HADHA

The HADHA gene provides instructions for making part of an enzyme complex called mitochondrial trifunctional protein. This enzyme complex functions in mitochondria, the energy-producing centers within cells. It is found in the mitochondria of several tissues, particularly the heart, liver, muscles, and the part of the eye that detects light and color (the retina).

Mitochondrial trifunctional protein is required to break down (metabolize) a group of fats called long-chain fatty acids. Long-chain fatty acids are found in foods such as milk and certain oils, and they are also stored in the body's fat tissues. Mitochondrial trifunctional protein is essential for converting long-chain fatty acids to the major source of energy used by the heart and muscles. During periods without food (fasting), this energy source is also important for the liver and other tissues.

Mitochondrial trifunctional protein is made of eight subunits. Four subunits called alpha are produced by the HADHA gene, and four subunits called beta are produced by the HADHB gene. As the name suggests, mitochondrial trifunctional protein performs three functions. It has three enzyme activities that are essential for fatty acid oxidation, which is the multistep process that metabolizes fats and converts them to energy. The alpha subunit performs two of the enzyme activities, known as long-chain 3-hydroxyacyl-coenzyme A dehydrogenase and long-chain 2-enoyl-coenzyme A hydratase. The beta subunit carries out the third enzyme activity.

long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency - caused by mutations in the HADHA gene

Researchers have identified several HADHA gene mutations that decrease the long-chain 3-hydroxyacyl-coenzyme A dehydrogenase enzyme activity of the mitochondrial trifunctional protein. (The protein's other enzyme activities remain normal or near normal.) Many of the HADHA mutations change one of the building blocks (amino acids) used to make the protein's alpha subunit. The most common mutation replaces the amino acid glutamic acid with the amino acid glutamine at position 474 in the alpha subunit. This mutation is written as Glu474Gln or E474Q. The Glu474Gln mutation and other amino acid replacements probably alter the structure of the alpha subunit, preventing it from functioning normally. Other types of HADHA mutations produce an abnormally small, unstable alpha subunit, which is unable to function.

With a shortage (deficiency) of functional alpha subunits, long-chain fatty acids cannot be metabolized and processed. As a result, these fatty acids are not converted to energy, which can lead to the characteristic features of long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, such as lack of energy (lethargy) and low blood sugar. Long-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the liver, heart, and retina, causing more serious complications.

mitochondrial trifunctional protein deficiency - caused by mutations in the HADHA gene

Researchers have identified several HADHA gene mutations that reduce all three enzyme activities of the mitochondrial trifunctional protein. Some mutations produce abnormally small, unstable alpha subunits, which leads to a decreased level of mitochondrial trifunctional protein. Other mutations replace one amino acid with another amino acid in the alpha subunit, which probably alters the subunit's structure and disrupts all three functions of the enzyme complex.

With a loss of mitochondrial trifunctional protein activity, long-chain fatty acids cannot be metabolized and processed. As a result, these fatty acids are not converted to energy, which can lead to the characteristic features of this disorder, such as lethargy and low blood sugar. Long-chain fatty acids or partially metabolized fatty acids may build up in tissues and damage the liver, heart, and muscles, causing more serious complications.

other disorders - increased risk from variations of the HADHA gene

In a small number of cases, HADHA mutations appear to increase the risk of two serious liver disorders that can develop in women during pregnancy. These disorders are acute fatty liver of pregnancy, which begins with abdominal pain and can rapidly progress to liver failure, and HELLP syndrome, characterized by the breakdown of red blood cells (hemolysis), elevated liver enzyme levels, and a low number of platelets (the cell fragments involved with blood clotting).

A woman is more likely to have acute fatty liver of pregnancy or HELLP syndrome if she has a mutation in one copy of the HADHA gene and the fetus she carries has two copies of a HADHA mutation, particularly the Glu474Gln mutation. Little is known about the relationship between HADHA mutations and liver problems in the mother during pregnancy. One possibility is that partially metabolized long-chain fatty acids produced by the fetus or placenta accumulate in the mother and are toxic to her liver. In very rare cases of maternal liver disease, the mother has one copy of an altered HADHA gene and the fetus is not affected. In these cases, the role of the mother's HADHA mutation in liver disease is unclear.