gs-458967 and Seizures

Pathogenic variants in SCN8A, encoding the voltage-gated sodium (Na+) channel α subunit Nav1.6, is a known cause of epilepsy. Here, we describe clinical and genetic features of all patients with SCN8A epilepsy evaluated at a single-tertiary care center, with biophysical data on identified Nav1.6 variants and pharmacological response to selected Na+ channel blockers.. SCN8A variants were identified via an exome-based panel of epilepsy-associated genes for next generation sequencing (NGS), or via exome sequencing. Biophysical characterization was performed using voltage-clamp recordings of ionic currents in heterologous cells.. We observed a range in age of onset and severity of epilepsy and associated developmental delay/intellectual disability. Na+ channel blockers were highly or partially effective in most patients. Nav1.6 variants exhibited one or more biophysical defects largely consistent with gain of channel function. We found that clinical severity was correlated with the presence of multiple observed biophysical defects and the extent to which pathological Na+ channel activity could be normalized pharmacologically. For variants not previously reported, functional studies enhanced the evidence of pathogenicity.. We present a comprehensive single-center dataset for SCN8A epilepsy that includes clinical, genetic, electrophysiologic, and pharmacologic data. We confirm a spectrum of severity and a variety of biophysical defects of Nav1.6 variants consistent with gain of channel function. Na+ channel blockers in the treatment of SCN8A epilepsy may correlate with the effect of such agents on pathological Na+ current observed in heterologous systems.

Topics: Cell Culture Techniques; Child; Cohort Studies; Epilepsy; Female; HEK293 Cells; Humans; Infant; Infant, Newborn; Male; Mutation; NAV1.6 Voltage-Gated Sodium Channel; Oxcarbazepine; Pyridines; Seizures; Sodium Channels; Triazoles

Dravet syndrome, an epileptic encephalopathy affecting children, largely results from heterozygous loss-of-function mutations in the brain voltage-gated sodium channel gene SCN1A. Heterozygous Scn1a knockout (Scn1a

Topics: Action Potentials; Animals; Epilepsies, Myoclonic; Ion Channel Gating; Mice, Inbred C57BL; Mice, Knockout; NAV1.1 Voltage-Gated Sodium Channel; NAV1.6 Voltage-Gated Sodium Channel; Neurons; Pyramidal Cells; Pyridines; Seizures; Survival Analysis; Triazoles

Evidence from basic neurophysiology and molecular genetics has implicated persistent sodium current conducted by voltage-gated sodium (NaV ) channels as a contributor to the pathogenesis of epilepsy. Many antiepileptic drugs target NaV channels and modulate neuronal excitability, mainly by a use-dependent block of transient sodium current, although suppression of persistent current may also contribute to the efficacy of these drugs. We hypothesized that a drug or compound capable of preferential inhibition of persistent sodium current would have antiepileptic activity.. We examined the antiepileptic activity of two selective persistent sodium current blockers ranolazine, a U.S. Food and Drug Administration (FDA)-approved drug for treatment of angina pectoris, and GS967, a novel compound with more potent effects on persistent current, in the epileptic Scn2a(Q54) mouse model. We also examined the effect of GS967 in the maximal electroshock model and evaluated effects of the compound on neuronal excitability, propensity for hilar neuron loss, development of mossy fiber sprouting, and survival of Scn2a(Q54) mice.. We found that ranolazine was capable of reducing seizure frequency by approximately 50% in Scn2a(Q54) mice. The more potent persistent current blocker GS967 reduced seizure frequency by >90% in Scn2a(Q54) mice and protected against induced seizures in the maximal electroshock model. GS967 greatly attenuated abnormal spontaneous action potential firing in pyramidal neurons acutely isolated from Scn2a(Q54) mice. In addition to seizure suppression in vivo, GS967 treatment greatly improved the survival of Scn2a(Q54) mice, prevented hilar neuron loss, and suppressed the development of hippocampal mossy fiber sprouting.. Our findings indicate that the selective persistent sodium current blocker GS967 has potent antiepileptic activity and that this compound could inform development of new agents.

Topics: Acetanilides; Animals; Anticonvulsants; Cells, Cultured; Female; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; NAV1.2 Voltage-Gated Sodium Channel; Neurons; Piperazines; Pyridines; Ranolazine; Seizures; Sodium Channel Blockers; Triazoles