Abstracts

Rationale: Epilepsy, the third most common neurological disorder in the United states, affects 1% of all children and has debilitating cognitive and psychosocial sequela. While antiepileptic drugs (AED) are the first line treatment for epilepsy, up to one-third of patients are medically recalcitrant, requiring aggressive treatment strategies, such as surgical resection. Temporal lobe epilepsy (TLE) is the most common form of intractable epilepsy in adults, and in children, is often associated with an inciting neurologic insult. The genetic etiology of TLE has not yet be elucidated, however, it has been postulated that a combination of germline inherited and somatic genetic mutations are associated with its pathogenesis. Known cortical dysplasias associated with seizures have been linked with disruptions in the mammalian target of rapamycin (mTOR) pathway. We believe that similar genetic alterations are found in pediatric patients with temporal lobe epilepsy without evidence of cortical malformation.  Methods: Fresh frozen temporal cortical specimen from pediatric patients with medically refractory temporal epilepsy without radiographic evidence of cortical malformations requiring operative intervention were collected and stored in the UCLA/Mathern Epilepsy Biorepository. Bulk DNA was then extracted and sent for Whole-Exome-Sequencing (WES) with up to 100X coverage. Exome data was subsequently evaluated for quality, aligned to the Genome Reference.Consortium Human Build 37 (GRCh37) and variants called using the snpEff variant annotator. The program GEMINI within the Galaxy online-platform was also used to assess for somatic mutations. Variants originating from MTOR pathway genes associated with known epileptiform syndromes were then identified.  Results: We identified 5 patients (3 males and two females) aged 7 to 17 years (average age of 13 years old) with medically non-lesional refractory epilepsy without MRI evidence of cortical dysplasia. WES analysis demonstrated an average of 89,117.8 variants per sample with approximately 1% accounting for 'high impact mutations.' Furthermore, these samples harbored an average of 68.8 MTOR pathway variants per sample, including approximately 13% specifically from the MTOR gene. There were no somatic mutations elucidated in this exome screening in any of the 5 samples. Conclusions: Non-lesional pediatric temporal lobe epilepsy may be associated with MTOR pathway mutations, similar to those found in known epileptiform syndromes, however further studies deeper sequencing are necessary to determine the etiology and clinical significance of these mutations.  Funding: NIH R25 Grant NS079198