Medium-chain acyl-coenzyme A dehydrogenase deficiency

Fats, fatty acids and fat metabolism

The majority (95%) of the fats in our food and also the fats stored in our body fat are triglycerides.

A triglyceride is made of one glycerol and 3 fatty acids.
Glycerol is some sort of sugar and is metabolised in the carbohydrate metabolism.

A fatty acid is made of 3 kinds of atoms: C (carbon), O (oxygen) and H (hydrogen). Fatty acids have 4 to 24 carbon atoms. Depending on the number of carbons they are called short chain fatty acids (C4 to C6), medium chain fatty acids (C6 to C12) and long or very long chain fatty acids (C12 and more).

Example of a fatty acid with 6 carbons (C6):

caproic acid

Example of a fatty acid with 16 carbons (C16):

palmitic acid

Fatty acids can be burnt or oxidized in order to produce energy.
The oxidation of fatty acids takes place in the mitochondria of the cell. A mitochondrion can be seen as the energy factory of the cell.

Activation of a fatty acid

As soon as a fatty acid arrives in the cell, it first has to be activated.
Activation is done using a specific enzyme and the result is what we call an acyl-CoA or acyl-coenzyme A. These acyl-CoA's have, just like the fatty acid out of which they are made, a several number of carbon atoms. Depending on the number of carbon atoms, we can speak of short chain, medium chain, long chain or very long chain acyl-CoA's.

The oxidation of the acyl-CoA happens inside the mitochondria, so the activated fatty acids first have to be transported through the membrane to the inside of the mitochondrion.

Transport of the acyl-CoA

Only the shorter acyl-CoA's can pass the membrane of the mitochondrion without any help. The longer acyl-CoA's (as of C10) need the help of a substance called carnitine.

The acyl-CoA will drop its CoA and replace it by a carnitine. The result is an acylcarnitine that can be transported through the membrane of the mitochondrion. Once the acylcarnitine is inside the mitochondrion the carnitine is removed and replaced again by a CoA. The acyl-CoA is now ready for being metabolised.

Metabolising of an acyl-CoA: beta-oxidation

Beta-oxidation is a biochemical process that happens in 4 steps. For each step a specific enzyme is needed. Each time the end product of a certain step will be used as the starting product for the next step.

The enzyme needed for the first step is called acyl-CoA dehydrogenase. There are 4 versions of this enzyme: one for short chain, medium chain, long chain and very long chain fatty acids.
The enzyme necessary for the oxidation of medium-chain fatty acids is then called medium-chain acyl-CoA dehydrogenase, or MCAD.

The enzymes needed for the 3 other steps are not important with regard to MCAD deficiency and are not further discussed in this text. But they are mentioned on the image below that schematically represents the cycle of beta-oxidation:

beta oxidation

The end product of beta-oxidation after the 4th step is 1 acetyl-CoA and 1 acyl-CoA that is 2 carbon atoms shorter that the acyl-CoA that was started with. In this process energy is released.

The acetyl-CoA will be further processed by an other biochemical process (called the citric acid cylce, Krebs cycle or TCA cycle). It can also be used to produce ketones. See the pages on the fed-fast cycle for more information about this.

The acyl-CoA that was also the result of the beta-oxidation, will undergo the beta-oxidation process again. This cycle will continue until the fatty acid is completely metabolized.

Medium-chain acyl-CoA dehydrogenase deficiency

MCAD deficiency is a deficiency (not properly working) of an enzym called acyl-CoA dehydrogenase necessary for the oxidation of medium chain fatty acids. This enzyme is called the MCAD enzyme elsewhere on this website.

In patients with MCAD deficiency the first step of beta-oxidation will not work properly on medium chain fatty acids, and as a consequence also the other steps of beta-oxidation will not work.

Long and very long chain fatty acids will partially be oxidized until they become medium chain fatty acids and will thus also need the MCAD enzyme.

Medium-chain acyl-CoA's are accumulated inside the mitochondrion because they cannot be further metabolised.
Especially in times when the fat metabolism is accelerated (when fasting or in case of illness with fever) the amount of acyl-CoA's can be very high and this is toxic. It can cause serious complications.

Furthermore the body cannot count on oxidation of fatty acids for energy and depends on the intake of sugar from food. In case of fasting or vomiting a lack of energy can occur, and also this can have serious consequences.

Luckily these acyl-CoA's don't have to be trapped inside the mitochondria for ever. The body knows of ways to eliminate these substances, and one of the key players is carnitine.