Introduction from Dr Markus Reuber, editor-in-chief of Seizure
Inheritance has been believed to make a significant contribution to the aetiology of epilepsy for a very long time. However, while genetic studies have provided amazing insights into the neurobiological underpinnings of rare forms of epilepsy, research into the genetic aspects of the “seizure threshold” or into genes determining an individuals’ risk of developing seizures after a brain insult – such as a stroke or traumatic brain injury (TBI) - has been less revealing. Despite the steady extension of genetic searches from linkage to exome and whole genome studies (associated with a need for increasingly large patient samples), this research has, so far, yielded limited findings. Having said that, the escalation of complexity of genetic research approaches has allowed us to move from the recognition of the role of ion channel genes in the aetiology of the epilepsies to a much broader understanding, also implicating processes such as chromatin remodeling, transcriptional regulation and the regulation of the mammalian target of rapamycin (mTOR) protein (1).
In my Editor’s Choice from the current volume of Seizure Cotter et al. review genetic studies which focus on the risk of individuals developing seizures after TBI (2). Posttraumatic epilepsy (PTE) accounts for one in 20 cases of epilepsy. In three quarters of patients PTE manifests within the first two years of the brain injury, but the risk of developing epilepsy remains elevated for several years after the traumatic insult. While there are many potentially important demographic differences between patients with PTE (especially the age at the time of the injury) as well as differences in terms of the TBI (such as the cause, severity and location of the injury) (3), this clinical scenario should allows us to identify genetic factors contributing to an individual’s risk to develop epilepsy perhaps in other clinical contexts as well.
Unfortunately, the findings in relation to the genetic underpinnings of PTE to date can only be described as preliminary. The most promising biomarkers identified were IL-1ß rs1143634 (a gene encoding a pro-inflammatory cytokine) and A1AR rs10920573 (a gene encoding the adenosine A1 receptor). Both of these genes are likely to affect an individual’s response to a traumatic insult – or the healing process from a TBI. These are encouraging early findings providing ideas for treatments capable of preventing PTE in patients who have suffered a TBI. However, more research is required.
(1) Myers CT and Mefford HC. Advancing epilepsy genetics in the genomic era. Genome Medicine 2015;7:91, DOI: 10.1186/s13073-015-0214-7
(2) Cotter D, Kelso A, Neligan A. Genetic Biomarkers of Posttraumatic Epilepsy (PTE): A Systematic Review. Seizure 2017;46, 53-58
(3) Gupta PK, Sayed N, Ding K, Agostini MA, Van Ness PC, Yablon S, et al. Subtypes of post-traumatic epilepsy: clinical, electrophysiological, and imaging features. J Neurotrauma 2014;31:1439-43.