Methylmalonic acidemia is a descriptive term. For this study, it refers to a group of inherited disorders in which the body is unable to process certain proteins and fats (lipids) properly. People with this disease can't change, or "metabolize," a substance called called methymalonyl-coenzyme A. The result is a buildup of methylmalonic acid in the body. Vitamin B12 deficiency states that are not due to genetic causes, such as vitamin B12 deficiency, can also cause methylmalonic acid to build up in the body and are not the subject of this study.
The effects of methylmalonic acidemia vary from mild to life-threatening. This condition, which can appear in early infancy or the first year of life, is characterized by excessive tiredness (lethargy), vomiting, dehydration, weak muscle tone (hypotonia), acid-base imbalance and in some patients, high levels of ammonia. Without treatment, the disorder can lead to coma and death in some cases. This condition may occur in 1 in 25,000 to 48,000 people but the precise incidence is not known.
Methylmalonic acidemia can be caused by mutations (or mistakes) in several genes. Individuals with methylmalonic acidemia can be divided into two groups: 1) patients with isolated MMA, where only methylmalonic acid is elevated 2) patients with combined defects who also have increased levels of homocysteine. Isolated methylmalonic acidemia is caused by mutations (or mistakes) in the MMAA, MMAB, and MUT genes. About half of the patients with isolated methylmalonic acidemia have mutations in the MUT gene. This gene provides instructions for making an enzyme called methylmalonyl CoA mutase, which is responsible for one step in the breakdown of several amino acids (the building blocks of proteins), certain lipids, and cholesterol. Mutations in the MUT gene alter the structure or reduce the amount of the enzyme, which prevents these molecules from being broken down properly. As a result, a substance called methylmalonyl-CoA and other potentially toxic compounds can accumulate, causing the signs and symptoms of methylmalonic acidemia.
Patients with methylmalonic acidemia that have mutations in the MUT gene are generally placed into two groups. When mutations in the MUT gene result in no enzyme activity patients are classified as "mut0". When mutations in the MUT gene change the structure of methylmalonyl CoA mutase but do not eliminate its activity completely, patients are designated "mut-". The precise distinction between these two groups is uncertain, but most would agree that detectable enzyme activity that increases when vitamin B12 is added in excess to the cells would characterize mut- patients. Also, patients that are classified into the "mut-" group may have a clinically milder form of the condition. For example, they may have fewer hospitalizations.
Isolated methylmalonic acidemia can also be caused by mutations in at least three other genes. The cobalamin A (cblA) type of methylmalonic acidemia is caused by mutations in the MMAA gene. The cobalamin B (cblB) type of methylmalonic acidemia is caused by mutations in the MMAB gene. Both of these conditions are similar to patients who have mut0 methylmalonic acidemia. However, most patients with cblA and cblB show clinical and metabolic improvement with supplementation with a form of vitamin B12 (hydroxycobalamin). It is unknown what the exact functions of the MMAA and MMAB enzymes are inside the body. These enzymes may help produce adenosylcobalamin (another form of vitamin B12) which is required for the methylmalonyl CoA mutase enzyme to function properly. Mutations that affect either of these enzymes (MMAA, MMAB) can impair the activity of methylmalonyl-CoA mutase, leading to methylmalonic acidemia.
Patients with combined defects have elevations of methylmalonic acid and homocysteine. These include cobalamin C (cblC), cobalamin D (cblD) and cobalamin F (cblF) deficiencies. CblC deficiency is the most common of the combined conditions. A gene called MMACHC is changed in this disorder. Affected patients have increased methylmalonic acid and homocysteine in body fluids and can have visual and neurological problems. CblD and cblF are more rare conditions and the genes responsible for them, called MMADHC and LMBRD1 respectively, have recently been identified. Other genes that have not yet been identified may also cause methylmalonic acidemia, either in isolation, or in combination with homocysteinemia.
Methylmalonic acidemia is inherited in an autosomal recessive manner. In an individual with methylmalonic acidemia, both copies of the gene ( MUT, MMAA, MMAB, MMACHC MMADHC and LMBRD1) have mutations or alterations. Most often, one copy of the altered gene is inherited from the mother and the other copy of the altered gene is inherited from the father. Therefore, each parent of an affected child has one copy of the gene that is altered and one that is unaltered. Parents are called "carriers" because they carry one copy of the altered gene but do not show signs and symptoms of the disorder. Both boys and girls are equally affected. This group of conditions is found in people of all racial and ethnic backgrounds.
Most types of methylmalonic acidemia are inherited in an autosomal recessive manner, meaning both parents of an affected child are carriers. Carriers are asymptomatic. With each pregnancy between two carrier parents, there is a 25 percent (1 in 4) chance that the child will be unaffected and not a carrier, 50 percent (1 in 2) chance that the child with be unaffected and a carrier, and a 25 percent (1 in 4) chance that the child will be affected with methylmalonic acidemia. Once an at-risk sibling is known to be unaffected, the chance of his/her being a carrier is 2/3 (66 percent). Siblings of a carrier parent have a ½ (50 percent) of being a carrier. Although the chances of being a carrier are increased for close family members, generally the risk of children of siblings and aunts/uncles having MMA is less than 1 percent in most cases. We recommend that individuals with a family history of methylmalonic acidemia or cobalamin disorders visit a genetic counselor or physician who specializes in genetics when they are considering starting a family.
Methylmalonic acidemia is treated primarily with a low-protein, high-calorie diet, certain medications, antibiotics and in some cases, organ transplantation. Medication treatment consists cobalamin (vitamin B12) given as an injection, carnitine, and antibiotics. The diet is protein restricted to limit the intake of isoleucine, threonine, methionine, and valine because these substances can turn into methylmalonic acid in an affected patient. Most patients also need to take a special formula missing certain amino acids but containing others to make sure they are getting enough protein for growth. Each patient needs an individually adjusted diet and medication regimen.
Unfortunately, there is no cure for methylmalonic acidemia. We hope that research will help doctors and scientists learn more about methylmalonic acidemia so that there will be better treatments in the future.
Last Reviewed: April 20, 2012