Metabolism
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Two boys with profound fasting hypoglycaemia and no ketone bodies
Key points from this exercise:
Acetoacetate is synthesised by reaction of 3 mol of acetyl CoA to form acetoacetyl CoA, then hydroxymethylglutaryl CoA (HMG CoA), followed by cleavage to yield acetyl CoA and acetoacetate.
Acetoacetate is chemically unstable, and undergoes non-enzymic decarboxylation to acetone, which is poorly metabolised (if at all). Therefore much of the acetoacetate synthesised in the liver id reduced to beta-hydroxybutyrate before export for use by muscle and other tissues as a metabolic fuel.
Genetic defects of HMG CoA synthase lead to profound hypoglycaemia on prolonged fasting, with very low concentrations of ketone bodies. Small amounts of acetoacetate and beta-hydroxybutyrate are formed from the amino acid leucine.
Genetic defects of HMG CoA lyase lead to profound hypoglycaemia on prolonged fasting, with no detectable ketone bodies. There is also metabolic acidosis due to accumulation of intermediates of leucine catabolism; HMG CoA is a normal intermediate in leucine metabolism.