Abstract
Succinyl-CoA:3-oxoacid CoA transferase (SCOT, gene symbol OXCT1) deficiency is an autosomal recessive disorder in ketone body utilization that results in severe recurrent ketoacidotic episodes in infancy, including neonatal periods. More than 30 patients with this disorder have been reported and to our knowledge, their heterozygous parents and siblings have had no apparent ketoacidotic episodes. Over 5 years (2008–2012), we investigated several patients that presented with severe ketoacidosis and identified a heterozygous OXCT1 mutation in four of these cases (Case1 p.R281C, Case2 p.T435N, Case3 p.W213*, Case4 c.493delG). To confirm their heterozygous state, we performed a multiplex ligation-dependent probe amplification analysis on the OXCT1 gene which excluded the presence of large deletions or insertions in another allele. A sequencing analysis of subcloned full-length SCOT cDNA showed that wild-type cDNA clones were present at reasonable rates to mutant cDNA clones. Over the following 2 years (2013–2014), we analyzed OXCT1 mutations in six more patients presenting with severe ketoacidosis (blood pH ≦7.25 and total ketone body ≧10 mmol/L) with non-specific urinary organic acid profiles. Of these, a heterozygous OXCT1 mutation was found in two cases (Case5 p.G391D, Case6 p.R281C). Moreover, transient expression analysis revealed R281C and T435N mutants to be temperature-sensitive. This characteristic may be important because most patients developed ketoacidosis during infections. Our data indicate that heterozygous carriers of OXCT1 mutations can develop severe ketoacidotic episodes in conjunction with ketogenic stresses.
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Abbreviations
- CT:
-
cytosolic acetoacetyl-CoA thiolase
- SCOT:
-
succinyl-CoA:3-oxoacid CoA transferase
- MCT1:
-
monocarboxylate transporter 1
- MLPA:
-
multiplex ligation-dependent probe amplification
References
Aoyama Y, Yamamoto T, Sakaguchi N et al (2015) Application of multiplex ligation-dependent probe amplification, and identification of a heterozygous Alu-associated deletion and a uniparental disomy of chromosome 1 in two patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. Int J Mol Med 35:1554–1560
Baric I, Sarnavka V, Fumic K et al (2001) A new case of succinyl-CoA:acetoacetate transferase deficiency: favourable course despite very low residual activity. J Inherit Metab Dis 24:81–82
Berry GT, Fukao T, Mitchell GA et al (2001) Neonatal hypoglycaemia in severe succinyl-CoA: 3-oxoacid CoA-transferase deficiency. J Inherit Metab Dis 24:587–595
Calvo SE, Tucker EJ, Compton AG et al (2010) High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat Genet 42:851–858
Cornblath M, Gingell RL, Fleming GA, Tildon JT, Leffler AT, Wapnir RA (1971) A new syndrome of ketoacidosis in infancy. J Pediatr 79:413–418
Cotter DG, Schugar RC, Wentz AE, d’Avignon DA, Crawford PA (2013) Successful adaptation to ketosis by mice with tissue-specific deficiency of ketone body oxidation. Am J Physiol Endocrinol Metab 304:E363–E374
Erdol S, Ture M, Yakut T et al (2016) A Turkish patient with succinyl-CoA:3-oxoacid CoA transferase deficiency mimicking diabetic ketoacidosis. J Inborn Errors Metab Screen 4:1–5
Fukao T, Song XQ, Watanabe H et al (1996) Prenatal diagnosis of succinyl-coenzyme a:3-ketoacid coenzyme a transferase deficiency. Prenat Diagn 16:471–474
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, 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 68:144–151
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, 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 89:280–282
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 92:216–221
Fukao T, Ishii T, Amano N et al (2010) 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. J Inherit Metab Dis 33(Suppl 3):S307–S313
Fukao T, Sass JO, Kursula P et al (2011) Clinical and molecular characterization of five patients with succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency. Biochim Biophys Acta 1812:619–624
Fukao T, Mitchell G, Sass JO, Hori T, Orii K, Aoyama Y (2014) Ketone body metabolism and its defects. J Inherit Metab Dis 37:541–551
Hori T, Fukao T, Murase K, Sakaguchi N, Harding CO, Kondo N (2013) Molecular basis of two-exon skipping (exons 12 and 13) by c.1248+5g>a in OXCT1 gene: study on intermediates of OXCT1 transcripts in fibroblasts. Hum Mutat 34:473–480
Hori T, Yamaguchi S, Shinkaku H et al (2015) Inborn errors of ketone body utilization. Pediatr Int 57:41–48
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 59:519–528
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 27:691–692
Maquat LE (2005) Nonsense-mediated mRNA decay in mammals. J Cell Sci 118:1773–1776
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 18:280–283
Mitchell GA, Fukao T (2001) Inborn errors of ketone body catabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) Metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 2327–2356
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 156:870–873
Niwa H, Yamamura K, Miyazaki J (1991) Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108:193–199
Perez-Cerda C, Merinero B, Sanz P et al (1992) A new case of succinyl-CoA: acetoacetate transferase deficiency. J Inherit Metab Dis 15:371–373
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 19:296–300
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 21:687–688
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 18:323–325
Shafqat N, Kavanagh KL, Sass JO et al (2013) A structural mapping of mutations causing succinyl-CoA:3-ketoacid CoA transferase (SCOT) deficiency. J Inherit Metab Dis 36:983–987
Snyderman SE, Sansaricq C, Middleton B (1998) Succinyl-CoA:3-ketoacid CoA-transferase deficiency. Pediatrics 101:709–711
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 201:478–485
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 1360:151–156
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 12:83–88
Tildon JT, Cornblath M (1972) Succinyl-CoA: 3-ketoacid CoA-transferase deficiency. A cause for ketoacidosis in infancy. J Clin Invest 51:493–498
van Hasselt PM, Ferdinandusse S, Monroe GR et al (2014) Monocarboxylate transporter 1 deficiency and ketone utilization. N Engl J Med 371:1900–1907
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
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 90:291–297
Zhi J, Hatchwell E (2008) Human MLPA probe design (H-MAPD): a probe design tool for both electrophoresis-based and bead-coupled human multiplex ligation-dependent probe amplification assays. BMC Genomics 9:407
Acknowledgements
We thank Reiko Horikawa (Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan), Toyohiro Yamauti (Department of General Pediatrics, Shizuoka Children’s Hospital, Shizuoka, Japan), Shoko Yurikusa (Department of Hematology and Oncology, Shizuoka Children’s Hospital, Shizuoka, Japan), Kaori Kumazaki (Department of Pediatrics, Gifu Prefectural General Medical Center, Gifu, Japan), Noriaki Shimura, Dr. Shinya Nakano (Pediatrics Emergency Center, Kitakyushu Municipal Yahata Hospital, Kitakyushu, Japan) for clinical follow-up of the patients. We also thank Ms. Naomi Sakaguchi (Technician; Gifu University) for her indispensable technical assistance.
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Toshiyuki Fukao has received Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan [grant numbers 26,114,708, 16 K09962]; Health and Labor Science Research Grant for Research on Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan; and a grant for the Practical Research Project for Rare/Intractable Diseases from the Japan Agency for Medical Research and Development (AMED). Osamu Ohara has received a grant for the Practical Research Project for Rare/Intractable Diseases from the Japan AMED. Hideo Sasai, Yuka Aoyama, Hiroki Otsuka, Elsayed Abdelkreem, Yasuhiro Naiki, Mitsuru Kubota, Yuji Sekine, Masatsune Itoh, Mina Nakama, Hidenori Ohnishi, and Ryoji Fujiki declare that they have no conflict of interest.
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This study was approved by the ethical committee for medical study in Gifu University. All procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients or their parents for being included in the study.
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Sasai, H., Aoyama, Y., Otsuka, H. et al. Heterozygous carriers of succinyl-CoA:3-oxoacid CoA transferase deficiency can develop severe ketoacidosis. J Inherit Metab Dis 40, 845–852 (2017). https://doi.org/10.1007/s10545-017-0065-z
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DOI: https://doi.org/10.1007/s10545-017-0065-z