The Kv1.1 null mouse, a model of sudden unexpected death in epilepsy (<scp>SUDEP</scp>)

Moore, Brian; Jou, Chuanchau J.; Tatalovic, Milos; Kaufman, Elizabeth S.; Kline, David D.; Kunze, Diana L.

doi:10.1111/epi.12793

Cited by 65 publications

(77 citation statements)

References 43 publications

(100 reference statements)

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“…Previous studies have reported that Kcna1‐ null mice model multiple SUDEP risk factors and terminal events because they have (1) spontaneous seizures and (2) a severe seizure phenotype with myoclonic and generalized tonic–clonic (GTC) seizures (3) that are refractory to traditional antiseizure drugs (e.g., carbamazepine, (Simeone TA, Kim DY, Simeone KA, Rho JM) unpublished data). (4) Kcna1‐ null mice are cognitively impaired and (5) have cardiac arrhythmias; the terminal events associated with their sudden death include (6) a GTC seizure followed by (7) enhanced postictal parasympathetic‐mediated bradyarrhythmias, and (8) asystole and death …”

Section: Discussionmentioning

confidence: 99%

“…Treatment with the KD has been reported to completely abolish seizures in up to 13% of patients and reduce seizure frequency by >50% in approximately two thirds of patients with refractory epilepsy . We have previously reported that the KD effectively reduces seizures in Kcna1 ‐null mutant mice, which model early onset epilepsy, multiple temporal lobe epilepsy syndromes , and SUDEP . Due to the broad‐spectrum efficacy of KD in controlling seizures, in the current study we asked whether KD treatment can increase longevity in Kcna1 ‐null mice.…”

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confidence: 95%

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Ketogenic diet treatment increases longevity in Kcna1‐null mice, a model of sudden unexpected death in epilepsy

et al. 2016

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Summary Individuals with poorly controlled epilepsy have a higher risk for Sudden Unexpected Death in Epilepsy (SUDEP). With approximately one third of people with epilepsy not achieving adequate seizure control with current anti-seizure drugs, there is a critical need to identify treatments that reduce risk factors for SUDEP. The Kcna1-null mutant mouse lacking the potassium channel Kv1.1alpha subunit model risk factors and terminal events associated with SUDEP. In the current study, we demonstrate the progressive nature of epilepsy and sudden death in this model (mean age of mortality, postnatal day (P) 42.8 ± 1.3) and tested the hypothesis that long-term treatment with the ketogenic diet (KD) will prolong the life of Kcna1-null mice. We found that the KD postpones disease progression by delaying the onset of severe seizures and increases the lifespan of these mutant mice by 47%. Future studies are needed to determine the mechanisms underlying the KD effects on longevity.

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Section: Discussionmentioning

confidence: 99%

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confidence: 95%

Ketogenic diet treatment increases longevity in Kcna1‐null mice, a model of sudden unexpected death in epilepsy

et al. 2016

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“…Overlapping neuronal and cardiac expression patterns of mutant ion channels are proposed to underlie the pathophysiology of a number of genetic diseases that exhibit both epilepsy and cardiac arrhythmia. In addition to mutations in genes encoding VGSC α-and β-subunits, mutations in the neurocardiac potassium channel genes KCNA1 (46,47), KCNH2 (48-51), KCNQ1 (52), and KCNT1 (53) as well as HCN1 (54,55) have been linked to SUDEP. Mutations in genes encoding proteins that modify ion channels in brain and heart, such as SENP-2, also lead to SUDEP in animal models (56).…”

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confidence: 99%

Cardiac arrhythmia in a mouse model of sodium channel SCN8A epileptic encephalopathy

Frasier

Wagnon

Bao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Patients with early infantile epileptic encephalopathy (EIEE) are at increased risk for sudden unexpected death in epilepsy (SUDEP). De novo mutations of the sodium channel gene SCN8A, encoding the sodium channel Na v 1.6, result in EIEE13 (OMIM 614558), which has a 10% risk of SUDEP. Here, we investigated the cardiac phenotype of a mouse model expressing the gain of function EIEE13 patient mutation p.Asn1768Asp in Scn8a (Na v 1.6-N1768D). We tested Scn8a N1768D/+ mice for alterations in cardiac excitability. We observed prolongation of the early stages of action potential (AP) repolarization in mutant myocytes vs. controls. Scn8a N1768D/+ myocytes were hyperexcitable, with a lowered threshold for AP firing, increased incidence of delayed afterdepolarizations, increased calcium transient duration, increased incidence of diastolic calcium release, and ectopic contractility. Calcium transient duration and diastolic calcium release in the mutant myocytes were tetrodotoxin-sensitive. A selective inhibitor of reverse mode Na/Ca exchange blocked the increased incidence of diastolic calcium release in mutant cells. Scn8a N1768D/+ mice exhibited bradycardia compared with controls. This difference in heart rate dissipated after administration of norepinephrine, and there were no differences in heart rate in denervated ex vivo hearts, implicating parasympathetic hyperexcitability in the Scn8a N1768D/+ animals. When challenged with norepinephrine and caffeine to simulate a catecholaminergic surge, Scn8a N1768D/+ mice showed ventricular arrhythmias. Two of three mutant mice under continuous ECG telemetry recording experienced death, with severe bradycardia preceding asystole. Thus, in addition to central neuron hyperexcitability, Scn8a N1768D/+ mice have cardiac myoycte and parasympathetic neuron hyperexcitability. Simultaneous dysfunction in these systems may contribute to SUDEP associated with mutations of Scn8a. sodium channel | epilepsy | arrhythmia | channelopathy | mutation

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“…In the K V 1.1-null mouse model, postictal bradyarrhythmias have been shown to immediately precede death. 17,18 Aberrant parasympathetic neurotransmission is partly to blame for these cardiac events. Enhanced parasympathetic effects on heart causing interictal and postictal bradycardia were also identified as the immediate antecedents to SUDEP in heterozygous Na V 1.1 knockout mice, a model of the epileptic encephalopathy Dravet syndrome.…”

Section: Circ Arrhythm Electrophysiolmentioning

confidence: 99%

Misplaced Brain Sodium Channels in Heart Kindle Sudden Death in Epilepsy

George

2015

Circ: Arrhythmia and Electrophysiology

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The Kv1.1 null mouse, a model of sudden unexpected death in epilepsy (SUDEP)

Cited by 65 publications

References 43 publications

Ketogenic diet treatment increases longevity in Kcna1‐null mice, a model of sudden unexpected death in epilepsy

Ketogenic diet treatment increases longevity in Kcna1‐null mice, a model of sudden unexpected death in epilepsy

Cardiac arrhythmia in a mouse model of sodium channel SCN8A epileptic encephalopathy

Misplaced Brain Sodium Channels in Heart Kindle Sudden Death in Epilepsy

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