Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Zaman, Tariq, Abou Tayoun, Ahmad, Goldberg, Ethan M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689675/
https://www.ncbi.nlm.nih.gov/pubmed/31402610
http://dx.doi.org/10.1002/acn3.50839
_version_ 1783443070257201152
author Zaman, Tariq
Abou Tayoun, Ahmad
Goldberg, Ethan M.
author_facet Zaman, Tariq
Abou Tayoun, Ahmad
Goldberg, Ethan M.
author_sort Zaman, Tariq
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6689675
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-66896752019-08-15 A single‐center SCN8A‐related epilepsy cohort: clinical, genetic, and physiologic characterization Zaman, Tariq Abou Tayoun, Ahmad Goldberg, Ethan M. Ann Clin Transl Neurol Research Articles 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. John Wiley and Sons Inc. 2019-07-23 /pmc/articles/PMC6689675/ /pubmed/31402610 http://dx.doi.org/10.1002/acn3.50839 Text en © 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Research Articles
Zaman, Tariq
Abou Tayoun, Ahmad
Goldberg, Ethan M.
A single‐center SCN8A‐related epilepsy cohort: clinical, genetic, and physiologic characterization
title A single‐center SCN8A‐related epilepsy cohort: clinical, genetic, and physiologic characterization
title_full A single‐center SCN8A‐related epilepsy cohort: clinical, genetic, and physiologic characterization
title_fullStr A single‐center SCN8A‐related epilepsy cohort: clinical, genetic, and physiologic characterization
title_full_unstemmed A single‐center SCN8A‐related epilepsy cohort: clinical, genetic, and physiologic characterization
title_short A single‐center SCN8A‐related epilepsy cohort: clinical, genetic, and physiologic characterization
title_sort single‐center scn8a‐related epilepsy cohort: clinical, genetic, and physiologic characterization
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689675/
https://www.ncbi.nlm.nih.gov/pubmed/31402610
http://dx.doi.org/10.1002/acn3.50839
work_keys_str_mv AT zamantariq asinglecenterscn8arelatedepilepsycohortclinicalgeneticandphysiologiccharacterization
AT aboutayounahmad asinglecenterscn8arelatedepilepsycohortclinicalgeneticandphysiologiccharacterization
AT goldbergethanm asinglecenterscn8arelatedepilepsycohortclinicalgeneticandphysiologiccharacterization
AT zamantariq singlecenterscn8arelatedepilepsycohortclinicalgeneticandphysiologiccharacterization
AT aboutayounahmad singlecenterscn8arelatedepilepsycohortclinicalgeneticandphysiologiccharacterization
AT goldbergethanm singlecenterscn8arelatedepilepsycohortclinicalgeneticandphysiologiccharacterization