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  • 1
    Online Resource
    Online Resource
    SCN8A encephalopathy: Research progress and prospects
    Wiley ; 2016
    In:  Epilepsia Vol. 57, No. 7 ( 2016-07), p. 1027-1035
    Details
    In: Epilepsia, Wiley, Vol. 57, No. 7 ( 2016-07), p. 1027-1035
    Abstract: On April 21, 2015, the first SCN 8A Encephalopathy Research Group convened in Washington, DC , to assess current research into clinical and pathogenic features of the disorder and prepare an agenda for future research collaborations. The group comprised clinical and basic scientists and representatives of patient advocacy groups. SCN 8A encephalopathy is a rare disorder caused by de novo missense mutations of the sodium channel gene SCN 8A , which encodes the neuronal sodium channel Na v 1.6. Since the initial description in 2012, approximately 140 affected individuals have been reported in publications or by SCN 8A family groups. As a result, an understanding of the severe impact of SCN 8A mutations is beginning to emerge. Defining a genetic epilepsy syndrome goes beyond identification of molecular etiology. Topics discussed at this meeting included (1) comparison between mutations of SCN 8A and the SCN 1A mutations in Dravet syndrome, (2) biophysical properties of the Na v 1.6 channel, (3) electrophysiologic effects of patient mutations on channel properties, (4) cell and animal models of SCN 8A encephalopathy, (5) drug screening strategies, (6) the phenotypic spectrum of SCN 8A encephalopathy, and (7) efforts to develop a bioregistry. A panel discussion of gaps in bioregistry, biobanking, and clinical outcomes data was followed by a planning session for improved integration of clinical and basic science research. Although SCN 8A encephalopathy was identified only recently, there has been rapid progress in functional analysis and phenotypic classification. The focus is now shifting from identification of the underlying molecular cause to the development of strategies for drug screening and prioritized patient care.
    Type of Medium: Online Resource
    ISSN: 0013-9580 , 1528-1167
    URL: Issue
    URL: Article
    DOI: 10.1111/epi.2016.57.issue-7
    DOI: 10.1111/epi.13422
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2002194-X
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  • 2
    Online Resource
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    The ClinGen Epilepsy Gene Curation Expert Panel—Bridging the divide between clinical domain knowledge and formal gene curation criteria
    Hindawi Limited ; 2018
    In:  Human Mutation Vol. 39, No. 11 ( 2018-11), p. 1476-1484
    Details
    In: Human Mutation, Hindawi Limited, Vol. 39, No. 11 ( 2018-11), p. 1476-1484
    Type of Medium: Online Resource
    ISSN: 1059-7794 , 1098-1004
    URL: Issue
    URL: Article
    DOI: 10.1002/humu.2018.39.issue-11
    DOI: 10.1002/humu.23632
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2018
    detail.hit.zdb_id: 1498165-8
    SSG: 12
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  • 3
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    The novel sodium channel modulator GS ‐458967 ( GS 967) is an effective treatment in a mouse model of SCN 8A encephalopathy
    Wiley ; 2018
    In:  Epilepsia Vol. 59, No. 6 ( 2018-06), p. 1166-1176
    Details
    In: Epilepsia, Wiley, Vol. 59, No. 6 ( 2018-06), p. 1166-1176
    Abstract: De novo mutations of SCN 8A , encoding the voltage‐gated sodium channel Na V 1.6, have been associated with a severe infant onset epileptic encephalopathy. Individuals with SCN 8A encephalopathy have a mean age of seizure onset of 4‐5 months, with multiple seizure types that are often refractory to treatment with available drugs. Anecdotal reports suggest that high‐dose phenytoin is effective for some patients, but there are associated adverse effects and potential for toxicity. Functional characterization of several SCN 8A encephalopathy variants has shown that elevated persistent sodium current is one of several common biophysical defects. Therefore, specifically targeting elevated persistent current may be a useful therapeutic strategy in some cases. Methods The novel sodium channel modulator GS 967 has greater preference for persistent as opposed to peak current and nearly 10‐fold greater potency than phenytoin. We evaluated the therapeutic effect of GS 967 in the Scn8a N1768D/+ mouse model carrying an SCN 8A patient mutation that results in elevated persistent sodium current. We also performed patch clamp recordings to assess the effect of GS 967 on peak and persistent sodium current and excitability in hippocampal neurons from Scn8a N1768D/+ mice. Results GS 967 potently blocked persistent sodium current without affecting peak current, normalized action potential morphology, and attenuated excitability in neurons from heterozygous Scn8a N1768D/+ mice. Acute treatment with GS 967 provided dose‐dependent protection against maximal electroshock–induced seizures in Scn8a N1768D/+ and wild‐type mice. Chronic treatment of Scn8a N1768D/+ mice with GS 967 resulted in lower seizure burden and complete protection from seizure‐associated lethality observed in untreated Scn8a N1768D/+ mice. Protection was achieved at a chronic dose that did not cause overt behavioral toxicity or sedation. Significance Persistent sodium current modulators like GS 967 may be an effective precision targeting strategy for SCN 8A encephalopathy and other functionally similar channelopathies when elevated persistent sodium current is the primary dysfunction.
    Type of Medium: Online Resource
    ISSN: 0013-9580 , 1528-1167
    URL: Issue
    URL: Article
    DOI: 10.1111/epi.2018.59.issue-6
    DOI: 10.1111/epi.14196
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2018
    detail.hit.zdb_id: 2002194-X
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  • 4
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    Cardiac arrhythmia in a mouse model of sodium channel SCN8A epileptic encephalopathy
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 45 ( 2016-11-08), p. 12838-12843
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 45 ( 2016-11-08), p. 12838-12843
    Abstract: 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 .
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1612746113
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
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    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 5
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    Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy
    Proceedings of the National Academy of Sciences ; 2017
    In:  Proceedings of the National Academy of Sciences Vol. 114, No. 9 ( 2017-02-28), p. 2383-2388
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 114, No. 9 ( 2017-02-28), p. 2383-2388
    Abstract: Patients with early infantile epileptic encephalopathy (EIEE) experience severe seizures and cognitive impairment and are at increased risk for sudden unexpected death in epilepsy (SUDEP). EIEE13 [Online Mendelian Inheritance in Man (OMIM) # 614558] is caused by de novo missense mutations in the voltage-gated sodium channel gene SCN8A . Here, we investigated the neuronal phenotype of a mouse model expressing the gain-of-function SCN8A patient mutation, p.Asn1768Asp (Na v 1.6-N1768D). Our results revealed regional and neuronal subtype specificity in the effects of the N1768D mutation. Acutely dissociated hippocampal neurons from Scn8a N1768D/+ mice showed increases in persistent sodium current ( I Na ) density in CA1 pyramidal but not bipolar neurons. In CA3, I Na,P was increased in both bipolar and pyramidal neurons. Measurement of action potential (AP) firing in Scn8a N1768D/+ pyramidal neurons in brain slices revealed early afterdepolarization (EAD)-like AP waveforms in CA1 but not in CA3 hippocampal or layer II/III neocortical neurons. The maximum spike frequency evoked by depolarizing current injections in Scn8a N1768D/+ CA1, but not CA3 or neocortical, pyramidal cells was significantly reduced compared with WT. Spontaneous firing was observed in subsets of neurons in CA1 and CA3, but not in the neocortex. The EAD-like waveforms of Scn8a N1768D/+ CA1 hippocampal neurons were blocked by tetrodotoxin, riluzole, and SN-6, implicating elevated persistent I Na and reverse mode Na/Ca exchange in the mechanism of hyperexcitability. Our results demonstrate that Scn8a plays a vital role in neuronal excitability and provide insight into the mechanism and future treatment of epileptogenesis in EIEE13.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1616821114
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2017
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 6
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    Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus : WAGNON et al.
    Hindawi Limited ; 2018
    In:  Human Mutation Vol. 39, No. 7 ( 2018-07), p. 965-969
    Details
    In: Human Mutation, Hindawi Limited, Vol. 39, No. 7 ( 2018-07), p. 965-969
    Type of Medium: Online Resource
    ISSN: 1059-7794
    URL: Issue
    URL: Article
    DOI: 10.1002/humu.2018.39.issue-7
    DOI: 10.1002/humu.23547
    Language: English
    Publisher: Hindawi Limited
    Publication Date: 2018
    detail.hit.zdb_id: 1498165-8
    SSG: 12
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  • 7
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    The MAP1B Binding Domain of Na v 1.6 Is Required for Stable Expression at the Axon Initial Segment
    Society for Neuroscience ; 2019
    In:  The Journal of Neuroscience Vol. 39, No. 22 ( 2019-05-29), p. 4238-4251
    Details
    In: The Journal of Neuroscience, Society for Neuroscience, Vol. 39, No. 22 ( 2019-05-29), p. 4238-4251
    Abstract: Na v 1.6 ( SCN8A ) is a major voltage-gated sodium channel in the mammalian CNS, and is highly concentrated at the axon initial segment (AIS). As previously demonstrated, the microtubule associated protein MAP1B binds the cytoplasmic N terminus of Na v 1.6, and this interaction is disrupted by the mutation p.VAVP(77–80)AAAA. We now demonstrate that this mutation results in WT expression levels on the somatic surface but reduced surface expression at the AIS of cultured rat embryonic hippocampal neurons from both sexes. The mutation of the MAP1B binding domain did not impair vesicular trafficking and preferential delivery of Na v 1.6 to the AIS; nor was the diffusion of AIS inserted channels altered relative to WT. However, the reduced AIS surface expression of the MAP1B mutant was restored to WT levels by inhibiting endocytosis with Dynasore, indicating that compartment-specific endocytosis was responsible for the lack of AIS accumulation. Interestingly, the lack of AIS targeting resulted in an elevated percentage of persistent current, suggesting that this late current originates predominantly in the soma. No differences in the voltage dependence of activation or inactivation were detected in the MAP1B binding mutant relative to WT channel. We hypothesize that MAP1B binding to the WT Na v 1.6 masks an endocytic motif, thus allowing long-term stability on the AIS surface. This work identifies a critical and important new role for MAP1B in the regulation of neuronal excitability and adds to our understanding of AIS maintenance and plasticity, in addition to identifying new target residues for pathogenic mutations of SCN8A . SIGNIFICANCE STATEMENT Na v 1.6 is a major voltage-gated sodium channel in human brain, where it regulates neuronal activity due to its localization at the axon initial segment (AIS). Na v 1.6 mutations cause epilepsy, intellectual disability, and movement disorders. In the present work, we show that loss of interaction with MAP1B within the Na v 1.6 N terminus reduces the steady-state abundance of Na v 1.6 at the AIS. The effect is due to increased Na v 1.6 endocytosis at this neuronal compartment rather than a failure of forward trafficking to the AIS. This work confirms a new biological role of MAP1B in the regulation of sodium channel localization and will contribute to future analysis of patient mutations in the cytoplasmic N terminus of Na v 1.6.
    Type of Medium: Online Resource
    ISSN: 0270-6474 , 1529-2401
    URL: Article
    DOI: 10.1523/JNEUROSCI.2771-18.2019
    Language: English
    Publisher: Society for Neuroscience
    Publication Date: 2019
    detail.hit.zdb_id: 1475274-8
    SSG: 12
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  • 8
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    Loss-of-function variants of SCN8A in intellectual disability without seizures
    Ovid Technologies (Wolters Kluwer Health) ; 2017
    In:  Neurology Genetics Vol. 3, No. 4 ( 2017-08), p. e170-
    Details
    In: Neurology Genetics, Ovid Technologies (Wolters Kluwer Health), Vol. 3, No. 4 ( 2017-08), p. e170-
    Abstract: To determine the functional effect of SCN8A missense mutations in 2 children with intellectual disability and developmental delay but no seizures. Methods: Genomic DNA was analyzed by next-generation sequencing. SCN8A variants were introduced into the Na v 1.6 complementary DNA by site-directed mutagenesis. Channel activity was measured electrophysiologically in transfected ND7/23 cells. The stability of the mutant channels was assessed by Western blot. Results: Both children were heterozygous for novel missense variants that altered conserved residues in transmembrane segments of Na v 1.6, p.Gly964Arg in D2S6 and p.Glu1218Lys in D3S1. Both altered amino acids are evolutionarily conserved in vertebrate and invertebrate channels and are predicted to be deleterious. Neither was observed in the general population. Both variants completely prevented the generation of sodium currents in transfected cells. The abundance of Na v 1.6 protein was reduced by the Glu1218Lys substitution. Conclusions: Haploinsufficiency of SCN8A is associated with cognitive impairment. These observations extend the phenotypic spectrum of SCN8A mutations beyond their established role in epileptic encephalopathy (OMIM#614558) and other seizure disorders. SCN8A should be considered as a candidate gene for intellectual disability, regardless of seizure status.
    Type of Medium: Online Resource
    ISSN: 2376-7839
    URL: Article
    DOI: 10.1212/NXG.0000000000000170
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2017
    detail.hit.zdb_id: 2818607-2
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  • 9
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    Recurrent and Non-Recurrent Mutations of SCN8A in Epileptic Encephalopathy
    Frontiers Media SA ; 2015
    In:  Frontiers in Neurology Vol. 6 ( 2015-05-15)
    Details
    In: Frontiers in Neurology, Frontiers Media SA, Vol. 6 ( 2015-05-15)
    Type of Medium: Online Resource
    ISSN: 1664-2295
    URL: Article
    DOI: 10.3389/fneur.2015.00104
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2015
    detail.hit.zdb_id: 2564214-5
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  • 10
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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
    detail.hit.zdb_id: 2002194-X
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