Medium-chain acyl-coenzyme A dehydrogenase deficiency
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| ICD-9 | 277.85 |
|---|---|
| OMIM | 201450 |
| eMedicine | ped/1392 |
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 causes of sudden infant death syndrome (SIDS, "cot death" or "crib death").
MCAD deficiency is considered sufficient explanation for sudden death. This condition is better described as a mimic, rather than a cause, of SIDS.
[edit] Background
Two main types of fat are found in the body
A triglyceride consists of a three carbon compound known as glycerol to which three fatty acids are attached by ester bonds. Fatty acids are also known as carboxylic acids. They comprise a carboxyl group (which imparts the acidic properties) and an aliphatic tail that consists of a carbon chain to which hydrogen atoms are attached. Different triglycerides that occur in living things feature fatty acids of different lengths. The fatty acids that occur in triglycerides in nature may be divided into very long chain, long chain, medium chain or short chain depending on the number of carbon atoms that are present. They always have an even number of carbon atoms. Fats may be metabolised to provide energy for cellular activities. Ultimately, under normal conditions, the fatty acids are converted into carbon dioxide and water with the liberation of energy during this process.
The fatty acids are broken down in stages by the successive removal of small molecules containing 2 carbon atoms. A complex of 7 enzymes is required to remove each 2-carbon molecule. As the process involves removal of hydrogen atoms (in a process of oxidation) the enzyme complex is known as a dehydrogenase. As the aliphatic chain that is attached to the carboxylic group in a fatty acid is known as an acyl group the enzyme complex is also known as acyl dehdrogenase. The acyl dehdrogenase complex includes proteins that hold the fatty acids whilst the 2-carbon molecules are removed. Different proteins are required to hold fatty acids of different lengths. The various complexes that result are known as
- 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. During the course of an investigation of an infant that has suffered a Crib 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 Crib 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.
During the investigation of Crib Death 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 insults.
Mutations in the ACADM gene lead to inadequate levels of an enzyme called medium-chain acyl coenzyme A (CoA) dehydrogenase. Without this enzyme, medium-chain fatty acids from food and from fats stored in the body cannot be broken down and processed. As a result, these fatty acids are not converted into energy, which can lead to characteristic signs and symptoms of this disorder, such as lethargy and low blood sugar. Levels of medium-chain fatty acids or partially degraded fatty acids may build up in tissues and can damage the liver and brain, causing more serious complications. This condition is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered.
