Question

A)Some individuals can suffer from medium-chain acyl-CoA dehydrogenase (MCAD) deficiency. Which intermediates accumulate in individuals with MCAD deficiency? Can other intermediates still be oxidized and if so, why?

Answer 1

A) Medium-chain acyl-coenzyme A dehydrogenase deficiency (MCAD) is an autosomal recessive inherited metabolic disorder caused by a deficiency of enzyme for metabolism of a group of fats called medium-chain fatty acids. MCAD deficiency is caused by mutations in the ACADM gene that code for the enzyme medium-chain acyl-CoA dehydrogenase (MCAD) that is involved in mitochondrial fatty acid beta oxidation.

Stored fats are used by the cells for generation of energy when glucose levels are depleted. Fats are generally stored as the long chain fats of C16, C18 series. They are oxidized in two carbon units by a series of four long chain-specific enzymes. The chain length is reduced to 8 -12 carbons as oxidation proceeds. These medium chain fatty acids are oxidized by the medium chain length-specific oxidative enzymes.

When there is deficiency of MCAD enzyme, the first stage of oxidation of medium chain fatty acid is inhibited. Fatty acid intermediates such as octanoic acid and decanoic acids are accumulated in this deficiency. As a result, there is impaired beta oxidation in mitochondria and accumulation of specific medium chain metabolites such as octanoylcarnitine, decanoylcarnitine, or decenoylcarnitine. The predominant metabolite seen is octanoylcarnitine as decanoyl CoA can be reconverted to octanoyl CoA by MCAD deficient cells. Fatty acids are incorporated as triglycerides, resulting in fat accumulation in liver.

Fatty acids can be metabolized by alpha, beta and omega oxidation. Alpha oxidation takes place in peroxisomes, while beta oxidation takes place in peroxisomes and mitochondria. In beta oxidation, different enzymes oxidized different fatty acids. There are very long chain acyl-CoA dehydrogenase (VLCAD), long chain acyl-CoA dehydrogenase (LCAD), medium chain acyl dehydrogenase (MCAD) and Short chain acyl dehydrogenase (SCAD) that metabolize different chain lengths of chain fatty acids.

Very long chain fatty acids are oxidized to long chain acyl CoA, which are then metabolized to medium chain acyl CoA. Medium chain acyl CoA are metabolized to short chain acyl CoA in beta oxidation and then finally to acetyl CoA. The long chain intermediates can be metabolized to medium chain intermediates in MCAD as the enzymes VLCAD and LCAD are present and functional. However, due to deficiency of MCAD, medium chain CoA cannot be oxidised to short chain CoA. This cause a marked inhibition in production of ketone bodies due to reduced acetyl CoA production (even though there is a functional SCAD0. CoA becomes the limiting factor if there is insufficient carnitine available for exchanging the CoA moiety and transporting the accumulated intermediates out of the mitochondria. Other pathways that use CoA can hence, be inhibited. The reduced production of ketones affects energy generation from ketones during fasting. Ketones are generally produced during fasting when fatty acids can be completely oxidized to acetyl CoA.