Research Will Compare Genes of 1,500 Epilepsy Patients

PHILADELPHIA, Pa. -- A scientist at the University of Pennsylvania School of Medicine has been awarded a $2 million federal research grant for a major study designed to establish the connection between the most common form of epilepsy and the way the DNA code may vary in a set of genes with suspected links to the disease.

Russell Buono, PhD, Research Assistant Professor in Penn's Department of Psychiatry, will use the grant from the National Institutes for Health for a four-year study to compare DNA samples from 1,500 epilepsy patients with samples from their immediate family members and from a control group. The DNA will be isolated from blood collected at sites in Philadelphia and in Ohio.

Buono will be examining the DNA sequences of the suspect genes to determine whether they can, in fact, be definitively associated with seizure disorders -- and if they can, whether those abnormal genes are clustered in particular ways.

"Scientists know that many diseases are caused by a combination of genetic and environmental factors," he said. "It's our belief that subtle variations in a small number of genes bring about conditions that predispose individuals for some common forms of seizure disorders."

For the nervous system to function properly, and send out normal electrical impulses, ion channels (which conduct sodium, potassium, calcium and chloride) must
maintain a balance between the ions inside and outside nerve cells. Current scientific thinking holds that seizure disorders result when the ion channels don't do their job.

Buono's research will encompass juvenile myoclonic epilepsy, temporal lobe epilepsy and childhood absence epilepsy. Several of the genes he will study are located on Chromosome 1, which has only recently been associated with temporal lobe epilepsy.

Every year during the study, Buono and his colleagues will collect 125 DNA samples from patients suffering from each of the three forms of epilepsy, along with genetic samples from their parents, siblings or children, and from a control group -- for a total of 500 DNA samples from each of the three patient groups and 3,500 from their close family relatives and controls by the end of the collection period.

"With that extensive database, we'll be able to see what genetic variations there may be (in the genes under study) in people who are affected and then compare our findings with information from their non-affected relatives and the control group," Buono said.

"Then, in a follow-up study, we will work to determine whether any of the genetic variations correlate with the patients' responses to various anti-convulsant drugs," he said. "Our long-term goal is to identify targets for drug development -- as well as to advance understanding of the disease itself.

"Establishing a pattern for an illness with such complex genetic traits is a major challenge," Buono added. "And it will be doubly challenging because our study relies on collaboration with so many people -- physicians, nurses, medical coordinators, technicians, statisticians, and hundreds of patients and their families."

The DNA material will be collected in Philadelphia at the the Hospital of the University of Pennsylvania, Thomas Jefferson University Hospital, and Children's Hospital of Philadelphia. It will also be collected at the University of Cincinnati Medical Center and the Children's Hospital of Cincinnati.

Others collaborating in the study are Wade Berrettini, MD, PhD; Thomas Ferraro, PhD, and Theresa Scattergood, RN, MSN, of Penn; Michael R. Sperling, MD, and Michael J. O'Connor, MD, of Thomas Jefferson Hospital; Michael Privitera, MD, of the University of Cincinnati, and Dennis Dlugos, MD, of Childrens Hospital.


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