Role of the sodium channel <i><scp>SCN</scp>9A</i> in genetic epilepsy with febrile seizures plus and Dravet syndrome

Mulley, John C.; Hodgson, Bree; McMahon, Jacinta M.; Iona, Xenia; Bellows, Susannah T.; Mullen, Saul A.; Farrell, Kevin; Mackay, Mark T; Sadleir, Lynette G.; Bleasel, Andrew; Gill, Deepak; Webster, Richard; Wirrell, Elaine; Harbord, Michael; Sisodiya, S; Andermann, Eva; Kivity, Sara; Berkovic, Samuel F.; Scheffer, Ingrid E.; Dibbens, Leanne M.

doi:10.1111/epi.12323

Cited by 63 publications

(63 citation statements)

References 12 publications

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“…In our study, the sodium channels in the differentiated NG108-15 cells are mainly due to Nav1.7 expression [39]. Other studies have provided evidence of a role of SCN9A which encodes Nav1.7 in human epilepsies [52], including febrile seizures plus and Dravet syndrome [53].…”

Section: Cellular Physiology and Biochemistrysupporting

confidence: 62%

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

Lai

Lin

Yeh

et al. 2018

Cell Physiol Biochem

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Background/Aims: Immunological mechanisms can be triggered as a response to central nervous system insults and can lead to seizures. In this study an investigation was made to determine if glatiramer acetate (GA), an immunomodulator currently used in the treatment of multiple sclerosis, could protect rats from pilocarpine-induced seizures and chronic epilepsy. Methods: Two groups of adult male Sprague-Dawley rats, experimental (GA) and control, were used in the study. The systemic IL-1α and IL-1β levels at baseline were checked as well as status epilepticus (SE), and the spontaneous recurrent seizure (SRS) stage by enzyme-linked immunosorbent assay. The GA group was given GA (150 μg/kg, ip) and the control group was given a saline injection prior to pilocarpine-induced seizures. Seizure susceptibility, severity and mortality were evaluated, using Racine seizure classification and hippocampal damage was evaluated by Nissl staining. The GA group received GA (150 μg/kg/day, ip) daily after SE, and the chronic spontaneous seizures were evaluated by long-term video recording, and mossy fiber sprouting was evaluated by Timm staining. The IL-1α and IL-1β levels were correlated with seizure activities. The TNF-α level in the hippocampus was determined at the SRS stage by immunohistochemistry. The effect of GA on ionic currents and action potentials (APs) in NG108-15 differentiated neurons was investigated using patch-clamp technology. Results: It was found that latency to severe seizures was significantly longer in the GA (p < 0.01) group, which also had SE of shorter duration and less frequent SRS (p < 0.01). GA attenuated acute hippocampal neuron loss and chronic mossy fiber sprouting in the CA3 and the SRS-reduction correlated with the reduction of IL-1α, but not with IL-1β or TNF-α levels. Mechanistically, GA reduced the peak amplitude of voltage-gated Na⁺ current (I_Na), with a negative shift in the inactivation curve of I_Na and reduced the amplitude of APs along with decreased firing of APs. Conclusion: GA might serve as a neuroexcitability modulator which attenuates pilocarpine-induced acute and chronic excitotoxicity. Sodium channel attenuation was partially independent of the immunomodulatory effect.

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Section: Cellular Physiology and Biochemistrysupporting

confidence: 62%

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

Lai

Lin

Yeh

et al. 2018

Cell Physiol Biochem

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“…Several other members of GABA receptor but not GABRE have been implicated in human epilepsy in human3435. Variants of SCN9A in heterozygote have been reported in patients of generalized epilepsy with febrile seizure plus (GEFS+), familiar febrile seizure, and other non-epilepsy related phenotypes36. Mutations in SCN9A that follow the recessive inheritance have been identified in family with pain insensitivity37.…”

Section: Resultsmentioning

confidence: 99%

Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing

Wang

Rao

et al. 2017

Sci Rep

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Genetic factors play a major role in the etiology of epilepsy disorders. Recent genomics studies using next generation sequencing (NGS) technique have identified a large number of genetic variants including copy number (CNV) and single nucleotide variant (SNV) in a small set of genes from individuals with epilepsy. These discoveries have contributed significantly to evaluate the etiology of epilepsy in clinic and lay the foundation to develop molecular specific treatment. However, the molecular basis for a majority of epilepsy patients remains elusive, and furthermore, most of these studies have been conducted in Caucasian children. Here we conducted a targeted exome-sequencing of 63 trios of Chinese epilepsy families using a custom-designed NGS panel that covers 412 known and candidate genes for epilepsy. We identified pathogenic and likely pathogenic variants in 15 of 63 (23.8%) families in known epilepsy genes including SCN1A, CDKL5, STXBP1, CHD2, SCN3A, SCN9A, TSC2, MBD5, POLG and EFHC1. More importantly, we identified likely pathologic variants in several novel candidate genes such as GABRE, MYH1, and CLCN6. Our results provide the evidence supporting the application of custom-designed NGS panel in clinic and indicate a conserved genetic susceptibility for epilepsy between Chinese and Caucasian children.

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“…However, mutations of this gene are usually associated with febrile seizure, GEFSP, and Dravet syndrome, 36 whereas the patient's phenotype was suggestive of an epileptic encephalopathy strongly resembling West syndrome with hypsarrhythmia, spasm, and psychomotor regression. Both his parents were healthy.…”

Section: Discussionmentioning

confidence: 95%

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

et al. 2014

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We analyzed by next-generation sequencing (NGS) 67 epilepsy genes in 19 patients with different types of either isolated or syndromic epileptic disorders and in 15 controls to investigate whether a quick and cheap molecular diagnosis could be provided. The average number of nonsynonymous and splice site mutations per subject was similar in the two cohorts indicating that, even with relatively small targeted platforms, finding the disease gene is not an univocal process. Our diagnostic yield was 47% with nine cases in which we identified a very likely causative mutation. In most of them no interpretation would have been possible in absence of detailed phenotype and familial information. Seven out of 19 patients had a phenotype suggesting the involvement of a specific gene. Disease-causing mutations were found in six of these cases. Among the remaining patients, we could find a probably causative mutation only in three. None of the genes affected in the latter cases had been suspected a priori. Our protocol requires 8-10 weeks including the investigation of the parents with a cost per patient comparable to sequencing of 1-2 medium-to-large-sized genes by conventional techniques. The platform we used, although providing much less information than whole-exome or whole-genome sequencing, has the advantage that can also be run on 'benchtop' sequencers combining rapid turnaround times with higher manageability.

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Role of the sodium channel SCN9A in genetic epilepsy with febrile seizures plus and Dravet syndrome

Cited by 63 publications

References 12 publications

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

The Novel Effect of Immunomodulator-Glatiramer Acetate on Epileptogenesis and Epileptic Seizures

Genetic Variants Identified from Epilepsy of Unknown Etiology in Chinese Children by Targeted Exome Sequencing

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

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