An SCN2A mutation in a family with infantile seizures from Madagascar reveals an increased subthreshold Na+ current

Missense mutations in SCN2A, encoding the brain sodium channel Na_V1.2, have been described in benign familial neonatal‐infantile seizures (BFNIS), a self‐limiting disorder, whereas several SCN2A de novo nonsense mutations have been found in patients with more severe phenotypes including epileptic encephalopathy. We report a family with BFNIS originating from Madagascar. Onset extended from 3 to 9 months of age. Interictal EEGs were normal. In two patients, ictal electroencephalography (EEG) studies showed partial seizure patterns with secondary generalization in one. Seizures remitted before 18 months of age, with or without medication. Intellectual development was normal. A novel missense mutation of SCN2A, c.4766A>G/p.Tyr1589Cys, was found in a highly conserved region of Na_V1.2 (D4/S2‐S3). Functional studies using heterologous expression in tsA201 cells and whole‐cell patch clamping revealed a depolarizing shift of steady‐state inactivation, increased persistent Na⁺ current, a slowing of fast inactivation and an acceleration of its recovery, thus a gain‐of‐function. Using an action potential waveform in a voltage‐clamp experiment we indicated an increased inward Na⁺ current at subthreshold voltages, which can explain a neuronal hyperexcitability. Our results suggest that this mutation induces neuronal hyperexcitability, resulting in infantile epilepsy with favorable outcome.     

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 function in vivo. The conditional R1872W mutation is activated by expression of CRE recombinase, permitting characterization of the effects of the mutation on different classes of neurons and at different points in postnatal development. Preclinical drug testing in these mouse models provides support for several new therapies for this devastating disorder. In contrast with the gain‐of‐function mutations in epilepsy, mutations of SCN8A that result in partial or complete loss of function are associated with intellectual disability and other disorders.     

Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach

Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0372-8) contains supplementary material, which is available to authorized users.Key Words: SCN8A, phenytoin, epileptic encephalopathy, sodium channel blockers     

Mutations of the SCN1A gene in acute encephalopathy

Purpose: Acute encephalopathy is the most serious complication of pediatric viral infections, such as influenza and exanthema subitum. It occurs worldwide, but is most prevalent in East Asia. Recently, there have been sporadic case reports of epilepsy/febrile seizure and acute encephalopathy with a neuronal sodium channel alpha 1 subunit (SCN1A) mutation. To determine whether SCN1A mutations are a predisposing factor of acute encephalopathy, we sought to identify SCN1A mutations in a large case series of acute encephalopathy including various syndromes. Methods: We analyzed the SCN1A gene in 87 patients with acute encephalopathy, consisting of 20 with acute necrotizing encephalopathy (ANE), 61 with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), and six with nonspecific (unclassified) acute encephalopathy. Key Findings: Three patients had distinct point mutations. Two of them had epileptic seizures prior to acute encephalopathy. Clinical and neuroradiologic findings of acute encephalopathy were diverse among the three patients, although all had a prolonged and generalized seizure at its onset. The first patient with V982L had partial epilepsy and AESD. The second patient with M1977L had febrile seizures and nonspecific acute encephalopathy. The third patient with R1575C had no seizures until the onset of ANE. M1977L was a novel mutation, whereas the remaining two, V982L and R1575C, have previously been reported in cases of Dravet syndrome and acute encephalopathy, respectively. Significance: These findings provide further evidence that SCN1A mutations are a predisposing factor for the onset of various types of acute encephalopathy.     

The therapeutic implication of a novel SCN2A mutation associated early-onset epileptic encephalopathy with Rett-like features

Epileptic encephalopathies are highly heterogeneous and phenotypical disorders with different underlying genetic defects. Mutations in the SCN2A gene cause different epilepsy syndromes, including epilepsy of infancy with migrating focal seizures, Ohtahara syndrome, and West syndrome. We utilized a targeted next generation sequencing (NGS) approach on a girl with early-onset seizures and Rett-like features, including autistic behavior, limited hand function with chorea, and profound intellectual disability, to identify novel missense mutation (c.1270G>A; p.V424M) in the SCN2A gene, which encodes the αII-subunit of the voltage-gated Na⁺ channel (Na_v1.2). The identified SCN2A mutation responsible for the development of the disease is confirmed to be de novo for the proband. Our findings broaden the clinical spectrum of SCN2A mutations, which resembles clinical phenotypes of SCN1A mutations by manifesting as fever sensitive seizures, and highlights that SCN2A mutations are an important cause of early-onset epileptic encephalopathies with movement disorders. In addition, the use of levetiracetam to treat SCN2A epileptic encephalopathy, when Na⁺ channel-blocking anticonvulsants are ineffective, is also recommended.     

Hyperexcitability and Pharmacological Responsiveness of Cortical Neurons Derived from Human iPSCs Carrying Epilepsy-Associated Sodium Channel Nav1.2-L1342P Genetic Variant

With the wide adoption of genomic sequencing in children having seizures, an increasing number of SCN2A genetic variants have been revealed as genetic causes of epilepsy. Voltage-gated sodium channel Nav1.2, encoded by gene SCN2A, is predominantly expressed in the pyramidal excitatory neurons and supports action potential (AP) firing. One recurrent SCN2A genetic variant is L1342P, which was identified in multiple patients with epileptic encephalopathy and intractable seizures. However, the mechanism underlying L1342P-mediated seizures and the pharmacogenetics of this variant in human neurons remain unknown. To understand the core phenotypes of the L1342P variant in human neurons, we took advantage of a reference human-induced pluripotent stem cell (hiPSC) line from a male donor, in which L1342P was introduced by CRISPR/Cas9-mediated genome editing. Using patch-clamping and microelectrode array (MEA) recordings, we revealed that cortical neurons derived from hiPSCs carrying heterozygous L1342P variant have significantly increased intrinsic excitability, higher sodium current density, and enhanced bursting and synchronous network firing, suggesting hyperexcitability phenotypes. Interestingly, L1342P neuronal culture displayed a degree of resistance to the anticonvulsant medication phenytoin, which recapitulated aspects of clinical observation of patients carrying the L1342P variant. In contrast, phrixotoxin-3 (PTx3), a Nav1.2 isoform-specific blocker, can potently alleviate spontaneous and chemically-induced hyperexcitability of neurons carrying the L1342P variant. Our results reveal a possible pathogenic underpinning of Nav1.2-L1342P mediated epileptic seizures and demonstrate the utility of genome-edited hiPSCs as an in vitro platform to advance personalized phenotyping and drug discovery.SIGNIFICANCE STATEMENT A mounting number of SCN2A genetic variants have been identified from patients with epilepsy, but how SCN2A variants affect the function of human neurons contributing to seizures is still elusive. This study investigated the functional consequences of a recurring SCN2A variant (L1342P) using human iPSC-derived neurons and revealed both intrinsic and network hyperexcitability of neurons carrying a mutant Nav1.2 channel. Importantly, this study recapitulated elements of clinical observations of drug-resistant features of the L1342P variant, and provided a platform for in vitro drug testing. Our study sheds light on cellular mechanism of seizures resulting from a recurring Nav1.2 variant, and helps to advance personalized drug discovery to treat patients carrying pathogenic SCN2A variant.     

Remarkable Phenytoin Sensitivity in 4 Children with <Emphasis Type="Italic">SCN8A</Emphasis>-related Epilepsy: A Molecular Neuropharmacological Approach

Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation.     

SCN2A mutation in an infant presenting with migrating focal seizures and infantile spasm responsive to a ketogenic diet

SCN2A mutations have been identified in various encephalopathy phenotypes, ranging from benign familial neonatal-infantile seizure (BFNIS) to more severe forms of epileptic encephalopathy such as Ohtahara syndrome or epilepsy of infancy with migrating focal seizure (EIMFS). Thus far, no particularly effective treatment is available for severe epileptic encephalopathy caused by SCN2A mutations in children.We present the case of a boy who developed seizures on the third day of life and received a diagnosis of EIMFS based on his clinical presentations and electroencephalography reports. Antiepileptic drugs, namely oxcarbazepine, phenytoin, valproate, levetiracetam, and clonazepam, as well as adrenocorticotropic hormone therapy failed to reduce the severity of the seizures. Seizure pattern changed to infantile spasm with extensor thrust since 5?months of age. A ketogenic diet consisting of a medium-chain triglyceride recipe was introduced at 8?months of age and the seizures were resolved in the following 10?months. A de novo mutation in SCN2A (c.573G?>?T; p.W191C) was proven through next-generation sequencing.     

SCN2A channelopathies: Mechanisms and models

Variants in the SCN2A gene, encoding the voltage‐gated sodium channel Na_V1.2, cause a variety of neuropsychiatric syndromes with different severity ranging from self‐limiting epilepsies with early onset to developmental and epileptic encephalopathy with early or late onset and intellectual disability (ID), as well as ID or autism without seizures. Functional analysis of channel defects demonstrated a genotype‐phenotype correlation and suggested effective treatment options for one group of affected patients carrying gain‐of‐function variants. Here, we sum up the functional mechanisms underlying different phenotypes of patients with SCN2A channelopathies and present currently available models that can help in understanding SCN2A‐related disorders.     

SCN1A/NaV1.1 channelopathies: Mechanisms in expression systems,animal models,and human iPSC models

Pathogenic SCN1A/Na_V1.1 mutations cause well‐defined epilepsies, including genetic epilepsy with febrile seizures plus (GEFS+) and the severe epileptic encephalopathy Dravet syndrome. In addition, they cause a severe form of migraine with aura, familial hemiplegic migraine. Moreover, SCN1A/Na_V1.1 variants have been inferred as risk factors in other types of epilepsy. We review here the advancements obtained studying pathologic mechanisms of SCN1A/Na_V1.1 mutations with experimental systems. We present results gained with in vitro expression systems, gene‐targeted animal models, and the induced pluripotent stem cell (iPSC) technology, highlighting advantages, limits, and pitfalls for each of these systems. Overall, the results obtained in the last two decades confirm that the initial pathologic mechanism of epileptogenic SCN1A/Na_V1.1 mutations is loss‐of‐function of Na_V1.1 leading to hypoexcitability of at least some types of γ‐aminobutyric acid (GABA)ergic neurons (including cortical and hippocampal parvalbumin‐positive and somatostatin‐positive ones). Conversely, more limited results point to Na_V1.1 gain‐of‐function for familial hemiplegic migraine (FHM) mutations. Behind these relatively simple pathologic mechanisms, an unexpected complexity has been observed, in part generated by technical issues in experimental studies and in part related to intrinsically complex pathophysiologic responses and remodeling, which yet remain to be fully disentangled.     

Partial epilepsy with antecedent febrile seizures and seizure aggravation by antiepileptic drugs: Associated with loss of function of Nav1.1

Purpose: Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI) are associated with sodium channel α‐subunit type‐1 gene (SCN1A) mutations. Febrile seizures and partial seizures occur in both GEFS+ and SMEI; sporadic onset and seizure aggravation by antiepileptic drugs (AEDs) are features of SMEI. We thus searched gene mutations in isolated cases of partial epilepsy with antecedent FS (PEFS+) that showed seizure aggravations by AEDs. Methods: Genomic DNA from four patients was screened for mutations in SCN1A, SCN2A, SCN1B, and GABRG2 using denaturing high‐performance liquid chromatography (dHPLC) and sequencing. Whole‐cell patch clamp analysis was used to characterize biophysical properties of two newly defined mutants of Na_v1.1 in tsA201 cells. Results: Two heterozygous de novo mutations of SCN1A (R946H and F1765L) were detected, which were proven to cause loss of function of Na_v1.1. When the functional defects of mutants reported previously are compared, it is found that all mutants from PEFS+ have features of loss of function, whereas GEFS+ shows mild dysfunction excluding loss of function, coincident with mild clinical manifestations. PEFS+ is similar to SMEI clinically with possible AED‐induced seizure aggravation and biophysiologically with features of loss of function, and different from SMEI by missense mutation without changes in hydrophobicity or polarity of the residues. Conclusions: Isolated milder PEFS+ may associate with SCN1A mutations and loss of function of Na_v1.1, which may be the basis of seizure aggravation by sodium channel–blocking AEDs. This study characterized phenotypes biologically, which may be helpful in understanding the pathophysiologic basis, and further in management of the disease.     

Induction of sodium channel Nax (SCN7A) expression in rat and human hippocampus in temporal lobe epilepsy

Purpose: In a recent large‐scale gene‐expression study in a rat model of temporal lobe epilepsy (TLE) a persistent up‐regulation in the expression of the SCN7A gene was revealed. The SCN7A gene encodes an atypical sodium channel (Na_x), which is involved in osmoregulation via a sensing mechanism for the extracellular sodium concentration. Herein we investigated the expression and cellular distribution of SCN7A mRNA and protein in normal and epileptic rat and human hippocampus. Methods: SCN7A/Na_x expression analysis was performed by polymerase chain reaction (PCR), immunocytochemistry, and western blot analysis. Results: Increased expression of SCN7A/Na_x mRNA/protein was observed during epileptogenesis and in the chronic epileptic phase in the post–status epilepticus (SE) model of TLE. The up‐regulation was confirmed in human hippocampal tissue resected from pharmacoresistant patients with hippocampal sclerosis (HS). In both epileptic rat and human hippocampus, increased Na_x expression was observed in neurons and reactive astrocytes compared to control tissue. Conclusions: The increased and persistent expression of SCN7A/Na_x in the epileptic rat and human hippocampus supports the possible involvement of this channel in the complex reorganization occurring within the hippocampus during the epileptogenic process in TLE. Further studies are needed for a complete understanding of the functional role of SCN7A in epilepsy.     

SCN8A-related developmental and epileptic encephalopathy with ictal asystole requiring cardiac pacemaker implantation

IntroductionSCN8A-related epilepsy has various phenotypes. In particular, patients with developmental and epileptic encephalopathy (DEE) are resistant to antiepileptic drugs and may present with autonomic symptoms, such as marked bradycardia and apnea during seizures, and thus have an increased risk of sudden death. Herein, we report a case of very severe SCN8A-related epilepsy necessitating cardiac pacemaker implantation because of repetitive ictal asystole.Case reportThe patient was a 14-month-old girl. Tremor and generalized tonic seizure occurred after birth. During seizures, bradycardia and perioral cyanosis occurred, and then, after developing tachycardia and apnea, marked bradycardia and generalized cyanosis occurred, which sometimes resulted in ictal asystole requiring cardiopulmonary resuscitation. Her seizures were refractory to antiepileptic drugs. As the seizures requiring resuscitation did not decrease, cardiac pacemaker implantation was performed four months after birth. Exome sequencing revealed a heterozygous de novo variant in SCN8A (NM_014191.3:c.4934T>C,p.(Met1645Thr)). Even though phenytoin was effective, seizures with bradycardia remained approximately once a month, and pacemaker activity was observed.ConclusionsThis is, to our knowledge, the first reported case of SCN8A-related DEE in whom pacemaker implantation was performed. Pacemaker implantation should be considered as a treatment option for critical patients with SCN8A-related DEE as in the present case, because the incidence of sudden unexpected death in epilepsy is reported to be approximately 10% in patients with SCN8A-related DEE.     

A sodium channel mutation linked to epilepsy increases ramp and persistent current of Nav1.3 and induces hyperexcitability in hippocampal neurons

Voltage-gated sodium channelopathies underlie many excitability disorders. Genes SCN1A, SCN2A and SCN9A, which encode pore-forming α-subunits Na_V1.1, Na_V1.2 and Na_V1.7, are clustered on human chromosome 2, and mutations in these genes have been shown to underlie epilepsy, migraine, and somatic pain disorders. SCN3A, the gene which encodes Na_V1.3, is part of this cluster, but until recently was not associated with any mutation. A charge-neutralizing mutation, K345Q, in the Na_V1.3 DI/S5-6 linker has recently been identified in a patient with cryptogenic partial epilepsy. Pathogenicity of the Na_V1.3/K354Q mutation has been inferred from the conservation of this residue in all sodium channels and its absence from control alleles, but functional analysis has been limited to the corresponding substitution in the cardiac muscle sodium channel Na_V1.5. Since identical mutations may produce different effects within different sodium channel isoforms, we assessed the K354Q mutation within its native Na_V1.3 channel and studied the effect of the mutant Na_V1.3/K354Q channels on hippocampal neuron excitability. We show here that the K354Q mutation enhances the persistent and ramp currents of Na_V1.3, reduces current threshold and produces spontaneous firing and paroxysmal depolarizing shift-like complexes in hippocampal neurons. Our data provide a pathophysiological basis for the pathogenicity of the first epilepsy-linked mutation within Na_V1.3 channels and hippocampal neurons.     

SCN1A‐related phenotypes: Epilepsy and beyond

SCN1A, encoding the alpha 1 subunit of the sodium channel, is associated with several epilepsy syndromes and a range of other diseases. SCN1A represents the archetypal channelopathy associated with a wide phenotypic spectrum of epilepsies ranging from genetic epilepsy with febrile seizures plus (GEFS+), to developmental and epileptic encephalopathies (DEEs). SCN1A disorders also result in other diseases such as hemiplegic migraine and autism spectrum disorder (ASD). Dravet syndrome (DS) is the prototypic DEE with an early onset of febrile status epilepticus, hemiclonic or generalized tonic‐clonic seizures, and later onset of additional seizure types. Electroencephalography (EEG) and magnetic resonance imaging (MRI) are normal at onset. Development is normal in the first year of life but plateaus rapidly, with most patients ultimately having intellectual disability. Epilepsy is drug‐resistant and necessitates polytherapy. Most pathogenic variants occur de novo in the affected child, but they are inherited from mosaic affected or unaffected parents in rare cases. The molecular finding of haploinsufficiency is consistent with a loss‐of‐function defect in cells and animal models. Although seizures are the most commonly reported symptom in DS, many additional issues critically affect patients’ cognitive and behavioral functioning. Hemiplegic migraine (HM) is a rare form of migraine with aura, characterized by the emergence of hemiparesis as part of the aura phase. All SCN1A mutations reported in sporadic/familial HM3 are missense mutations. Most of the experimental results show that they cause a gain of function of Na_V1.1 as opposed to the loss of function of the epileptogenic Na_V1.1 mutations. SCN1A and SCN2A pathogenic variants have been identified in genetic studies of cohorts of patients with ASD. In addition, ASD features are often reported in patients with Dravet syndrome and other DEEs.     

Molecular basis of severe myoclonic epilepsy in infancy

Severe myoclonic epilepsy (SMEI) or Dravet syndrome is caused by mutations of the SCN1A gene that encodes voltage-gated sodium channel alpha-1 subunit. Recently, we generated and characterized a knock-in (KI) mice with an SCN1A nonsense mutation that appeared in three independent SMEI patients. The SCN1A-KI mice well reproduced the SMEI disease phenotypes. Both homozygous and heterozygous knock-in mice developed epileptic seizures within the first postnatal month. In heterozygous knock-in mice, trains of evoked action potentials in inhibitory neurons exhibited pronounced spike amplitude decrement late in the burst but not in pyramidal neurons. We further showed that in wild-type mice the Nav1.1 protein is expressed dominantly in axons and moderately in somata of parbalbumin (PV) – positive inhibitory interneurons. Our immunohistochemical observations of the Nav1.1 are clearly distinct to the previous studies, and our findings has corrected the view of the Nav1.1 protein distribution. The data indicate that Nav1.1 plays critical roles in the spike output from PV interneurons and further, that the specifically altered function of these inhibitory circuits may contribute to epileptic seizures in the mice. These information should contribute to the understanding of molecular pathomechanism of SMEI and to develop its effective therapies.     

Impaired θ-γ Coupling Indicates Inhibitory Dysfunction and Seizure Risk in a Dravet Syndrome Mouse Model

Dravet syndrome (DS) is an epileptic encephalopathy that still lacks biomarkers for epileptogenesis and its treatment. Dysfunction of Na_V1.1 sodium channels, which are chiefly expressed in inhibitory interneurons, explains the epileptic phenotype. Understanding the network effects of these cellular deficits may help predict epileptogenesis. Here, we studied θ-γ coupling as a potential marker for altered inhibitory functioning and epileptogenesis in a DS mouse model. We found that cortical θ-γ coupling was reduced in both male and female juvenile DS mice and persisted only if spontaneous seizures occurred. θ-γ Coupling was partly restored by cannabidiol (CBD). Locally disrupting Na_V1.1 expression in the hippocampus or cortex yielded early attenuation of θ-γ coupling, which in the hippocampus associated with fast ripples, and which was replicated in a computational model when voltage-gated sodium currents were impaired in basket cells (BCs). Our results indicate attenuated θ-γ coupling as a promising early indicator of inhibitory dysfunction and seizure risk in DS.     

Dravet syndrome or genetic (generalized) epilepsy with febrile seizures plus?

Dravet syndrome and genetic epilepsy with febrile seizures plus (GEFS+) can both arise due to mutations of SCN1A, the gene encoding the alpha 1 pore-forming subunit of the sodium channel. GEFS+ refers to a familial epilepsy syndrome where at least two family members have phenotypes that fit within the GEFS+ spectrum. The GEFS+ spectrum comprises a range of mild to severe phenotypes varying from classical febrile seizures to Dravet syndrome. Dravet syndrome is a severe infantile onset epilepsy syndrome with multiple seizure types, developmental slowing and poor outcome. More than 70% of patients with Dravet syndrome have mutations of SCN1A; these include both truncation and missense mutations. In contrast, only 10% of GEFS+ families have SCN1A mutations and these comprise missense mutations. GEFS+ has also been associated with mutations of genes encoding the sodium channel beta 1 subunit, SCN1B, and the GABA_A receptor gamma 2 subunit, GABRG2. The phenotypic heterogeneity that is characteristic of GEFS+ families is likely to be due to modifier genes. Interpretation of the significance of a SCN1A missense mutation requires a thorough understanding of the phenotypes in the GEFS+ spectrum whereas a de novo truncation mutation is likely to be associated with a severe phenotype. Early recognition of Dravet syndrome is important as aggressive control of seizures may improve developmental outcome.     

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 is characterized by intractable seizures beginning in the first months of life. The seizures are often prolonged focal hypomotor and occur in clusters, with prominent vegetative symptoms (apnea, cyanosis, mydriasis), evolving to clonic or bilateral tonic‐clonic manifestations. Spasm‐like episodes, cortical myoclonus, and recurrent episodes of status epilepticus are also common. Electroencephalograms (EEGs) show progressive background deterioration and multifocal abnormalities, predominant in the posterior regions. (2) Sporadic and familial patients with mild‐to‐moderate intellectual disability, discrete neurological signs, and treatable epilepsy. EEG is abnormal in half of the cases, showing multifocal or diffuse epileptiform abnormalities. (3) Familial cases with benign infantile seizures, sometimes associated with paroxysmal dyskinesia later in life, with no other neurological deficits, normal cognition, and usually normal interictal EEG. (4) Patients without epilepsy but with cognitive and/or behavioral disturbances, or with movement disorders. Extrapyramidal features, such as dyskinesia, ataxia, and choreoathetosis are common in all groups. Early death has been reported in about 5% of the patients, most often in the subgroup of severe DEE. Premature death occurs during early childhood and often for causes other than sudden unexpected death in epilepsy. All epilepsy subgroups exhibit better seizure control with sodium channel blockers, usually at supratherapeutic doses in the severe cases. In severe SCN8A‐DEE, ketogenic diet often has a good effect, whereas levetiracetam has a negative effect, if any. The familial SCN8A‐related epilepsies show an autosomal dominant pattern of inheritance, whereas the vast majority of SCN8A‐DEEs occur de novo.