Several genes previously implicated only in rare, severe forms of pediatric epilepsy may also contribute to common forms of the disorder, according to a report published online ahead of print January 13 in Lancet Neurology. “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,” said study leader David B. Goldstein, PhD, Director of the Institute for Genomic Medicine and Professor in the Departments of Genetics and Development and Neurology at Columbia University Medical Center in New York City.
David B. Goldstein, PhD
In recent years, researchers have identified 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 diet for patients with Dravet syndrome or GLUT-1 deficiency syndrome. 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 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,” said Dr. Goldstein.
To learn more about the genetics of epilepsy, Dr. Goldstein and his colleagues conducted a study to identify the genetic contributions to more common forms of epilepsy. Analyses were conducted at Columbia University Medical Center’s Institute for Genomic Medicine, in collaboration with NewYork-Presbyterian, as part of Epi4K, an international consortium of epilepsy clinicians and researchers. Most of the patients were recruited through the Epilepsy Phenome/Genome Project.
The researchers separately compared the sequence data from 640 individuals with familial genetic generalized epilepsy and 525 individuals with familial non-acquired focal epilepsy to the same group of 3,877 controls. The researchers found significantly higher rates of ultra-rare deleterious variation in genes established as causative for dominant epilepsy disorders (familial genetic generalized epilepsy, odd ratio 2.3; familial non-acquired focal epilepsy, odds ratio 3.6). Comparison of an additional cohort of 662 individuals with sporadic non-acquired focal epilepsy to controls did not identify study-wide significant signals.
Five Genes Implicated
For the individuals with familial non-acquired focal epilepsy, the researchers found that five known epilepsy genes—DEPDC5, LG11, PCDH19, SCN1A, and GRIN2A—ranked as the top five genes enriched for ultra-rare deleterious variation. “After accounting for the control carrier rate, we estimate that these five genes contribute to the risk of epilepsy in approximately 8% of individuals with familial non-acquired focal epilepsy,” said Erin Heinzen Cox, PhD, Assistant Professor in the Department of Pathology and Cell Biology and Deputy Director of the Institute for Genomic Medicine at Columbia University Medical Center.
Erin Heinzen Cox, PhD
Treatment Targeted to Epilepsy Subtype
The findings have important implications for clinical practice and for 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.”
“This is a very exciting breakthrough in the treatment of epilepsy, in which current treatment is based on whether a child has focal seizures … or generalized seizures,” said James J. Riviello, MD, the Sergievsky Family Professor of Neurology and Pediatrics and Chief of Child Neurology at NewYork-Presbyterian Morgan Stanley Children’s Hospital in New York City. “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 the epilepsy has guided our treatment choices.”
James J. Riviello, MD
Additional studies, which will analyze 10,000 to 12,000 samples, are planned for the coming year. “With a larger analysis, we expect to find additional genetic variations that contribute to common epilepsies,” said Dr. Goldstein.
Suggested Reading
Epi4K consortium, Epilepsy Phenome/Genome Project. Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. Lancet Neurol. 2017;16(2):135-143.