Medium-chain acyl-coenzyme A dehydrogenase deficiency
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Medium-chain acyl-coenzyme A dehydrogenase deficiency is one of a group of conditions that is associated with inborn errors of metabolism in fatty acid oxidation. It is due to defects in the enzyme complex known as medium-chain acyl dehydrogenase (MCAD) and reduced activity of this complex.
It is recognised as one of the rarer causes of sudden infant death syndrome (SIDS, "cot death" or "crib death"); although it is better described as a mimic, rather than a cause, of SIDS.
Background
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. Triglycerides occur in living things with fatty acids of different lengths. These may be divided into very long-chain, long-chain, medium-chain or short-chain depending on the number of carbon atoms that are present.
Metabolic enzymes
The fatty acids are broken down in stages by the successive removal of small molecules containing 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. A complex of seven enzymes is required to remove each 2-carbon molecule. As the process 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:
- Very long-chain acyl-coenzyme A dehydrogenase deficiency (VLCAD)
- Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCAD)
- Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD)
- Short-chain acyl-coenzyme A dehydrogenase deficiency (SCAD)
In individuals that have reduced activity of MCAD there is an impairment of fatty acid oxidation. Under conditions of health this may not cause significant problems. However, when such individuals become unwell for some other reason, the impairment of fatty acid oxidation may lead to hypoglycemia, hyperammonemia and, possibly, sudden death.
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 MCAD 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.
Investigation of "cot death"
During the course of an investigation of an infant that has suffered a "cot death", a sample of blood may be taken to measure the concentration of acyl carnitines. MCAD deficiency may be inferred when the levels of acyl carnitines in the blood are raised in a typical pattern.
If the interval between "cot death" and post-mortem examination (autopsy) is not too long, it is sometimes possible to culture cells called fibroblasts from the dermis of a sample of skin taken during the course of the examination. It is possible to add fatty acids that contain radioactive carbon atoms (carbon-14) to the culture medium. If the cells oxidise these fatty acids during the course of their metabolism, radioactive carbon dioxide will be produced, which may be detected using suitable apparatus. The rate of production of radioactive carbon dioxide from fatty acid chains of differing lengths may be used as a test to evaluate whether the cells have a deficiency in any of the various acyl dehydrogenases. This type of test may be used to support a diagnosis of MCAD deficiency when it is suspected from the pattern of acyl carnitines in the blood.
The diagnosis of MCAD deficiency should also be considered in the presence of prominent fatty change (also known as steatosis) within the liver and proximal renal tubules of the kidney. However, steatosis is recognised as a non-specific response to a variety of injuries.
Genetics
Mutations in the ACADM gene lead to inadequate levels of the medium-chain acyl-coenzyme A dehydrogenase enzyme. This condition is inherited in an autosomal recessive pattern, which means two copies of the faulty gene in each cell are required for the condition to be manifested; if only one copy is faulty then the individual is a carrier and does not have symptoms of the disease.
See also
External links
- Medium-chain acyl-coenzyme A dehydrogenase deficiency at NLM Genetics Home Reference
- CDC
- newbornscreening.info
- Gladwin Medical Blog
- Template:GPnotebook
nl:Medium Chain Acyl co-enzym-A Dehydrogenase deficiëntie de:Medium-Chain Acyl-Coenzym A Dehydrogenase Mangel