Unlocking the complex genetics of epilepsy

In two-thirds of people with epilepsy, the cause is unknown. Although genetics is believed to play an important role in many epilepsy syndromes, few specific genes have been implicated. Learning more about the genetic causes of epilepsy may facilitate the development of better targeted therapies for this complex disorder.

The Epilepsy Phenome/Genome Project (EPGP), one of the largest epilepsy research studies ever attempted, is examining the pathophysiology and clinical expression of idiopathic epileptic syndromes. All Mayo Clinic campuses are among the 27 centers participating in this international study.

Detailed phenotypic and genetic information has been collected from almost 3,000 patients with idiopathic or genetically based epilepsies. The study cohort also includes parents of participants with epilepsies that have a strong genetic predisposition.

"The purpose of the study is to identify relationships among family history, genetic factors and different types of seizures," says Gregory D. Cascino, M.D., a consultant in the Department of Neurology at Mayo Clinic's campus in Rochester, Minnesota. "What we've seen thus far looks very promising in terms of better understanding the causes of epilepsy and the prognosis for specific types of patients."

De novo mutations

The study results underline the complexity of genetically based epilepsies. "We're finding that these genes are influenced by a host of other factors that we don't yet fully grasp. This isn't going to be as easy as good old-fashioned Mendelian genetics," says Joseph I. Sirven, M.D., a consultant in the Department of Neurology at Mayo Clinic's campus in Phoenix, Arizona.

Indeed, people with genetically based epilepsy often have no family history of the disease. In a research letter published in Nature in 2013, EPGP researchers identified novel de novo mutations implicating at least two genes — GABRB3 and ALG13 — in infantile spasms and Lennox-Gastaut syndrome (LGS).

Several other gene mutations also were seen in the exomes of EPGP patients with infantile spasms or LGS, suggesting that genetic diagnostics will need to focus on the entire genome. In addition, the study found that many of the mutations seemed to converge on certain specific biological pathways.

"These findings are very important because they point out that a spontaneous gene mutation may predispose people to a genetic epilepsy even if they lack a family history," Dr. Cascino says. "The specific biological pathways also suggest a direction for drug development and treatment personalization in epileptic encephalopathies."

Other EPGP findings

The EPGP researchers have also found:

  • A spectrum of clinical, electroencephalogram (EEG) and developmental characteristics among 135 study participants with LGS of unknown cause. In research published in the November 2013 issue of Epilepsia, the EPGP researchers also found that half of adults in the study with LGS of unknown cause had completed secondary school, indicating that these patients can attain cognitive achievements.
  • Evidence of a shared genetic susceptibility to epilepsy and migraine. In a study published in the February 2013 issue of Epilepsia, the EPGP researchers found the shared genetic susceptibility applied to study participants with focal and generalized epilepsies, and migraine with aura.

Data for treatment breakthroughs

A principal goal of EPGP is the creation of a DNA repository and data bank. The size of the study cohort and range of epilepsies represented (Figure) is unique. The strength of the data offers potential for eventual breakthroughs that individualize patient treatment.

"In the future I believe we will treat our patients based on what we know about the genetics of their diseases," says William Tatum, D.O., a consultant in the Department of Neurology at Mayo Clinic's campus in Jacksonville, Florida. "Individuals may have a genetically predisposed susceptibility to side effects of a medication. We may be able to select medications based on the channels of the brain that are operational in patients with particular epilepsies. Our work with the human genome is making this a reality."

Enrolling patients in new study

Mayo Clinic's campus in Rochester, Minnesota, is enrolling patients in the Human Epilepsy Project, a multicenter, prospective study of people with newly diagnosed focal epilepsy. The study's purpose is to identify clinical characteristics and biomarkers predictive of disease outcome, progression and treatment response.

The researchers also seek to identify patients at high risk of pharmacoresistance who may benefit from more-aggressive initial therapy and earlier consideration for surgical treatment. Study participants must:

  • Be between the ages of 12 and 60
  • Have had at least two focal seizures in the previous 12 months
  • Have taken seizure medication for less than four months

Participants will be followed for three years to characterize their clinical course and evolution of neuroimaging, electrophysiology, neuropsychiatric comorbidities and biochemical features.

"We know that about a third of patients who develop epilepsy ultimately will have difficulty controlling their seizures," Dr. Cascino says. "With this study, we hope to learn more about who is likely to have a benign disease that responds to therapy."

For more information

Allen AS, et al. De novo mutations in epileptic encephalopathies. Nature. 2013;501:217.

Winawer MR, et al. Evidence for a shared susceptibility to migraine and epilepsy. Epilepsia. 2013;54:288.

Widdess-Walsh P, et al. Lennox-Gastaut syndrome of unknown cause: Phenotypic characteristics of patients in the Epilepsy Phenome/Genome Project. Epilepsia. 2013;54:1898.