**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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