Shared Mutations Between Common and Rare Epilepsies Uncovered

January 11, 2017
Shared Mutations Between Common and Rare Epilepsies Uncovered
Source: Sebastian Kaulitzki/Fotolia

A new study by an international team of scientists lead by researchers at Columbia University Medical Center (CUMC), and New York-Presbyterian has just found that several genes previously implicated only in rare, severe forms of pediatric epilepsy also contribute to common forms of the disorder. The findings from the study were published recently in The Lancet Neurology through an article entitled "Ultra-rare genetic variation in common epilepsies: a case-control sequencing study."

"Our findings raise hopes that the emerging paradigm for the treatment of rare epilepsies, where therapies are targeted to the precise genetic cause of disease, may also extend to a proportion of common epilepsy syndromes," explained lead study investigator David Goldstein, Ph.D., director of the Institute for Genomic Medicine and professor in the Departments of Genetics and Development and Neurology at CUMC.

Over the past several years, scientists have uncovered dozens of genes that alone, or in combination with other factors, cause rare pediatric epilepsies. 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 Dravet syndrome or a GLUT-1 deficiency. Other therapies such as quinidine, a medication to treat heart arrhythmias, and memantine, an Alzheimer's disease treatment, 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 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," Dr. Goldstein noted.

In order to discern more about the genetics of epilepsy, the investigators conducted a study to identify the genetic contributions to the more common forms of epilepsy. The researchers used whole exome sequencing (WES) to compare the protein-coding regions of 1,140 individuals with two of the most common types of epilepsy—using the exomes of 3,877 unrelated epilepsy-free individuals as controls. The analyses were conducted at CUMC's Institute for Genomic Medicine, in collaboration with NewYork-Presbyterian, as part of Epi4K, an international consortium of epilepsy clinicians and researchers, with most of the patients being recruited through the Epilepsy Phenome/Genome Project.

To their surprise, the research team found a significant excess of mutations in five genes, 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. A similar pattern was also observed for another common type of epilepsy, genetic generalized epilepsy.

"We estimate that these five genes contribute to epilepsy risk in approximately eight percent of people with this common form of the disorder," remarked study co-author Erin Heinzen Cox, Ph.D., assistant professor in the department of pathology and cell biology and deputy director of the Institute for Genomic Medicine at CUMC.

The findings have important implications for clinical practice and research. "At present, all common epilepsies are treated the same way, with the same group of medications," said Dr. Goldstein. "But as we identify more of these epilepsy genes that span a much wider range of types of epilepsy than previously thought, we can begin to try targeted therapies across these patient populations. As this genetically driven treatment paradigm becomes more established, our field, which is accustomed to undertaking large clinical trials in broad patient populations, will need to take a new approach to clinical research, focusing on patients based on their genetic subtype."

Study co-author James Riviello, M.D., professor of neurology and pediatrics and chief of child neurology at Morgan Stanley Children's Hospital/NewYork-Presbyterian added "this is a very exciting breakthrough in the treatment of epilepsy, in which current treatment is based on whether a child has focal seizures, which begin in one area of the brain, or generalized seizures. Genetic testing for epilepsy may allow us to identify the specific anticonvulsant medication that potentially works best for an individual patient. We have already identified children in whom knowing the underlying genetic basis of epilepsy has guided our treatment choices."

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