Methylmalonic acidemia

Methylmalonic acidemia is an inherited disorder in which the body is unable to process certain proteins and fats (lipids) properly. The effects of methylmalonic acidemia, which usually appear in early infancy, vary from mild to life-threatening. Affected infants experience vomiting, dehydration, weak muscle tone (hypotonia), excessive tiredness (lethargy), and failure to gain weight and grow at the expected rate (failure to thrive). Long-term complications can include feeding problems, intellectual disability, chronic kidney disease, and inflammation of the pancreas (pancreatitis). Without treatment, this disorder can lead to coma and death in some cases.

This condition occurs in an estimated 1 in 50,000 to 100,000 people.

Mutations in the MMAA, MMAB, and MUT genes cause methylmalonic acidemia.

About half of methylmalonic acidemia cases are caused by mutations in the MUT gene. This gene provides instructions for making an enzyme called methylmalonyl CoA mutase. This enzyme works with vitamin B12 to break down several protein building blocks (amino acids), certain lipids, and cholesterol. Mutations in the MUT gene alter the enzyme's 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 in the body's organs and tissues, causing the signs and symptoms of methylmalonic acidemia.

Mutations in the MUT gene that prevent the production of any functional enzyme result in a form of the condition designated mut⁰. Mut⁰ is the most severe form of methylmalonic acidemia and has the poorest outcome. Mutations that change the structure of methylmalonyl CoA mutase but do not eliminate its activity cause a form of the condition designated mut^-. The mut^- form is typically less severe, with more variable symptoms than the mut⁰ form.

Other cases of methylmalonic acidemia are caused by mutations in the MMAA or MMAB genes. To function properly, methylmalonyl CoA mutase must work together with the proteins produced from these genes. Mutations that affect either of these proteins can impair the activity of methylmalonyl CoA mutase, leading to methylmalonic acidemia. The long term effects of methylmalonic acidemia depend on which gene is mutated and how the enzyme is affected by the mutation.

It is likely that other unidentified genes also cause methylmalonic acidemia.

Read more about the MMAA, MMAB, and MUT genes.

This condition is inherited in an autosomal recessive pattern, which means both copies of the MUT, MMAA, or MMAB gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive condition are carriers of one copy of the mutated gene but do not show signs and symptoms of the condition.