Abstract
Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency affects both isoleucine catabolism and ketone body metabolism. The disorder is characterized by intermittent ketoacidotic episodes. We report three Japanese patients. One patient (GK69) experienced two ketoacidotic episodes at the age of 9 months and 3 years, and no further episodes until the age of 25 years. She had two uncomplicated pregnancies. GK69 was a compound heterozygote of the c.431A>C (H144P) and c.1168T>C (S390P) mutations in T2 (ACAT1) gene. She was not suspected of having T2 deficiency during her childhood, but she was diagnosed as T2 deficient at the age of 25 years by enzyme assay using fibroblasts. The other two patients were identical twin siblings who presented their first ketoacidotic crisis simultaneously at the age of 3 years 4 months. One of them (GK77b) died during the first crisis and the other (GK77) survived. Even during severe crises, C5-OH and C5:1 were within normal ranges in their blood acylcarnitine profiles and trace amounts of tiglylglycine and small amounts of 2-methyl-3-hydroxybutyrate were detected in their urinary organic acid profiles. They were H144P homozygotes. This H144P mutation has retained the highest residual T2 activity in the transient expression analysis of mutant cDNA thus far, while the S390P mutation did not retain any residual T2 activity. The “mild” H144P mutation may result in subtle profiles in blood acylcarnitine and urinary organic acid analyses. T2-deficient patients with “mild” mutations have severe ketoacidotic crises but their chemical phenotypes may be subtle even during acute crises.
Competing interests: None declared.
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Abbreviations
- SCOT:
-
Succinyl-CoA:3-ketoacid CoA transferase
- T2:
-
Mitochondrial acetoacetyl-CoA thiolase
References
Daum RS, Lamm PH, Mamer OA, Scriver CR (1971) A “new” disorder of isoleucine catabolism. Lancet 2:1289–1290
Fukao T, Yamaguchi S, Kano M et al (1990) 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, Orii T, Hashimoto T (1995) Molecular basis of beta-ketothiolase deficiency: mutations and polymorphisms in the human mitochondrial acetoacetyl-coenzyme A thiolase gene. Hum Mutat 5:113–120
Fukao T, Song XQ, Mitchell GA et al (1997) Enzymes of ketone body utilization in human tissues: protein and messenger RNA levels of succinyl-coenzyme A (CoA):3-ketoacid CoA transferase and mitochondrial and cytosolic acetoacetyl-CoA thiolases. Pediatr Res 42:498–502
Fukao T, Nakamura H, Song XQ et al (1998) Characterization of N93S, I312T, and A333P missense mutations in two Japanese families with mitochondrial acetoacetyl-CoA thiolase deficiency. Hum Mutat 12:245–254
Fukao T, Scriver CR, Kondo N (2001) The clinical phenotype and outcome of mitochondrial acetoacetyl-CoA thiolase deficiency (beta-ketothiolase or T2 deficiency) in 26 enzymatically proved and mutation-defined patients. Mol Genet Metab 72:109–114
Fukao T, Nakamura H, Nakamura K et al (2002) Characterization of six mutations in five Spanish patients with mitochondrial acetoacetyl-CoA thiolase deficiency: effects of amino acid substitutions on tertiary structure. Mol Genet Metab 75:235–243
Fukao T, Zhang GX, Sakura N et al (2003) The mitochondrial acetoacetyl-CoA thiolase (T2) deficiency in Japanese patients: urinary organic acid and blood acylcarnitine profiles under stable conditions have subtle abnormalities in T2-deficient patients with some residual T2 activity. J Inherit Metab Dis 26:423–431
Fukao T, Shintaku H, Kusubae R et al (2004) Patients homozygous for the T435N mutation of succinyl-CoA:3-ketoacid CoA Transferase (SCOT) do not show permanent ketosis. Pediatr Res 56:858–863
Fukao T, Zhang G, Rolland MO et al (2007) Identification of an Alu-mediated tandem duplication of exons 8 and 9 in a patient with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Mol Genet Metab 92:375–378
Fukao T, Boneh A, Aoki Y, Kondo N (2008) A novel single-base substitution (c.1124A > G) that activates a 5-base upstream cryptic splice donor site within exon 11 in the human mitochondrial acetoacetyl-CoA thiolase gene. Mol Genet Metab 94:417–421
Fukao T, Horikawa R, Naiki Y et al (2010a) A novel mutation (c.951 C > T) in an exonic splicing enhancer results in exon 10 skipping in the human mitochondrial acetoacetyl-CoA thiolase gene. Mol Genet Metab 100:339–344
Fukao T, Nguyen HT, Nguyen NT et al (2010b) A common mutation, R208X, identified in Vietnamese patients with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Mol Genet Metab 100:37–41
Haapalainen AM, Merilainen G, Pirila PL, Kondo N, Fukao T, Wierenga RK (2007) Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function. Biochemistry 46:4305–4321
Kano M, Fukao T, Yamaguchi S, Orii T, Osumi T, Hashimoto T (1991) Structure and expression of the human mitochondrial acetoacetyl-CoA thiolase-encoding gene. Gene 109:285–290
Kimura M, Yamamoto T, Yamaguchi S (1999) Automated metabolic profiling and interpretation of GC/MS data for organic acidemia screening: a personal computer-based system. Tohoku J Exp Med 188:317–334
Kobayashi H, Hasegawa Y, Endo M, Purevsuren J, Yamaguchi S (2007) A retrospective ESI-MS/MS analysis of newborn blood spots from 18 symptomatic patients with organic acid and fatty acid oxidation disorders diagnosed either in infancy or in childhood. J Inherit Metab Dis 30:606
Lehnert W (1994) Long-term results of selective screening for inborn errors of metabolism. Eur J Pediatr 153:S9–S13
Nakamura K, Fukao T, Perez-Cerda C et al (2001) A novel single-base substitution (380 C > T) that activates a 5-base downstream cryptic splice-acceptor site within exon 5 in almost all transcripts in the human mitochondrial acetoacetyl-CoA thiolase gene. Mol Genet Metab 72:115–121
Niwa H, Yamamura K, Miyazaki J (1991) Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108:193–199
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 Pediatr 95:228–233
Sakurai S, Fukao T, Haapalainen AM et al (2007) Kinetic and expression analyses of seven novel mutations in mitochondrial acetoacetyl-CoA thiolase (T2): identification of a Km mutant and an analysis of the mutational sites in the structure. Mol Genet Metab 90:370–378
Wakazono A, Fukao T, Yamaguchi S et al (1995) Molecular, biochemical, and clinical characterization of mitochondrial acetoacetyl-coenzyme A thiolase deficiency in two further patients. Hum Mutat 5:34–42
Zhang GX, Fukao T, Rolland MO et al (2004) Mitochondrial acetoacetyl-CoA thiolase (T2) deficiency: T2-deficient patients with “mild” mutation(s) were previously misinterpreted as normal by the coupled assay with tiglyl-CoA. Pediatr Res 56:60–64
Zhang G, Fukao T, Sakurai S, Yamada K, Michael Gibson K, Kondo N (2006) Identification of Alu-mediated, large deletion-spanning exons 2–4 in a patient with mitochondrial acetoacetyl-CoA thiolase deficiency. Mol Genet Metab 89:222–226
Acknowledgments
We thank professor Jörn Oliver Sass (Freiburg Univ) for quantification of urinary 2-methyl-3-hydroxybutyrate and tiglylglycine, Drs Hironori Kobayashi and Yuichi Mushimoto (Shimane University) for urinary organic acid analysis and tandem mass analysis, Dr Tamayo Ishikawa (Kagoshima University) for patients’ care, and Ms Keiko Murase and Ms Naomi Sakaguchi (Gifu University) for technical assistance. We also thank Paul Langman, PhD for his assistance with scientific English usage.
This study was in part supported by Health and Labor Science Research Grants for Research on Intractable Diseases and for Research on Children and Families from The Ministry of Health, Labor and Welfare of Japan and by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan.
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Communicated by: K. Michael Gibson.
Appendices
Concise One-Sentence Take-Home Message
Patients with beta-ketothiolase deficiency having a mutation which retains some residual activity showed subtle abnormality in urinary organic acid analysis and blood acylcarnitine analysis even during acute ketoacidotic episodes.
Details of the Contributions of Individual Authors
Toshiyuki Fukao and Naomi Kondo performed the enzyme assays, immunoblot/mutation analysis, and expression analysis of cDNAs. Toshiyuki Fukao mainly wrote this manuscript. Shinsuke Maruyama, Toshihiro Ohura, Mitsuo Toyoshima, Naomi Kuwada, and Mari Imamura are the physicians responsible for the patients. Yuki Hasegawa and Seiji Yamaguchi performed gas chromatography-mass spectrometry and tandem mass spectrometry analyses and first suspected the disorder. Isao Yuasa confirmed GK77 and 77b as identical twins by DNA analyses. Antti M Haapalainen and Rik K Wierenga analyzed the tertiary structural effects of the mutations.
References to Electronic Databases
Alpha-methylacetoacetic acidura, mitochondrial acetoacetyl-CoA thiolase deficiency (OMIM 203750, 607809)
Mitochondrial acetoacetyl-CoA thiolase, acetyl-CoA acetyltransferase 1 (EC 2.3.1.9)
ACAT1 gene (gene ID 38, NM_000019.3)
Details of Funding
This study was in part supported by Health and Labor Science Research Grants for Research on Intractable Diseases and Research on Children and Families from the Ministry of Health, Labor and Welfare of Japan and by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan
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This study has been approved by the Ethical Committee of the Graduate School of Medicine, Gifu University.
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Fukao, T. et al. (2011). Three Japanese Patients with Beta-Ketothiolase Deficiency Who Share a Mutation, c.431A>C (H144P) in ACAT1 . In: JIMD Reports - Case and Research Reports, 2011/3. JIMD Reports, vol 3. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2011_72
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DOI: https://doi.org/10.1007/8904_2011_72
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