Specific Causes of Congenital Keto Acidosis in Infants

Keto acidosis may occur in infants as a result of specific genetic defects, in addition to its occurrence in association with several other organic acidurias, for example propionic acidaemia (ketotic hyperglycinaemia). Chapter 10, Section 10.4.1 on 2-methylacetoacetyl-CoA thiolase deficiency also discussed a report by Robinson et al. (1979) of a patient with apparent combined deficiencies of this enzyme and of 3-oxoacyl-CoA thiolase, which they considered to be identical enzymes. A report of a case of specific 3-oxoacyl-CoA thiolase deficiency has increased interest in these enzymes as causes of congenital keto acidosis, and these are discussed further below, as are patients with a different cause of a similar biochemical condition, succinyl-CoA 3-keto acid-CoA transferase deficiency. 

This chapter describes the case reports of these enzyme deficiencies and the underlying biochemistry of the disorders and their associations. It is not the intention to discuss keto acidosis associated with other diseases, for example juvenile diabetes, or ketogenesis and its control which are reviewed elsewhere (Wildenhoff, 1975, 1977 McGarry and Foster, 1976 Halperin, 1977). In addition to the common occurrence of 3-hydroxybutyrate and acetoacetate in body fluids of patients with keto acidosis, secondary organic acids have been observed in urine, including adipic and suberic acids (Pettersen et aL, 1972), 3-hydroxyisovaleric acid (Landaas, 1974), 3-hydroxyisobutyric acid and 2-methyl-3-hydroxybutyric acid (Landaas, 1975). The dicarboxylic acids occur as a result of initial co-oxidation of accumulating long-chain fatty acids followed by )8-oxidation (Pettersen, 1972), and metabolites of the branched-chain amino acids occur because of inhibition of their metabolic pathways by 3-hydroxybutyrate and acetoacetate (Landaas and Jakobs, 1977). 

This disorder (McKusick 24505) was first described by Comblath et al. (1971) and Tildon and Comblath (1972), who reported a full-term baby of unrelated American Negro parents who presented from the second day of life with tachypnoea and feeding difficulties, and with an acid urine. At 51 days he was stuperous, moderately dehydrated, with a severe metabolic acidosis (blood pH 6.93), ketonuria, ketonaemia and hyperuricaemia. The latter was almost certainly due to renal retention of urate caused by the accumulation of 

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 second case was reported briefiy with a slightly different presentation at 7 months of age in a family in which two siblings had died earlier at 6 months. Blood 3-hydroxybutyrate and acetoacetate concentrations were 29 and 1.3 mmol 1 respectively during acidotic periods and less than 0.2 during symptom-free periods. Liver 3-hydroxybutyrate dehydrogenase activity and kidney, brain and cultured fibroblast acetoacetyl-CoA thiolase activities were normal, but succinyl-CoA 3-keto acid-CoA transferase activity was absent from these tissues (Spence et aL, 1973). However, no detailed report has yet appeared to substantiate these observations. 

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Specific causes of congenital keto acidosis in infants... 

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