Impaired NaV1.2 function and reduced cell surface expression in benign familial neonatal-infantile seizures

Purpose: Mutations in SCN2A, the gene encoding the brain voltage‐gated sodium channel α‐subunit Na _V 1.2, are associated with inherited epilepsies including benign familial neonatal‐infantile seizures (BFNIS). Functional characterization of three BFNIS mutations was performed to identify defects in channel function that underlie this disease. Methods: We examined three BFNIS mutations (R1319Q, L1330F, and L1563V) using whole‐cell patch‐clamp recording of heterologously expressed human Na _V 1.2. Membrane biotinylation was employed to examine the cell surface protein expression of the four Na _V 1.2 alleles. Results: R1319Q displayed mixed effects on activation and fast inactivation gating, consistent with a net loss of channel function. L1563V exhibited impaired fast inactivation predicting a net gain of channel function. The L1330F mutation significantly decreased overall channel availability during repetitive stimulation. Patch‐clamp analysis also revealed that cells expressing BFNIS mutants exhibited lower levels of sodium current compared to wild type (WT) Na _V 1.2. Biochemical experiments demonstrated that all three BFNIS mutations exhibited a significant reduction in cell surface expression compared to WT. Discussion: Our findings indicate that BFNIS is associated with a range of biophysical defects accompanied by reduced levels of channel protein at the plasma membrane.     

Painful neuropathies: the emerging role of sodium channelopathies

Pain is a frequent debilitating feature reported in peripheral neuropathies with involvement of small nerve (Aδ and C) fibers. Voltage‐gated sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where Na_V1.7, Na_V1.8, and Na_V1.9 sodium channels (encoded by SCN9A, SCN10A, and SCN11A) are preferentially expressed. The human genetic pain conditions inherited erythromelalgia and paroxysmal extreme pain disorder were the first to be linked to gain‐of‐function SCN9A mutations. Recent studies have expanded this spectrum with gain‐of‐function SCN9A mutations in patients with small fiber neuropathy and in a new syndrome of pain, dysautonomia, and small hands and small feet (acromesomelia). In addition, painful neuropathies have been recently linked to SCN10A mutations. Patch‐clamp studies have shown that the effect of SCN9A mutations is dependent upon the cell‐type background. The functional effects of a mutation in dorsal root ganglion (DRG) neurons and sympathetic neuron cells may differ per mutation, reflecting the pattern of expression of autonomic symptoms in patients with painful neuropathies who carry the mutation in question. Peripheral neuropathies may not always be length‐dependent, as demonstrated in patients with initial facial and scalp pain symptoms with SCN9A mutations showing hyperexcitability in both trigeminal ganglion and DRG neurons. There is some evidence suggesting that gain‐of‐function SCN9A mutations can lead to degeneration of peripheral axons. This review will focus on the emerging role of sodium channelopathies in painful peripheral neuropathies, which could serve as a basis for novel therapeutic strategies.     

Pure haploinsufficiency for Dravet syndrome Na(V)1.1 (SCN1A) sodium channel truncating mutations

Purpose: Dravet syndrome (DS), a devastating epileptic encephalopathy, is mostly caused by mutations of the SCN1A gene, coding for the voltage‐gated Na⁺ channel Na_V1.1 α subunit. About 50% of SCN1A DS mutations truncate Na_V1.1, possibly causing complete loss of its function. However, it has not been investigated yet if Na_V1.1 truncated mutants are dominant negative, if they impair expression or function of wild‐type channels, as it has been shown for truncated mutants of other proteins (e.g., Ca_V channels). We studied the effect of two DS truncated Na_V1.1 mutants, R222* and R1234*, on coexpressed wild‐type Na⁺ channels. Methods: We engineered R222* or R1234* in the human cDNA of Na_V1.1 (hNa_V1.1) and studied their effect on coexpressed wild‐type hNa_V1.1, hNa_V1.2 or hNa_V1.3 cotransfecting tsA‐201 cells, and on hNa_V1.6 transfecting an human embryonic kidney (HEK) cell line stably expressing this channel. We also studied hippocampal neurons dissociated from Na_V1.1 knockout (KO) mice, an animal model of DS expressing a truncated Na_V1.1 channel. Key Findings: We found no modifications of current amplitude coexpressing the truncated mutants with hNa_V1.1, hNa_V1.2, or hNa_V1.3, but a 30% reduction coexpressing them with hNa_V1.6. However, we showed that also coexpression of functional full‐length hNa_V1.1 caused a similar reduction. Therefore, this effect should not be involved in the pathomechanism of DS. Some gating properties of hNa_V1.1, hNa_V1.3, and hNa_V1.6 were modified, but recordings of hippocampal neurons dissociated from Na_V1.1 KO mice did not show any significant modifications of these properties. Therefore, Na_V1.1 truncated mutants are not dominant negative, consistent with haploinsufficiency as the cause of DS. Significance: We have better clarified the pathomechanism of DS, pointed out an important difference between pathogenic truncated Ca_V2.1 mutants and hNa_V1.1 ones, and shown that hNa_V1.6 expression can be reduced in physiologic conditions by coexpression of hNa_V1.1. Moreover, our data may provide useful information for the development of therapeutic approaches.     

Somatostatin-Positive Interneurons Contribute to Seizures in SCN8A Epileptic Encephalopathy

SCN8A epileptic encephalopathy is a devastating epilepsy syndrome caused by mutant SCN8A, which encodes the voltage-gated sodium channel Na_V1.6. To date, it is unclear if and how inhibitory interneurons, which express Na_V1.6, influence disease pathology. Using both sexes of a transgenic mouse model of SCN8A epileptic encephalopathy, we found that selective expression of the R1872W SCN8A mutation in somatostatin (SST) interneurons was sufficient to convey susceptibility to audiogenic seizures. Patch-clamp electrophysiology experiments revealed that SST interneurons from mutant mice were hyperexcitable but hypersensitive to action potential failure via depolarization block under normal and seizure-like conditions. Remarkably, GqDREADD-mediated activation of WT SST interneurons resulted in prolonged electrographic seizures and was accompanied by SST hyperexcitability and depolarization block. Aberrantly large persistent sodium currents, a hallmark of SCN8A mutations, were observed and were found to contribute directly to aberrant SST physiology in computational modeling and pharmacological experiments. These novel findings demonstrate a critical and previously unidentified contribution of SST interneurons to seizure generation not only in SCN8A epileptic encephalopathy, but epilepsy in general.SIGNIFICANCE STATEMENT SCN8A epileptic encephalopathy is a devastating neurological disorder that results from de novo mutations in the sodium channel isoform Na_v1.6. Inhibitory neurons express Na_V1.6, yet their contribution to seizure generation in SCN8A epileptic encephalopathy has not been determined. We show that mice expressing a human-derived SCN8A variant (R1872W) selectively in somatostatin (SST) interneurons have audiogenic seizures. Physiological recordings from SST interneurons show that SCN8A mutations lead to an elevated persistent sodium current which drives initial hyperexcitability, followed by premature action potential failure because of depolarization block. Furthermore, chemogenetic activation of WT SST interneurons leads to audiogenic seizure activity. These findings provide new insight into the importance of SST inhibitory interneurons in seizure initiation, not only in SCN8A epileptic encephalopathy, but for epilepsy broadly.     

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.     

No mutations in the voltage‐gated NaV1.7 sodium channel α1 subunit gene SCN9A in familial complex regional pain syndrome

Background: Mutations in the voltage‐gated Na_V1.7 Na⁺ channel α1 gene SCN9A have been linked to pain disorders, such as inherited primary erythromelalgia and paroxysmal extreme pain disorder. Both show clinical overlap with complex regional pain syndrome (CRPS), a condition that is characterized by pain in association with combinations of vasomotor, sudomotor, sensory, and motor disturbances. Therefore, we here investigated the involvement of the SCN9A gene in familial CRPS. Methods: We performed a mutation analysis of the SCN9A gene in four index cases of families with CRPS. All 26 coding exons and adjacent sequences of the SCN9A gene were analyzed for mutations using direct sequencing analysis. Results: No causal gene mutations were identified in the SCN9A gene in any of the patients. Conclusions: Despite the fact that the SCN9A gene is an excellent candidate, we did not find evidence that it plays a major role in familial CRPS.     

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.     

Familial hemiplegic migraine

Familial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCNA1A, encoding the pore-forming α₁ subunits of the neuronal voltage-gated Ca²⁺ channels Ca_v2.1 and Na⁺ channels Na_v1.1, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the α₂ subunit of the Na⁺, K⁺ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHM1 knockin mice and of several FHM mutants in heterologous expression systems (12 FHM1, 8 FHM2, and 1 FHM3). These studies show the following: (1) FHM1 mutations produce gain-of-function of the Ca_v2.1 channel and, as a consequence, increased Ca_v2.1-dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phenomenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the α₂ Na⁺,K⁺-ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na_v1.5 (and presumably Na_v1.1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K⁺ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K⁺ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategics that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment.     

Exome sequencing identifies a de novo SCN2A mutation in a patient with intractable seizures,severe intellectual disability,optic atrophy,muscular hypotonia,and brain abnormalities

Epilepsy is a phenotypically and genetically highly heterogeneous disorder with >200 genes linked to inherited forms of the disease. To identify the underlying genetic cause in a patient with intractable seizures, optic atrophy, severe intellectual disability (ID), brain abnormalities, and muscular hypotonia, we performed exome sequencing in a 5‐year‐old girl and her unaffected parents. In the patient, we detected a novel, de novo missense mutation in the SCN2A (c.5645G>T; p.R1882L) gene encoding the α_II‐subunit of the voltage‐gated sodium channel Na_v1.2. A literature review revealed 33 different SCN2A mutations in 14 families with benign forms of epilepsy and in 21 cases with severe phenotypes. Although almost all benign mutations were inherited, the majority of severe mutations occurred de novo. Of interest, de novo SCN2A mutations have also been reported in five patients without seizures but with ID (n = 3) and/or autism (n = 3). In the present study, we successfully used exome sequencing to detect a de novo mutation in a genetically heterogeneous disorder with epilepsy and ID. Using this approach, we expand the phenotypic spectrum of SCN2A mutations. Our own and literature data indicate that SCN2A‐linked severe phenotypes are more likely to be caused by de novo mutations. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here .     

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.     

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.     

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.     

Missense mutation of the sodium channel gene SCN2A causes Dravet syndrome

Mutations of the gene encoding the α2 subunit of the neuronal sodium channel, SCN2A, have been found in benign familial neonatal-infantile seizures (BFNIS). In Dravet syndrome, only one nonsense mutation of SCN2A was identified, while hundreds of mutations were found in the paralogue gene, SCN1A, which encodes the α1 subunit. This study examines whether SCN2A mutations are associated with Dravet syndrome. We screened for mutations of SCN1A, SCN2A and GABRG2 (the gene encoding γ2 subunit of the GABA_A receptor) in 59 patients with Dravet syndrome and found 29 SCN1A mutations and three missense SCN2A mutations. Among the three, one de novo SCN2A mutation (c.3935G>C: R1312T) identified in a patient was thought to affect an arginine residue in a voltage sensor of the channel and hence, to be pathogenic. This finding suggests that both nonsense mutations and missense SCN2A mutations cause Dravet syndrome.     

SCN1A testing for epilepsy: Application in clinical practice

This report is a practical reference guide for genetic testing of SCN1A, the gene encoding the α1 subunit of neuronal voltage‐gated sodium channels (protein name: Na_v1.1). Mutations in this gene are frequently found in Dravet syndrome (DS), and are sometimes found in genetic epilepsy with febrile seizures plus (GEFS+), migrating partial seizures of infancy (MPSI), other infantile epileptic encephalopathies, and rarely in infantile spasms. Recommendations for testing: (1) Testing is particularly useful for people with suspected DS and sometimes in other early onset infantile epileptic encephalopathies such as MPSI because genetic confirmation of the clinical diagnosis may allow optimization of antiepileptic therapy with the potential to improve seizure control and developmental outcome. In addition, a molecular diagnosis may prevent the need for unnecessary investigations, as well as inform genetic counseling. (2) SCN1A testing should be considered in people with possible DS where the typical initial presentation is of a developmentally normal infant presenting with recurrent, febrile or afebrile prolonged, hemiclonic seizures or generalized status epilepticus. After age 2, the clinical diagnosis of DS becomes more obvious, with the classical evolution of other seizure types and developmental slowing. (3) In contrast to DS, the clinical utility of SCN1A testing for GEFS+ remains questionable. (4) The test is not recommended for children with phenotypes that are not clearly associated with SCN1A mutations such as those characterized by abnormal development or neurologic deficits apparent at birth or structural abnormalities of the brain. Interpreting test results: (1) Mutational testing of SCN1A involves both conventional DNA sequencing of the coding regions and analyses to detect genomic rearrangements within the relevant chromosomal region: 2q24. Interpretation of the test results must always be done in the context of the electroclinical syndrome and often requires the assistance of a medical geneticist, since many genomic variations are possible and it is essential to differentiate benign polymorphisms from pathogenic mutations. (2) Missense variants may have no apparent effect on the phenotype (benign polymorphisms) or may represent mutations underlying DS, MPSI, GEFS+, and related syndromes and can provide a challenge in interpretation. (3) Conventional methods do not detect variations in introns or promoter or regulatory regions; therefore, a negative test does not exclude a pathogenic role of SCN1A in a specific phenotype. (4) It is important to note that a negative test does not rule out the clinical diagnosis of DS or other conditions because genes other than SCN1A may be involved. Obtaining written informed consent and genetic counseling should be considered prior to molecular testing, depending on the clinical situation and local regulations.     

A thermoprotective role of the sodium channel β1 subunit is lost with the β1 (C121W) mutation

Purpose: A mutation in the β₁ subunit of the voltage‐gated sodium (Na_V) channel, β₁(C121W), causes genetic epilepsy with febrile seizures plus (GEFS+), a pediatric syndrome in which febrile seizures are the predominant phenotype. Previous studies of molecular mechanisms underlying neuronal hyperexcitability caused by this mutation were conducted at room temperature. The prevalence of seizures during febrile states in patients with GEFS+, however, suggests that the phenotypic consequence of β₁(C121W) may be exacerbated by elevated temperature. We investigated the putative mechanism underlying seizure generation by the β₁(C121W) mutation with elevated temperature. Methods: Whole‐cell voltage clamp experiments were performed at 22 and 34°C using Chinese Hamster Ovary (CHO) cells expressing the α subunit of neuronal Na_V channel isoform, Na_V1.2. Voltage‐dependent properties were recorded from CHO cells expressing either Na_V1.2 alone, Na_V1.2 plus wild‐type (WT) β₁ subunit, or Na_V1.2 plus β₁(C121W). Key Findings: Our results suggest WT β₁ is protective against increased channel excitability induced by elevated temperature; protection is lost in the absence of WT β₁ or with expression of β₁(C121W). At 34°C, Na_V1.2 + β₁(C121W) channel excitability increased compared to NaV1.2 + WT β₁ by the following mechanisms: decreased use‐dependent inactivation, increased persistent current and window current, and delayed onset of, and accelerated recovery from, fast inactivation. Significance: Temperature‐dependent changes found in our study are consistent with increased neuronal excitability of GEFS+ patients harboring C121W. These results suggest a novel seizure‐causing mechanism for β₁(C121W): increased channel excitability at elevated temperature.     

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.     

Confirming an expanded spectrum of SCN2A mutations: a case series

Mutations in sodium channel genes are highly associated with epilepsy. Mutation of SCN1A, the gene encoding the voltage gated sodium channel (VGSC) alpha subunit type 1 (Nav1.1), causes Dravet syndrome spectrum disorders. Mutations in SCN2A have been identified in patients with benign familial neonatal‐infantile epilepsy (BFNIE), generalised epilepsy with febrile seizures plus (GEFS+), and a small number of reported cases of other infantile‐onset severe intractable epilepsy. Here, we report three patients with infantile‐onset severe intractable epilepsy found to have de novo mutations in SCN2A. While a causal role for these mutations cannot be directly established, these findings contribute to growing evidence that mutation of SCN2A is associated with a range of epilepsy phenotypes including severe infantile‐onset epilepsy.     

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.