Abstract:
OBJECTIVE: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. METHODS: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. RESULTS: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. INTERPRETATION: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.
journal_name
Ann Clin Transl Neuroljournal_title
Annals of clinical and translational neurologyauthors
Zaman T,Abou Tayoun A,Goldberg EMdoi
10.1002/acn3.50839subject
Has Abstractpub_date
2019-08-01 00:00:00pages
1445-1455issue
8issn
2328-9503journal_volume
6pub_type
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journal_title:Annals of clinical and translational neurology
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更新日期:2015-12-08 00:00:00
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pub_type: 临床试验,杂志文章
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doi:10.1002/acn3.35
更新日期:2014-02-01 00:00:00
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pub_type: 杂志文章
doi:10.1002/acn3.58
更新日期:2014-05-01 00:00:00
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pub_type: 杂志文章
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更新日期:2020-05-01 00:00:00
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pub_type: 杂志文章
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.276
更新日期:2015-12-21 00:00:00
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pub_type: 杂志文章,随机对照试验
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pub_type: 杂志文章
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
doi:10.1002/acn3.220
更新日期:2015-08-01 00:00:00
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journal_title:Annals of clinical and translational neurology
pub_type: 杂志文章
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