Role of circadian genes in the pathogenesis of Paediatric Focal Epilepsy

According to research presented at the 2015 American Epilepsy Society annual meeting in Philadelphia, dysfunction of brain circuits in pediatric patients with focal epilepsy results from a significant reduction in Circadian Locomotor Output Cycles Kaput (Clock) expression.

The researchers including Judy Liu MD PhD and her colleagues at the Children’s National Medical Center in Washington studied patients with focal epilepsy enrolled under their epilepsy surgery program. They used high-resolution 3t magnetic resonance imaging to determine epileptogenic foci and collected samples directly from the operating room for transcriptome analysis performed by microarray using Illumina® Gene Expression Bead Chip Array technology.

Studies in mice were also conducted for histological and gene expression analyses, whole cell patch-clamp electrophysiology, and pentylenetetrazole (ptz) seizure induction.
They found that compared with normal brain tissue the epileptogenic tissue showed a significant reduction of Circadian Locomotor Output Cycles Kaput (Clock) expression in 20 out of the 25 patients. Patients with decreased Clock included those with focal cortical dysplasias, tuberous sclerosis complex, Sturge-Weber syndrome, and Rasmussen's encephalitis.

The protein encoded by the Clock gene plays a central role in the regulation of circadian rhythms. Polymorphisms in this gene may be associated with behavioral changes, obesity, and metabolic syndrome. Two transcripts encoding the same protein have been found for this gene.

Deletion of the circadian clock in excitatory neurons in mice was associated with loss of spines in the apical dendrite and primary branches, a phenotype also seen in epileptogenic tissue of human pyramidal neurons.

These results point towards the key role of circadian genes in the pathogenesis of focal epilepsy in children and provide a link between the sleep-wake cycle and seizure threshold.
In addition it opens up the prospects of the circadian pathway being a promising target for therapeutic intervention.

Citation: Liu J, Fu X, Li P, et al. Abstract 3.019|A.01. Loss of Clock results in dysfunction of brain circuits that underlie pediatric focal epilepsy. Presented at: American Epilepsy Society Annual Meeting; Dec. 4-8, 2015; Philadelphia.