acid

Methylmalonic acid is a malonic acid derivative which is a vital intermediate in the metabolism of fat and protein. Methylmalonic acid is a substance produced in very small amounts and is necessary for human metabolism and energy production. In one step of metabolism, vitamin B12 (cobalamin) promotes the conversion of methylmalonyl CoA (a form of methylmalonic acid) to succinyl Coenzyme A by methylmalonyl-CoA mutase in a reaction that requires vitamin B12 as a cofactor. If there is not enough vitamin B12 available, then the methylmalonic acid concentration begins to rise, resulting in an increase of methylmalonic acid in the blood and urine. The measurement of elevated amounts of methylmalonic acid in the blood or urine serves as a sensitive and early indicator of vitamin B12 deficiency. Elevated levels of methylmalonic acid can also result from inherited defects of enzymes involved in methylmalonic acid metabolism called methylmalonic acidemia (methylmalonic aciduria). Methylmalonic acidemia disease is attributed to a block in the enzymatic conversion of methylmalonyl CoA to succinyl CoA.

Over time, vitamin B12 deficiency can cause blood cell changes, leading to anemia and the production of large red blood cells (macrocytes). It can also cause signs and symptoms of neuropathy, such as numbness and tingling in the hands and feet and/or, in advanced cases, mental or behavioral changes such as cognitive impairment, confusion, irritability, and depression. An increased concentration of methylmalonic acid is often detectable before blood cell changes and before full-blown symptoms are apparent, though some people may have some degree of neuropathy.

The relationship between methylmalonic acid and B12 has been known for over 40 years, but the use of methylmalonic acid testing is not widespread nor is there agreement on its clinical utility. Because a relatively large amount of the B12 found in the blood is bound to proteins and is not biologically active, some in the medical community think that methylmalonic acid may be a better measure of bioavailable B12 than the usual vitamin B12 test. Others believe that methylmalonic acid and homocysteine (which may also be elevated when either B12 or folate is deficient) are valuable in detecting early and mild cases of B12 deficiency. Still others argue that many of the mild deficiencies detected do not progress to more severe deficiencies and do not necessarily need to be identified or treated.

Testing newborns for high levels of methylmalonic acid may help diagnose methylmalonic acidemia, a rare metabolic disorder that occurs in about 1 in 25,000 to 100,000 people. Screening for this disorder is part of mandatory programs in all 50 states in the U.S. Babies with methylmalonic acidemia are unable to convert methylmalonyl CoA to succinyl CoA. They appear normal at birth, but as they consume protein, they begin to show symptoms such as excessive tiredness, vomiting, dehydration, weak muscle tone, seizures, mental retardation, strokes, and severe metabolic acidosis

Methylmalonic acid is also found to be associated with other inborn errors of metabolism, including cobalamin deficiency, cobalamin malabsorption, malonyl-CoA decarboxylase deficiency, and transcobalamin II deficiency. When present in sufficiently high levels, methylmalonic acid can act as an acidogen and a metabotoxin. An acidogen is an acidic compound that induces acidosis, which has multiple adverse effects on many organ systems. A metabotoxin is an endogenously produced metabolite that causes adverse health effects at chronically high levels. Chronically high levels of methylmalonic acid are associated with at least 5 inborn errors of metabolism, including Malonyl CoA decarboxylase deficiency, Malonic Aciduria, Methylmalonate Semialdehyde Dehydrogenase Deficiency, Methylmalonic Aciduria and Methylmalonic Aciduria Due to Cobalamin-Related Disorders.

Methylmalonic acid is an organic acid and abnormally high levels of organic acids in the blood (organic acidemia), urine (organic aciduria), the brain, and other tissues lead to general metabolic acidosis. Acidosis typically occurs when arterial pH falls below 7. 35. In infants with acidosis, the initial symptoms include poor feeding, vomiting, loss of appetite, weak muscle tone (hypotonia), and lack of energy (lethargy). These can progress to heart abnormalities, kidney abnormalities, liver damage, seizures, coma, and possibly death. These are also the characteristic symptoms of the untreated inborn errors of metabolism mentioned above. Many affected children with organic acidemias experience intellectual disability or delayed development. In adults, acidosis or acidemia is characterized by headaches, confusion, feeling tired, tremors, sleepiness, and seizures.

Methylmalonic acid test

The methylmalonic acid blood test measures the amount of methylmalonic acid in the blood. The methylmalonic acid test may be used to help diagnose an early or mild vitamin B12 deficiency. It may be ordered by itself or along with a homocysteine test as a follow-up to a vitamin B12 test result that is in the lower end of the normal range.

Methylmalonic acid is a substance produced in very small amounts in the body. It is necessary for metabolism and energy production. In one step of metabolism, vitamin B12 promotes the conversion of methylmalonyl CoA (a form of methylmalonic acid) to succinyl Coenzyme A. If there is not enough B12 available, then the methylmalonic acid level begins to rise, resulting in an increase of methylmalonic acid in the blood and urine. Measuring methylmalonic acid in the blood or urine can help detect early vitamin B12 deficiency.

There are currently no guidelines for screening asymptomatic adults for vitamin B12 deficiency, but confirmation with methylmalonic acid and/or homocysteine may be necessary for those at high risk without symptoms, such as the elderly, or when certain medications have been taken for a long time.

Methylmalonic acid is a very sensitive test in indicating a B12 deficiency. It is more specific than homocysteine and is the confirmatory test of choice for a B12 deficiency.

Occasionally, specialized methylmalonic acid testing may be ordered to help diagnose methylmalonic acidemia, a rare inherited metabolic disorder. Newborn screening programs in all 50 states in the U.S. now require testing for this disorder.

Can either blood or urine be used for the methylmalonic acid test?

In most cases, it is okay to use blood or urine for this test. Sometimes, a healthcare provider may want to test both blood and urine in order to compare the methylmalonic acid results. Since homocysteine is a blood test, it may be more efficient and convenient to draw blood for both the methylmalonic acid and homocysteine tests when they are ordered together.

When is methylmalonic acid test ordered?

Methylmalonic acid is usually ordered, sometimes along with a homocysteine test, when a vitamin B12 test result is in the lower portion of the normal range, especially when a person has symptoms associated with B12 deficiency.

Signs and symptoms of B12 deficiency may include:

  • Diarrhea
  • Dizziness
  • Fatigue, muscle weakness
  • Loss of appetite
  • Pale skin
  • Rapid heart rate, irregular heartbeats
  • Shortness of breath
  • Sore tongue and mouth
  • Tingling, numbness, and/or burning in the feet, hands, arms, and legs (with B12 deficiency)
  • Confusion or forgetfulness
  • Paranoia

Methylmalonic acid is also ordered for asymptomatic adults who have a higher likelihood of having vitamin B12 deficiency, such as the elderly, or for those taking certain drugs, like metformin, for a long time. An methylmalonic acid test also may be ordered as a follow-up to an elevated homocysteine level if the two tests are not ordered together.

Methylmalonic acid testing may be ordered when a health practitioner suspects that an acutely ill infant may have inherited methylmalonic acidemia.

Methylmalonic acid normal range

Normal methylmalonic acid levels are 0.07 to 0.27 micromoles per liter. Some studies have found a high variation in methylmalonic acid levels when they are measured over time.

Normal value ranges may vary slightly among different laboratories. Some labs use different measurements or test different samples. Talk to your doctor about the meaning of your specific test results.

Elevated methylmalonic acid

If methylmalonic acid and homocysteine levels are increased and the vitamin B12 level is mildly decreased, then an early or mild B12 deficiency may be present. This may indicate a decrease in available B12 at the tissue level. An elevated methylmalonic acid test may indicate a B12 deficiency, but the amount of methylmalonic acid measured does not necessarily reflect the severity of the deficiency, its likelihood of progressing, or the presence or severity of any symptoms.

If only the homocysteine level is elevated and not methylmalonic acid, then the person may have a folate deficiency. This distinction is important because giving folate to some who is B12-deficient will treat the anemia but does not treat the neurologic damage, which may be irreversible.

If both methylmalonic acid and homocysteine levels are normal, then it is unlikely that there is a B12 deficiency.

Moderately to severely elevated levels of methylmalonic acid may be seen in infants with the rare inherited disease methylmalonic acidemia.

If an individual has kidney disease, he may have a falsely high level of methylmalonic acid in his blood. If the kidneys are not functioning properly, they cannot properly eliminate methylmalonic acid in the urine, causing methylmalonic acid to accumulate in the blood.

If I have an elevated methylmalonic acid, why might my doctor hesitate to diagnose me with vitamin B12 deficiency?

If your vitamin B12 test result is in the lower end of the normal range and you do not present with significant clinical symptoms, your healthcare provider may feel that you have adequate vitamin B12 and will rely on these findings rather than an elevated methylmalonic acid. This may be especially true if your homocysteine level is normal. Your healthcare provider may want to monitor your condition over time and may be reluctant to start you on what could be lifelong treatment with vitamin B12 injections and/or oral supplementation unless it is truly necessary.

Low methylmalonic acid level

A decreased level of methylmalonic acid is not common and is not considered clinically significant.