Summary
A review is presented of 22 published cases of verified or probable mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency, a disorder of isoleucine and ketone body metabolism. The clinical expression, characterized by ketoacidosis, vomiting and lethargy, is highly variable. Typical age of onset is between 6 and 24 months. The disorder, which has been observed in several ethnic groups, is apparently inherited as an autosomal, recessive trait. The prognosis is relatively good if acute episodes of ketoacidosis and dehydration are adequately treated. There is abnormal urinary excretion of 2-methyl-3-hydroxybutyric acid, tiglylglycine, and in some instances also 2-methyl-acetoacetic acid. However, such a pattern of organic aciduria has also been found in cases with normal thiolase activity. Genetic complementation analyses have demonstrated considerable heterogeneity. The cDNA for human methyl-acetoacetyl-CoA thiolase has been cloned and sequenced. Studies in one patient showed a G-to-A substitution at position 1138 of the mRNA, causing 347Ala to Thr change in the mature enzyme. Studies in other patients have shown variable enzyme amount and/or stability.
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Aramaki S, Lehotay D, Sweetman L, Nyhan WL, Winter SC, Middleton B (1991) Urinary excretion of 2-methylacetoacetate, 2-methyl-3-hydroxybutyrate, and tiglylglycine after isoleucine loading in the diagnosis of 2-methylacetoacetyl-CoA thiolase deficiency.J Inher Metab Dis 14: 63–74.
Bennett MJ, Littlewood JM, MacDonald A, Pollitt RJ, Thompson J (1983) A case of β-ketothiolase deficiency.J Inher Metab Dis 6: 157.
Daum RS, Mamer OA, Lamm PH, Scriver CR (1971) A ‘new’ disorder of isoleucine catabolism.Lancet 2: 1289–1290.
Daum RS, Scriver CR, 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 C, Hulstaert CE, Hommes FA (1977) A patient with severe neurologic symptoms and acetoacetyl-CoA thiolase deficiency.Pediatr Res 11: 1112–1116.
Fukao T, Kamijo K, Osumi T et al (1989) Molecular cloning and nucleotide sequencing of cDNA encoding the entire precursor of rat mitochondrial acetoacetyl-CoA thiolase.J Biochem 106: 197–204.
Fukao T, Yamaguchi S, Kano M et al (1990a) Molecular cloning and sequence of the complementary DNA encoding human mitochondrial acetoacetyl-coenzyme A thiolase and study of the variant enzymes in cultured fibroblasts from patients with 3-ketothiolase deficiency.J Clin Invest 86: 2086–2092.
Fukao T, Yamaguchi S, Nagasawa H et al (1990b) Molecular cloning of cDNA for human mitochondrial acetoacetyl-CoA thiolase and molecular analysis of 3-ketothiolase deficiency.J Inher Metab Dis 13: 757–760.
Fukao T, Yamaguchi S, Tomatsu S et al (1991) Evidence for a structural mutation (347Ala to Thr) in a German family with 3-ketothiolase deficiency.Biochem Biophys Res Commun 179: 124–129.
Gehring U, Riepertinger C, Lynen F (1968) Reinigung und Kristallisation der thiolase, untersuchungen zum wirkungsmechanismus.Eur J Biochem 6: 264–280.
Gompertz D, Saudubray JM, Charpentier C, Bartlett K, Goodey PA, Draffan GH (1974) A defect inl-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.
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: 754–757.
Hillman RE, Keating JP (1974) Beta-ketothiolase deficiency as a cause of the ‘Ketotic hyperglycinemia syndrome’.Pediatrics 53: 221–225.
Hiyama K, Sakura N, Matsumoto T, Kuhara T (1986) Deficient β-ketothiolase activity in leukocytes from a patient with 2-methylacetoacetic aciduria.Clin Chim Acta 155: 189–194.
Iden P, Gibson KM, Søvik O, Sweetman L (1986) A macromolecular labelling assay for the study of defects in the isoleucine metabolic pathway.Soc Study Inborn Errors Metab 24th Annual Symposium, Amersfoort, The Netherlands, 25A.
Iden P, Søvik O, Sweetman L, Gibson KM (1987) 3-Ketothiolase deficiency: Biochemical investigation of 15 cases.Pediatr Res 22: 236A.
Iden P, Middleton B, Robinson BH et al (1990) 3-Oxothiolase activities and (14C)-2-methylbutanoic acid incorporation in cultured fibroblasts from 13 cases of suspected 3-oxothiolase deficiency.Pediatr Res 28: 518–522.
Keating JP, Feigin RD, Tenenbaum SM, Hillman RE (1972) Hyperglycinemia with ketosis due to a defect in isoleucine metabolism: A preliminary report.Pediatrics 50: 890–895.
Leonard JV, Middleton B, Seakins JWT (1987) Acetoacetyl CoA thiolase deficiency presenting as ketotic hypoglycemia.Pediatr Res 21: 211–213.
Merinero B, Pérez-Cerdá C, Garcia MJ et al (1987) β-Ketothiolase deficiency: Two siblings with different clinical conditions.J Inher Metab Dis 10 (Suppl. 2): 276–278.
Middleton B (1973a) The oxoacyl-coenzyme A thiolases of animal tissues.Biochem J 132: 717–730.
Middleton B (1973b) The acetoacetyl-coenzyme A thiolases of rat brain and their relative activities during postnatal development.Biochem J 132: 731–737.
Middleton B (1978a) Enzymatic aspects of ketone body metabolism: the role of mitochondrial acetoacetyl CoA thiolase isoenzymes. In Søling HD, Senfert CD, eds.Biochemical and Clinical Aspects of Ketone Body Metabolism. Stuttgart: Georg Thieme, 1–9.
Middleton B (1978b) Identification of heterozygotes for the defect of mitochondrial 3-ketoacyl CoA thiolase causing 2-methyl-3-hydroxybutyric aciduria.J Inher Metab Dis 10 (Suppl. 2): 270–272.
Middleton B, Bartlett K (1983) The synthesis and characterisation of 2-methylacetoacetyl coenzyme A and its use in the identification of the site of the defect in 2-methylacetoacetic and 2-methyl-3-hydroxybutyric aciduria.Clin Chim Acta 128: 291–305.
Middleton B, Gray RGF, Bennett MJ (1984) Two cases of β-ketothiolase deficiency: A comparison.J Inher Metab Dis 7 (Suppl. 2): 131–132.
Middleton B, Bartlett K, Romanos A et al (1986) 3-Ketothiolase deficiency.Eur J Pediatr 144: 586–589.
Miyasawa S, Osumi T, Hashimoto T (1980) The presence of a new 3-oxoacyl-CoA thiolase in rat liver peroxisomes.Eur J Biochem 103: 589–596.
Nagasawa H, Yamaguchi S, Orii T, Schutgens RBH, Sweetman L, Hashimoto T (1989) Heterogeneity of defects in mitochondrial acetoacetyl-CoA thiolase biosynthesis in fibroblasts from four patients with 3-ketothiolase deficiency.Pediatr Res 26: 145–149.
Ozasa H, Furuta S, Miyasawa S et al (1984) Biosynthesis of enzymes of rat-liver mitochondrial β-oxidation.Eur J Biochem 144: 453–458.
Pollitt RJ (1983) The occurrence of substituted 3-methyl-3-hydroxyglutaric acids in urine in propionic acidaemia and β-ketothiolase deficiency.Biomed Mass Spectrom 10: 253–257.
Robinson BH, Sherwood WG, Taylor J, Williamson Balfe J, Mamer OA (1979) Acetoacetyl CoA thiolase deficiency: A cause of severe ketoacidosis in infancy simulating salicylism.J Pediatr 95: 228–233.
Sabetta G, Bachmann C, Giardini O et al (1987) β-Ketothiolase deficiency with favourable evolution.J Inher Metab Dis 10: 405–406.
Schutgens RBH, Middleton B, v.d. Blij JF et al (1982) β-Ketothiolase deficiency in a family confirmed by in vitro enzymatic assays in fibroblasts.Eur J Pediatr 139: 39–42.
Sweetman L (1989) Branched chain organic acidurias. In Scriver CR, Beaudet A, Sly WS, Valle DV, eds.The Metabolic Basis of Inherited Disease, 6th edn. New York: McGraw-Hill, 791–820.
Søvik O, Saudubray J-M, Munnich A, Sweetman L (1992) Genetic complementation analysis of mitochondrial 2-methyl-acetoacetyl-CoA thiolase deficiency in cultured fibroblasts.J Inher Metab Dis 15: 359–362.
Williamson DH, Bates MW, Page MA, Krebs HA (1971) Activities of enzymes involved in acetoacetate utilization in adult mammalian tissues.Biochem J 121: 41–47.
Yamaguchi S, Orii T, Sakura N, Miyazawa S, Hashimoto T (1988a) Immunochemical studies of cultured fibroblasts from a patient with 3-ketothiolase deficiency.J Inher Metab Dis 11: 345–347.
Yamaguchi S, Orii T, Sakura N, Miyasawa S, Hashimoto T (1988b) Defect in biosynthesis of mitochondrial acetoacetyl-coenzyme A thiolase in cultured fibroblasts from a boy with 3-ketothiolase deficiency.J Clin Invest 81: 813–817.
Yamaguchi S, Fukao T, Nagasawa H et al (1990) 3-Ketothiolase deficiency: Molecular heterogeneity of the enzyme defect and cloning of cDNA. InFatty Acid Oxidation: Clinical, Biochemical, and Molecular Aspects. New York: Alan R. Liss, 673–679.
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Søvik, O. Mitochondrial 2-methylacetoacetyl-CoA thiolase deficiency: An inborn error of isoleucine and ketone body metabolism. J Inherit Metab Dis 16, 46–54 (1993). https://doi.org/10.1007/BF00711314
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DOI: https://doi.org/10.1007/BF00711314