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Member Research and Reports

Columbia Researcher Reports Common Epilepsies Share Genetic Overlap with Rare Types

An international study at Columbia University Medical Center and the Mailman School of Public Health found that several genes previously implicated only in rare familial epilepsies or severe forms of pediatric epilepsy also contribute to common forms of the disorder. Results of the study are published online in The Lancet Neurology.

ruth-ottman
[Photo: Dr. Ruth Ottman]

The findings raise hopes that the emerging paradigm for the treatment of rare epilepsies, where therapies may be targeted to the precise genetic cause of disease, may also extend to some people with common epilepsy syndromes.

“Genome sequencing of very large groups of patients, assembled through multisite collaborative efforts, is enabling us to see genetic effects that could not be seen before,” said contributing author Dr. Ruth Ottman, professor of epidemiology at the Mailman School of Public Health and deputy director for Research at the G.H. Sergievsky Center, Columbia College of Physicians and Surgeons.

Until recently, genes affecting risk for epilepsy were found primarily in rare families containing multiple affected individuals.  In recent years, extensive research on rare, severe pediatric epilepsies has uncovered dozens of genes that cause these syndromes, alone or in combination with other factors. These discoveries have led to the use of targeted therapies for some seizure disorders, such as the ketogenic (high-fat, low-carbohydrate) diet in patients with GLUT-1 deficiency. Other therapies such as medications for heart arrhythmias and Alzheimer’s disease have been tried in children with certain gene mutations. These attempts have not proved universally effective for all patients with these mutations, but suggest the potential to repurpose existing medicines to treat rare genetic forms of epilepsy.

Unlike very rare types of epilepsies, previous studies had shed little light on the genetic underpinnings of common epilepsies, which suggested that this precision medicine paradigm may have a very narrow application, noted the authors.

To learn more about the genetics of epilepsy, the investigators conducted a study to identify the genetic contributions to more common forms of epilepsy. In the study, the first of its kind, researchers compared the exomes (protein-coding genes) of 1,140 individuals with two of the most common types of epilepsy with the exomes of 3,877 unrelated epilepsy-free controls.

The researchers found an excess of mutations in five genes, all of which had been previously implicated only in rare forms of epilepsy, in some of the individuals with familial non-acquired focal epilepsy, one of the more common types.

The findings have important implications for clinical practice and for research. At present, common epilepsies are treated the same way, with the same group of medications, but as more of these epilepsy genes that span a much wider range of types of epilepsy than previously thought are identified, targeted therapies across these patient populations can be tried. Additional studies, analyzing 10,000 to 12,000 samples, are planned for the coming year.

The study was supported by grants from the National Institute of Neurological Disorders and Stroke (NS053998, NS077274, NS077303, NS077367, NS077276) and Epilepsy-Research UK (grant P1104). Other contributors are from CUMC and CUMC’s Institute for Genomic Medicine, in collaboration with New York-Presbyterian.