DNA methylation, somatic mutations, and polymicrogyria

MCDs. Malformation of cortical developments are a frequent cause of intractable epilepsies and, if appropriate, surgical resection may be warranted. Malformations represent a wide range of cortical lesions resulting from derangements of normal intrauterine developmental processes affecting the formation of the cortical mantle. Polymicrogyria (PMG) is one of the most common malformations of cortical development. However, while somatic mutations affecting the mTOR pathway are a known cause of certain subtypes of MCD, the polymicrogyrias have remained elusive. The underlying cause remains unknown in more than 80% of cases and, if identified, may be due to a wide range of underlying genetic causes. In a recent publication, mosaic trisomy 1q was identified as a novel and relatively frequent cause of polymicrogyria, emphasizing the role of somatic mutation detection in malformation of cortical development. Continue reading

Epigenetic signatures – profiling the epilepsies beyond genetics

What is epigenetics? In a single idea: the molecular memory of a cell. The system stores information of previously external (e.g. environmental) or internal (e.g. developmental) stimuli, learns from this experience and responds. A collection of specific tags tells genes whether to be ON or OFF. Hardcore epigeneticists claim that an epigenetic tag should be meiotically and/or mitotically heritable, self-perpetuating, and reversible. DNA methylation is the mechanism coming closest to this ideal. A more liberal definition not focusing on heritability refers to any structural adaptation of the chromatin template that regulates gene expression. This would also include posttranslational histone tail modifications, incorporation of histone variants, chromatin remodeling processes, and action of non-coding RNAs. The large variety, flexibility, interdependence and potential synergistic effects of epigenetic mechanisms could provide the molecular basis for any phenotypic variation in physiological and pathological conditions. In epilepsy research this is especially interesting with regard to the stimulus-driven activity and connectivity of post-mitotic neurons in the adult brain. We set out to study methylation for the most common form of epilepsy in adults. Continue reading