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Epilepsy Benchmark IB1

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Brandy Fureman, Ph.D.
Program Director, Channels Synapses & Circuits Cluster

Deborah Hirtz, M.D.
Program Director, Division of Extramural Research

John Kehne, Ph.D.
Program Director, Anticonvulsant Screening Program

Randall Stewart, Ph.D.
Program Director, Extramural Research Program

Vicky Whittemore, Ph.D.
Program Director, Channels, Synapses & Neural Circuits Cluster


Epilepsy Benchmark IB1

Benchmark Area I: Understanding basic mechanisms of epileptogenesis

Section B: Continue the progress of identifying the genes predisposing to epilepsy

Specific Benchmark 1: Create and enhance national research collaborations between physicians, human geneticists, and families to identify and clone the gene of pedigrees with monogenic epilepsy syndromes.

2005 Report submitted by Benchmark Steward(s):
Ruth Ottman, Ph.D. (Columbia University)

Background of the benchmark goal:
Discovery of genes that raise risk for monogenic epilepsy syndromes provides important information about basic mechanisms of epileptogenesis.  This information could lead to the development of new treatments or mechanisms to prevent onset of seizures in some individuals.  Most of the work is carried out by single research groups, rather than through collaborative efforts, although the work involved is necessarily collaborative because it requires input from clinicians, geneticists, and families.  

Current status of field:
Researchers in the U.S. and elsewhere have continued intensive efforts to identify epilepsy genes in families with Mendelian forms of epilepsy.  These groups are also actively researching the range of phenotypic manifestations of mutations in the identified genes, and the prevalence of mutations in different populations.  A major limitation is the scarcity of families with Mendelian modes of transmission.  Also, few researchers have the expertise or funding resources to collect data from such families when they are identified.  Over the last few years, the rate of gene identification in Mendelian forms of epilepsy seems to have slowed somewhat, and efforts to study genetically complex epilepsies have increased, with a profusion of publication of allelic association studies.  None of these studies has produced a consistently replicated finding.

Activities update: 
Efforts to ensure that epilepsy clinicians remain aware of the importance of genetic research are continuing.  At the American Epilepsy Society meetings, a genetics Special Interest Group was initiated 2003, and the Annual Course was on genetics in 2004.  At the 2003 International Epilepsy Congress in Lisbon, genetics was a dominant theme, with two plenary sessions (Presidential Symposium:  Genetics of Epilepsy in the Third Millenium, and Epilepsy in the Post Genomic Era:  Focus on the Genetics of Inhibition and three parallel sessions (Genetic Counseling in the Epilepsies, Genetics of Epilepsy in the Mediterranean Region, and Inclusion of Genetic Information Concerning Etiology of Epilepsy Syndromes in Axis 4 of ILAE’s Proposed Scheme).  Also in Lisbon, an informal workshop was held for attendees interested in genetics; this was organized by Elving Anderson and intended to create or reinforce networks, to enhance collaboration. 

The Epilepsy Foundation Gene Discovery Project is a good potential source of families.  However, although several investigators have been approved to use it, only two have actually done so, and only one is continuing to do so.  The explanation for this is unclear – one possibility is that investigators prefer to ascertain families from their own epilepsy centers, to maximize clinical information on the cases.  The Foundation has not devoted much effort to maintaining the database over the last year, partly because the person responsible for this job left the Foundation, and her replacement did not make it a priority.  Due to the apparent lack of interest by investigators, they are evaluating whether or not to continue the project.  Drs. Noebels and Ottman strongly advised them to continue.

Top priorities for next 5-10 years:

  • Continue efforts to identify families with Mendelian forms of epilepsy, clinically characterize them, and identify the genes involved. 
  • Strengthen efforts to educate clinicians and patients to ensure that adequate family histories are taken and research contacts made when they are likely to be fruitful.
  • Strengthen referral networks to ensure that researchers learn about families that could be of interest

Roadblocks to progress:

  • Most epileptologists are too busy to collect the detailed family history data needed for this type of study.  They are uncertain which families are of interest, and do not know whom to contact when they find potentially interesting families.
  • Families with Mendelian modes of inheritance are extremely rare.  We need to cast a very wide net to identify them, nationally and internationally.
  • Although epilepsy genetics requires input from clinicians, geneticists, and people with epilepsy, resistance to collaboration sometimes slows progress in gene identification.  This is especially true for geneticists, for whom discovery of a gene is a major success accompanied by great recognition.  Hence competition has sometimes interfered with collaboration.  


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Last Modified October 20, 2015