Abstract
A boy of 6.5 years and his 36-year-old father were found to excrete elevated amounts of urinary 2-methyl-3-hydroxybutyric acid and tiglylglycine, as is found in patients with a presumed β-ketothiolase deficiency. Psychomotor development of both patients was normal. The clinical picture was mild, as only during periods with infections does metabolic acidosis develop and clinical abnormalities become noticeable. In vivo loading tests with protein and especially with L(+) isoleucine resulted in massive excretion of 2-methyl-3-hydroxy-butyric acid and tiglyglycine. Enzymatic activity of 3-keto-acyl-CoA thiolase was not detectable in patients fibroblasts using 2-methyl-acetoacetyl-CoA as substrate, whereas with acetoacetyl-CoA as substrate, a lowered activity was found. As ketogenesis in these patients was normal, these findings strongly suggest that the inborn metabolic defect known as β-ketothiolase deficiency is caused by a deficiency of the mitochondrial acetoacyl-CoA specific thiolase isoenzyme involved in thiolysis of (2-methyl) acetoacetyl-CoA, whereas the isoenzyme involved in ketogenesis is not affected.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Daum RS, Scriver RC, Mamer OA, Delvin E, Lamm P, Goldman H (1973) An inherited disorder of isoleucine catabolism causing accumulation of α-methylacetoacetate and α-methyl-β-hydroxybutyrate, and intermittent metabolic acidosis. Pediatr Res 7:149–160
De Groot CJ, Luit-de Haan G, Hulstaert CE, Hommes FA (1977) A patient with severe neurologic symptoms and acetoacetyl-CoA thiolase deficiency. Pediatr Res 11:1112–1117
Duran M, Bruinvis L, Ketting O, Kamerling JP, Wadman SK, Schutgens RBH (1982) The identification of (E)-2-methylgulutaconic acid, a new isoleucine metabolite in the urine of patients with β-ketothiolase deficiency, propionic acidaemia and methylmalonic acidaemia. Biomed Mass Spectrom 9:1–5
Gompertz D, Saudubray JM, Charpentier C, Bartlett K, Goodey PA, Draffan GH (1974) A defect in L-isoleucine metabolism associated with α-methyl-β-hydroxybutyric and α-methylacetoacetic aciduria: Quantitative in vivo and in vitro studies. Clin Chim Acta 57:269–281
Guynn RW, Veech RL (1974) Direct enzymatic determination of acetate in tissue extracts in the presence of labile acetate esters. Anal Biochem 61:6–15
Halvorsen S, Stokke O, Jellum E (1979) A variant form of 2-methyl-3-hydroxybutyric and 2-methylacetoacetic aciduria. Acta Paediatr Scand 68:123–128
Henry CG, Strauss AW, Keating JP, Hillman RE (1981) Congestive cardiomyopathy associated with β-ketothiolase deficiency. J Pediatr 99:754–758
Hillman RE, Keating JP (1974) Beta-ketothiolase deficiency as a cause of the “ketotic hyperglycinemia syndrome”. Pediatrics 53: 221–226
Kamerling JP, Brouwer M, Ketting D, Wadman SK (1979) Gas chromatography of urinary N-phenylacetylgutamine. J Chromatogr 164:217–221
Keating JP, Feiging RD, Tenenbaum SM, Hillman RE (1972) Hyperglycinemia with ketosis due to a defect in isoleucine metabolism: A preliminary report. Pediatrics 50:890–896
Landaas S (1975) Accumulation of 3-hydroxy isobutyric acid, 2-methyl-3-hydroxybutyric acid and 3-hydroxyisovaleric acid in ketoacidosis. Clin Chim Acta 64:143–154
Middleton B (1973) The oxoacyl-coenzyme A thiolases of animal tissues. Biochem J 132:717–730
Middleton B (1972) The kinetic mechanism of 3-hydroxy-3-methylglutaryl-coenzyme A synthase from Baker's yeast. Biochem J 126:35–47
Middleton B (1972) The acetoacetyl-coenzyme A thiolases of rat brain and their relative activities during postnatal development. Biochem J 132:731–737
Middleton B (1978) Enzymatic aspects of ketone body metabolism: the role of mitochondrial acetoacetyl CoA thiolase isoenzymes. In: Söling HD, Senfert CD (eds) Biochemical and clinical aspects of ketone body metabolism. Georg Thieme, Stuttgart, pp 1–9
Middleton B, Bartlett K (1982) Synthesis and characterisation of 2-methylacetoacetyl-CoA and its use in identification of the defect in 2-methyl-3-hydroxybutyric aciduria. Clin Chim Acta (submitted for publication)
Robinson BH, Sherwood WG, Taylor J, Balfe JW, Mamer OA (1979) Acetoacetyl CoA thiolase deficiency: A cause of severe ketoacidosis in infancy simulating salicylism. J Pediatrics 95:228–233
Sedmak JJ, Grosberg SE (1977) A rapid sensitive and versatile assay for protein using Coomassie Brilliant Blue G 250. Anal Biochem 79:544–552
Srere PA, Brazil H, Gonen L (1963) Citrate condensing enzyme of pigeon breast muscle and moth files muscle. Acta Chem Scand 17:S129-S134
Sweetman L, Weyler W, Nyhan WL, de Céspedes C, Rosa Loria A, Estrada Y (1978) Abnormal metabolites of isoleucine in a patient with propionyl CoA carboxylase deficiency. Biomed Mass Spectrom 5:198–208
Williamson JR, Corkey BE (1969) Assays of intermediates of the citric acid cycle and related compounds. In: Colowick SP, Kaplan NO (eds) Methods in enzymology, vol 13. Academic Press, London, pp 435–513
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Schutgens, R.B.H., Middleton, B., Blij, J.F.v.d. et al. Beta-ketothiolase deficiency in a family confirmed by in vitro enzymatic assays in fibroblasts. Eur J Pediatr 139, 39–42 (1982). https://doi.org/10.1007/BF00442077
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00442077