Abstracts

Cortical dysplasia (CD) is a group of brain malformations associated with epilepsy. The malformations are often characterized by the presence of large, cytomegalic and dysmorphic neurons, which can occur in focal or widespread areas of the cortex and potentially contribute to the insurgency of seizures. For those children whose disorder resists medical treatment, surgical resection of epileptogenic foci is the best therapeutic option. However, not all children remain seizure-free after surgery. To gain further insight into this form of epilepsy and be able to generate better diagnostic and predictive tools, we generated genomic profiles of dysmorphic cytomegalic and normal-sized neurons found in surgical specimens. We hypothesize that genetic or environmental factors cause mutations leading to alterations in the transcription of genes associated with neuronal development and function that differ between cytomegalic and morphologically normal neurons. We used laser capture microdissection to isolate cytomegalic and normal appearing neurons from resected CD tissues (6 cases of focal cortical dysplasia and 6 hemimegalencephaly), and analyzed their gene expression profiles using Affymetrix microarrays. The data was normalized using RMA and analyzed using a variety of statistical algorithms developed in the Shaw Laboratory. By comparing the profiles of dysplastic versus normal neurons, we identified aberrant expression of genes involved in presynaptic vesicle formation, trafficking, and signal transduction. Molecular changes in these pathways, particularly those that lead to increased neurotransmitter release, could contribute to the epileptogenic process and therefore may represent potential targets for therapeutic intervention. We have validated the aberrant expression of many genes detected by microarray by independent assays, including quantitative RT-PCR (Q-PCR), immunohistochemistry, and [italic]in situ[/italic] hybridization. Correlations between gene expression signatures in the aberrant cells and clinical parameters such as age at seizure onset, pathology, and outcome will be discussed. We are expanding this analysis to a larger number of cases to identify targets for therapeutic intervention and to develop a molecular classification scheme for CD. (Supported by Citizens United for Research in Epilepsy (CURE) to G.D and NIH RO1 NS38992 to GWM.)