Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/30352
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dc.contributor.authorSoh, Ming S-
dc.contributor.authorBagnall, Richard D-
dc.contributor.authorSemsarian, Christopher-
dc.contributor.authorScheffer, Ingrid E-
dc.contributor.authorBerkovic, Samuel F-
dc.contributor.authorReid, Christopher A-
dc.date2022-
dc.date.accessioned2022-06-23T00:38:21Z-
dc.date.available2022-06-23T00:38:21Z-
dc.date.issued2022-06-
dc.identifier.citationEpilepsia 2022; 63(6): e57-e62en
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/30352-
dc.description.abstractSudden unexpected death in epilepsy (SUDEP) is a leading cause of premature death in epilepsy. The underlying pathological mechanisms are likely to be multifactorial. Cardiac arrhythmia has been suggested as a cause of death in some patients with SUDEP. SCN5A encodes the cardiac Nav 1.5 sodium channel. SCN5A variants that result in either loss or gain of channel function cause cardiac arrhythmias. Rare SCN5A variants have been reported in SUDEP cases, but the impact of these variants on channel function is unknown. Here, we use whole-cell voltage clamp recordings to perform functional analyses of rare SCN5A SUDEP variants, p.V223G, p.I397V, and p.R523C. Expression and biophysical properties, including activation, inactivation, and recovery from inactivation, were probed. Each SCN5A variant significantly impacted human NaV 1.5 channel function, indicating that they could cause cardiac arrhythmias. The patient carrying the p.R523C variant was on lamotrigine, an antiseizure medication implicated in SUDEP. Therapeutic concentration of lamotrigine caused a slowing of the rate of recovery from inactivation and a hyperpolarizing shift in the voltage of inactivation of human NaV 1.5 wild-type, but not p.R523C channels, implicating a gene-by-drug interaction. These data suggest that SCN5A arrhythmogenic variants may confer increased risk of sudden death in individuals with epilepsy.en
dc.language.isoeng
dc.subjectSUDEPen
dc.subjectcardiac arrhythmiaen
dc.subjectepilepsyen
dc.subjectgeneticsen
dc.subjection channelsen
dc.titleRare sudden unexpected death in epilepsy SCN5A variants cause changes in channel function implicating cardiac arrhythmia as a cause of death.en
dc.typeJournal Articleen
dc.identifier.journaltitleEpilepsiaen
dc.identifier.affiliationDepartment of Paediatrics, University of Melbourne, Royal Children's Hospital, Victoria, Australia..en
dc.identifier.affiliationEpilepsy Research Centreen
dc.identifier.affiliationThe Florey Institute of Neuroscience and Mental Healthen
dc.identifier.affiliationAgnes Ginges Centre for Molecular Cardiology, Centenary Institute, University of Sydney, Sydney, New South Wales, Australia..en
dc.identifier.affiliationFaculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia..en
dc.identifier.affiliationMurdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia..en
dc.identifier.pubmedurihttps://pubmed.ncbi.nlm.nih.gov/35397174/en
dc.identifier.doi10.1111/epi.17254en
dc.type.contentTexten
dc.identifier.orcidhttps://orcid.org/0000-0002-5689-2082en
dc.identifier.orcidhttps://orcid.org/0000-0002-2311-2174en
dc.identifier.orcidhttps://orcid.org/0000-0003-4580-841Xen
dc.identifier.orcidhttps://orcid.org/0000-0002-1457-8028en
dc.identifier.pubmedid35397174
local.name.researcherBerkovic, Samuel F
item.cerifentitytypePublications-
item.languageiso639-1en-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.grantfulltextnone-
item.openairetypeJournal Article-
item.fulltextNo Fulltext-
crisitem.author.deptEpilepsy Research Centre-
crisitem.author.deptEpilepsy Research Centre-
crisitem.author.deptNeurology-
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