Variants (also called mutations) in the MMUT, MMAA, MMAB, MMADHC, and MCEE genes cause methylmalonic acidemia. The long-term effects of methylmalonic acidemia depend on which gene is altered and the severity of the variant.
About 60 percent of individuals with methylmalonic acidemia have variants in the MMUT gene. This gene provides instructions for making an enzyme called methylmalonyl-CoA mutase. This enzyme works with vitamin B12 (also called cobalamin) to break down several protein building blocks (amino acids), certain lipids, and cholesterol. Variants in the MMUT 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 methylmalonic acid and other potentially toxic compounds can accumulate in the body's organs and tissues, causing the signs and symptoms of methylmalonic acidemia.
Variants in the MMUT gene that prevent the production of any functional methylmalonyl-CoA mutase result in a form of the condition designated mut0. Mut0 is the most severe form of methylmalonic acidemia and has the poorest outcomes. Variants 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.
Some cases of methylmalonic acidemia are caused by variants in the MMAA, MMAB, or MMADHC gene. Proteins produced from the MMAA, MMAB, and MMADHC genes are required for the proper function of methylmalonyl-CoA mutase. Specifically, these proteins help produce and regulate vitamin B12, which methylmalonyl-CoA mutase needs to function. Variants that affect proteins produced from these three genes can impair the activity of methylmalonyl-CoA mutase, leading to methylmalonic acidemia.
A few other cases of methylmalonic acidemia are caused by variants in the MCEE gene. This gene provides instructions for producing an enzyme called methylmalonyl CoA epimerase. Like methylmalonyl CoA mutase, this enzyme also plays a role in the breakdown of amino acids, certain lipids, and cholesterol. Disruption in the function of methylmalonyl CoA epimerase leads to a form of methylmalonic acidemia with varied signs and symptoms.
Because variants in these genes only cause elevations in the levels of methylmalonic acid, this condition is sometimes referred to as isolated methylmalonic acidemia. This helps distinguish it from related conditions, such as methylmalonic acidemia with homocystinuria.
It is possible that variants in other, unidentified genes also cause methylmalonic acidemia.