Acetoacetyl-CoA thiolase deficiency

De Groot et aL (1977) reported a patient who was the first child of unrelated parents, presenting from 4 months of age with delayed motor development, ataxic and choreoathetoid movements, involuntary eye movements and hypotonia. Blood lactate and pyruvate were constantly above normal and a mild metabolic acidosis was observed. Blood 3-hydroxybutyrate and acetoacetate concentrations were 4.47 and 0.84 mmol 1 respectively. The keto acidosis responded to intravenous glucose and bicarbonate, but she 

Investigations of liver biopsy material for enzymes involved in lactic acidosis and ketogenesis showed normal activites of pyruvate carboxylase, citrate synthetase, isocitrate dehydrogenase, glutamate-pyruvate transaminase, reduced activity of fructose 1,6-bisphosphatase and notably reduced activity of cytosolic acetoacetyl-CoA thiolase. The latter was found to be due to altered kinetic properties of the enzyme and this was confirmed in cultured skin fibroblasts, the enzyme being much more sensitive to coenzyme A inhibition than the normal enzyme. Activity of succinyl-CoA 3-keto acid-CoA transferase was not reported. 

A second case dscribed as one of acetoacetyl-CoA thiolase deficiency, has been reported by Robinson et al (1979) (Section 10.4.1), in which urinary metabolites included 3-hydroxybutyrate, acetoacetate, 2-methyl-3-hydroxy-butyrate, 2-methylacetoacetate and tiglylglycine. The authors postulated an enzyme deficiency of short-chain mitochondrial 3-keto acid-CoA thiolase, affecting both acetoacetyl-CoA and 2-methylacetoacetyl-CoA metabolism, ascribing a common enzyme to both metabolic pathways. The presentation of this case was very different from that of de Groot et al, (1977), and further study of 2-methylacetoacetyl-CoA thiolase activity by more direct enzyme assays may resolve the question of the distinction of these enzyme systems (see Section 12.3 below also). 

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Acetoacetyl-CoA thiolase deficiency 3-Hydroxybutyric and acetoacetic acids Cytosolic acetoacetyl-CoA thiolase 12.2... 

The patients all appear to have partial deficiencies of 2-methylacetoacetyl-CoA thiolase of varying degrees and the enzyme deficiency is expressed in fibroblasts. Inheritance is probably autosomal recessive and prenatal diagnosis should be possible. The occurrence of a common disorder affecting both 2-methylacetoacetyl-CoA thiolase and acetoacetyl-CoA thiolase is also possible, and further detailed enzymological studies on the disease are necessary. The 3-oxoacyl-CoA thiolases are discussed further in Chapter 12. 

Examination of tissues post mortem showed normal acetoacetate oxidation by muscle and normal ketogenesis in liver. The severity of ketosis eliminated non-metabolic causes such as starvation and salicylism, and further investigation of post-mortem tissues for acetoacetyl-CoA thiolase, 3-hydroxybutyrate dehydrogenase and succinyl-CoA 3-keto acid-CoA transferase activities revealed grossly deficient activity of the latter enzyme in brain, kidney, muscle and cultured fibroblasts, in the presence of normal activities of the other enzymes. 

A good example is provided by the spectra from individuals with a deficiency in methylacetoacetyl CoA thiolase (MACT). The conversion of 2-methyl-acetoacetyl CoA into acetyl-CoA and propionyl-CoA is inhibited and an accumulation of abnormal catabolic products is observed in the urine. Both ID and 2D iH NMR spectroscopy have been used to investigate the urinary metabolites of patients with this disorder. The urine spectra from the patients clearly showed the presence of both 2-methyl-3-hydroxybu-tyrate and tiglylglycine, which is characteristic for MACT deficiency due to the build up of metabolites close to the position of enzyme deficiency. 

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