Methylmalonic acidemia (MMA) is a group of disorders characterized by the accumulation of methylmalonic acid in the fluids of the affected individual. The first recognized cases of these disorders were described in 1967. All known genetic forms of MMA are non-sex linked (autosomal) and recessive. Some non-genetic cases have been reported in which the affected individuals were vegetarians who had been on prolonged cobalamin (vitamin B12) deficient diets.
Methylmalonic acidemia (MMA) is characterized by an accumulation of methylmalonic acid in the blood stream, which leads to an abnormally low pH (high acidity) in nearly every cell in the body (metabolic acidosis). A higher than normal accumulation of ketones in the blood stream (ketosis) similar to that seen in instances of diabetes mellitus is also associated with MMA. If left untreated, metabolic acidosis is often fatal.
Methylmalonic acid is an intermediate in the metabolism of fats and proteins. This chemical accumulates in the bodies of individuals affected with MMA because of a partial or complete inability of these individuals to convert methylmalonyl-CoA to succinyl-CoA in the tricarboxlic acid (TCA) cycle.
MMA is one of the genetic disorders that cause problems with mitochondrial metabolism. The mitochondria are the organelles inside cells that are responsible for energy production and respiration at the cellular level. One of the most important processes in the mitochondria is the TCA cycle (also known as the Krebs cycle). The TCA cycle produces the majority of the ATP (chemical energy) necessary for maintenance (homeostasis) of the cell. When blood sugar (glucose) is broken down in preparation to enter the TCA cycle, it is broken down into a chemical known as acetyl-CoA. It is this acetyl-CoA that is then further broken down in the TCA cycle to yield carbon dioxide, water, and ATP. When some fatty acids and certain amino acids from proteins (specifically isoleucine, valine, threonine, methionine, thymine, and uracil) are broken down in preparation to enter the TCA cycle, they are broken down into propionyl-CoA, rather than acetyl-CoA. This propionyl-CoA is then converted into methylmalonyl-CoA, which is next converted to succinyl-CoA. It is succinyl-CoA that enters the TCA cycle to eventually yield carbon dioxide, water, and the ATP needed by the cells.
The conversion of methylmalonyl-CoA to succinyl-CoA involves the apoenzyme methylmalonyl-CoA mutase. An apoenzyme is an enzyme that cannot function without the aid of other chemicals (cofactors). One of the cofactors for this apoenzyme is cobalamin (vitamin B12). Genetic MMA is a result of either a deficiency in the methylmalonyl-CoA mutase apoenzyme or a defect in the mechanism inside the cells that converts dietary vitamin B12 into its useable form for this chemical reaction.
An enzyme is a chemical that facilitates (catalyzes) the chemical reaction of another chemical or of other chemicals; it is neither a reactant nor a product in the chemical reaction that it facilitates. As a result, enzymes are not used up in chemical reactions; they are recycled. One molecule of an enzyme may be used to facilitate the same chemical reaction over and over again several hundreds of thousands of times. All the enzymes necessary for catalyzing the various reactions of human life are produced within the body by genes. In the case of the enzyme deficiency that causes MMA, the enzyme consists of a genetically produced apoenzyme and a cofactor (vitamin B12) that comes from dietary sources.
The gene responsible for MMA has been mapped to 6p21.2-p12. At least 30 mutations in this gene have been identified which lead to a broad spectrum of clinical symptoms and severities.
The exact frequency of MMA is not known. It is believed to occur with a frequency of approximately one in every 48,000 live births in the United States. As in all recessive non-sex linked (autosomal) genetic disorders, both parents must carry the gene mutation in order for their child to have the disorder. Therefore, in cases where the parents are related by blood (consanguineous), the occurrence rate is higher than in the rest of the population. Parents with one child affected by MMA have a 25% likelihood that their next child will also be affected with MMA.
No increased likelihood for the disease on the basis of sex or ethnicity has been observed in cases of MMA.
Signs and symptoms
The abnormally high levels of acid in the blood of individuals affected with MMA can produce drowsiness, seizures, and in severe cases, coma and/or stroke. Prolonged acidemia can cause mental retardation. In the very rare instances of a complete apoenzyme absence, MMA is associated with sudden infant death syndrome (SIDS) and at least one known case of sudden child death at an age of 11 months.
Dehydration and failure to thrive are generally the first signs of MMA. These symptoms are generally accompanied by lethargy, lack of muscle tone (hypotonia), and "floppiness" in newborns.
Developmental delay is typically experienced in all individuals affected with MMA if treatment is not instigated early in life.
Some individuals affected with MMA have facial dysmorphisms. These include a broad nose, a high forehead, a skin fold of the upper eyelid (epicanthal folds), and a lack of the normal groove in the skin between the nose and the upper lip (the philtrum). In a few individuals affected with MMA, skin lesions resulting from yeast infections (candidosis) may be present, particularly in the mouth and facial area.
Occasionally, enlargement of the liver (hepatomegaly) is seen in MMA affected individuals.
Uncoordinated muscle movements (choreoathetosis), disordered muscle tone (dystonia ), slurred speech (dysarthria), and difficulty swallowing (dysphagia), when observed in individuals affected with MMA may be signs of an acidemia-induced stroke.
In newborns, a history of poor feeding, increasing lethargy, and vomiting are typical symptoms of MMA. In older infants, an episode of lethargy, often accompanied by seizures, is symptomatic. In children or adolescents, the symptoms may include muscle weakness, loss or diminishment of sensation in the legs, and/or blood clots.
Kidney (renal) disease may be observed in affected individuals with long untreated MMA.
A blood test to detect high levels of MMA is a decisive test for MMA. It may also be detected via a urine test for abnormally high levels of the chemical methylmalonate.
Prenatally, MMA may be diagnosed by measuring the activity of the apoenzyme methylmalonyl-CoA mutase in cultured cells grown from the cells obtained during an amniocentesis .
In one MMA-related case, a woman named Patricia Stallings was sentenced to life imprisonment for the presumed poisoning of her infant son with ethylene glycol, an ingredient in antifreeze. It was not until she gave birth in prison to a second son affected with MMA (and properly diagnosed) that forensic investigators discovered that the gas chromatography peak originally assigned to ethylene glycol (and used to convict Ms. Stallings) was, in fact, methylmalonic acid. All charges against Ms. Stallings were dropped and she was released from prison. This is an extreme case, but it certainly shows the importance of proper medical diagnosis of MMA.
Family history is often used to diagnose MMA when there are affected siblings or siblings that died shortly after birth for unclear reasons.
Treatment and management
Individuals affected with MMA are generally placed on low, or no, protein diets supplemented with carnitine and cobalamin (vitamin B12) and alkalinizing agents (such as bicarbonate) to neutralize the excess acid caused by MMA. Intravenous administration of glucose may be necessary during acute attacks. In individuals who do not respond to carnitine and/or cobalamin, the anti-bacterial drug, metronidazole, may be prescribed. This drug kills some of the naturally occurring bacteria in the lower digestive tract and thereby reduces the production of propionate, a precursor chemical to methylmalonic acid.
In cases of severe MMA, kidney and/or liver transplants may be called for.
With appropriate care and diet, MMA is a controllable disease that offers no threat of death or permanent disability in patients beyond the first year of life. However, if unchecked, MMA can lead to permanent, irreversible disabilities or conditions, or even death. Some infants affected with extremely severe genetic mutations are stillborn or die prior to an appropriate diagnosis of MMA being made.
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National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
Organic Acidemia Association. 13210 35th Ave. North, Plymouth, MN 55441. (763) 559-1797. Fax: (863) 694-0017. <http://www.oaanews.org>.
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Paul A. Johnson