SCN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis

Abstract

ObjectiveThe aim of this study was to analyze the phenotypic spectrum, treatment, and prognosis of 72 Chinese children with SCN2A variants.MethodsThe SCN2A variants were detected by next-generation sequencing. All patients were followed up at a pediatric neurology clinic in our hospital or by telephone.ResultsIn 72 patients with SCN2A variants, the seizure onset age ranged from the first day of life to 2 years and 6 months. The epilepsy phenotypes included febrile seizures (plus) (n = 2), benign (familial) infantile epilepsy (n = 9), benign familial neonatal-infantile epilepsy (n = 3), benign neonatal epilepsy (n = 1), West syndrome (n = 16), Ohtahara syndrome (n = 15), epilepsy of infancy with migrating focal seizures (n = 2), Dravet syndrome (n = 1), early infantile epileptic encephalopathy (n = 15), and unclassifiable developmental and epileptic encephalopathy (n = 8). Approximately 79.2% (57/72) patients had varying degrees of developmental delay. All patients had abnormal MRI findings with developmental delay. 91.7% (55/60) patients with de novo SCN2A variants had development delay, while only 16.7% (2/12) patients with inherited SCN2A variants had abnormal development. 83.9% (26/31) SCN2A variants that were located in transmembrane regions of the protein were detected in patients with development delay. Approximately 69.2% (9/13) SCN2A variants detected in patients with normal development were located in the non-transmembrane regions. Approximately 54.2% (39/72) patients were seizure-free at a median age of 8 months. Oxcarbazepine has been used by 38 patients, and seizure-free was observed in 11 of them (11/38, 28.9%), while 6 patients had seizure worsening by oxcarbazepine. All 3 patients used oxcarbazepine and with seizure onset age > 1 year presented seizure exacerbation after taking oxcarbazepine. Valproate has been used by 53 patients, seizure-free was observed in 22.6% (12/53) of them.ConclusionThe phenotypic spectrum of SCN2A-related epilepsy was broad, ranging from benign epilepsy in neonate and infancy to severe epileptic encephalopathy. Oxcarbazepine and valproate were the most effective drugs in epilepsy patients with SCN2A variants. Sodium channel blockers often worsen seizures in patients with seizure onset beyond 1 year of age. Abnormal brain MRI findings and de novo variations were often related to poor prognosis. Most SCN2A variants located in transmembrane regions were related to patients with developmental delay.

Do All Roads Lead to Rome? Genes Causing Dravet Syndrome and Dravet Syndrome-Like Phenotypes

“…published from 2009 to 2021 in English or Chinese. Regarding the studies included, six studies on PCDH19 (27,(29)(30)(31)(32)(33)(34), three on SCN2A (36)(37)(38), two on SCN8A (27,39), five on SCN1B (40)(41)(42)(43)(44), two on GABRA1 (28,45), three on GABRB3 (47-49), three on GABRG2 (50-52), and three on STXBP1 (27,28,46) were included. Only one study was recorded for CHD2 (54), CPLX1, HCN1, and KCNA2, respectively (35,53,55,56).…”

“…This mutation is thought to affect the position of arginine at the channel voltage sensor, which in turn causes conformational changes in the ion channel and opens the otherwise closed channel pore, which may be responsible for the pathogenesis of DS (38). Chinese scholars Zeng et al retrospectively analyzed 21 patients with SCN2A mutation and found that one of them was diagnosed with DS (37). The gene mutation in this patient was inherited from his mother.…”

Functional analysis of a novel de novo SCN2A variant in a patient with seizures refractory to oxcarbazepine

“…The Na v 1.2 channel is expressed in the axon initial segment and Ranvier nodes of fetal myelinated nerve fibers, OPEN ACCESS EDITED BY Hu et al 10.3389/fnmol.2023.1159649 Frontiers in Molecular Neuroscience 02 frontiersin.org which may explain the major impact of SCN2A variants on fetal neural development and early-onset neurological diseases (Wolff et al, 2017). Missense mutation is the most common type of mutations in SCN2A gene (Wolff et al, 2017;Zeng et al, 2022). Minor changes in amino acid sequence caused by missense variants may lead to different functional outcomes in sodium channels, including gain-of-function (GOF), loss-of-function (LOF), or mixed dysfunctional type (GOF/LOF; Hedrich et al, 2019).…”

“…Missense mutation is the most common type of mutations in SCN2A gene ( Wolff et al, 2017 ; Zeng et al, 2022 ). Minor changes in amino acid sequence caused by missense variants may lead to different functional outcomes in sodium channels, including gain-of-function (GOF), loss-of-function (LOF), or mixed dysfunctional type (GOF/LOF; Hedrich et al, 2019 ).…”

“…Minor changes in amino acid sequence caused by missense variants may lead to different functional outcomes in sodium channels, including gain-of-function (GOF), loss-of-function (LOF), or mixed dysfunctional type (GOF/LOF; Hedrich et al, 2019 ). Previous studies have shown that hereditary variants mainly manifest as benign (familial) neonatal/infant epilepsy ( Zara et al, 2013 ; Kim et al, 2020 ), whereas de novo variants mostly manifest as developmental and epileptic encephalopathy (DEE), such as Ohtahara syndrome, epilepsy of infancy with migrating focal seizures (EIMFS), West syndrome, Dravet syndrome, Lennox–Gastaut syndrome, and unclassifiable early-onset epileptic encephalopathy (EOEE; Wolff et al, 2017 ; Zeng et al, 2022 ). Patients with seizure onset at less than 3-month-old often carry the SCN2A GOF variants of the SCN2A gene ( Wolff et al, 2017 ).…”