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Medium-chain acyl-coenzyme A dehydrogenase deficiency is a fatty acid oxidation disorder associated with inborn errors of metabolism. It is due to defects in the enzyme complex known as medium-chain acyl dehydrogenase (MCAD) and reduced activity of this complex.
It is recognized as one of the more rare causes of sudden infant death syndrome (SIDS), although it may be better described as a mimic, rather than a cause, of SIDS.[citation needed]
Two main types of fat are found in the body: triglycerides and waxes. A triglyceride consists of a three-carbon compound known as glycerol to which three fatty acids (carboxylic acids) are attached by ester bonds. The length of the fatty acids chains can vary; they may be classified as very long-chain, long-chain, medium-chain or short-chain depending on the number of carbon atoms in the chain.
The fatty acids are broken down in stages by the successive removal of molecules of acetyl-coenzyme A, which contains 2 carbon atoms. Ultimately, under normal conditions, the fatty acids are converted into carbon dioxide and water with the liberation of energy during this process. Once a fatty acid molecule is “activated” (attached to coenzyme A), a series of four reactions, each catalyzed by a different enzyme, is required to remove each acetyl-coenzyme A molecule. As the first step involves removal of hydrogen atoms (i.e. an oxidation) from an acyl group, the enzyme complex is known as an acyl dehydrogenase. Different enzymes are required to hold fatty acids of different lengths, and the deficiencies connected with these various proteins are:
In individuals that have reduced activity of MCADD, there is an impairment of fatty acid oxidation. Under conditions of health this may not cause significant problems. However, when such individuals do not eat for prolonged periods or have increased energy requirements, the impairment of fatty acid oxidation may lead to fatty acid buildup, hypoglycemia, hyperammonemia, and, possibly, sudden death. First symptoms of such an episode, termed a “metabolic crisis,” are vomiting and lethargy, and typically present before the onset of hypoglycemia. 20-25% of undiagnosed cases are fatal, and many survivors are left with severe brain damage after particularly severe crises.
The oxidation of fatty acids occurs within mitochondria. Fatty acids from the cytoplasm are attached to a molecule called carnitine to transport them across the mitochondrial membrane. The combination of carnitine with a fatty acid is known as acyl carnitine. In individuals with MCADD deficiency, there is an increase in the concentration of medium-chain acyl carnitines in the cytoplasm of their cells; these acyl carnitines leak into the blood stream. The presence of these acyl carnitines, especially octanoyl-carnitine, is a major diagnostic characteristic of MCADD deficiency.
There is no cure for MCAD deficiency, but once diagnosed, adverse effects can be prevented by proper management. The most important part of treatment is to insure that patients never go without food for longer than 10-12 hours (a typical overnight fast). Patients with an illness causing loss of appetite or severe vomiting may need intravenous glucose to make sure that the body is not dependent on fatty acids for energy. Patients also usually adhere to a low-fat diet. Patients may also take daily doses of carnitine, which helps reduce toxic accumulation of fatty acids by forming acyl carnitines, which are excreted in the urine. Severity of symptoms seems to decrease after puberty, but crises may be brought about by particularly long fasts or heavy alcohol consumption.
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