Combined malonic and methylmalonic aciduria (CMAMMA) is a condition characterized by high levels of certain chemicals, known as malonic acid and methylmalonic acid, in the body. A distinguishing feature of this condition is higher levels of methylmalonic acid than malonic acid in the urine, although both are elevated.

The signs and symptoms of CMAMMA can begin in childhood. In some children, the buildup of acids causes the blood to become too acidic (ketoacidosis), which can damage the body's tissues and organs. Other signs and symptoms may include involuntary muscle tensing (dystonia), weak muscle tone (hypotonia), developmental delay, an inability to grow and gain weight at the expected rate (failure to thrive), low blood glucose (hypoglycemia), and coma. Some affected children have an unusually small head size (microcephaly).

Other people with CMAMMA do not develop signs and symptoms until adulthood. These individuals usually have neurological problems, such as seizures, loss of memory, a decline in thinking ability, or psychiatric diseases.

Mutations in the ACSF3 gene cause CMAMMA. This gene provides instructions for making an enzyme that plays a role in the formation (synthesis) of fatty acids. Fatty acids are building blocks used to make fats (lipids). The ACSF3 enzyme performs a chemical reaction that converts malonic acid to malonyl-CoA, which is the first step of fatty acid synthesis in cellular structures called mitochondria. Based on this activity, the enzyme is classified as a malonyl-CoA synthetase. The ACSF3 enzyme also converts methylmalonic acid to methylmalonyl-CoA, making it a methylmalonyl-CoA synthetase as well.

The effects of ACSF3 gene mutations are unknown. Researchers suspect that the mutations lead to altered enzymes that have little or no function. Because the enzyme cannot convert malonic and methylmalonic acids, they build up in the body. Damage to organs and tissues caused by accumulation of these acids may be responsible for the signs and symptoms of CMAMMA, although the mechanisms are unclear.

Normal Function

The ACSF3 gene provides instructions for making an enzyme involved in the formation (synthesis) of fatty acids, which are building blocks used to make fats (lipids). The ACSF3 enzyme performs a chemical reaction that converts malonic acid to malonyl-CoA, which is the first step of fatty acid synthesis. Based on this activity, the enzyme is classified as a malonyl-CoA synthetase. The ACSF3 enzyme also converts methylmalonic acid to methylmalonyl-CoA, making it a methylmalonyl-CoA synthetase as well.

Fatty acid synthesis occurs through two pathways, one of which takes place in cellular structures called mitochondria. Mitochondria convert the energy from food into a form that cells can use, and fatty acid synthesis in these structures is thought to be important for their proper functioning. The ACSF3 enzyme is found only in mitochondria and is involved in mitochondrial fatty acid synthesis.

Health Conditions Related to Genetic Changes

Combined malonic and methylmalonic aciduria

About a dozen mutations in the ACSF3 gene have been found in people with combined malonic and methylmalonic aciduria (CMAMMA), a condition characterized by elevated levels of chemicals known as malonic acid and methylmalonic acid in the body. This condition can cause development and growth problems beginning in childhood or neurological problems beginning in adulthood.

Most ACSF3 gene mutations involved in CMAMMA change single protein building blocks (amino acids) in the ACSF3 enzyme. The altered enzyme likely has little or no function. Because the enzyme cannot convert malonic and methylmalonic acids, they build up in the body. Damage to organs and tissues caused by accumulation of malonic and methylmalonic acids may be responsible for the signs and symptoms of CMAMMA, although the mechanisms are unclear.

Other Names for This Gene

• ACSF3_HUMAN
• acyl-CoA synthetase family member 3, mitochondrial
• acyl-CoA synthetase family member 3, mitochondrial precursor

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

CMAMMA appears to be a rare disease. Approximately a dozen cases have been reported in the scientific literature.