Hideo Sasai1, Yuka Aoyama1, Hiroki Otsuka1, Elsayed Abdelkreem1, Yasuhiro Naiki2, Mitsuru Kubota3, Yuji Sekine4, Masatsune Itoh5, Mina Nakama6, Hidenori Ohnishi1, Ryoji Fujiki7, Osamu Ohara7, Toshiyuki Fukao1
1Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan;2Division of Endocrinology and Metabolism, National Center for Child Health and Development, Tokyo, Japan;3Department of General Pediatrics and Interdisciplinary Medicine, National Center for Child Health and Development, Tokyo, Japan;4Department of General Pediatrics, Shizuoka Children’s Hospital, Shizuoka, Japan;5Department of Pediatrics, Kanazawa Medical University, Kanazawa, Japan;6Division of Clinical Genetics, Gifu University Hospital, Gifu, Japan;7Department of Technology Development, Kazusa DNA Research Institute, Kisarazu, Japan
Background: Succinyl-CoA:3-oxoacid CoA transferase (SCOT, gene symbol OXCT1) deficiency is an autosomal recessive disorder of ketone body utilization that results in severe recurrent ketoacidotic episodes in infancy. 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.
Methods: PCR-sequencing, multiplex ligation-dependent probe amplification analysis on the OXCT1 gene was performed to identify mutations. Study of pathogenic mechanism of the mutants identified was performed.
Results: 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.
Conclusions: Our data indicate that heterozygous carriers of OXCT1 mutations can develop severe ketoacidotic episodes in conjunction with ketogenic stresses.
Keywords: Succinyl-CoA:3-oxoacid CoA transferase deficiency (SCOT); ketoacidosis; heterozygous carriers
doi: 10.21037/atm.2017.s076
