Common epilepsies share genetic overlap with rare types

January 10, 2017, Columbia University Medical Center

An international study led by Columbia University Medical Center (CUMC) and NewYork-Presbyterian researchers has found that several genes previously implicated only in rare, severe forms of pediatric epilepsy also contribute to common forms of the disorder.

"Our findings raise hopes that the emerging paradigm for the treatment of rare epilepsies, where therapies are targeted to the precise cause of disease, may also extend to a proportion of common 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 CUMC.

The findings were published online today in The Lancet Neurology.

In recent years, researchers 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," 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. 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 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. Most of the patients were recruited through the Epilepsy Phenome/Genome Project.

The researchers 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. "We estimate that these five genes contribute to epilepsy risk in approximately 8 percent of people with this common form of the disorder," 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 CUMC. A similar pattern was also observed for another common type of epilepsy, genetic generalized epilepsy.

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, which begin in one area of the brain, or generalized seizures," said James J. Riviello, MD, the Sergievsky Family Professor of Neurology and Pediatrics and Chief of Child Neurology at Morgan Stanley Children's Hospital/NewYork-Presbyterian. "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."

Additional studies, analyzing 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.

The study is titled, "Ultra-rare genetic variation in common epilepsies: a case-control sequencing study."

Explore further: Study identifies druggable brain gene network implicated in epilepsy

Related Stories

Study identifies druggable brain gene network implicated in epilepsy

December 12, 2016
A new study has identified a network of genes in the brain that, when disrupted, causes epilepsy; the results also predicted that a known anti-epileptic drug works to restore the network's function. This discovery has not ...

New technology is key to better epilepsy treatment

March 22, 2013
(Medical Xpress)—University of Adelaide scientists are making a major impact on the understanding and diagnosis of epilepsy, which will lead to individualised treatments for sufferers.

Large study pinpoints synapse genes with major roles in severe childhood epilepsies

September 25, 2014
An international research team has identified gene mutations causing severe, difficult-to-treat forms of childhood epilepsy. Many of the mutations disrupt functioning in the synapse, the highly dynamic junction at which nerve ...

Some psychotic disorders may be induced by drugs designed to combat effects of epilepsy

August 9, 2016
Today Brain publishes a new study indicating that antiepileptic drugs designed to reduce seizures, may also induce psychotic disorders in some patients.

All in the family: A genetic link between epilepsy and migraine

January 7, 2013
New research reveals a shared genetic susceptibility to epilepsy and migraine. Findings published in Epilepsia, a journal of the International League Against Epilepsy (ILAE), indicate that having a strong family history of ...

New epilepsy gene located in dogs

March 23, 2012
A new epilepsy gene for idiopathic epilepsy in Belgian Shepherds has been found in the canine chromosome 37. The research of Professor Hannes Lohi and his group conducted at the University of Helsinki and the Folkhälsan ...

Recommended for you

Research reveals atomic-level changes in ALS-linked protein

January 18, 2018
For the first time, researchers have described atom-by-atom changes in a family of proteins linked to amyotrophic lateral sclerosis (ALS), a group of brain disorders known as frontotemporal dementia and degenerative diseases ...

Fragile X finding shows normal neurons that interact poorly

January 18, 2018
Neurons in mice afflicted with the genetic defect that causes Fragile X syndrome (FXS) appear similar to those in healthy mice, but these neurons fail to interact normally, resulting in the long-known cognitive impairments, ...

How your brain remembers what you had for dinner last night

January 17, 2018
Confirming earlier computational models, researchers at University of California San Diego and UC San Diego School of Medicine, with colleagues in Arizona and Louisiana, report that episodic memories are encoded in the hippocampus ...

Recording a thought's fleeting trip through the brain

January 17, 2018
University of California, Berkeley neuroscientists have tracked the progress of a thought through the brain, showing clearly how the prefrontal cortex at the front of the brain coordinates activity to help us act in response ...

Midbrain 'start neurons' control whether we walk or run

January 17, 2018
Locomotion comprises the most fundamental movements we perform. It is a complex sequence from initiating the first step, to stopping when we reach our goal. At the same time, locomotion is executed at different speeds to ...

Miles Davis is not Mozart: The brains of jazz and classical pianists work differently

January 16, 2018
Keith Jarret, world-famous jazz pianist, once answered in an interview when asked if he would ever be interested in doing a concert where he would play both jazz and classical music: "No, that's hilarious. [...] It's like ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.