Can mutation‐mediated effects occurring early in development cause long‐term seizure susceptibility in genetic generalized epilepsies?

Abstract

Epilepsy has a strong genetic component, with an ever-increasing number of disease-causing genes being discovered. Most epilepsy-causing mutations are germ line and thus present from conception. These mutations are therefore well positioned to have a deleterious impact during early development. Here we review studies that investigate the role of genetic lesions within the early developmental window, specifically focusing on genetic generalized epilepsy (GGE). Literature on the potential pathogenic role of sub-mesoscopic structural changes in GGE is also reviewed. Evidence from rodent models of genetic epilepsy support the idea that functional and structural changes can occur in early development, leading to altered seizure susceptibility into adulthood. Both animal and human studies suggest that sub-mesoscopic structural changes occur in GGE. The existence of sub-mesoscopic structural changes prior to seizure onset may act as biomarkers of excitability in genetic epilepsies. We also propose that presymptomatic treatment may be essential for limiting the long-term consequences of disease-causing mutations in genetic epilepsies.

Developmental decrease in parvalbumin‐positive neurons precedes increase in flurothyl‐induced seizure susceptibility in the Brd2+/− mouse model of juvenile myoclonic epilepsy

“…Our findings support the idea that mutation‐mediated structural (and possibly also functional) changes can occur early in development and lead to altered seizure susceptibility later on through maturation 50 …”

Peripapillary retinal nerve fibre layer thinning in genetic generalized epilepsy

“…Recently, an exome-based case-control study suggested that disruptive and rare variants in genes encoding GABA-A receptor subunits could increase the risk of GGE [27]. Apart from loss of function, there is evidence that mutations in GABA receptors might also be associated with abnormal development of neuronal networks, which could be one of the critical mechanisms leading to GGE [9]. During brain development, GABA acts as an excitatory neurotransmitter, playing a key role in various aspects of the maturation process, such as neuronal migration [28].…”

“…The RGCs are the output neurons of the retina, and their axons travel through the RNFL. The issue of mutations previously described in GGE that could influence the organization and composition of inhibitory neural circuits during development [9,38], modifying not only the thalamocortical network connections [9,31] but also RGCs, opens new and interesting lines of inquiry.…”

“…MRI volumetry and voxel-based morphometry studies have demonstrated regional changes, particularly thalamic volume loss, in GGE patients [4,7,8]. Potential pathogenic sub-mesoscopic structural and functional changes that occur during early development could explain altered seizure susceptibility into adulthood for GGE [9].…”

Pediatric Epilepsy Mechanisms: Expanding the Paradigm of Excitation/Inhibition Imbalance

“…It might be reasoned that patients with a permanently altered E/I imbalance would have seizures constantly, rather than intermittently. In addition, as elaborated below, many recently discovered epileptogenic mutations would not lead to the prediction of increased excitation or decreased inhibition, and mutation-specific alterations of excitability can affect different brain areas at different developmental time points [24]. In other disorders in which E/I imbalance has been proposed, such as autism, the E/I hypothesis is also being reconsidered [25].…”