Methylmalonic acidemia (Methylmalonic Academy) - Genes MUT, MMAA, MoEF, MMADHC and ESCM.
Methylmalonic acidemia is an inherited disease in which the body is unable to process certain lipids properly. Signs and symptoms of methylmalonic acidemia, which usually appear in early childhood and can range from mild to life threatening, can include vomiting, dehydration, hypotonia, developmental delay, lethargy, hepatomegaly and growth retardation. Long - term complications can include feeding problems, mental retardation, chronic kidney disease, and pancreatitis. If left untreated, this disease can lead to coma and death in some cases.
This process is due to changes in the MUT, MMAA, MoEF, MMADHC and ESCM genes. The long - term effects of methylmalonic acidemia depend on which gene is mutated and the severity of the mutation. In about 60% of cases, the disease is due to mutations in the gene MUT. It is likely that mutations in other unidentified genes also lead to methylmalonic acidemia.
MUT gene, located on the long arm of chromosome 12 (6p12.3), encodes an enzyme called methylmalonyl-CoA mutase. This enzyme acts with vitamin B12 (cobalamin) to decompose various amino acids (specifically isoleucine, methionine, threonine and valine), certain lipids and cholesterol. There are more than 200 mutations in the MUT gene in people with methylmalonic acidemia. Mutations in the gene MUT alter the structure of the enzyme encoded or reduce the amount of the enzyme, which prevents these molecules decompose properly. Consequently, methylmalonyl-CoA and other potentially toxic compounds, can accumulate in organs and tissues, leading to the signs and symptoms of methylmalonic acidemia. Mutations in the MUT gene coding inhibit any functional enzyme leads to a form of the disease called mut0. Mut0 is the most severe form of methylmalonic acidemia. Meanwhile, mutations that change the structure of methylmalonyl-CoA mutase, but do not eliminate its activity lead to a form of the disease called muting. In general, the way muting is less severe, with more variables than the symptoms mut0 form.
The MMAA gene, located on the long arm of chromosome 4 (4q31.21) and MoEF gene, located on the long arm of chromosome 12 (12q24), encoding a protein that is involved in the formation of a compound called adenosylcobalamin ( AdoCbl). AdoCbl, which is derived from vitamin B12 is necessary for normal function of methylmalonyl-CoA mutase. It is believed that MMYY and MoEF proteins may play a role in one of the last steps in the formation AdoCbl, transport of vitamin B12 in the mitochondria. It is also likely that the protein MMAA help stabilize methylmalonyl-CoA mutase. They have identified more than 25 mutations in the gene MMYY and 25 other mutations in the gene responsible for MoEF methylmalonic acidemia. Some of these mutations added, removed or duplicated a small amount of genetic material into the gene. Other mutations change a single amino acid used in encoding the proteins MMYY and MoEF. These mutations can lead to unstable encoding proteins or an abnormally small version, both non - functional proteins. Although it is unclear how the abnormal proteins MMYY and MoEF lead to serious medical problems associated with methylmalonic acidemia, it is likely that without the activity of these proteins, AdoCbl not formed properly. Lack of AdoCbl impairs the function of methylmalonyl-CoA mutase, which leads to incomplete breakdown of certain proteins and lipids. As a result, toxic compounds accumulate in organs and tissues.
The MMADHC gene, located on the long arm of chromosome 2 (2q23.2), encoding a protein that helps convert vitamin B12 into one of two molecules, adenosylcobalamin (AdoCbl) or methylcobalamin (MeCbl). AdoCbl required for normal function of methylmalonyl-CoA mutase enzyme. This helps break down certain amino acids, lipids and cholesterol. AdoCbl is a cofactor because it helps methylmalonyl-CoA mutase to carry out its function. MeCbl is also a cofactor, but for an enzyme known as methionine synthase. This enzyme converts the amino acid homocysteine in the amino acid methionine. The body uses methionine to produce proteins and other important compounds. In addition, it is likely that MMADHC protein plays a role in one of the final steps in the formation of AdoCbl and MeCbl. They have been described at least five mutations in the gene MMADHC in people with methylmalonic acidemia. These mutations lead to a protein that can not produce AdoCbl. Lack of AdoCbl impairs the function of methylmalonyl-CoA mutase. As a result, certain proteins and lipids not decompose properly, allowing toxic compounds accumulate in organs and tissues.
ESCM gene, located on the short arm of chromosome 2 (2p13.3), encoding methylmalonyl-CoA epimerase enzyme that converts one form of methylmalonyl-CoA molecule to another. Specifically, the enzyme converts D-methylmalonyl-CoA to L-methylmalonyl-CoA. This conversion takes place within the pathway that converts propionyl CoA to succinyl-CoA molecule. This pathway is important in the breakdown of certain amino acids, lipids and cholesterol. They have identified at least 3 mutations in the gene ESCM leading to methylmalonic acidemia. It is believed that these mutations result in coding a methylmalonyl-CoA epimerase enzyme with little or no function. People with methylmalonic acidemia due to mutations in the gene ESCM often have signs and symptoms milder than people whose disease is due to mutations in other genes. The features may be milder because there an alternative pathway for the conversion of propionyl-CoA to succinyl-CoA involves no methylmalonyl-CoA epimerase, so some succinyl-CoA occur even when there are mutations in the gene ESCM. However, this alternative route can not compensate the breakdown of certain molecules produced in the ordinary way, so that people with genetic mutations ESCM have an accumulation of byproducts of some amino acids and certain fats. Consequently, these toxic compounds accumulate in organs and tissues, leading to the signs and symptoms of methylmalonic acidemia.
This disease is inherited in an autosomal recessive pattern, that is, both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with methylmalonic acidemia, by complete PCR amplification of the exons of the MUT, MMAA, MoEF, MMADHC and ESCM genes, respectively, and subsequent sequencing.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).