Hammer Lab Publications

SCN8A Publications

2025

SCN8A 2025

Structural brain MRI abnormalities in SCN1A-, SCN2A-, SCN3A-, and SCN8A-related epilepsies: a cohort study
CONCLUSION: Contrary to earlier assumptions, structural MRI abnormalities are common in SCN-related epilepsies, particularly in SCN2A-and SCN8A-related epilepsies. MRI may aid in the diagnosis, phenotypic stratification, and prognostication of genetic epilepsy involving voltage-gated sodium channels.
Neurologist's Black Swan: Molecular Basis of Prenatal Seizures
One of the least studied but clinically severe forms of epilepsy is seizures with prenatal manifestations. Our understanding of epilepsy disorders has advanced substantially; numerous disease-associated genes have been identified, classifications have been refined, and underlying mechanisms and diagnostic approaches have been elucidated. However, one group of patients-those with seizures before the birth-has remained largely […]
Identification of Neurite Outgrowth and Synaptic Plasticity-related Genes Showing Sustained Hypermethylation of Promoter Region in the Hippocampal Dentate Gyrus of Rats Exposed Maternally To Neurotoxicants To Induce Persistent Disruption of Hippocampal Neurogenesis
We previously identified a set of genes with hypermethylated promoter regions that expressed reduced levels of mRNAs by next-generation sequencing in the hippocampal dentate gyrus (DG) of weaned rats [postnatal day (PND) 21] after maternal exposure to valproic acid, propylthiouracil (PTU), or glycidol, compounds that induce persistent disruption of hippocampal neurogenesis until adulthood at PND […]
Longitudinal analyses of electronic medical records reveal dynamic developmental trajectories for patients with SCN8A-related disorders
OBJECTIVES: Despite providing significant insights into the phenotypic spectrum and genotype-phenotype correlations in SCN8A-related disorders (SCN8A-RD), cohort and registry-based studies typically lack sufficient longitudinal data to characterize disease progression or treatment-response trajectories. Here we utilize data from electronic medical records (EMRs) of 80 patients as a complementary approach to advance understanding of the natural history […]
Clinical and genetic analysis of epilepsy in children with SCN8A gene variants
CONCLUSION: Typically, SCN8A gene variants cause early-onset childhood epilepsy, often within the first year of life, even in the neonatal period, and most cases are caused by de novo variants. Sodium channel blockers show some efficacy, but often require higher doses, and single-drug therapy is usually insufficient. The clinical phenotype of de novo variants is […]
Diagnostic value of genetic testing, with focus on CACNA1A, in children with episodic neurologic disorders: a single-centre retrospective study
CONCLUSIONS: Genetic testing provides important insights in the evaluation of paediatric patients with episodic neurologic disorders, particularly in those with developmental delay, paroxysmal tonic upgaze, or episodic ataxia. Although the overall diagnostic yield remained low, consistent with other paroxysmal movement disorders, these findings support the integration of genetic testing into the diagnostic algorithm and underscore […]
Clinical and Genetic Spectrum of SCN8A-Related Disorders: A Retrospective Study From the Gulf Region
This multicenter retrospective study examined the clinical characteristics and outcomes of 26 patients with sodium channel protein type 8 subunit alpha (SCN8A)-related epilepsy and/or neurodevelopmental disorders across the Gulf region. Data were collected from August 2024 to January 2025. Most patients (80.77%) experienced epilepsy onset within the first year of life, with a mean onset […]
Cardiac Genetic Variants in Sudden, Unexpected Death in Epilepsy: From Challenging DNA Extraction Methods to Updated NGS Panels for Improved Genetic Analysis
CONCLUSIONS: As expected, very low coverage of the target base was observed for FFPE tissue samples because of the complexity of the biological material. Therefore, the presence of any significant variants in unamplified regions cannot be excluded in the FFPE samples. As suggested by the literature, the variants found in the blood samples are potentially […]
Developmental epileptic encephalopathy caused by a de novo mutation in the SCN8A gene
Developmental epileptic encephalopathy is characterized by a malignant course of refractory epilepsy and a growing defect in mental and motor development. To date, determinant genes have been identified for most of these conditions. This condition is also caused by mutations in the SCN8A gene of a voltage-gated sodium channel, which is detected in about 1% […]
Amyloid precursor protein modulates cerebellar Purkinje cell activity and motor function through regulation of Nav1.6 currents
Amyloid precursor protein (APP)-null mice exhibit significant deficits in motor performance, including reduced grip strength and impaired locomotion; however, the underlying neurophysiological mechanisms remain unclear. In this study, we show that conditional knockdown of APP selectively in Purkinje cells (PCs) recapitulates these motor deficits, while exogenous expression of APP in APP-null mice rescues motor function. […]

2024

SCN8A 2024

Beyond seizures: SCN8A heterozygous mutation presenting with epilepsy and paroxysmal dyskinesia
No abstract
Infantile epileptic spasms syndrome: an etiologic study of 361 patients with infantile epileptic spasms syndrome
CONCLUSION: The predominant etiology of IESS is structural, succeeded by genetic factors, with significant pathogenic genes comprising TSC2, NF1, SCN8A, and KCNQ2. The genetic classifications exhibit geographic variability. Genetic and structural etiologies are frequently linked to an unfavorable prognosis. Genetic testing can help clarify the etiology of IESS when metabolic screening and brain MRI results […]
Patients carrying pathogenic SCN8A variants with loss- and gain-of-function effects can be classified into five subgroups exhibiting varying developmental and epileptic components of encephalopathy
OBJECTIVE: Phenotypic heterogeneity presents challenges in providing clinical care to patients with pathogenic SCN8A variants, which underly a wide disease spectrum ranging from neurodevelopmental delays without seizures to a continuum of mild to severe developmental and epileptic encephalopathies (DEEs). An important unanswered question is whether there are clinically important subgroups within this wide spectrum. Using […]
The Power of Delphi and Advocacy: Consensus in SCN8A-Related Epilepsy and Neurodevelopmental Disorders
No abstract
Transcriptomic Profiling of Human Myocardium at Sudden Death to Define Vulnerable Substrate for Lethal Arrhythmias
CONCLUSIONS: RNA profiling of the myocardium at SCD identifies active fibrosis, undetectable by conventional clinical methods, in the presence of fixed scar and selected ion-channel dysregulation (more pronounced among female cases) as an acute vulnerable substrate for fatal arrhythmias. These findings may represent novel directions to identify patients at elevated near-term risk for SCD and […]
Voltage-Gated Ion Channel Compensatory Effect in DEE: Implications for Future Therapies
Developmental and Epileptic Encephalopathies (DEEs) represent a clinically and genetically heterogeneous group of rare and severe epilepsies. DEEs commonly begin early in infancy with frequent seizures of various types associated with intellectual disability and leading to a neurodevelopmental delay or regression. Disease-causing genomic variants have been identified in numerous genes and are implicated in over […]
Upregulation of Nav1.6 expression in the ventral posterolateral nucleus of thalamus contributes to hyperalgesia in a model of Parkinson's disease
Pain is the most common non-motor manifestation of Parkinson's disease (PD), affecting the quality of life for patients. Nav1.6 is the most abundant subtype of voltage-gated sodium channels (VGSCs) in the brain of adult mammals. Here we investigated the expression patterns of Nav1.6 in the ventral posterolateral (VPL) nucleus of the thalamus and its involvement […]
Parvalbumin interneuron impairment causes synaptic transmission deficits and seizures in SCN8A developmental and epileptic encephalopathy
SCN8A developmental and epileptic encephalopathy (DEE) is a severe epilepsy syndrome resulting from mutations in the voltage-gated sodium channel Nav1.6, encoded by the gene SCN8A. Nav1.6 is expressed in excitatory and inhibitory neurons, yet previous studies primarily focus on how SCN8A mutations affect excitatory neurons, with limited studies on the importance of inhibitory interneurons. Parvalbumin […]
Non-epileptic stimulus-sensitive myoclonus in a newborn with developmental and epileptic encephalopathy associated with the SCN8A gene
No abstract
Persistent Na(+) current couples spreading depolarization to seizures in Scn8a gain of function mice
Spreading depolarization (SD) is a slowly propagating wave of massive cellular depolarization that transiently impairs the function of affected brain regions. While SD typically arises as an isolated hemispheric event, we previously reported that reducing M-type potassium current (I(KM)) by ablation of Kcnq2 in forebrain excitatory neurons results in tightly coupled spontaneous bilateral seizure-SD complexes […]

2023

SCN8A 2023

Clinical and electrophysiological features of SCN8A variants causing episodic or chronic ataxia
BACKGROUND: Variants in SCN8A are associated with a spectrum of epilepsies and neurodevelopmental disorders. Ataxia as a predominant symptom of SCN8A variation has not been well studied. We set out to investigate disease mechanisms and genotype-phenotype correlations of SCN8A-related ataxia.
Clinical characteristics and genetic analysis of pediatric patients with sodium channel gene mutation-related childhood epilepsy: a review of 94 patients
CONCLUSION: Sodium channel gene variants involve different epileptic syndromes, and the treatment responses also vary. We herein reported 42 novel variants, and we are also the first ever to report two patients with SCN11A variants, thereby increasing the gene spectrum and phenotypic profile of sodium channel dysfunction. We provide a basis for precision treatment and […]
Neurodevelopmental outcomes in a cohort of Australian families with self-limited familial epilepsy of neonatal/infantile onset
CONCLUSIONS: Individuals with SeLFE have a small risk of recurrent seizures (20%) and neurodevelopmental disability. Significant predictors are higher seizure number and longer epilepsy duration. Developmental surveillance is imperative.
Common genes and recurrent causative variants in 957 Asian patients with pediatric epilepsy
OBJECTIVE: We aimed to identify common genes and recurrent causative variants in a large group of Asian patients with different epilepsy syndromes and subgroups.
What does better look like in individuals with severe neurodevelopmental impairments? A qualitative descriptive study on SCN2A-related developmental and epileptic encephalopathy
CONCLUSION: Meaningful change thresholds have not been evaluated in the DEE literature. This study was a preliminary qualitative approach to inform future studies that will aim to determine quantitative values of change, applicable to groups and within-person, to inform interpretation of specific clinical outcome assessments in individuals with a DEE.
Molecular and Cellular Context Influences SCN8A Variant Function
Pathogenic variants in SCN8A , which encodes the voltage-gated sodium (Na (V) ) channel Na (V) 1.6, are associated with neurodevelopmental disorders including epileptic encephalopathy. Previous approaches to determine SCN8A variant function may be confounded by the use of a neonatal-expressed alternatively spliced isoform of Na (V) 1.6 (Na (V) 1.6N), and engineered mutations to […]
Evidence for involvement of the alcohol consumption WDPCP gene in lipid metabolism, and liver cirrhosis
Biological pathways between alcohol consumption and alcohol liver disease (ALD) are not fully understood. We selected genes with known effect on (1) alcohol consumption, (2) liver function, and (3) gene expression. Expression of the orthologs of these genes in Caenorhabditis elegans and Drosophila melanogaster was suppressed using mutations and/or RNA interference (RNAi). In humans, association […]
CircFNTA promotes tumorigenesis and progression of gastric cancer via miR-604/miR-647/SCN8A axis
Gastric cancer (GC) is a major contributor to cancer-related deaths and is characterized by high heterogeneity in epidemiology and histopathology worldwide. Increasing evidence indicates that circular RNAs (circRNAs) play multifaceted roles in cellular processes in human cancers. Here, we demonstrated that circFNTA high expression increases the proliferation, metastasis, and epithelial-mesenchymal transition process and tumorigenicity of […]
Greater female than male resilience to mortality and morbidity in the Scn8a mouse model of pediatric epilepsy
CONCLUSIONS: These results support the hypothesis that factors associated with sexual differentiation play a role in the neurobiology of epilepsy and point to the importance of including both sexes in the design of studies to identify new epilepsy therapies.
Reduction of Kcnt1 is therapeutic in mouse models of SCN1A and SCN8A epilepsy
Developmental and epileptic encephalopathies (DEEs) are severe seizure disorders with inadequate treatment options. Gain- or loss-of-function mutations of neuronal ion channel genes, including potassium channels and voltage-gated sodium channels, are common causes of DEE. We previously demonstrated that reduced expression of the sodium channel gene Scn8a is therapeutic in mouse models of sodium and potassium […]

2022

SCN8A 2022

Characterizing Genotypes and Phenotypes Associated with Dysfunction of Channel-Encoding Genes in a Cohort of Patients with Intellectual Disability
CONCLUSION: The results of this study broaden the molecular spectrum of channel pathogenic variants associated with different clinical presentations in individuals with ID and/or DD.
Exploring the genetic landscape of diphtheria, tetanus and pertussis vaccination-associated seizures or subsequent epilepsies
BACKGROUND: Diphtheria, Tetanus, and whole-cell Pertussis (DTwP) vaccination-associated seizures form the commonest type of serious adverse event following immunization in India and are an important reason for vaccine hesitancy. Our study explored the genetic explanation of DTwP vaccination-associated seizures or subsequent epilepsies.
Genetic analysis of suicide: a sample study in Tuscany (Central Italy)
Many studies have examined the genetic contribution to suicide. However, data on suicide in the Italian population are scarce. We therefore aimed to address this gap by investigating a cohort of 111 Italians for whom a verdict of suicide had been declared in court in Florence, Italy between 2007 and 2017. This cohort included 86 […]
Perioperative Management and Considerations for Patients With Voltage-Gated Sodium Channel Mutations: A Pediatric Case Report
A 13-year-old girl with a voltage-gated sodium channel mutation (SCN8A)-associated intractable epilepsy presented for bilateral mastectomy for painful juvenile fibroadenomatosis. Sodium channel mutations are more frequently diagnosed with continued advances in genetic testing. Understanding the effects of sodium channel mutations is important to provide safe anesthetic care to these patients. In this article, we discuss […]
Bioinformatics and network pharmacology analysis of drug targets and mechanisms related to the comorbidity of epilepsy and migraine
CONCLUSION: Our systematic and comprehensive analyses of disease-gene-target-drug interaction networks identified several biological processes and molecular functions common to migraine and epilepsy, most of which were related to neuroactive ligand-receptor interactions. These data provide a new theoretical basis and reference for the clinical treatment of comorbid epilepsy and migraine and may aid in the development […]
Detection of mosaic variants using genome sequencing in a large pediatric cohort
The increased use of next-generation sequencing has expanded our understanding of the involvement and prevalence of mosaicism in genetic disorders. We describe a total of eleven cases: nine in which mosaic variants detected by genome sequencing (GS) and/or targeted gene panels (TGPs) were considered to be causative for the proband's phenotype, and two of apparent […]
Upregulation of Nav1.6 Mediated by the p38 MAPK Pathway in the Dorsal Root Ganglia Contributes to Cancer-Induced Bone Pain in Rats
Cancer-induced bone pain (CIBP) occurs frequently among advanced cancer patients. Voltage-gated sodium channels (VGSCs) have been associated with chronic pain, but how VGSCs function in CIBP is poorly understood. Here, we aimed to investigate the specific role of VGSCs in the dorsal root ganglia (DRGs) in CIBP. A CIBP rat model was generated by the […]
Neuraxial block anesthetic technique in a patient with SCN8A encephalopathy: case report
Mutations in SCN8A gene lead to changes in sodium channels in the brain, which are correlated with severe epileptic syndrome. Due to the rarity, there are few studies that support anesthesia in that population. The present study aims to report alternatives to inhalation anesthesia at epileptic encephalopathy. CASE REPORT: Male, 4 years old, with SCN8A […]
In vitro effects of eslicarbazepine (S-licarbazepine) as a potential precision therapy on SCN8A variants causing neuropsychiatric disorders
CONCLUSIONS AND IMPLICATIONS: S-lic has not only substance-specific effects but also variant-specific effects. Personalized treatment regimens optimized to achieve such variant-specific pharmacological modulation may help to reduce adverse side effects and improve the overall therapeutic outcome of SCN8A-related disease.
SCN1A gain-of-function mutation causing an early onset epileptic encephalopathy
OBJECTIVE: Loss-of-function variants in SCN1A cause Dravet syndrome, the most common genetic developmental and epileptic encephalopathy (DEE). However, emerging evidence suggests separate entities of SCN1A-related disorders due to gain-of-function variants. Here, we aim to refine the clinical, genetic, and functional electrophysiological features of a recurrent p.R1636Q gain-of-function variant, identified in four individuals at a single […]

2021

SCN8A 2021

Neuraxial block anesthetic technique in a patient with SCN8A encephalopathy: case report
Mutations in SCN8A gene lead to changes in sodium channels in the brain, which are correlated with severe epileptic syndrome. Due to the rarity, there are few studies that support anesthesia in that population. The present study aims to report alternatives to inhalation anesthesia at epileptic encephalopathy. CASE REPORT: Male, 4 years old, with SCN8A […]
Peri-Ictal Autonomic Control of Cardiac Function and Seizure-Induced Death
Sudden unexpected death in epilepsy (SUDEP) accounts for the deaths of 8-17% of patients with epilepsy. Although the mechanisms of SUDEP are unknown, one proposed mechanism is abnormal control of the heart by the autonomic nervous system (ANS). Our objective was to determine whether the broad changes in ictal heart rate experienced by mouse models […]
Correction of the hypomorphic Gabra2 splice site variant in mouse strain C57BL/6J modifies the severity of Scn8a encephalopathy
De novo gain-of-function mutations of SCN8A are a significant cause of developmental and epileptic encephalopathy (DEE) (MIM: 614558). The severely affected individuals exhibit refractory seizures, developmental delay, and cognitive disabilities, often accompanied by impaired movement. Individuals with the identical SCN8A variant often differ in clinical course, suggesting a role for modifier genes in disease severity. […]
Phenotypic and genetic spectrum in Chinese children with SCN8A-related disorders
CONCLUSION: The phenotypic spectrum of SCN8A-related disorders in Chinese children ranged from severe developmental delay without epilepsy to severe DEE. Three new variants were associated with SCN8A-BIE. Sodium channel blockers were effective in treating seizures for some SCN8A-related disorders however may not be relevant to the mutant location.
One Size Doesn't Fit All: Variant-Specific Effects in SCN8A Encephalopathy
No abstract
Pathogenic in-Frame Variants in SCN8A: Expanding the Genetic Landscape of SCN8A-Associated Disease
Numerous SCN8A mutations have been identified, of which, the majority are de novo missense variants. Most mutations result in epileptic encephalopathy; however, some are associated with less severe phenotypes. Mouse models generated by knock-in of human missense SCN8A mutations exhibit seizures and a range of behavioral abnormalities. To date, there are only a few Scn8a […]
A SCN8A variant associated with severe early onset epilepsy and developmental delay: Loss- or gain-of-function?
SCN8A, encoding the voltage-gated sodium channel subunit Na(V)1.6, has been associated with a wide spectrum of neuropsychiatric disorders. Missense variants in SCN8A which increase the channel activity can cause a severe developmental and epileptic encephalopathy (DEE). One DEE variant (p.(Arg223Gly)) was described to cause a predominant loss-of-function (LOF) mechanism when expressed in neuroblastoma cells, which […]
Voltage-Gated Sodium Channels as Potential Biomarkers and Therapeutic Targets for Epithelial Ovarian Cancer
Abnormal ion channel expression distinguishes several types of carcinoma. Here, we explore the relationship between voltage-gated sodium channels (VGSC) and epithelial ovarian cancer (EOC). We find that EOC cell lines express most VGSC, but at lower levels than fallopian tube secretory epithelial cells (the cells of origin for most EOC) or control fibroblasts. Among patient […]
SUDEP risk and autonomic dysfunction in genetic epilepsies
The underlying pathophysiology of sudden unexpected death in epilepsy (SUDEP) remains unclear. This phenomenon is likely multifactorial, and there is considerable evidence that genetic factors play a role. There are certain genetic causes of epilepsy in which the risk of SUDEP appears to be increased relative to epilepsy overall. For individuals with pathogenic variants in […]
Expression and Physiology of Voltage-Gated Sodium Channels in Developing Human Inner Ear
Sodium channel expression in inner ear afferents is essential for the transmission of vestibular and auditory information to the central nervous system. During development, however, there is also a transient expression of Na^(+) channels in vestibular and auditory hair cells. Using qPCR analysis, we describe the expression of four Na^(+) channel genes, SCN5A (Nav1.5), SCN8A […]

2020

SCN8A 2020

Early-Onset Developmental and Epileptic Encephalopathies of Infancy: An Overview of the Genetic Basis and Clinical Features
Our current knowledge of genetically determined forms of epilepsy has shortened the diagnostic pathway usually experienced by the families of infants diagnosed with early-onset developmental and epileptic encephalopathies. Genetic causes can be found in up to 80% of infants presenting with early-onset developmental and epileptic encephalopathies, often in the context of an uneventful perinatal history […]
Association of early-onset epileptic encephalopathy with involuntary movements - Case series and literature review
Epileptic-dyskinetic encephalopathies are rare epilepsies characterized by early-onset epileptic encephalopathies (EOEEs) with involuntary movement. Herein, we investigated the impact of gene variants in epileptic-dyskinetic encephalopathies. Four independent patients from four families who exhibited involuntary movements were recruited from Tokyo Metropolitan Neurological Hospital. The inclusion criteria were as follows: onset within 1 year after birth, frequent […]
Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy
Fibroblast growth factor homologous factors (FHFs) are intracellular proteins which regulate voltage-gated sodium (Na(v)) channels in the brain and other tissues. FHF dysfunction has been linked to neurological disorders including epilepsy. Here, we describe two sibling pairs and three unrelated males who presented in infancy with intractable focal seizures and severe developmental delay. Whole-exome sequencing […]
Dual diagnosis in a child with familial SCN8A-related encephalopathy complicated by a 1p13.2 deletion involving NRAS gene
No abstract
Gabra2 is a genetic modifier of Scn8a encephalopathy in the mouse
OBJECTIVE: SCN8A encephalopathy is a developmental epileptic encephalopathy typically caused by de novo gain-of-function mutations in Na(v) 1.6. Severely affected individuals exhibit refractory seizures, developmental delay, cognitive disabilities, movement disorders, and elevated risk of sudden death. Patients with the identical SCN8A variant can differ in clinical course, suggesting a role for modifier genes in determining […]
SCN8A splicing mutation causing skipping of the exon 15 associated with intellectual disability and cortical myoclonus
No abstract
Excitatory and inhibitory neuron defects in a mouse model of Scn1b-linked EIEE52
OBJECTIVE: Human variants in voltage-gated sodium channel (VGSC) α and β subunit genes are linked to developmental and epileptic encephalopathies (DEEs). Inherited, biallelic, loss-of-function variants in SCN1B, encoding the β1/β1B subunits, are linked to early infantile DEE (EIEE52). De novo, monoallelic variants in SCN1A (Nav1.1), SCN2A (Nav1.2), SCN3A (Nav1.3), and SCN8A (Nav1.6) are also linked […]
Variant-specific changes in persistent or resurgent sodium current in SCN8A-related epilepsy patient-derived neurons
Missense variants in the SCN8A voltage-gated sodium channel gene are linked to early-infantile epileptic encephalopathy type 13, also known as SCN8A-related epilepsy. These patients exhibit a wide spectrum of intractable seizure types, severe developmental delay, movement disorders, and elevated risk of sudden unexpected death in epilepsy. The mechanisms by which SCN8A variants lead to epilepsy […]
Three-dimensional neuron-astrocyte construction on matrigel enhances establishment of functional voltage-gated sodium channels
This study aimed to investigate and compare cell growth manners and functional differences of primary cortical neurons cultured on either poly-d-lysine (PDL) and or Matrigel, to delineate the role of extracellular matrix on providing resemblance to in vivo cellular interactions in nervous tissue. Primary cortical neurons, obtained from embryonic day 15 mice pups, seeded either […]
Alterations of functional connectivity density in a Chinese family with a mild phenotype associated with a novel inherited variant of SCN8A
CONCLUSIONS: We identified a novel SCN8A variant with a mild familial epilepsy phenotype. A similar pattern of FCD alterations in patients and their unaffected siblings might represent an endophenotype of benign epilepsy associated with the SCN8A inherited variant, and more extensive alterations in mesial frontal regions may help us to further understand the pathogenesis of […]

2019

SCN8A 2019

SCN8A Mutation in Infantile Epileptic Encephalopathy: Report of Two Cases
Early infantile epileptic encephalopathy type 13 is a severe form of epilepsy caused by mutations in the sodium channel 8 alpha (SCN8A) gene. This gene encodes the neuronal voltage-gated sodium channel which plays vital role in neuronal excitability. Here we present two cases with SCN8A encephalopathy. Both cases had mutation in p.Arg1872Gin the SCN8A gene, […]
Changes in the Fluorescence Tracking of NaV1.6 Protein Expression in a BTBR T+Itpr3tf/J Autistic Mouse Model
The axon initial segment (AIS), the site of action potential initiation in neurons, is a critical determinant of neuronal excitability. Growing evidence indicates that appropriate recruitment of the AIS macrocomplex is essential for synchronized firing. However, disruption of the AIS structure is linked to the etiology of multiple disorders, including autism spectrum disorder (ASD), a […]
Differential excitatory vs inhibitory SCN expression at single cell level regulates brain sodium channel function in neurodevelopmental disorders
The four voltage-gated sodium channels SCN1/2/3/8A have been associated with heterogeneous types of developmental disorders, each presenting with disease specific temporal and cell type specific gene expression. Using single-cell RNA sequencing transcriptomic data from humans and mice, we observe that SCN1A is predominantly expressed in inhibitory neurons. In contrast, SCN2/3/8A are profoundly expressed in excitatory […]
SCN8A encephalopathy: Mechanisms and models
De novo mutations of the neuronal sodium channel SCN8A have been identified in approximately 2% of individuals with epileptic encephalopathy. These missense mutations alter the biophysical properties of sodium channel Nav1.6 in ways that lead to neuronal hyperexcitability. We generated two mouse models carrying patient mutations N1768D and R1872W to examine the effects on neuronal […]
Phenotypic and genetic spectrum of SCN8A-related disorders, treatment options, and outcomes
Pathogenic variants in SCN8A have originally been described in patients with developmental and epileptic encephalopathy (DEE). However, recent studies have shown that SCN8A variants can be associated with a broader phenotypic spectrum, including the following: (1) Patients with early onset, severe DEE, developing severe cognitive and motor regression, pyramidal/extrapyramidal signs, and cortical blindness. Severe SCN8A-DEE […]
Recent advances in treatment of epilepsy-related sodium channelopathies
Voltage-gated sodium channels (VGSCs) play a crucial role in generation of action potentials. Pathogenic variants in the five human brain expressed VGSC genes, SCN1A, SCN2A, SCN3A, SCN8A and SCN1B have been associated with a spectrum of epilepsy phenotypes and neurodevelopmental disorders. In the last decade, next generation sequencing techniques have revolutionized the way we diagnose […]
A multi-disciplinary clinic for SCN8A-related epilepsy
CONCLUSIONS: This is the first report of a large series of patients with epilepsy due to SCN8A variants evaluated in a single multi-disciplinary clinic. By utilizing a more comprehensive and consistent evaluation, we clarify specific seizure and epilepsy types, describe a distinct epilepsy phenotype in a patient with a nonsense variant, delineate patterns of developmental […]
Nav1.6 promotes inflammation and neuronal degeneration in a mouse model of multiple sclerosis
CONCLUSION: Taken together, our results are consistent with Nav1.6 promoting inflammation and contributing to axonal degeneration following demyelination.
Distinct functional alterations in SCN8A epilepsy mutant channels
KEY POINTS: Mutations in the SCN8A gene cause early infantile epileptic encephalopathy. We characterize a new epilepsy-related SCN8A mutation, R850Q, in the human SCN8A channel and present gain-of-function properties of the mutant channel. Systematic comparison of R850Q with three other SCN8A epilepsy mutations, T761I, R1617Q and R1872Q, identifies one common dysfunction in resurgent current, although […]
The genomic and clinical landscape of fetal akinesia
CONCLUSION: Our analysis indicates that genetic defects leading to primary skeletal muscle diseases might have been underdiagnosed, especially pathogenic variants in RYR1. We discuss three novel putative fetal akinesia genes: GCN1, IQSEC3 and RYR3. Of those, IQSEC3, and RYR3 had been proposed as neuromuscular disease-associated genes recently, and our findings endorse them as FA candidate […]

2018

SCN8A 2018

Exome sequencing identifies molecular diagnosis in children with drug-resistant epilepsy
OBJECTIVE: Early onset drug-resistant epilepsy is a neurologic disorder in which 2 antiepileptic drugs fail to maintain the seizure-free status of the patient. Heterogeneous clinical presentations make the diagnosis challenging. We aim to identify the underlying genetic causes of a pediatric cohort with drug-resistant epilepsy and evaluate whether the findings can provide information on patient […]
Curcumin's antiepileptic effect, and alterations in Nav1.1 and Nav1.6 expression in iron-induced epilepsy
The present study was carried out to evaluate: the antiepileptic effect of dietary curcumin, and the effect of epileptic state and curcumin on the molecular expression of voltage-activated Na^(+) channel subtypes Na(v)1.1 and Na(v)1.6 in the iron-induced experimental epilepsy in the rat. Rats were divided into four groups; Group I (control rats), Group II (epileptic […]
Identification of peptidomimetics as novel chemical probes modulating fibroblast growth factor 14 (FGF14) and voltage-gated sodium channel 1.6 (Nav1.6) protein-protein interactions
The voltage-gated sodium (Nav) channel is the molecular determinant of action potential in neurons. Protein-protein interactions (PPI) between the intracellular Nav1.6 C-tail and its regulatory protein fibroblast growth factor 14 (FGF14) provide an ideal and largely untapped opportunity for development of neurochemical probes. Based on a previously identified peptide FLPK, mapped to the FGF14:FGF14 PPI […]
Electrophysiological characterization of Tityus obscurus β toxin 1 (To1) on Na+-channel isoforms
To1, previously named Tc49b, is a peptide neurotoxin isolated from venom of the scorpion Tityus obscurus that is responsible for lethal human poisoning cases in the Brazilian Amazonian region. Previously, To1 was shown to be lethal to mice and to change Na^(+) permeation in cerebellum granular neurons from rat brain. In addition, To1 did not […]
12q13.12q13.13 microdeletion encompassing ACVRL1 and SCN8A genes: Clinical report of a new contiguous gene syndrome
Hereditary hemorrhagic telangiectasia is usually linked to the presence of a pathogenic mutation ACVRL1 or ENG. Thus, apparently there is no benefit to perform an array CGH in case of HHT. However, ENG has been involved in a contiguous gene syndrome due to a de novo 9q33.3q34.11 microdeletion. We describe here a new contiguous gene […]
Axon initial segment plasticity accompanies enhanced excitation of visual cortical neurons in aged rats
Recent studies have indicated that the structure of the axon initial segment (AIS) of neurons is highly plastic in response to changes in neuronal activity. Whether an age-related enhancement of neuronal responses in the visual cortex is coupled with plasticity of AISs is unknown. Here, we compare the AIS length and the distribution of Nav1.6, […]
Whole-Exome Sequencing Implicates SCN2A in Episodic Ataxia, but Multiple Ion Channel Variants May Contribute to Phenotypic Complexity
Although the clinical use of targeted gene sequencing-based diagnostics is valuable, whole-exome sequencing has also emerged as a successful diagnostic tool in molecular genetics laboratories worldwide. Molecular genetic tests for episodic ataxia type 2 (EA2) usually target only the specific calcium channel gene (CACNA1A) that is known to cause EA2. In cases where no mutations […]
Upregulation of Nav1.6 expression in the rostral ventrolateral medulla of stress-induced hypertensive rats
The rostral ventrolateral medulla (RVLM) plays a key role in mediating the development of stress-induced hypertension (SIH) by excitation and/or inhibition of sympathetic preganglionic neurons. The voltage-gated sodium channel Nav1.6 has been found to contribute to neuronal hyperexcitability. To examine the expression of Nav1.6 in the RVLM during SIH, a rat model was established by […]
Molecular basis of trigeminal nerve disorders and healing
CONCLUSIONS: More investigations regarding the gain-of-function mutation of NaV1.6 sodium channels are essential for the diagnosis and treatment of trigeminal nerve disorders, regardless of whether these are associated with vascular compression or not.
Inhibitory effects of cannabidiol on voltage-dependent sodium currents
Cannabis sativa contains many related compounds known as phytocannabinoids. The main psychoactive and nonpsychoactive compounds are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), respectively. Much of the evidence for clinical efficacy of CBD-mediated antiepileptic effects has been from case reports or smaller surveys. The mechanisms for CBD's anticonvulsant effects are unclear and likely involve noncannabinoid receptor pathways. […]

2017

SCN8A 2017

Gene panel analysis for nonsyndromic cryptogenic neonatal/infantile epileptic encephalopathy
OBJECTIVE: Epileptic encephalopathy (EE) is a heterogeneous condition associated with deteriorations of cognitive, sensory and/or motor functions as a consequence of epileptic activity. The phenomenon is the most common and severe in infancy and early childhood. Genetic-based diagnosis in EE patients is challenging owing to genetic and phenotypic heterogeneity of numerous monogenic disorders and the […]
Phenytoin as a last-resort treatment in SCN8A encephalopathy
SCN8A encodes Nav1.6, one of the main voltage-gated sodium channel subunits in the brain, and SCN8A mutations lead to epileptic encephalopathy. Particular mutations render the mutant channel more susceptible to inhibition by phenytoin. Yet, the potentially severe side effects of phenytoin maintenance therapy, especially cognitive impairment, are undesirable in these already cognitively impaired patients. We […]
Elucidating distinct ion channel populations on the surface of hippocampal neurons via single-particle tracking recurrence analysis
Protein and lipid nanodomains are prevalent on the surface of mammalian cells. In particular, it has been recently recognized that ion channels assemble into surface nanoclusters in the soma of cultured neurons. However, the interactions of these molecules with surface nanodomains display a considerable degree of heterogeneity. Here, we investigate this heterogeneity and develop statistical […]
A Novel Inherited Mutation of SCN8A in a Korean Family with Benign Familial Infantile Epilepsy Using Diagnostic Exome Sequencing
Mutations in SCN8A, which codes for the voltage-gated sodium channel Na(V)1.6, have been described in relation to infantile onset epilepsy with developmental delay and cognitive impairment. Here, we report the case of an infant and her father with early onset benign familial infantile epilepsy, but without cognitive or neurological impairment. In this patient, diagnostic exome […]
Intraspecific variation of Centruroides sculpturatus scorpion venom from two regions of Arizona
This study investigated geographic variability in the venom of Centruroides sculpturatus scorpions from different biotopes. Venom from scorpions collected from two different regions in Arizona; Santa Rita Foothills (SR) and Yarnell (Yar) were analyzed. We found differences between venoms, mainly in the two most abundant peptides; SR (CsEv2e and CsEv1f) and Yar (CsEv2 and CsEv1c) […]
Early onset epileptic encephalopathy in a patient with mutation in SCN8A
TITLE: Encefalopatia epileptica de inicio precoz en un paciente con mutacion en SCN8A.
Neurotransmitters and Sodium Channelopathies; Possible Link?
Investigators from the University of British Columbia, Great Ormond Street Hospital for Children, and the National Hospital reported their findings on neurotransmitter deficiencies in two patients with mutations in voltage-gated sodium genes (SCN2A and SCN8A) discovered by whole exome sequencing.
Prevalence of Genetic Disorders and GLUT1 Deficiency in a Ketogenic Diet Clinic
Between July of 2012 and December of 2014, 39 patients were enrolled prospectively to investigate the prevalence of glucose transporter 1 (GLUT1) deficiency in a ketogenic diet clinic. None of them had GLUT1 deficiency. All patients seen in the same clinic within the same period were reviewed retrospectively. A total of 18 of these 85 […]
Early-onset epileptic encephalopathy with de novo SCN8A mutation
Early-onset epileptic encephalopathies (EOEEs) are clinically and genetically heterogeneous disorders characterized by intractable seizures and unremitting interictal paroxysmal epileptiform activity. Consequently, these syndromes impair neurodevelopment during the first year of life. Currently, the etiology of these disorders is largely unknown. In this study, Childhood-Onset Epilepsy Gene Panel Testing (containing 511 epilepsy-related genes) was performed in […]
De novo variants in the alternative exon 5 of SCN8A cause epileptic encephalopathy
PurposeAs part of the Epilepsy Genetics Initiative, we re-evaluated clinically generated exome sequence data from 54 epilepsy patients and their unaffected parents to identify molecular diagnoses not provided in the initial diagnostic interpretation.MethodsWe compiled and analyzed exome sequence data from 54 genetically undiagnosed trios using a validated analysis pipeline. We evaluated the significance of the […]

2016

SCN8A 2016

Consequences of acute Nav1.1 exposure to deltamethrin
CONCLUSION: Collectively, these data provide evidence that Na(v)1.1 is indeed vulnerable to deltamethrin modification at lower concentrations than Na(v)1.6, and this effect is primarily mediated during the resting state.
Amyloid precursor protein modulates Nav1.6 sodium channel currents through a Go-coupled JNK pathway
Amyloid precursor protein (APP), commonly associated with Alzheimer's disease, also marks axonal degeneration. In the recent studies, we demonstrated that APP aggregated at nodes of Ranvier (NORs) in myelinated central nervous system (CNS) axons and interacted with Nav1.6. However, the physiological function of APP remains unknown. In this study, we described reduced sodium current densities […]
Genetics and treatment of early infantile epileptic encephalopathies
Epileptic encephalopathies (EE) are the group of progressive conditions with various etiologies that can produce neurocognitive deficit both per se and due to constant epileptiform discharges. Epileptic encephalopathies constitute about 15% of epilepsy in childhood and 40% of all seizures occurring in the first 3 years of life. Ten syndrome forms of EE are identified. […]
FGF14 is a regulator of KCNQ2/3 channels
KCNQ2/3 (Kv7.2/7.3) channels and voltage-gated sodium channels (VGSCs) are enriched in the axon initial segment (AIS) where they bind to ankyrin-G and coregulate membrane potential in central nervous system neurons. The molecular mechanisms supporting coordinated regulation of KCNQ and VGSCs and the cellular mechanisms governing KCNQ trafficking to the AIS are incompletely understood. Here, we […]
Remarkable alterations of Nav1.6 in reactive astrogliosis during epileptogenesis
Voltage-gated sodium channels (VGSCs) play a vital role in controlling neuronal excitability. Nav1.6 is the most abundantly expressed VGSCs subtype in the adult central nervous system and has been found to contribute to facilitate the hyperexcitability of neurons after electrical induction of status epilepticus (SE). To clarify the exact expression patterns of Nav1.6 during epileptogenesis, […]
SCN8A mutation in a child presenting with seizures and developmental delays
The SCN8A gene encodes the sodium voltage-gated channel alpha subunit 8. Mutations in this gene have been associated with early infantile epileptic encephalopathy type 13. With the use of whole-exome sequencing, a de novo missense mutation in SCN8A was identified in a 4-yr-old female who initially exhibited symptoms of epilepsy at the age of 5 […]
De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis
CONCLUSIONS: Variants in SCN8A may be responsible for a spectrum of epilepsies as well as other neurodevelopmental disorders without seizures. The predominant pathogenic mechanism appears to involve disruption of channel inactivation, leading to gain-of-function effects.
Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes
Targeted resequencing gene panels are used in the diagnostic setting to identify gene defects in epilepsy. We performed targeted resequencing using a 30-genes panel and a 95-genes panel in 349 patients with drug-resistant epilepsies beginning in the first years of life. We identified 71 pathogenic variants, 42 of which novel, in 30 genes, corresponding to […]
Altered gene expression profile in a mouse model of SCN8A encephalopathy
SCN8A encephalopathy is a severe, early-onset epilepsy disorder resulting from de novo gain-of-function mutations in the voltage-gated sodium channel Na(v)1.6. To identify the effects of this disorder on mRNA expression, RNA-seq was performed on brain tissue from a knock-in mouse expressing the patient mutation p.Asn1768Asp (N1768D). RNA was isolated from forebrain, cerebellum, and brainstem both […]
SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders
CLINICAL CHARACTERISTICS: SCN8A-related epilepsy and/or neurodevelopmental disorders encompasses a spectrum of phenotypes. Epilepsy phenotypes include developmental and epileptic encephalopathy (DEE) associated with severe developmental delays and usually pharmacoresistant epilepsy with multiple seizure types; mild-to-moderate developmental and epileptic encephalopathy (mild/modDEE, or intermediate epilepsy) with partially treatable epilepsy; self-limited familial infantile epilepsy (SeLFIE,...

2015

SCN8A 2015

Spectrum of SCN8A-Related Epilepsy
Investigators from the EuroEPINOMICS European research consortium studied 17 patients with epileptic encephalopathy due to SCN8A mutations and reported the specific genetic and phenotypic features.
Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy
OBJECTIVE: The early infantile epileptic encephalopathy type 13 (EIEE13, OMIM #614558) results from de novo missense mutations of SCN8A encoding the voltage-gated sodium channel Nav1.6. More than 20% of patients have recurrent mutations in residues Arg1617 or Arg1872. Our goal was to determine the functional effects of these mutations on channel properties.
Effects of the β1 auxiliary subunit on modification of Rat Na(v)1.6 sodium channels expressed in HEK293 cells by the pyrethroid insecticides tefluthrin and deltamethrin
We expressed rat Nav1.6 sodium channels with or without the rat β1 subunit in human embryonic kidney (HEK293) cells and evaluated the effects of the pyrethroid insecticides tefluthrin and deltamethrin on whole-cell sodium currents. In assays with the Nav1.6 α subunit alone, both pyrethroids prolonged channel inactivation and deactivation and shifted the voltage dependence of […]
Secondary neurotransmitter deficiencies in epilepsy caused by voltage-gated sodium channelopathies: A potential treatment target?
We describe neurotransmitter abnormalities in two patients with drug-resistant epilepsy resulting from deleterious de novo mutations in sodium channel genes. Whole exome sequencing identified a de novo SCN2A splice-site mutation (c.2379+1G>A, p.Glu717Gly.fs*30) resulting in deletion of exon 14, in a 10-year old male with early onset global developmental delay, intermittent ataxia, autism, hypotonia, epileptic encephalopathy […]
The Expanding SCN8A-Related Epilepsy Phenotype
No abstract
Downregulation of the sodium channel Nav1.6 by potential transcriptomic deregulation may explain sensory deficits in critical illness neuropathy
AIMS: Sepsis patients and other patients in the critical care settings are at very high risk of mortality due to the primary illness. However, a fraction of patients, even after showing initial clinical improvement, deteriorates relentlessly at later stages. Increasingly, it is being identified that this is mostly due to dysfunction of the neurological system.
Characterization of maturation of neuronal voltage-gated sodium channels SCN1A and SCN8A in rat myocardium
CONCLUSIONS: Heart- and brain-type sodium channels are differentially expressed during ontogenesis. The high expression level of SCN1A in the perinatal period and early infancy indicates its importance in preserving a regular cardiac rhythm in this early phase of life. Altered regulation of sodium channels might result in severe cardiac rhythm disturbances.
An update on transcriptional and post-translational regulation of brain voltage-gated sodium channels
Voltage-gated sodium channels are essential proteins in brain physiology, as they generate the sodium currents that initiate neuronal action potentials. Voltage-gated sodium channels expression, localisation and function are regulated by a range of transcriptional and post-translational mechanisms. Here, we review our understanding of regulation of brain voltage-gated sodium channels, in particular SCN1A (NaV1.1), SCN2A (NaV1.2), […]
An Scn1a epilepsy mutation in Scn8a alters seizure susceptibility and behavior
Understanding the role of SCN8A in epilepsy and behavior is critical in light of recently identified human SCN8A epilepsy mutations. We have previously demonstrated that Scn8a(med) and Scn8a(med-jo) mice carrying mutations in the Scn8a gene display increased resistance to flurothyl and kainic acid-induced seizures; however, they also exhibit spontaneous absence seizures. To further investigate the […]
Navβ4 regulates fast resurgent sodium currents and excitability in sensory neurons
CONCLUSION: INaRs are associated with inherited and acquired pain disorders. However, our ability to selectively target and study this current has been hindered due to limited understanding of how it is generated in sensory neurons. This study identified Navβ4 as an important regulator of INaR and excitability in sensory neurons. As such, Navβ4 is a […]

2014

SCN8A 2014

Novel phenotype associated with a mutation in the KCNA1(Kv1.1) gene
Episodic ataxia type 1 (EA1) is an autosomal dominant K(+) channelopathy which manifests with short attacks of cerebellar ataxia and dysarthria, and may also show interictal myokymia. Episodes can be triggered by emotional or physical stress, startle response, sudden postural change or fever. Here we describe a 31-year-old man displaying markedly atypical symptoms, including long-lasting […]
SWDreader: a wavelet-based algorithm using spectral phase to characterize spike-wave morphological variation in genetic models of absence epilepsy
BACKGROUND: Spike-wave discharges (SWD) found in neuroelectrical recordings are pathognomonic to absence epilepsy. The characteristic spike-wave morphology of the spike-wave complex (SWC) constituents of SWDs can be mathematically described by a subset of possible spectral power and phase values. Morlet wavelet transform (MWT) generates time-frequency representations well-suited to identifying this SWC-associated subset.
De novo expression of Nav1.7 in injured putative proprioceptive afferents: Multiple tetrodotoxin-sensitive sodium channels are retained in the rat dorsal root after spinal nerve ligation
Tetrodotoxin-sensitive (TTX-s) spontaneous activity is recorded from the dorsal roots after peripheral nerve injury. Primary sensory neurons in the dorsal root ganglion (DRG) express multiple TTX-s voltage-gated sodium channel α-subunits (Navs). Since Nav1.3 increases, whereas all other Navs decrease, in the DRG neurons after peripheral nerve lesion, Nav1.3 is proposed to be critical for the […]
Glial reaction in the spinal cord of the degenerating muscle mouse (Scn8a (dmu))
The glial reaction was investigated in the spinal cord of the degenerating muscle (dmu) mouse, which harbours a null mutation in the voltage-gated sodium channel gene Scn8a and does not produce functional Nav1.6 channel. Glial fibrillary acidic protein (GFAP)- and Iba1-immunoreactivity were detected in numerous cells throughout the spinal cord of wild type mice. These […]
Characterization of a de novo SCN8A mutation in a patient with epileptic encephalopathy
CONCLUSION: The new de novo SCN8A mutation is clearly deleterious, resulting in an unstable protein with reduced channel activity. This differs from the gain-of-function attributes of the first SCN8A mutation in epileptic encephalopathy, pointing to heterogeneity of mechanisms. Since Nav1.6 is expressed in both excitatory and inhibitory neurons, a differential effect of a loss-of-function of […]
Convulsive seizures and SUDEP in a mouse model of SCN8A epileptic encephalopathy
De novo mutations of the voltage-gated sodium channel gene SCN8A have recently been recognized as a cause of epileptic encephalopathy, which is characterized by refractory seizures with developmental delay and cognitive disability. We previously described the heterozygous SCN8A missense mutation p.Asn1768Asp in a child with epileptic encephalopathy that included seizures, ataxia, and sudden unexpected death […]
The sodium channel isoform transition at developing nodes of Ranvier in the peripheral nervous system: dependence on a Genetic program and myelination-induced cluster formation
Among sodium channel isoforms, Nav 1.6 is selectively expressed at nodes of Ranvier in both the CNS and the PNS. However, non-Nav 1.6 isoforms such as Nav 1.2 are also present at the CNS nodes in early development but gradually diminish later. It has been proposed that myelination is part of a glia-neuron signaling mechanism […]
Contribution of sodium channels to lamellipodial protrusion and Rac1 and ERK1/2 activation in ATP-stimulated microglia
Microglia are motile resident immune cells of the central nervous system (CNS) that continuously explore their territories for threats to tissue homeostasis. Following CNS insult (e.g., cellular injury, infection, or ischemia), microglia respond to signals such as ATP, transform into an activated state, and migrate towards the threat. Directed migration is a complex and highly-coordinated […]
Whole-exome sequencing broadens the phenotypic spectrum of rare pediatric epilepsy: a retrospective study
Whole-exome sequencing (WES) has transformed our ability to detect mutations causing rare diseases. FORGE (Finding Of Rare disease GEnes) and Care4Rare Canada are nation-wide projects focused on identifying disease genes using WES and translating this technology to patient care. Rare forms of epilepsy are well-suited for WES and we retrospectively selected FORGE and Care4Rare families […]
Early onset epileptic encephalopathy caused by de novo SCN8A mutations
OBJECTIVE: De novo SCN8A mutations have been reported in patients with epileptic encephalopathy. Herein we report seven patients with de novo heterozygous SCN8A mutations, which were found in our comprehensive genetic analysis (target capture or whole-exome sequencing) for early onset epileptic encephalopathies (EOEEs).

2013

SCN8A 2013

De novo SCN8A mutation identified by whole-exome sequencing in a boy with neonatal epileptic encephalopathy, multiple congenital anomalies, and movement disorders
Epileptic encephalopathies represent a clinically and genetically heterogeneous group of disorders, majority of which are of unknown etiology. We used whole-exome sequencing of a parent-offspring trio to identify the cause of early infantile epileptic encephalopathy in a boy with neonatal seizures, movement disorders, and multiple congenital anomalies who died at the age of 17 months […]
Introducing treatment strategy for cerebellar ataxia in mutant med mice: combination of acetazolamide and 4-aminopyridine
Purkinje neurons are the sole output neuron of the cerebellar cortex, and they generate high-frequency action potentials. Electrophysiological dysfunction of Purkinje neurons causes cerebellar ataxia. Mutant med mice have the lack of expression of the Scn8a gene. This gene encodes the NaV1.6 protein. In med Purkinje neurons, regular high-frequency firing is slowed, and med mice […]
Modeling human epilepsy by TALEN targeting of mouse sodium channel Scn8a
To evaluate the efficiency of TALEN technology for introducing mutations into the mouse genome we targeted Scn8a, a member of a multigene family with nine closely related paralogs. Our goal was to generate a model of early onset epileptic encephalopathy by introduction of the Scn8a missense mutation p.Asn1768Asp. We used a pair of TALENs that […]
Combination of BK channel opener and Kv4 channel inhibitor for treatment of cerebellar ataxia in mutant med mice
No abstract
Sodium channel SCN8A (Nav1.6): properties and de novo mutations in epileptic encephalopathy and intellectual disability
The sodium channel Nav1.6, encoded by the gene SCN8A, is one of the major voltage-gated channels in human brain. The sequences of sodium channels have been highly conserved during evolution, and minor changes in biophysical properties can have a major impact in vivo. Insight into the role of Nav1.6 has come from analysis of spontaneous […]
Scn8a voltage-gated sodium channel mutation alters seizure and anxiety responses to acute stress
Stress is known to trigger seizures in patients with epilepsy, highlighting the physiological stress response as a possible therapeutic target for epilepsy treatment. Nevertheless, little is currently known about how a genetic predisposition to epilepsy interacts with the stress response to influence seizure outcome. To address this question, we examined the effect of acute stress […]
Plasticity at axon initial segment of hippocampal CA3 neurons in rat after status epilepticus induced by lithium-pilocarpine
CONCLUSIONS: Nav1.6 and ankyrin G may participate in the plastic changes in the AIS of hippocampus CA3 neurons after PISE and play potential roles in epileptogenesis by regulating neuronal excitability.
NaV1.7: stress-induced changes in immunoreactivity within magnocellular neurosecretory neurons of the supraoptic nucleus
CONCLUSIONS: NaV1.7 is present within neurosecretory neurons of rat supraoptic nucleus, where the level of immunoreactivity is dynamic, increasing in response to osmotic stress. Whether NaV1.7 levels are up-regulated within the human hypothalamus in response to environmental factors or stress, and whether NaV1.7 plays a functional role in human hypothalamus, is not yet known. Until […]
FUS-regulated region- and cell-type-specific transcriptome is associated with cell selectivity in ALS/FTLD
FUS is genetically and pathologically linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). To clarify the RNA metabolism cascade regulated by FUS in ALS/FTLD, we compared the FUS-regulated transcriptome profiles in different lineages of primary cells from the central nervous system. The profiles of FUS-mediated gene expression and alternative splicing in motor […]
FGF14 localization and organization of the axon initial segment
The axon initial segment (AIS) is highly enriched in the structural proteins ankyrin G and βIV-spectrin, the pore-forming (α) subunits of voltage-gated sodium (Nav) channels, and functional Nav channels, and is critical for the initiation of action potentials. We previously reported that FGF14, a member of the intracellular FGF (iFGF) sub-family, is expressed in cerebellar […]

2012

SCN8A 2012

A role for Schwann cell-derived neuregulin-1 in remyelination
After peripheral nerve injury, axons regenerate and become remyelinated by resident Schwann cells. However, myelin repair never results in the original myelin thickness, suggesting insufficient stimulation by neuronal growth factors. Upon testing this hypothesis, we found that axonal neuregulin-1 (NRG1) type III and, unexpectedly, also NRG1 type I restored normal myelination when overexpressed in transgenic […]
Heterologous expression of a glial Kir channel (KCNJ10) in a neuroblastoma spinal cord (NSC-34) cell line
Heterologous expression of Kir channels offers a tool to modulate excitability of neurons which provide insight into Kir channel functions in general. Inwardly-rectifying K+ channels (Kir channels) are potential candidate proteins to hyperpolarize neuronal cell membranes. However, heterologous expression of inwardly-rectifying K+ channels has previously proven to be difficult. This was mainly due to a […]
Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice
Mice deficient for CELF4, a neuronal RNA-binding protein, have a complex seizure disorder that includes both convulsive and non-convulsive seizures, and is dependent upon Celf4 gene dosage and mouse strain background. It was previously shown that Celf4 is expressed predominantly in excitatory neurons, and that deficiency results in abnormal excitatory synaptic neurotransmission. To examine the […]
Resurgent-like currents in mouse vas deferens myocytes are mediated by NaV1.6 voltage-gated sodium channels
Patch-clamp experiments were performed to investigate the molecular properties of resurgent-like currents in single smooth muscle cells dispersed from mouse vas deferens, utilizing both Na(V)1.6-null mice (Na(V)1.6(-/-)), lacking the expression of the Scn8a Na(+) channel gene, and their wild-type littermates (Na(V)1.6(+/+)). Na(V)1.6 immunoreactivity was clearly visible in dispersed smooth muscle cells obtained from Na(V)1.6(+/+), but […]
Inhibition of NaV1.6 sodium channel currents by a novel series of 1,4-disubstituted-triazole derivatives obtained via copper-catalyzed click chemistry
We have synthesized and evaluated a series of 1,4-disubstituted-triazole derivatives for inhibition of the rat Na(V)1.6 sodium channel isoform, an isoform thought to play an important role in controlling neuronal firing. Starting from a series of 2,4(1H)-diarylimidazoles previously published, we decided to extend the SAR study by replacing the imidazole with a different heterocyclic scaffold […]
Sodium channels and the neurobiology of epilepsy
Voltage-gated sodium channels (VGSCs) are integral membrane proteins. They are essential for normal neurologic function and are, currently, the most common recognized cause of genetic epilepsy. This review summarizes the neurobiology of VGSCs, their association with different epilepsy syndromes, and the ways in which we can experimentally interrogate their function. The most important sodium channel […]
Motor endplate disease affects neuromuscular junction maturation
Postnatal formation of the neuromuscular synapse requires complex interactions among nerve terminal, muscle fibres and terminal Schwann cells. In motor endplate disease (med) mice, neuromuscular transmission is severely impaired without alteration of axonal conduction and a lethal paralytic phenotype occurs during the postnatal period. The med phenotype appears at a crucial stage of the neuromuscular […]
Anticancer drug oxaliplatin induces acute cooling-aggravated neuropathy via sodium channel subtype Na(V)1.6-resurgent and persistent current
Infusion of the chemotherapeutic agent oxaliplatin leads to an acute and a chronic form of peripheral neuropathy. Acute oxaliplatin neuropathy is characterized by sensory paresthesias and muscle cramps that are notably exacerbated by cooling. Painful dysesthesias are rarely reported for acute oxaliplatin neuropathy, whereas a common symptom of chronic oxaliplatin neuropathy is pain. Here we […]
Interaction of voltage-gated sodium channel Nav1.6 (SCN8A) with microtubule-associated protein Map1b
The mechanism by which voltage-gated sodium channels are trafficked to the surface of neurons is not well understood. Our previous work implicated the cytoplasmic N terminus of the sodium channel Na(v)1.6 in this process. We report that the N terminus plus the first transmembrane segment (residues 1-153) is sufficient to direct a reporter to the […]
Differential state-dependent modification of inactivation-deficient Nav1.6 sodium channels by the pyrethroid insecticides S-bioallethrin, tefluthrin and deltamethrin
Pyrethroid insecticides disrupt nerve function by modifying the gating kinetics of transitions between the conducting and nonconducting states of voltage-gated sodium channels. Pyrethroids modify rat Na(v)1.6+β1+β2 channels expressed in Xenopus oocytes in both the resting state and in one or more states that require channel activation by repeated depolarization. The state dependence of modification depends […]