HADH

The HADH gene provides instructions for making an enzyme called 3-hydroxyacyl-coenzyme A (CoA) dehydrogenase that is important for converting certain fats to energy. Through a process called fatty acid oxidation, several enzymes work in a step-wise fashion to break down (metabolize) fats and convert them to energy. The role of 3-hydroxyacyl-CoA dehydrogenase in this process is to metabolize groups of fats called medium-chain fatty acids and short-chain fatty acids. These fatty acids are found in foods such as milk and certain oils and are produced when larger fatty acids are metabolized.

3-hydroxyacyl-CoA dehydrogenase functions in mitochondria, the energy-producing centers within cells. It is found in mitochondria of the heart, liver, kidneys, muscles, and pancreas. The pancreas provides enzymes that help digest food, and it also produces insulin, which controls how much sugar is passed from the blood into cells for conversion to energy.

3-hydroxyacyl-CoA dehydrogenase is essential for converting medium-chain and short-chain fatty acids to the major source of energy used by the heart and muscles. During prolonged periods without food (fasting) or when energy demands are increased, this energy source is also important for the liver and other tissues.

3-hydroxyacyl-coenzyme A dehydrogenase deficiency - caused by mutations in the HADH gene

Researchers have identified a few mutations in the HADH gene that cause 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. These mutations replace one of the building blocks (amino acids) used to make the 3-hydroxyacyl-CoA dehydrogenase enzyme with an incorrect amino acid. These changes probably alter the 3-dimensional shape of the enzyme, which impairs its normal function.

With a shortage (deficiency) of functional 3-hydroxyacyl-CoA dehydrogenase, medium-chain and short-chain fatty acids are not metabolized properly. As a result, these fats are not converted to energy, which can lead to signs and symptoms of 3-hydroxyacyl-coenzyme A dehydrogenase deficiency such as lack of energy (lethargy) and low blood sugar. Medium-chain and short-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 - caused by mutations in the HADH gene

Mutations in the HADH gene have been reported in a small number of cases of a disorder called familial hyperinsulinemic hypoglycemia. This disorder is characterized by abnormally high levels of insulin and unusually low levels of blood sugar.

Researchers have identified three HADH mutations that severely reduce 3-hydroxyacyl-CoA dehydrogenase activity, either by impairing the enzyme's function or by decreasing the amount of this enzyme in cells. One mutation changes one of the building blocks (amino acids) used to make this enzyme. Specifically, the amino acid proline is replaced with the amino acid leucine at position 258 (written as Pro258Leu). This mutation probably alters the 3-dimensional shape of the 3-hydroxyacyl-CoA dehydrogenase enzyme, which makes it unstable. Another mutation deletes a small section of the HADH gene, which likely leads to an unstable enzyme that is missing 30 amino acids. These unstable versions of 3-hydroxyacyl-CoA dehydrogenase rapidly decay or, if present, have severely reduced activity. Another type of mutation disrupts how information from the HADH gene is spliced together to make a blueprint for the production of 3-hydroxyacyl-CoA dehydrogenase. The resulting blueprint is distorted, which reduces production of the enzyme. Researchers believe that inadequate 3-hydroxyacyl-CoA dehydrogenase activity in the pancreas leads to impaired control of insulin and blood sugar levels.