De novo mutations of voltage-gated sodium channel α
            <sub>II</sub>
            gene
            <i>SCN2A</i>
            in intractable epilepsies

Ogiwara, Ikuo; Ito, Koichi; Sawaishi, Yukio; Osaka, Hitoshi; Mazaki, Emi; Inoue, Ikuyo; Montal, Mauricio; Hashikawa, Tsutomu; Shike, Toshihide; Fujiwara, Tateki; Inoue, Yushi; Kaneda, Makoto; Yamakawa, Kazuhiro

doi:10.1212/wnl.0b013e3181b9cebc

Cited by 195 publications

(185 citation statements)

References 30 publications

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“…While the observation of seizure improvement is based only on retrospective clinical review, this finding reinforces previous observations of drug response: withdrawal of phenytoin provoking status epilepticus in one case, status treated with fosphenytoin in another, 2 seizure-free on lamotrigine, and one with seizure control on lidocaine. 6,12,14 Phenytoin did not, however, significantly improve development in the patients with seizure improvement and was not associated with clear seizure improvement in all patients, although seizures were not exacerbated. The reasons for these differential effects within and between patients are unclear and warrant further study.…”

Section: -Ax T-ap E-hv/t/ht I Gi-c Sf T2-wm T1-bg T-s T-ests Usmentioning

confidence: 72%

“…6,8,[10][11][12][13]15 Despite variability in age at onset and severity of outcome, there are common features in SCN2A encephalopathy. Our patients presented at a median of 2 days with multiple types of brief focal seizures that cluster, reaching maximal frequency of multiple hourly seizures within 3 months of onset.…”

Section: -Ax T-ap E-hv/t/ht I Gi-c Sf T2-wm T1-bg T-s T-ests Usmentioning

confidence: 99%

“…[4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Our analysis suggests that patients fall into 3 phenotypic groups: a severe neonatalinfantile phenotype, an intermediate neonatal-infantile phenotype, and a childhood phenotype (figure 4). The numbers in the latter groups are small; further cases are required to confirm distinct subgroups or, alternatively, a spectrum of severity.…”

Section: -Ax T-ap E-hv/t/ht I Gi-c Sf T2-wm T1-bg T-s T-ests Usmentioning

confidence: 99%

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SCN2A encephalopathy

et al. 2015

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Objective: De novo SCN2A mutations have recently been associated with severe infantile-onset epilepsies. Herein, we define the phenotypic spectrum of SCN2A encephalopathy.Methods: Twelve patients with an SCN2A epileptic encephalopathy underwent electroclinical phenotyping.Results: Patients were aged 0.7 to 22 years; 3 were deceased. Seizures commenced on day 1-4 in 8, week 2-6 in 2, and after 1 year in 2. Characteristic features included clusters of brief focal seizures with multiple hourly (9 patients), multiple daily (2), or multiple weekly (1) seizures, peaking at maximal frequency within 3 months of onset. Multifocal interictal epileptiform discharges were seen in all. Three of 12 patients had infantile spasms. The epileptic syndrome at presentation was epilepsy of infancy with migrating focal seizures (EIMFS) in 7 and Ohtahara syndrome in 2. Nine patients had improved seizure control with sodium channel blockers including supratherapeutic or high therapeutic phenytoin levels in 5. Eight had severe to profound developmental impairment. Other features included movement disorders (10), axial hypotonia (11) with intermittent or persistent appendicular spasticity, early handedness, and severe gastrointestinal symptoms. Mutations arose de novo in 11 patients; paternal DNA was unavailable in one.Conclusions: Review of our 12 and 34 other reported cases of SCN2A encephalopathy suggests 3 phenotypes: neonatal-infantile-onset groups with severe and intermediate outcomes, and a childhood-onset group. Here, we show that SCN2A is the second most common cause of EIMFS and, importantly, does not always have a poor developmental outcome. Sodium channel blockers, particularly phenytoin, may improve seizure control. Neurology ® 2015;85:958-966 GLOSSARY BFNIS 5 benign familial neonatal infantile seizures; EE 5 epileptic encephalopathy; EIMFS 5 epilepsy of infancy with migrating focal seizures; MIP 5 molecular inversion probe; SUDEP 5 sudden unexpected death in epilepsy; WES 5 whole-exome sequencing.

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Section: -Ax T-ap E-hv/t/ht I Gi-c Sf T2-wm T1-bg T-s T-ests Usmentioning

confidence: 72%

Section: -Ax T-ap E-hv/t/ht I Gi-c Sf T2-wm T1-bg T-s T-ests Usmentioning

confidence: 99%

Section: -Ax T-ap E-hv/t/ht I Gi-c Sf T2-wm T1-bg T-s T-ests Usmentioning

confidence: 99%

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SCN2A encephalopathy

et al. 2015

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“…Patients with BFNIS have a good prognosis, and medication can be stopped early. However, there are very few patients described so far with more severe epilepsy [16], and some with epileptic encephalopathy [17]. In those, nonsense or missense mutations in the voltage sensor are often found, whereas BFNIS-associated mutations have never been described to be nonsense or with severe biophysical defects.…”

Section: Good Prognosismentioning

confidence: 99%

“…Furthermore, electrophysiological studies could predict response to retigabine for individual mutations, as specific mutations rarely reduce the sensitivity of K V 7.2 channels to retigabine [12]. In the case of severe SCN2A mutations with a loss of function [17], sodium channel blockers (similar to SMEI) should probably be avoided, whereas they should be beneficial in benign cases with gain-of-function mutations [14,15]. These theoretical considerations need to be confirmed by clinical data, but indicate the importance of genetic information and its potential for innovative individualized drug therapy in epilepsy.…”

Section: Role Of Pathophysiology Of Epilepsy For Pharmacoresponsementioning

confidence: 99%

Genetic Biomarkers in Epilepsy

et al. 2014

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The identification of valid biomarkers for outcome prediction of diseases and improvement of drug response, as well as avoidance of side effects is an emerging field of interest in medicine. The concept of individualized therapy is becoming increasingly important in the treatment of patients with epilepsy, as predictive markers for disease prognosis and treatment outcome are still limited. Currently, the clinical decision process for selection of an antiepileptic drug (AED) is predominately based on the patient's epileptic syndrome and side effect profiles of the AEDs, but not on effectiveness data. Although standard dosages of AEDs are used, supplemented, in part, by therapeutic monitoring, the response of an individual patient to a specific AED is generally unpredictable, and the standard care of patients in antiepileptic treatment is more or less based on trial and error. Therefore, there is an urgent need for valid predictive biomarkers to guide patient-tailored individualized treatment strategies in epilepsy, a research area that is still in its infancy. This review focuses on genomic factors as part of an individual concept for AED therapy summarizing examples that influence the prognosis of the disease and the response to AEDs, including side effects.

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Excitatory and inhibitory neuron defects in a mouse model of Scn1b‐linked EIEE52

Hull

O’Malley²,

Chen

et al. 2020

Ann Clin Transl Neurol

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Objective: Human variants in voltage-gated sodium channel (VGSC) α and β subunit genes are linked to developmental and epileptic encephalopathies (DEEs). Inherited, biallelic, loss-of-function variants in SCN1B, encoding the β1/β1B subunits, are linked to early infantile DEE (EIEE52). De novo, monoallelic variants in SCN1A (Nav1.1), SCN2A (Nav1.2), SCN3A (Nav1.3), and SCN8A (Nav1.6) are also linked to DEEs. While these VGSC-linked DEEs have similar presentations, they have diverse mechanisms of altered neuronal excitability. Mouse models have suggested that Scn2a-, Scn3a-, and Scn8a-linked DEE variants are, in general, gain of function, resulting in increased persistent or resurgent sodium current (I Na) and pyramidal neuron hyperexcitability. In contrast, Scn1a-linked DEE variants, in general, are loss-of-function, resulting in decreased I Na and hypoexcitability of fast-spiking interneurons. VGSC β1 subunits associate with Nav1.1, Nav1.2, Nav1.3, and Nav1.6 and are expressed throughout the brain, raising the possibility that insults to both pyramidal and interneuron excitability may drive EIEE52 pathophysiology. Methods: We investigated excitability defects in pyramidal and parvalbumin-positive (PV +) interneurons in the Scn1b −/− model of EIEE52. We also used Scn1b FL/FL mice to delete Scn1b in specific neuronal populations. Results: Scn1b −/− cortical PV + interneurons were hypoexcitable, with reduced I Na density. Scn1b −/− cortical pyramidal neurons had population-specific changes in excitability and impaired I Na density. Scn1b deletion in PV + neurons resulted in 100% lethality, whereas deletion in Emx1 + or Camk2a + neurons did not affect survival. Interpretation: This work suggests that SCN1B-linked DEE variants impact both excitatory and inhibitory neurons, leading to the increased severity of EIEE52 relative to other DEEs.

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De novo mutations of voltage-gated sodium channel α _II gene SCN2A in intractable epilepsies

Abstract: Background: Mutations of voltage-gated sodium channel ␣ II gene, SCN2A, have been described in

Cited by 195 publications

References 30 publications

SCN2A encephalopathy

SCN2A encephalopathy

Genetic Biomarkers in Epilepsy

Excitatory and inhibitory neuron defects in a mouse model of Scn1b‐linked EIEE52

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De novo mutations of voltage-gated sodium channel α II gene SCN2A in intractable epilepsies

Abstract: Background: Mutations of voltage-gated sodium channel ␣ II gene, SCN2A, have been described in

Cited by 195 publications

References 30 publications

SCN2A encephalopathy

SCN2A encephalopathy

Genetic Biomarkers in Epilepsy

Excitatory and inhibitory neuron defects in a mouse model of Scn1b‐linked EIEE52

Contact Info

Product

Resources

About

De novo mutations of voltage-gated sodium channel α _II gene SCN2A in intractable epilepsies