Hyperketotic States Due to Inherited Defects of Ketolysis

Abstract

From the description of 2 unrelated patients with succinyl-CoA transferase (3- OAT) deficiency and 1 patient with acetoacetyl-CoA thiolase (AAT) deficiency, we have attempted to draw the clinical and metabolic consequences of such defects. The association of recurrent attacks of severe ketoacidosis with blood glucose levels generally high or normal, low lactacidemia and low ammonemia is the most common presentation of these disorders. In 3-OAT deficiency, a potentially fatal disorder, there is a permanent ketosis with the only excretion of 3-hydroxybutyrate, acetoacetate and 3-hydroxyisovalerate. AAT patients usually excrete, in addition to the usual ketone bodies, 2-methyl-3-hydroxybutyrate and tiglylglycine; 2-methyl-acetoacetate may also be present. Both conditions can be identified by enzymatic analysis in cultured fibroblast. These disorders can mimic diabetic ketoacidosis or salicylism and can easily be missed. The knowledge of these ketolytic defects must severely question the complacent diagnosis of ‘fasting ketoacidosis’ or ‘idiopathic ketotic hypoglycemia’, mainly when severe metabolic acidosis is present.

Patients Homozygous for the T435N Mutation of Succinyl-CoA:3-Ketoacid CoA Transferase (SCOT) Do Not Show Permanent Ketosis

“…In contrast with most organic acidemias, no diagnostic metabolites are observed in blood and urine samples from SCOT-deficient patients although the ketone bodies acetoacetate and 3-hydroxybutyrate are elevated. Since the first description of SCOT deficiency (2), only 11 affected probands have been reported (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Because of the nonspecific metabolite profile of SCOT-deficient patients, in vitro methods of diagnosis are particularly important.…”

Cloning and Characterization of Helicobacter pyloriSuccinyl CoA:Acetoacetate CoA-transferase, a Novel Prokaryotic Member of the CoA-transferase Family

“…In the mitochondrion of these tissues, acetoacetate is converted to acetoacetyl CoA, which is further broken down to two acetyl CoA molecules capable of entering the tricarboxylic acid cycle. Therefore, this enzyme plays a crucial role in ketone body metabolism (18) as exemplified by the inborn error in humans (25).…”

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency: Two pathogenic mutations, V133E and C456F, in Japanese siblings

“…Since ketosis occurs readily in children, SCOT deficiency is a frequent consideration in pediatrics. However, only eight families with SCOT deficiency have been reported (Tildon et al, 1972;Spence et al, 1973;Saudubray et al, 1987;Middleton et al, 1987;Perez-Cerda et al, 1992;Sakazaki et al, 1995;Fukao et al, 1996a;Pretorius et al, 1996), suggesting that SCOT deficiency is either rare or underdiagnosed.…”