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Refractory very early-onset inflammatory bowel disease associated with cytosolic isoleucyl-tRNA synthetase deficiency: A case report


BACKGROUND: Aminoacyl tRNA synthetases/ligases (ARSs) are highly conserved enzymes involved in attaching amino acids to tRNA promoting protein synthesis. Although deficiencies of ARSs localized to the mitochondria classically present with neuropathology, the clinical features of cytosolic ARS deficiencies are more variable. They have previously been associated with neonatal hepatitis, but never with early-onset inflammatory bowel disease. CASE SUMMARY: A nine-year-old Bangladeshi boy presented with neonatal liver failure and deranged clotting, transaminitis and cholestasis. His parents were first cousins. Two older brothers and a sister were well. The patient suffered from loose stools from early infancy which became more troublesome and persistent from five years old with ten bloody motions a day. Repeated endoscopies showed persistent pancolitis, which was refractory to mesalazine, corticosteroids, azathioprine, sirolimus and anti-TNF (adalimumab) therapy, but has improved recently with subcutaneous methotrexate.Whole Genome Sequencing revealed a novel pathogenic missense variant (c.290A > G) in the cytosolic isoleucyl-tRNA synthetase gene, leading to an amino acid substitution (p.Asp97Gly). Pathogenic variants in other genes associated with inflammatory bowel disease (IBD) (ADAM17, EGFR, FOXP3, IL10RA, IL10RB, IL21R, NCF4, STAT3) were excluded. Cytokine assays demonstrated markedly elevated IL-2, IL-5, IL-13, IL-9 and IL-10 by the patient's CD4(+) T-cells, while IL-17A, IL-17F, IFNbeta were lower, and TNFalpha not significantly different when compared to healthy controls. CONCLUSION: This case report provides evidence that recessive mutations in cytosolic isoleucyl-tRNA synthetase are a novel monogenic cause of IBD, which should be considered, particularly in infants and children with a history of neonatal hepatitis and very early-onset IBD poorly responsive to treatment.

Type Journal
ISBN 2219-2840 (Electronic) 1007-9327 (Linking)
Authors Fagbemi, A.; Newman, W. G.; Tangye, S. G.; Hughes, S. M.; Cheesman, E.; Arkwright, P. D.
Responsible Garvan Author Prof Stuart Tangye
Published Date 2020-04-30
Published Volume 26
Published Issue 15
Published Pages 1841-1846
Status Published in-print
DOI 10.3748/wjg.v26.i15.1841
URL link to publisher's version