Journal of Inherited Metabolic Disease

, Volume 33, Supplement 3, pp 307–313 | Cite as

A neonatal-onset succinyl-CoA:3-ketoacid CoA transferase (SCOT)-deficient patient with T435N and c.658-666dupAACGTGATT p.N220_I222dup mutations in the OXCT1 gene

  • Toshiyuki Fukao
  • Tomohiro Ishii
  • Naoko Amano
  • Petri Kursula
  • Masaki Takayanagi
  • Keiko Murase
  • Naomi Sakaguchi
  • Naomi Kondo
  • Tomonobu Hasegawa
Research Report
First Online:
Received:
Revised:
Accepted:

Abstract

Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency causes episodic ketoacidotic crises and no apparent symptoms between them. Here, we report a Japanese case of neonatal-onset SCOT deficiency. The male patient presented a severe ketoacidotic crisis, with blood pH of 7.072 and bicarbonate of 5.8 mmol/L at the age of 2 days and was successfully treated with intravenous infusion of glucose and sodium bicarbonate. He was diagnosed as SCOT deficient by enzymatic assay and mutation analysis. At the age of 7 months, he developed a second ketoacidotic crisis, with blood pH of 7.059, bicarbonate of 5.4 mmol/L, and total ketone bodies of 29.1 mmol/L. He experienced two milder ketoacidotic crises at the ages of 1 year and 7 months and 3 years and 7 months. His urinary ketone bodies usually range from negative to 1+ but sometimes show 3+ (ketostix) without any symptoms. Hence, this patient does not show permanent ketonuria, which is characteristic of typical SCOT-deficient patients. He is a compound heterozygote of c.1304C > A (T435N) and c.658-666dupAACGTGATT p.N220_I222dup. mutations in the OXCT1 gene. The T435N mutation was previously reported as one which retained significant residual activity. The latter novel mutation was revealed to retain no residual activity by transient expression analysis. Both T435N and N220_I222 lie close to the SCOT dimerization interface and are not directly connected to the active site in the tertiary structure of a human SCOT dimer. In transient expression analysis, no apparent interallelic complementation or dominant negative effects were observed. Significant residual activity from the T435N mutant allele may prevent the patient from developing permanent ketonuria.

Keywords

Protein Data Bank Ketone Body Organic Acidemia Transient Expression Analysis T435N Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

SCOT

succinyl-CoA:3-ketoacid CoA transferase

TKB

total ketone bodies

FFA

free fatty acids

This is a preview of subscription content, log in to check access.

Notes

Acknowledgements

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

References

  1. Adams PD, Afonine PV, Bunkoczi G et al (2010) PHENIX: a comprehensive Python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr 66:213–221PubMedCrossRefGoogle Scholar
  2. Berry GT, Fukao T, Mitchell GA et al (2001) Neonatal hypoglycaemia in severe succinyl-CoA: 3-oxoacid CoA-transferase deficiency. J Inherit Metab Dis 24:587–595PubMedCrossRefGoogle Scholar
  3. Bonnefont JP, Specola NB, Vassault A et al (1990) The fasting test in paediatrics: application to the diagnosis of pathological hypo- and hyperketotic states. Eur J Pediatr 150:80–85PubMedCrossRefGoogle Scholar
  4. Cornblath M, Gingell RL, Fleming GA, Tildon JT, Leffler AT, Wapnir RA (1971) A new syndrome of ketoacidosis in infancy. J Pediatr 79:413–418PubMedCrossRefGoogle Scholar
  5. Emsley P, Cowtan K (2004) Coot: model-building tools for molecular graphics. Acta Crystallogr D Biol Crystallogr 60:2126–2132PubMedCrossRefGoogle Scholar
  6. Fukao T, Song XQ, Watanabe H et al (1996) Prenatal diagnosis of succinyl-coenzyme A:3-ketoacid coenzyme A transferase deficiency. Prenat Diagn 16:471–474PubMedCrossRefGoogle Scholar
  7. 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 42:498–502PubMedCrossRefGoogle Scholar
  8. Fukao T, Mitchell GA, Song XQ et al (2000) Succinyl-CoA:3-ketoacid CoA transferase (SCOT): cloning of the human SCOT gene, tertiary structural modeling of the human SCOT monomer, and characterization of three pathogenic mutations. Genomics 68:144–151PubMedCrossRefGoogle Scholar
  9. 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 56:858–863PubMedCrossRefGoogle Scholar
  10. Fukao T, Sakurai S, Rolland MO et al (2006) A 6-bp deletion at the splice donor site of the first intron resulted in aberrant splicing using a cryptic splice site within exon 1 in a patient with succinyl-CoA: 3-Ketoacid CoA transferase (SCOT) deficiency. Mol Genet Metab 89:280–282PubMedCrossRefGoogle Scholar
  11. Fukao T, Kursula P, Owen EP, Kondo N (2007) Identification and characterization of a temperature-sensitive R268H mutation in the human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene. Mol Genet Metab 92:216–221PubMedCrossRefGoogle Scholar
  12. Kassovska-Bratinova S, Fukao T, Song XQ et al (1996) Succinyl CoA: 3-oxoacid CoA transferase (SCOT): human cDNA cloning, human chromosomal mapping to 5p13, and mutation detection in a SCOT-deficient patient. Am J Hum Genet 59:519–528PubMedGoogle Scholar
  13. Longo N, Fukao T, Singh R et al (2004) Succinyl-CoA:3-ketoacid transferase (SCOT) deficiency in a new patient homozygous for an R217X mutation. J Inherit Metab Dis 27:691–692PubMedCrossRefGoogle Scholar
  14. Merron S, Akhtar R (2009) Management and communication problems in a patient with succinyl-CoA transferase deficiency in pregnancy and labour. Int J Obstet Anesth 18:280–283PubMedCrossRefGoogle Scholar
  15. Mitchell GA, Fukao T (2001) Chapter 102. Inborn errors of ketone body catabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) Metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill Inc, New York, pp 2327–2356Google Scholar
  16. Niezen-Koning KE, Wanders RJ, Ruiter JP et al (1997) Succinyl-CoA:acetoacetate transferase deficiency: identification of a new patient with a neonatal onset and review of the literature. Eur J Pediatr 156:870–873PubMedCrossRefGoogle Scholar
  17. Perez-Cerda C, Merinero B, Sanz P et al (1992) A new case of succinyl-CoA: acetoacetate transferase deficiency. J Inherit Metab Dis 15:371–373PubMedCrossRefGoogle Scholar
  18. Pretorius CJ, Loy Son GG, Bonnici F, Harley EH (1996) Two siblings with episodic ketoacidosis and decreased activity of succinyl-CoA:3-ketoacid CoA-transferase in cultured fibroblasts. J Inherit Metab Dis 19:296–300PubMedCrossRefGoogle Scholar
  19. Rolland MO, Guffon N, Mandon G, Divry P (1998) Succinyl-CoA:acetoacetate transferase deficiency. Identification of a new case; prenatal exclusion in three further pregnancies. J Inherit Metab Dis 21:687–688PubMedCrossRefGoogle Scholar
  20. Sakazaki H, Hirayama K, Murakami S et al (1995) A new Japanese case of succinyl-CoA: 3-ketoacid CoA-transferase deficiency. J Inherit Metab Dis 18:323–325PubMedCrossRefGoogle Scholar
  21. Saudubray JM, Specola N, Middleton B, Lombes A, Bonnefont JP, Jakobs C, Vassault A, Charpentier C, Day R (1987) Hyperketotic states due to inherited defects of ketolysis. Enzyme 38:80–90PubMedGoogle Scholar
  22. Snyderman SE, Sansaricq C, Middleton B (1998) Succinyl-CoA:3-ketoacid CoA-transferase deficiency. Pediatrics 101:709–711PubMedCrossRefGoogle Scholar
  23. Song XQ, Fukao T, Yamaguchi S, Miyazawa S, Hashimoto T, Orii T (1994) Molecular cloning and nucleotide sequence of complementary DNA for human hepatic cytosolic acetoacetyl-coenzyme A thiolase. Biochem Biophys Res Commun 201:478–485PubMedCrossRefGoogle Scholar
  24. Song XQ, Fukao T, Mitchell GA et al (1997) Succinyl-CoA:3-ketoacid coenzyme A transferase (SCOT): development of an antibody to human SCOT and diagnostic use in hereditary SCOT deficiency. Biochim Biophys Acta 1360:151–156PubMedCrossRefGoogle Scholar
  25. Song XQ, Fukao T, Watanabe H et al (1998) Succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency: two pathogenic mutations, V133E and C456F, in Japanese siblings. Hum Mutat 12:83–88PubMedCrossRefGoogle Scholar
  26. Tildon JT, Cornblath M (1972) Succinyl-CoA: 3-ketoacid CoA-transferase deficiency. A cause for ketoacidosis in infancy. J Clin Invest 51:493–498PubMedCrossRefGoogle Scholar
  27. Yamada K, Fukao T, Zhang G et al (2007) Single-base substitution at the last nucleotide of exon 6 (c.671G > A), resulting in the skipping of exon 6, and exons 6 and 7 in human succinyl-CoA:3-ketoacid CoA transferase (SCOT) gene. Mol Genet Metab 90:291–297PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer 2010

Authors and Affiliations

  • Toshiyuki Fukao
    • 1
    • 2
    • 3
  • Tomohiro Ishii
    • 4
  • Naoko Amano
    • 4
  • Petri Kursula
    • 5
  • Masaki Takayanagi
    • 6
  • Keiko Murase
    • 1
  • Naomi Sakaguchi
    • 1
  • Naomi Kondo
    • 1
  • Tomonobu Hasegawa
    • 4
  1. 1.Department of Pediatrics, Graduate School of MedicineGifu UniversityGifuJapan
  2. 2.Medical Information Sciences Division, United Graduate School of Drug Discovery and Medical Information SciencesGifu UniversityGifuJapan
  3. 3.Clinical Research DivisionNagara Medical CenterGifuJapan
  4. 4.Department of PediatricsKeio University School of MedicineShinjukuJapan
  5. 5.Department of BiochemistryUniversity of OuluOuluFinland
  6. 6.Chiba Children’s HospitalChibaJapan

Personalised recommendations