Clinical study of 19 patients with SCN8A‐related epilepsy: Two modes of onset regarding EEG and seizures

Abstract

Summary Objective To describe the mode of onset of SCN8A‐related severe epilepsy in order to facilitate early recognition, and eventually early treatment with sodium channel blockers. Methods We reviewed the phenotype of patients carrying a mutation in the SCN8A gene, among a multicentric cohort of 638 patients prospectively followed by several pediatric neurologists. We focused on the way clinicians made the diagnosis of epileptic encephalopathy, the very first symptoms, electroencephalography (EEG) findings, and seizure types. We made genotypic/phenotypic correlation based on epilepsy‐associated missense variant localization over the protein. Results We found 19 patients carrying a de novo mutation of SCN8A, representing 3% of our cohort, with 9 mutations being novel. Age at onset of epilepsy was 1 day to 16 months. We found two modes of onset: 12 patients had slowly emerging onset with rare and/or subtle seizures and normal interictal EEG (group 1). The first event was either acute generalized tonic–clonic seizure (GTCS; Group 1a, n = 6) or episodes of myoclonic jerks that were often mistaken for sleep‐related movements or other movement disorders (Group 1b, n = 6). Seven patients had a sudden onset of frequent tonic seizures or epileptic spasms with abnormal interictal EEG leading to rapid diagnosis of epileptic encephalopathy. Sodium channel blockers were effective or nonaggravating in most cases. Significance SCN8A is the third most prevalent early onset epileptic encephalopathy gene and is associated with two modes of onset of epilepsy.

Genetic Neonatal-Onset Epilepsies and Developmental/Epileptic Encephalopathies with Movement Disorders: A Systematic Review

“…A total of 49 studies on 27 genes satisfied the inclusion criteria. We identified more than one paper for eight genes: ATP1A3 (one case series [13], one case report [14]); GNAO1 (four original articles [15][16][17][18], one case report [19]); KCNQ2 (two original articles [20,21], one case series [22], two case reports [23,24]); SCN8A (three original articles [6,25,26], two case reports [27,28]); SLC13A5 (two original articles [29,30]); STXBP1 (two original articles [31,32], one case series [33], one case report [34]); SCN2A (three original articles [35][36][37] and two case reports [38,39]); and SYNJ1 (one original article [40] and one case report [41]).…”

“…Classification according to gene function is reported in Table 1. The main seizure types at onset include "focal" (30 patients, 14 with clonic seizures), tonic (24), epileptic spasms (ES) (14), and myoclonic (10) [6,15,[17][18][19]22,[25][26][27][28][31][32][33][34][35]39,[42][43][44][45][46][47][48][49][50][51][52][53][54][55][56]. Thirteen patients had tonic-clonic seizures [6,15,16,26,33,54,56,57], twelve had subtle seizures [19,29,30,36,38,39,41,44,…”

Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review

“…This (Vanoye et al, 2014) *Non genetic origin mutations reported: Mutations described through clinical diagnosis, but the mutation type (Mendelian or de novo) were not reported, mainly due to the lack of parents to perform genotyping and difficulty in contacting the family. DII (S1) Missense NR (Butler et al, 2017b;Hewson et al, 2018;Lindy et al, 2018;Costain et al, 2019;Johannesen et al, 2019) T767I DII (S1) Missense Decreased current density Increased current amplitude provokes by voltage ramp protocol (Estacion et al, 2014;Gardella et al, 2018;Lindy et al, (Fung et al, 2015;Zhang et al, 2015;Lindy et al, 2018;Kim et al, 2019;Tsang et al, 2019;Pan and Cummins, 2020;Schreiber et al, DIII (S6)-DIV (S1) Missense NR (Pons et al, 2018;Denis et al, 2019) G1475R DIII (S6)-DIV (S1) Missense Enhanced persistent current (Hussain et al, 2016;Ortiz Madinaveitia et al, 2017;Parrini et al, 2017;Wang et al, 2017a;Gardella et al, 2018;Lindy et al, 2018;Xiao et al, 2018;Kim et al, 2019;Trivisano et al, 2019;Zaman et al, 2019;Ranza et al, 2020;Schreiber et al, 2020) G1476S DIII (S6)-DIV (S1) Missense NR (Lindy et al, 2018) I1479V DIII (S6)-DIV (S1) Missense NR (Larsen et al, 2015;Lindy et al, 2018;Schreiber et al, 2020) E1483K DIII (S6)-DIV (S1) Missense NR (Johannesen et al, 20...…”

“…Pathogenic mutated residues are situated in the highly evolutionarily conserved portions of the channel: transmembrane segments, intracellular inactivation gate loop, and the proximal 2/3 of the C-terminal domain (Blanchard et al, 2015;Wagnon and Meisler, 2015). The final 1/3 portion of the C-terminal and cytoplasmic interdomain loops 1 and 2 are less conserved (Denis et al, 2019). The proximal 2/3 of the C-terminal are involved in the interaction of several binding sites for proteins and accessory molecules, like beta subunits b1 and b3, fibroblast growth factors (molecules implicated in neural development), calmodulin (regulatory protein in neuronal function and hyperexcitability) and G protein (Bähler and Rhoads, 2002;Spampanato, 2004;Wittmack et al, 2004;Laezza et al, 2009;Yang et al, 2010).…”

A single‐center SCN8A‐related epilepsy cohort: clinical, genetic, and physiologic characterization

“…De novo pathogenic missense variants in SCN8A are associated with a spectrum of epilepsy severity, from benign familial infantile seizures (BFIS), infantile convulsions, and paroxysmal choreoathetosis (ICCA), to early infantile epileptic encephalopathy (EIEE)/developmental and epileptic encephalopathy (DEE) . In general, variants associated with severe childhood‐onset epilepsy are de novo missense variants, and electrophysiological studies of such variants typically reveal “gain of (channel) function” consistent with enhanced Na+ current .…”