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  • 1
    Online Resource
    Online Resource
    Prax330 reduces persistent and resurgent sodium channel currents and neuronal hyperexcitability of subiculum neurons in a mouse model of SCN8A epileptic encephalopathy
    Elsevier BV ; 2019
    In:  Neuropharmacology Vol. 158 ( 2019-11), p. 107699-
    Details
    In: Neuropharmacology, Elsevier BV, Vol. 158 ( 2019-11), p. 107699-
    Type of Medium: Online Resource
    ISSN: 0028-3908
    URL: Article
    DOI: 10.1016/j.neuropharm.2019.107699
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
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  • 2
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    Biallelic inherited SCN8A variants, a rare cause of SCN8A ‐related developmental and epileptic encephalopathy
    Wiley ; 2019
    In:  Epilepsia Vol. 60, No. 11 ( 2019-11), p. 2277-2285
    Details
    In: Epilepsia, Wiley, Vol. 60, No. 11 ( 2019-11), p. 2277-2285
    Abstract: Monoallelic de novo gain‐of‐function variants in the voltage‐gated sodium channel SCN8A are one of the recurrent causes of severe developmental and epileptic encephalopathy (DEE). In addition, a small number of de novo or inherited monoallelic loss‐of‐function variants have been found in patients with intellectual disability, autism spectrum disorder, or movement disorders. Inherited monoallelic variants causing either gain or loss‐of‐function are also associated with less severe conditions such as benign familial infantile seizures and isolated movement disorders. In all three categories, the affected individuals are heterozygous for a SCN8A variant in combination with a wild‐type allele. In the present study, we describe two unusual families with severely affected individuals who inherited biallelic variants of SCN8A . Methods We identified two families with biallelic SCN8A variants by diagnostic gene panel sequencing. Functional analysis of the variants was performed using voltage clamp recordings from transfected ND7/23 cells. Results We identified three probands from two unrelated families with DEE due to biallelic SCN8A variants. Each parent of an affected individual carried a single heterozygous SCN8A variant and exhibited mild cognitive impairment without seizures. In both families, functional analysis demonstrated segregation of one allele with complete loss‐of‐function, and one allele with altered biophysical properties consistent with partial loss‐of‐function. Significance These studies demonstrate that SCN8A DEE may, in rare cases, result from inheritance of two variants, both of which exhibit reduced channel activity. In these families, heterozygosity for the dominant variants results in less severe disease than biallelic inheritance of two variant alleles. The clinical consequences of variants with partial and complete loss of SCN8A function are variable and likely to be influenced by genetic background.
    Type of Medium: Online Resource
    ISSN: 0013-9580 , 1528-1167
    URL: Issue
    URL: Article
    DOI: 10.1111/epi.v60.11
    DOI: 10.1111/epi.16371
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2019
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    detail.hit.zdb_id: 2002194-X
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  • 3
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    Online Resource
    Somatostatin-Positive Interneurons Contribute to Seizures in SCN8A Epileptic Encephalopathy
    Society for Neuroscience ; 2021
    In:  The Journal of Neuroscience Vol. 41, No. 44 ( 2021-11-03), p. 9257-9273
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 41, No. 44 ( 2021-11-03), p. 9257-9273
    Abstract: SCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant SCN8A , which encodes the voltage-gated sodium channel Na V 1.6. To date, it is unclear if and how inhibitory interneurons, which express Na V 1.6, influence disease pathology. Using both sexes of a transgenic mouse model of SCN8A epileptic encephalopathy, we found that selective expression of the R1872W SCN8A mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility to audiogenic seizures. Patch-clamp electrophysiology experiments revealed that SST interneurons from mutant mice were hyperexcitable but hypersensitive to action potential failure via depolarization block under normal and seizure-like conditions. Remarkably, GqDREADD-mediated activation of WT SST interneurons resulted in prolonged electrographic seizures and was accompanied by SST hyperexcitability and depolarization block. Aberrantly large persistent sodium currents, a hallmark of SCN8A mutations, were observed and were found to contribute directly to aberrant SST physiology in computational modeling and pharmacological experiments. These novel findings demonstrate a critical and previously unidentified contribution of SST interneurons to seizure generation not only in SCN8A epileptic encephalopathy, but epilepsy in general. SIGNIFICANCE STATEMENT SCN8A epileptic encephalopathy is a devastating neurological disorder that results from de novo mutations in the sodium channel isoform Na v 1.6. Inhibitory neurons express Na V 1.6, yet their contribution to seizure generation in SCN8A epileptic encephalopathy has not been determined. We show that mice expressing a human-derived SCN8A variant (R1872W) selectively in somatostatin (SST) interneurons have audiogenic seizures. Physiological recordings from SST interneurons show that SCN8A mutations lead to an elevated persistent sodium current which drives initial hyperexcitability, followed by premature action potential failure because of depolarization block. Furthermore, chemogenetic activation of WT SST interneurons leads to audiogenic seizure activity. These findings provide new insight into the importance of SST inhibitory interneurons in seizure initiation, not only in SCN8A epileptic encephalopathy, but for epilepsy broadly.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    URL: Article
    DOI: 10.1523/JNEUROSCI.0718-21.2021
    DOI: 10.1523/JNEUROSCI.0718-21.2021.video.1
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2021
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    detail.hit.zdb_id: 604637-X
    SSG: 12
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  • 4
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    Online Resource
    Postictal Death Is Associated with Tonic Phase Apnea in a Mouse Model of Sudden Unexpected Death in Epilepsy
    Wiley ; 2021
    In:  Annals of Neurology Vol. 89, No. 5 ( 2021-05), p. 1023-1035
    Details
    In: Annals of Neurology, Wiley, Vol. 89, No. 5 ( 2021-05), p. 1023-1035
    Abstract: Sudden unexpected death in epilepsy (SUDEP) is an unpredictable and devastating comorbidity of epilepsy that is believed to be due to cardiorespiratory failure immediately after generalized convulsive seizures. Methods We performed cardiorespiratory monitoring of seizure‐induced death in mice carrying either a p.Arg1872Trp or p.Asn1768Asp mutation in a single Scn8a allele—mutations identified from patients who died from SUDEP—and of seizure‐induced death in pentylenetetrazole‐treated wild‐type mice. Results The primary cause of seizure‐induced death for all mice was apnea, as (1) apnea began during a seizure and continued for tens of minutes until terminal asystole, and (2) death was prevented by mechanical ventilation. Fatal seizures always included a tonic phase that was coincident with apnea. This tonic phase apnea was not sufficient to produce death, as it also occurred during many nonfatal seizures; however, all seizures that were fatal had tonic phase apnea. We also made the novel observation that continuous tonic diaphragm contraction occurred during tonic phase apnea, which likely contributes to apnea by preventing exhalation, and this was only fatal when breathing did not resume after the tonic phase ended. Finally, recorded seizures from a patient with developmental epileptic encephalopathy with a previously undocumented SCN8A likely pathogenic variant (p.Leu257Val) revealed similarities to those of the mice, namely, an extended tonic phase that was accompanied by apnea. Interpretation We conclude that apnea coincident with the tonic phase of a seizure, and subsequent failure to resume breathing, are the determining events that cause seizure‐induced death in Scn8a mutant mice. ANN NEUROL 2021;89:1023–1035
    Type of Medium: Online Resource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    URL: Article
    DOI: 10.1002/ana.v89.5
    DOI: 10.1002/ana.26053
    Language: English
    Publisher: Wiley
    Publication Date: 2021
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    detail.hit.zdb_id: 2037912-2
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