The Epilepsy Phenome/Genome Project:
A New Initiative to Understand the Genetic Causes of Epilepsy

Daniel H. Lowenstein, M.D.,
Director, UCSF Epilepsy Center,
Department of Neurology
University of California, San Francisco

Ruben Kuzniecky, M.D.,
Director, NYU Epilepsy Research Program,
Department of Neurology,
NYU School of Medicine

The past decade has seen a number of remarkable advances in the area of epilepsy research, most notably the identification of specific mutations in genes that appear to be the cause of certain inherited forms of epilepsy. Researchers had long suspected that the genes involved in epilepsy would include those involved in the control of the excitability of brain cells, and this has indeed proved to be the case with the gene mutations discovered thus far – a number of them are so-called “ion channels,” which allow the passage of electrically-charged ions into and out of the cell. However, all of the gene mutations identified to date have been found in a small number of families around the world with relatively rare forms of epilepsy. Yet it is very clear that genetics has a much more widespread influence on epilepsy beyond what is found in these rare families. In addition to seizures being caused by a single gene mutation, scientists know that a combination of more subtle gene mutations in multiple genes is likely the basis for most forms of inherited epilepsy. Also, there are strong reasons to suspect that the ability of anti-seizure medication to control seizures is at least partly determined by genetic causes.

For example, certain genes encode proteins that control the rate of metabolism of drugs, and it is well-established that some people have genes that make them “fast metabolizers” while other people are “slow metabolizers.” Other genes are crucial for the transport of drugs into brain cells. These genetic changes could help explain why certain people do or do not respond to anti-seizure medications.

Unraveling the more complex genetics of epilepsy, in particular, in patients with intractable epilepsy represents an enormous challenge. Questions about genetics will only be answered by studying the clinical, laboratory and genetic characteristics of thousands of patients with epilepsy. To meet this challenge, NYU and UCSF have organized a group of epilepsy researchers around the country and initiated “The Epilepsy Phenome/Genome Project” (or EPGP, for short). EPGP brings together 12 prominent epilepsy centers throughout the U.S. into a collaboration based on the recognition that no single center can ever hope to study a sufficient number of patients to make the next major breakthrough in epilepsy genetics.

Although still in the planning phase, EPGP will create a comprehensive, sophisticated database that contains detailed information on the clinical characteristics of a patient’s seizure disorder (phenome) and information derived from the analysis of a patient’s DNA (genome). By enrolling a large number of patients into EPGP (i.e. an expected 5,000 patients over 5 years), and using state-of-the-art techniques for managing and analyzing huge volumes of data, EPGP will provide the infrastructure for making a number of discoveries that, until now, have been impossible to approach. Some of these will be the identification of gene mutations that cause the more common forms of epilepsy. Others will be identification of genes that cause specific abnormalities in brain development leading to epilepsy. Such discoveries hold the promise of the development of more specific and effective therapies that can be tailored to an individual’s seizure disorder.

EPGP will also help identify the gene mutations that explain drug-responsiveness. In the future, such information will enable doctors to predict the likelihood of a medicine working for a given patient. Recognizing the pivotal importance of this type of large-scale, collaborative research in epilepsy, FACES has awarded a grant of $150,000 to help the EPGP team in the planning phase of the project. These funds will be used to design the bio-informatics infrastructure for the study, create and test data collection systems, and support planning conferences by the group so they can prepare a multi-million dollar grant proposal for the National Institutes of Health.

For more information, please visit the EPGP website.