Abstracts

Rationale: Focal Cortical Dysplasia (FCD) describes a malformation of cortical development that is increasingly recognised as morphological substrate for severe therapy-refractory epilepsy in children and young adults. FCDs present with variable histopathological patterns, including architectural, cytoarchitectural or white matter abnormalities. The most frequent subtype comprises FCD type II, which in general occurs as isolated lesion and is histopathologically characterized by dysmorphic neurons (type IIA) and balloon cells (type IIB). Somatic mutations in key genes that regulate neuronal cell growth and migration, including mainly mTOR pathway associated genes have been suggested as the underlying disease mechanism in FCD type II. However, these mutations can be identified in only a limited number of patients and thus other pathomechanisms may well be considered. Methods: Recent data in experimental and human temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) suggest epigenetic regulation of gene expression as a robust hallmark of epileptogenesis and propagation into a chronic disease state. Nothing is known about epigenetic mechanisms in the pathogenesis of FCD. Here we used deep sequencing to analyze DNA methylation, gene expression, histone modifications, as well as genomic variation in human surgical brain specimens obtained from FCD type II patients, anatomical intact temporal neocortex of TLE-HS patients and autopsy control cases. Results: We report for the first time the epigenomic signatures of specific FCD subtypes (i.e. type IIA and IIB). Integration of genomic, molecular, and physiological data indicate interplay of different epigenetic layers in the regulation of distinct, pathology-specific functional pathways. A linear regression model further suggests FCD type IIA and TypeIIB as temporally molecular variants of the same disease. Conclusions: Our data provide new insight into the molecular pathomechanisms underlying or associated with FCD type II. We consider that our genome-wide analyses provide a comprehensive profile of DNA and histone methylation mediated gene expression changes, and may help to identify new regulatory targets in severe childhood epilepsy associated with FCD, which again could be addressed by novel treatment strategies. By defining the principal events mediating epigenomic changes it is anticipated that novel approaches will be developed to inhibit, attenuate or reverse the persistent deleterious consequences of seizures in the epileptic brain.   Funding: Our work was supported by the European Union's Seventh Framework Program (DESIRE project, grant agreement #602531).