title: IDH1 mutation is associated with seizures and protoplasmic subtype in patients with low-grade gliomas.
abstract: OBJECTIVE
  The isocitrate dehydrogenase 1 (IDH1) R132H mutation is the most common mutation in World Health Organization (WHO) grade II gliomas, reported to be expressed in 70-80%, but only 5-10% of high grade gliomas. Low grade tumors, especially the protoplasmic subtype, have the highest incidence of tumor associated epilepsy (TAE). The IDH1 mutation leads to the accumulation of 2-hydroxyglutarate (2HG), a metabolite that bears a close structural similarity to glutamate, an excitatory neurotransmitter that has been implicated in the pathogenesis of TAE. We hypothesized that expression of mutated IDH1 may play a role in the pathogenesis of TAE in low grade gliomas.
  
  
  METHODS
  Thirty consecutive patients with WHO grade II gliomas were analyzed for the presence of the IDH1-R132H mutation using immunohistochemistry. The expression of IDH1 mutation was semiquantified using open-source biologic-imaging analysis software.
  
  
  RESULTS
  The percentage of cells positive for the IDH1-R132H mutation was found to be higher in patients with TAE compared to those without TAE (median and interquartile range (IQR) 25.3% [8.6-53.5] vs. 5.2% [0.6-13.4], p = 0.03). In addition, we found a significantly higher median IDH1 mutation expression level in the protoplasmic subtype of low grade glioma (52.2% [IQR 19.9-58.6] vs. 13.8% [IQR 3.9-29.4], p = 0.04).
  
  
  CONCLUSIONS
  Increased expression of the IDH1-R132H mutation is associated with seizures in low grade gliomas and also with the protoplasmic subtype. This supports the hypothesis that this mutation may play a role in the pathogenesis of both TAE and low grade gliomas.
authors.affiliation: Department of Neurosurgery, The Royal Melbourne Hospital, Parkville, Victoria, Australia; The Department of Surgery (RMH), The University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Simon V
authors.initials: SV
authors.lastname: Liubinas
authors.forename: Giovanna M
authors.initials: GM
authors.lastname: D'Abaco
authors.forename: Bradford M
authors.initials: BM
authors.lastname: Moffat
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzales
authors.forename: Frank
authors.initials: F
authors.lastname: Feleppa
authors.forename: Cameron J
authors.initials: CJ
authors.lastname: Nowell
authors.forename: Alexandra
authors.initials: A
authors.lastname: Gorelik
authors.forename: Katharine J
authors.initials: KJ
authors.lastname: Drummond
authors.forename: Terence J
authors.initials: TJ
authors.lastname: O'Brien
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Kaye
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Morokoff
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001120:Arginine / Q000235:genetics; D001254:Astrocytoma / Q000150:complications* / Q000235:genetics*; D001932:Brain Neoplasms / Q000235:genetics*; D015331:Cohort Studies; D004827:Epilepsy / Q000209:etiology; D005260:Female; D056726:Genetic Association Studies; D006639:Histidine / Q000235:genetics; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D012640:Seizures / Q000150:complications / Q000235:genetics; D055815:Young Adult
chemical_list: D006639:Histidine; D001120:Arginine; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: Epilepsy; Glioma; Glutamate; IDH1; Protoplasmic astrocytoma; Seizure