Medium-chain Acyl-coenzyme A Dehydrogenase Deficiency - Signs and Symptoms

Signs and Symptoms

MCADD presents in early childhood with hypoketotic hypoglycemia and liver dysfunction, often preceded by extended periods of fasting or an infection with vomiting. Infants who are exclusively breast-fed may present in this manner shortly after birth, due to poor feeding. In some individuals the first manifestation of MCADD may be sudden death following a minor illness. A number of individuals with MCADD may remain completely asymptomatic, provided they never encounter a situation that sufficiently stresses their metabolism. With the advent of expanded newborn screening, some mothers have been identified with MCADD after their infants had positive newborn screens for low carnitine levels.

The enzyme MCAD is responsible for the dehydrogenation step of fatty acids with chain lengths between 6 and 12 carbons as they undergo beta-oxidation in the mitochondria. Fatty acid beta-oxidation provides energy after the body has used up its stores of glucose and glycogen. This typically occurs during periods of extended fasting or illness when caloric intake is reduced, and energy needs are increased. Beta-oxidation of long chain fatty acids produces two carbon units, acetyl-CoA and the reducing equivalents NADH and FADH2. NADH and FADH2 enter the electron transport chain and are used to make ATP. Acetyl-CoA enters the Krebs Cycle and is also used to make ATP via the electron transport chain and substrate level phosphorylation. When the supply of acetyl-CoA (coming from the beta-oxidation of fatty acids) exceeds the capacity of the Krebs Cycle to metabolize acetyl-CoA, the excess acetyl-CoA molecules are converted to ketone bodies (acetoacetate and beta-hydroxybutyrate) by HMG-CoA synthase in the liver. Ketone bodies can also be used for energy especially by the brain and heart; in fact they become the main sources of energy for those two organs after day three of starvation.