Epilepsy Causes and Treatment in TSC
Abstract
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder occurring in 1/6,000 individuals with mutations in one of two tumor suppressor genes, TSC1 or TSC2, leading to hyperactivity of the mechanistic target of rapamycin complex 1 (mTORC1). Although TSC affects many organ systems, the neurological symptoms, in particular epilepsy, cause the most significant disability. Eighty to 90 percent of TSC individuals will experience seizures of different types, including infantile spasms and generalized seizures. While infantile spasms are well-controlled by treatment with vigabatrin, remaining seizures are mostly refractory to treatment and require surgical resection. Recent studies in small groups of patients suggest that treatment with the mTORC1 blocker rapamycin effectively limits seizure activity, but one study also reported increased seizure frequency. In addition, rapamycin has serious side effects that should not be ignored since lifelong treatment will be required to treat epilepsy based on animal studies. As a result, the only viable option at the present time for patients with epilepsy is brain surgery. Even with such an invasive procedure, only approximately 50 percent of the TSC patients will properly manage their seizures. There is thus a serious need to improve epilepsy treatment in TSC patients. With this goal in mind, we have generated a novel model of focal cortical malformations that display most pathological hallmarks of cortical tubers and are associated with recurrent convulsive seizures. Using our newly developed model, we have identified the abnormal expression of a channel in tuber neurons that could confer the increased excitability and pacemaker activity required for these neurons to generate seizures. The present project aims at further characterizing the expression profile of these channels in tuber neurons in mouse and human tissue obtained from TSC patients undergoing surgery for epilepsy. Importantly, we will examine whether removing these abnormally expressed channels or blocking their activity will prevent convulsive seizures in mice as a preclinical study.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610164
Entities
People
- Angélique Bordey
Organizations
- United States Army
- Yale University