MMADHC

Variants (also known as mutations) in the MMADHC gene cause a condition called homocystinuria, which is characterized by developmental delay, neurological problems, eye defects, and blood abnormalities. The MMADHC gene variants that cause homocystinuria result in a protein that cannot transport vitamin B12 to the cytoplasm, where MeCbl is produced. The resulting shortage of MeCbl impairs methionine synthase's conversion of homocysteine to methionine. As a result, homocysteine builds up in the bloodstream and methionine is depleted. Some of the excess homocysteine is excreted in urine. Altered levels of homocysteine and methionine lead to the health problems associated with homocystinuria.

Variants in the MMADHC gene have been found to cause methylmalonic acidemia, a condition characterized by feeding difficulties, life-threatening episodes of low blood glucose and the build-up of toxic substances in the blood (metabolic crisis), and long-term health problems. The MMADHC gene variants that cause this condition result in a protein that cannot transport vitamin B12 to mitochondria for the production of AdoCbl. A lack of AdoCbl impairs the function of methylmalonyl CoA mutase. As a result, certain proteins and lipids are not broken down properly. This defect allows toxic compounds to build up in the body's organs and tissues, causing the signs and symptoms of methylmalonic acidemia.

Variants in the MMADHC gene can cause methylmalonic acidemia with homocystinuria, cblD type, which is one form of a condition that has features of both of the two conditions described above. People with this combined condition have developmental delay, eye defects, neurological problems, and blood abnormalities. The MMADHC gene variants that cause this condition result in the production of a protein that cannot transport vitamin B12 to either the mitochondria or the cytoplasm, which disrupts production of both AdoCbl and MeCbl. Because both of these cofactors are missing, the enzymes that require them (methylmalonyl CoA mutase and methionine synthase) do not function normally. As a result, certain amino acids, fatty acids, and cholesterol are not broken down and homocysteine cannot be converted to methionine. This dual defect results in a buildup of toxic compounds, including homocysteine, and a decrease in the production of methionine within the body. This combination of imbalances leads to the signs and symptoms of methylmalonic acidemia with homocystinuria.