Ketolysis Defects

Summary

The serum concentration of ketone bodies [acetoacetate (AA) + D 3-hydroxybutyrate (3OHB)] represents the balance between their production by the liver and their utilization by peripheral tissues. After a 24-h fast, in normal children aged between 1 and 7 years ketone body levels of 3–6 mmol/liter are reached [1–5]. By analogy to the definition of lactic acidosis, a ketoacidosis is considered to occur when concentrations of ketone bodies are greater than 7 mmol/liter [6]. Many metabolic disorders of childhood may lead to ketoacidosis including insulin-dependent diabetes, the inborn errors of branched-chain amino acid catabolism (MSUD, MMA, PA, IVA), the congenital lactic acidoses like multiple carboxylase and pyruvate carboxylase deficiencies, and inherited defects in enzymes of gluconeogenesis. In these four categories of disorder, hyperketosis is thought to be mainly related to an excess of ketone body production. As opposed to these disorders, hyperketotic states due to ketolytic defects are mainly associated with decreased peripheral ketone body utilization. 3-Oxoacid CoA transferase (3OAT) deficiency is a very rare autosomal recessive disorder characterized by recurrent attacks of severe ketoacidosis with or without hypoglycemia, low lactacidemia, and low ammonemia. Intravenous glucose infusion results in a rapid improvement. Investigation of urinary organic acids during attacks demonstrates the presence of high concentrations of 3OHB and AA only without any other specific organic acids. Clinical diagnosis depends on the evidence of a permanent ketosis both in urine (acetest+) and in plasma (3OHB+AA more than 0.2 mmol/l even in the postprandial period) with a tendency to increase from morning through the day. A fasting test results in a highly abnormal increase in blood ketones, compared with the simultaneous blood glucose and free fatty acid levels. Ketosis is also related to the protein intake and can be triggered by a leucine-loading test. The diagnosis can be confirmed by the demonstration in cultured fibroblasts of a defective C14 AA oxidation and on the very low enzymatic activity of 3OAT.

Mitochondrial acetoacetyl CoA thiolase (AAT) and 2-methyl acetoacetyl CoA thiolase (2MAAT) deficiencies present with very similar clinical and biological pictures. The most frequent presentation is recurrent attacks of severe ketoacidosis, reversed by bicarbonate and glucose infusion. Both conditions are triggered by catabolism, during intercurrent infectious diseases, fasting, and high protein intake. In 2MAAT the urinary organic profile is highly characteristic with association of 3OHB, 2-methyl 3OHB, and tiglylglycine. Excretion of the last two compounds is largely dependent on the protein intake, and during the remission phases can be elicited by acute or chronic isoleucine load. These compounds have not been found in any case of AAT deficiency. Differentiation of the two conditions depends on the study in cultured fibroblasts of K-dependent mitochondrial activities of AAT, and 2MAAT using C14 AACoA and C14 2MAACoA as substrates. Treatment of these disorders consists of avoiding prolonged fast and of a moderately protein restricted diet. One gram sodium bicarbonate should be given orally every 8 h when the acetest is 3 +.

Cytosolic AAT deficiency is a rather different disorder, which presents with severe mental retardation, hypotonia, and a tendency for ketone bodies to accumulate, without significant organic acid excretion. This condition could easily be missed as its clinical presentation is nonspecific and persistent ketosis may be the only initial abnormality. No efficient treatment is available.