Abstracts

Rationale: Malformations of cortical development (MCD) is a leading cause of medically refractory focal epilepsy. The phenotypic variability amongst children with MCD in terms of onset and progression of seizure activity, response to treatment, and refractoriness to medications remains poorly understood and may have an epigenetic basis. Knowledge of underlying genetic predispositions and epigenetic mechanisms may serve as an important tool to understand the pathophysiological processes unique to different etiologies and provide newer targets to optimize treatment. The present study was aimed at comparative analysis of epigenetic changes in the methylation profile of patients with malformations of cortical development (MCD) compared with patients who have idiopathic epilepsy (IE). As a secondary measure, the changes were compared to patients with tuberous sclerosis (TS) to identify consistencies and variability in methylation patterns. Methods: We evaluated methylation profiles in brain tissue samples as well as blood samples of patients with and without MCD using Illumina® 450k Methylation Microarray. Data obtained was analyzed using Bioconductor packages. Blood samples of patients with Tuberous Sclerosis (TS) were analyzed in a similar manner which allowed comparison with MCD samples. Results: Differential methylation was observed in the Ephrin pathway genes in both tissue as well as blood samples of patients with MCD when compared with IE. Hypermethylation of potassium channel related genes KCNQ5 and KCNG4 indicated reduced expression of these proteins in patients with MCD. GST (Glutathione-S-transferase) pathway genes were found to be differentially methylated only in brain tissue samples. Interestingly, none of the above mentioned genes constituted the list of top hits of differentially methylated genes in patients with TS. In fact, we observed reduced methylation of NOTCH pathway gene in TS patients. Conclusions: Unique patterns of methylation are observed in patients with MCD compared with those who have idiopathic epilepsy. In addition to changes in cell migration pathways (ephrin), reduced expression of potassium channel related genes in patients with MCD may cause increased cortical excitability and account for epileptogenicity. Tissue-specific oxidative injury (as seen with GST methylation exclusively in brain samples) may be a cause or effect of seizures in these patients. Further studies with larger sample size may help elucidate the pathophysiological and clinical significance of these patterns. Although this is a preliminary study that requires further validation, our results hold a promise of identifying disease subtype specific epigenetic signatures. Funding: None