Sodium Channel Gene Variation in the Treatment of Epilepsy

Summary

Principal Investigator: Katherine D Holland
Abstract: PROJECT SUMMARY/ABSTRACT Initial antiepileptic treatment fails in over 40% of people with epilepsy, resulting in significant personal, financial, and societal hardships. The objective of this proposal is to determine the influence of genetic alterations in sodium channel genes on response to carbamazepine (CBZ), one of the main first line treatments for epilepsy. It is hypothesized that single nucleotide polymorphisms (SNPs) in sodium channel genes which change the amino acid composition of the resultant channel (nonsynonymous SNPs) alter the channel's responsiveness to CBZ resulting in treatment failure in some people with epilepsy. To achieve the objective of this application the specific aims are to (1) Identify single nucleotide polymorphisms in sodium channel [unreadable]- subunit genes expressed in the central nervous system that occur more frequently in patients with epilepsy unresponsive to initial CBZ therapy than in patients with CBZ-responsive epilepsy;and (2) Determine how SNPs in sodium channel [unreadable]-subunit genes affect electrophysiological and pharmacological properties of sodium channels in vitro. To accomplish these aims, first nonsynonymous variations in sodium channel genes occurring people with epilepsy that is unresponsive to CBZ will be identified and the frequency of these SNPs will be compared between patients with epilepsy that is unresponsive to CBZ, patients with epilepsy that responds to CBZ, and gender and ethnicity matched controls. Subsequently, the functional consequences of these sodium channel SNPs will be studied in vitro with whole cell patch clamp techniques using heterologously expressed recombinant human sodium channels. The motivation of the proposed research is that once the influence of sodium channel SNPs on CBZ responsiveness is understood, more efficacious therapies for epilepsy can be developed both by providing a way to pre-select treatment tailored to individual patients and by promoting the development of more effective genetic based therapies. This work is innovative because it links phenotype (CBZ resistant epilepsy), genotype (sodium channel SNPs) and functionality (alteration in channel responsiveness to AEDs);it is also innovative because the design of the pharmacogenetic association study involves a consecutive cohort of newly diagnosed patients taking a single AED whose response to treatment will be rigorously assessed. It is expected that sodium channel gene polymorphisms will be identified that are clinically associated with CBZ failure and alter sodium channel CBZ responsiveness;this will lead to a future prospective study to test whether CBZ responsiveness can be predict pre-treatment in patients with newly diagnosed epilepsy. From the functionality studies, in vitro methods for screening new AEDs can be developed. These results will have a positive impact by advancing understanding of how failure of first-line CBZ treatment occurs. This is significant because it is expected to provide information needed to better treat patients with newly diagnosed epilepsy and will contribute to future genetic therapeutic approaches.
Funding Period: 2009-04-01 - 2014-03-31
more information: NIH RePORT

Top Publications

  1. pmc Valproate in children with newly diagnosed idiopathic generalized epilepsy
    K D Holland
    Division of Neurology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Acta Neurol Scand 121:149-53. 2010
  2. pmc Pretreatment EEG in childhood absence epilepsy: associations with attention and treatment outcome
    Dennis Dlugos
    Children s Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA
    Neurology 81:150-6. 2013
  3. pmc mRNA blood expression patterns in new-onset idiopathic pediatric epilepsy
    Hansel M Greiner
    Division of Neurology, Department of Pediatrics, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229 3039, USA
    Epilepsia 54:272-9. 2013
  4. pmc Selecting anti-epileptic drugs: a pediatric epileptologist's view, a computer's view
    J Pestian
    Division of Biomedical Informatics, Cincinnati Children s Hospital Medical Center, Cincinnati, OH, USA
    Acta Neurol Scand 127:208-15. 2013
  5. ncbi Status epilepticus in children
    Katherine Holland
    Cincinnati Children s Hospital Medical Center, Cincinnati, OH, USA
    Handb Clin Neurol 108:795-812. 2012
  6. pmc Resection of ictal high-frequency oscillations leads to favorable surgical outcome in pediatric epilepsy
    Hisako Fujiwara
    Division of Neurology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229, USA
    Epilepsia 53:1607-17. 2012
  7. ncbi Nonconvulsive status epilepticus: the encephalopathic pediatric patient
    Hansel M Greiner
    Division of Child Neurology, Department of Pediatrics, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Pediatrics 129:e748-55. 2012
  8. pmc Ictal MEG onset source localization compared to intracranial EEG and outcome: improved epilepsy presurgical evaluation in pediatrics
    Hisako Fujiwara
    Division of Neurology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH, USA
    Epilepsy Res 99:214-24. 2012
  9. pmc Multimodality imaging in the surgical treatment of children with nonlesional epilepsy
    J H Seo
    Division of Pediatric Neurology, Department of Radiology, Cincinnati Children s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229 3339, USA
    Neurology 76:41-8. 2011
  10. ncbi Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG)
    Iván Sánchez Fernández
    Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children s Hospital, Harvard Medical School, Boston, MA, United States Department of Child Neurology, Hospital Sant Joan de Deu, University of Barcelona, Spain
    Seizure 23:87-97. 2014

Detail Information

Publications11

  1. pmc Valproate in children with newly diagnosed idiopathic generalized epilepsy
    K D Holland
    Division of Neurology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Acta Neurol Scand 121:149-53. 2010
    ..The aim of this study is to characterize the therapeutic dose of valproate in children with newly diagnosed IGE...
  2. pmc Pretreatment EEG in childhood absence epilepsy: associations with attention and treatment outcome
    Dennis Dlugos
    Children s Hospital of Philadelphia, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA, USA
    Neurology 81:150-6. 2013
    ..In children with newly diagnosed childhood absence epilepsy (CAE), determine pretreatment EEG features and their associations with baseline neuropsychological function and short-term treatment outcome...
  3. pmc mRNA blood expression patterns in new-onset idiopathic pediatric epilepsy
    Hansel M Greiner
    Division of Neurology, Department of Pediatrics, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229 3039, USA
    Epilepsia 54:272-9. 2013
    ..Determine the differential expression patterns between epilepsy patients with generalized onset or partial onset seizures compared to healthy controls...
  4. pmc Selecting anti-epileptic drugs: a pediatric epileptologist's view, a computer's view
    J Pestian
    Division of Biomedical Informatics, Cincinnati Children s Hospital Medical Center, Cincinnati, OH, USA
    Acta Neurol Scand 127:208-15. 2013
    ..To identify which clinical characteristics are important to include in clinical decision support systems developed for Antiepileptic Drug (AEDs) selection...
  5. ncbi Status epilepticus in children
    Katherine Holland
    Cincinnati Children s Hospital Medical Center, Cincinnati, OH, USA
    Handb Clin Neurol 108:795-812. 2012
    ....
  6. pmc Resection of ictal high-frequency oscillations leads to favorable surgical outcome in pediatric epilepsy
    Hisako Fujiwara
    Division of Neurology, Cincinnati Children s Hospital Medical Center, Cincinnati, Ohio 45229, USA
    Epilepsia 53:1607-17. 2012
    ..However, HFOs can be difficult to detect because of their low amplitude. Therefore, the prevalence of ictal HFOs and their role in localization of epileptogenic zone on intracranial EEG are unknown...
  7. ncbi Nonconvulsive status epilepticus: the encephalopathic pediatric patient
    Hansel M Greiner
    Division of Child Neurology, Department of Pediatrics, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA
    Pediatrics 129:e748-55. 2012
    ..This study examines prevalence of pediatric NCSE regardless of inpatient setting and retrospectively identifies risk factors indicating a need for urgent continuous EEG...
  8. pmc Ictal MEG onset source localization compared to intracranial EEG and outcome: improved epilepsy presurgical evaluation in pediatrics
    Hisako Fujiwara
    Division of Neurology, Cincinnati Children s Hospital Medical Center, Cincinnati, OH, USA
    Epilepsy Res 99:214-24. 2012
    ..We investigated whether ictal MEG onset source localization further improves results of interictal MEG in defining the SOZ...
  9. pmc Multimodality imaging in the surgical treatment of children with nonlesional epilepsy
    J H Seo
    Division of Pediatric Neurology, Department of Radiology, Cincinnati Children s Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229 3339, USA
    Neurology 76:41-8. 2011
    ..To evaluate the diagnostic value of individual noninvasive presurgical modalities and to study their role in surgical management of nonlesional pediatric epilepsy patients...
  10. ncbi Gaps and opportunities in refractory status epilepticus research in children: a multi-center approach by the Pediatric Status Epilepticus Research Group (pSERG)
    Iván Sánchez Fernández
    Division of Epilepsy and Clinical Neurophysiology, Department of Neurology, Boston Children s Hospital, Harvard Medical School, Boston, MA, United States Department of Child Neurology, Hospital Sant Joan de Deu, University of Barcelona, Spain
    Seizure 23:87-97. 2014
    ....