Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review

1Epilepsy is a disease known worldwide, affecting around 70 million people in the world. It has been considered a disease and no longer a disorder or a family of disorders since 2014 by International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsy is conceptually defined as a disease in which an individual has at least two unprovoked or reflex seizures in a period greater than 24 h apart, one unprovoked or reflex seizure and a probability of having another seizure similar to the general recurrence risk after two unprovoked seizures (greater than or equal to 60%) over the next ten years or an epilepsy syndrome.

2When abnormal brain activity begins in one or more identified regions, epilepsy is called focal, whereas, when it occurs in both hemispheres with a wide distribution, it is called generalized. Finally, when it cannot be classified as either focal or generalized, it is called unknown.

3Epilepsy can affect anyone, regardless of gender, age, and income levels. Understanding the etiology of epilepsy is crucial for clinical management of patients and for conducting neurobiological research that will direct future therapies. The ILAE Task Force has defined six etiologic categories; they are not hierarchical and more than one might often apply (structural, genetic, infectious, metabolic, immune, and unknown).

4Among those genetically caused, it is possible to identify several epilepsy-related genes. For example, voltage-gated potassium channel, voltage-gated calcium channel and voltage-gated chloride channel genes, GABA receptors, nicotinic acetylcholine receptors, polymerase (DNA) Gamma genes and voltage-gated sodium channel genes.

5Voltage-gated sodium channels (NaV) can be found mainly in the central nervous system (CNS), peripheral nervous systems (PNS), skeletal, and cardiac muscles. NaVs are distributed throughout the body and play an important role in the generation and propagation of action potential. Structurally, NaVs are composed by an α subunit organized in four homologous ligated domains (DI-DIV), each domain composed by six transmembrane segments (S1-S6), and one or more β subunits associated by non-covalent interactions or disulfide bond. The domains of an α subunit present a high degree of conservation with each other, presenting the region known as the voltage sensor domains (VSD) located in transmembranes S1-S4, especially S4 helix, which contains positively charged residues, and the pore-forming (PM) domain located in S5-S6 segments, structuring a four VSD around a central pore.

6The S4 helix of DI, DII, and DIII domains moves faster than the S4 helix of DIV during membrane depolarization, and this asynchronous movement is an essential feature in the steady activation voltage-dependent process, which provokes movement of S4-S5 intracellular links followed by the displacement of the S6 segments to initiate Na+ influx. The movement of the S4 helix of DIV initiates the process of fast inactivation, since the movement of the voltage sensor in domain DIV is associated with the displacement of an intracellular loop between DIII and DIV within an IFM (isoleucine, phenylalanine, and methionine) motif that binds intracellular to PM and terminate Na+ influx. A second type of reversible inactivation occurs after repetitive or prolonged stimulation and results in steady-state inactivation whose asymmetric movement of S6 segments collapses the pore. Consequently, electrophysiological changes such as increased current density, shifting steady-state activation, and inactivation to negative and positive values, respectively, enhanced persistent current, accelerated recovery from inactivation, and delayed fast inactivation can cause gain-of-function (GoF) in the channel. Also, decreased current density, positive shift in steady-state activation, negative shift in steady-state inactivation, and slower recovery from inactivation can cause loss-of-function (LoF).

7Currently, there are nine different alpha subtypes of NaVs (NaV1.1-NaV1.9), and mutations in these channels can cause diseases known as channelopathies. NaV1.1 (SCN1A), NaV1.2 (SCN2A), NaV1.3 (SCN3A), NaV1.6 (SCN8A) and NaV1.7 (SCN9A) are genes whose mutations are related to epilepsy. So far, there is no correlation of mutations in NaV1.4 (SCN4A), NaV1.5 (SCN5A), NaV1.8 (SCN10A), and NaV1.9 (SCN11A) with epilepsy, which is to be expected, since these channels are mainly expressed in skeletal muscles, cardiac tissues, dorsal root ganglia, trigeminal sensory neurons, nociceptive neurons of the dorsal root and trigeminal ganglia, respectively. Both α and β subunits (SCN1B) have been reported as the cause of epilepsy phenotype.

8NaV channels rank amongst the 2% most conserved proteins in the human genome, with an extremely low rate of coding variation, accounting for nearly 5% of known epileptic encephalopathies. Pathogenic mutated residues are situated in the highly evolutionarily conserved portions of the channel: transmembrane segments, intracellular inactivation gate loop, and the proximal 2/3 of the C-terminal domain. The final 1/3 portion of the C-terminal and cytoplasmic interdomain loops 1 and 2 are less conserved. The proximal 2/3 of the C-terminal are involved in the interaction of several binding sites for proteins and accessory molecules, like beta subunits β1 and β3, fibroblast growth factors (molecules implicated in neural development), calmodulin (regulatory protein in neuronal function and hyperexcitability) and G protein. Moreover, the C-terminal has been shown to interact with the inactivated channel via ionic interaction between its positively charged residues and negatively charged residues at the inactivation gate. A shift in any of the charges can brake electrostatic interaction and affect normal channel inactivation.

9The N-terminal region seems to play a more important role on protein trafficking than on channel activity. This domain interacts with the light chain of microtubule-associated protein MAP1B, facilitating the traffic of the NaV channel to the neuronal cell surface. In addition, mutation in the N-terminal leads to protein retention in the endoplasmic reticulum.

10Newer genomic approaches, especially next generation sequencing (NGS), improve the rate and reduce the costs associated with genetic epilepsy diagnosis, since traditional cytogenetic and microarray-based tests are lengthy, expensive, and diagnostic yield is incredibly low. The use of gene panels and whole-exome sequencing (WES) provides a powerful tool to change the paradigm of genetic epilepsy diagnosis. These techniques have been widely used to elucidate suspected inherited neurological diseases in the last years, contributing to dramatically increase the number of patients diagnosed with genetic epilepsy. Both mendelian and de novo genetic epilepsy can be detected with these methods, but doubtless, de novo mutations are the most prevalent mutations related to epilepsy-related voltage-gated sodium channel mutations.

11Gene therapy is promising as an effective approach to treat genetic diseases. Personalized epilepsy therapies are in development and have shown promising results, ranging from antisense oligonucleotides and small peptides to modulation of gene expression through epigenetics. Even eating habits may be related to an improvement in the patient's clinical condition. Ketogenic diet has been described as an effective treatment in epilepsy. Moreover, the combination of traditional antiepileptic drugs with new compounds displayed a synergic and improved efficacy, since these molecules do not compete for the same interaction site. Each specific epilepsy-related NaV isoform will be presented and discussed in detail in the following sections.

12The SCN1A gene encodes for the α subunit NaV1.1, and is allocated at the 2q24.3 chromosome between 165,984,641 and 166,149,161 base pairs, same gene cluster of SCN2A-SCN3A genes, being the most frequent target of mutation in genetic epilepsy syndromes (OMIM#182389). NaV1.1 is widely expressed in the CNS, predominant in inhibitory GABAergic interneurons, regulating neuronal excitability, and the reduction of its activity is one of the factors that cause epileptic diseases due to imbalance between inhibition and excitation.

13Epilepsy syndromes, such as generalized epilepsy with febrile seizures plus (GEFS+; Online Mendelian Inheritance in Man [OMIM] #604233), severe myoclonic epilepsy (SME) and SMEI, also known as Dravet syndrome (OMIM #607208), are associated with mutations in the SCN1A gene.

14In the SCN1A mutation database (http://www.caae.org.cn/gzneurosci/scn1adatabase/data), among 1727 mutations described for the SCN1A gene, 1528 are related to epileptic diseases ( Table 1 and for the full description of mutations in the SCN1A gene, see Supplementary Table S1 ). Among the epilepsy-related mutations, 945 are related to severe myoclonic epilepsy of infancy (SMEI), 263 are related to severe myoclonic epilepsy (SME), 151 are related to severe myoclonic epilepsy borderline (SMEB), 18 are related to partial epilepsy (PE), 31 are related to partial epilepsy and febrile seizures plus (PEFS +), 8 are related to generalized epilepsy (GE), and 55 are related to generalized epilepsy with febrile seizures plus (GEFS +).

15Mutations in the NaV1.1 channel are described in almost all regions of the protein and may cause GoF or LoF. Among the 52 mutations in SCN1A related to epilepsy with functional studies, 35 mutations (67.30%) exclusively display characteristics of LoF, 6 mutations (11.53%) display characteristics unique to GoF, and 11 mutations (21,15%) display characteristics of GoF+LoF, whereas, in GoF+LoF mutations, the main characteristic that gives GoF features is enhanced persistent current, present in 10 out of the 11 GoF+LoF mutations listed ( Tables 1 and S1 ).

16Due to the role of the NaV1.1 channels in the regulation of electrical excitability by the inhibitory interneurons, prescription of AEDs non-selective sodium channel blockers (SCB) for SMEI or GEFS + syndromes is contraindicated, for it may aggravate crises due to the enhanced suppress status of the NaV1.1 channels. The first-line drug-based therapy for SCN1A epilepsy diseases is the enhancement of postsynaptic GABAergic transmission with allosteric activation of GABAA receptors as target by Clobazam and/or an increase in GABA concentration in synaptic cleft resulting from increased GABA production and decreased GABA degradation as target by Valproic acid. Antisense nucleotides (ASO) therapy to increase mRNA of SCN1A for NaV1.1 channel expression in normal levels is a promising strategy for genetic disorders involving haploinsufficiency. Drug-resistant Dravet syndrome cases may thrive on alternative therapeutic strategies based on ketogenic diets. A recent study with 20 patients with medically intractable Dravet syndrome caused by missense, non-sense, insertion, deletions and splicing mutations presents efficacy during three months of treatment in 17 patients, decreasing seizure frequency in more than 50%. Besisdes that, Epidiolex is an FDA approved CBD-based drug approved in June 2018 for the treatment of severe forms of epilepsy, as Dravet and Lennox-Gastaut syndromes (U.S. Food and Drug Administration [website]., 2018). Clinical trials using CBD in DS and LGS shown reduced frequency of seizures in monthly average. Voltage-gated sodium channel are inhibit by CBD in low micromolar concentrations, IC50 between 1.9 and 3.8 μM, NaV1.4 and NaV1.1 being the most sensitive channels to CBD, 1.9 and 2.0 μM respectively, probably the mechanism of action is reducing channel availability due shift to more hyperpolarized potential in steady-state inactivation (Ghovanloo et al., 2019).

17NaV1.2 is encoded by the SCN2A gene. It is located on chromosome 2q24.3 and expressed in the CNS, especially in excitatory neurons and glutamatergic neurons, unlike the NaV1.1 channel, which is highly expressed in the GABAergic interneurons.

18More than 100 mutations have already been described for this gene, with approximately 300 patients studied yet ( Table 2 ). The most common diseases related with SCN2A mutation are West syndrome (WS; OMIM #308350), epilepsy of infancy with migrating focal seizures (EIMFS; OMIM #616645), and benign familial neonatal-infantile seizures (BFNIS; OMIM #607745). Although epilepsy-related mutations are present throughout the channel, several hotspots such as the ion selectivity filter, the voltage-sensing domain, the intracellular N-terminal, and the C-terminal domain can be highlighted.

19NaV1.2 channels are expressed in the excitatory neurons; therefore, GoF mutations are related to epilepsy because it causes neuronal hyperexcitability. On the other hand, LoF mutations are related to autism and intellectual disability phenotype. Nevertheless, some studies have already related loss of function to epilepsy, as described by with R1312T mutation. Normally, LoF SCN2A gene mutations for epilepsy are related to late-onset epilepsy; however, the mechanism of action is unclear.

20In some cases, NaV1.2 seizures are not controlled not even by various antiepileptic drugs, as with the patient described by. The proband, even after being treated with oxcarbazepine (OXC), valproic acid, topiramate, sulthiame, phenytoin, among other drugs, kept on having seizures. Furthermore, the SCB drugs can assist the patient during the treatment as described by. The patient had seizures controlled after administration of phenytoin. In addition, cite benefits treatments using SCB such as carbamazepine, mexiletine, oxcarbazepine, phenytoin, lidocaine, and lamotrigine for patients with early onset epilepsies. Besides, Peters and colleagues studied a substance commercially used as an antianginal drug (human heart) called ranolazine that has been shown to affect NaV1.2 channels, reducing macroscopic currents and delaying the recovery of fast and slow inactivation of the NaV1.2 channel, consequently with more future studies ranolazine could be a efficacious therapy for epilepsy.

21Drugs can be important to modulate channel kinetics for both GoF and LoF, but some precautions must be observed. For example, the degree of conservation between subtypes, such as NaV1.2 and other sodium channels as NaV1.5 and the excessive decrease in channel function or the excessive increase in function obtained by the drug.

22Organizations like the FamilieSCN2A Foundation (www.scn2a.org) might be essential in the search for new treatments. Understanding the genotype-phenotype of gain and loss of function is essential because science-patient relationship may be helpful in the search for new therapies.

23SCN3A is a gene that encodes for type 3 voltage-gated Na+ channel α subunit, the NaV1.3, located on human chromosome 2q24, in a cluster with SCN1A and SCN2A. NaV1.3 is expressed predominantly in the CNS during embryonic and neonatal development, being extremely low or sometimes undetectable in postnatal individuals. Subsequently, during infancy, it is gradually replaced by increased expression of the NaV1.1 isoform. On the other hand, studies regarding nervous system injury and neuropathic pain showed an increasing presence of NaV1.3 channels in affected tissues, suggesting a pivotal hole of these transmembrane proteins in these processes and diseases. For the reasons mentioned above, in the last decades, NaV1.3-associated pathogenesis has been restricted to pain. Recently, a genetic linkage between NaV1.3 mutated variants and epilepsy has been suggested, especially in cryptogenic epilepsy cases (OMIM#182391).

24K354Q was the first described NaV1.3 epilepsy-related mutation that revealed harmful electrophysiological alterations. In fact, mutations can change many functional characteristics of NaV1.3 affecting biophysical properties differently; however, these changes result predominantly in neuronal hyper-responsiveness ( Table 3 ). Previous reports correlate heterozygous variants in SCN3A in association with moderate forms of epilepsy, while homozygosis is related with severe cognitive damage and premature mortality, resulting in a broad range of epileptic phenotypes.

25Different hereditary mutations on NaV1.3 have been reported to date in patients with epilepsy. In general, the biophysical characterization of these mutations reveals GoF, only one mutation (N302S) is related with LoF, but both GoF and LoF may lead to an increased seizure susceptibility.

26Moreover, several de novo mutations in SCN3A have been described in the last three years, related with severe infantile neurological dysfunctions and cognitive impairments. These mutations may alter the functionality of NaV1.3 channels, neurons organization, migration, and proliferation during the embryonic development. Epileptic encephalopathy and polymicrogyria are the main features related with these pathogenic variants, and, so far, polymicrogyria was not reported in other channelopathies, being an exclusive characteristic of SCN3A mutants.

27There is a lack of clinical data on SCN3A-related epilepsies, especially regarding treatment and the use of specific medication. However, in vitro studies reported that mutations related with GoF effect respond favorably to treatment using SCB, like phenytoin, carbamazepine, lacosamide, and topiramate. The anticonvulsant valproic acid represents a novel and promising epigenetic therapeutic approach. The compound modulates the SCN3A gene through methylation, downregulating the expression of NaV1.3 and, consequently, decreasing biophysical alterations in the channel.

28The SCN8A gene encodes for type 8 voltage-gated Na+ channel α subunit, the NaV1.6, located in chromosome 12q13.13. The first case of SCN8A pathogenic variant associated with epilepsy was reported eight years ago. Thereafter, due to advances in genome sequencing technology, especially the WES, the number of epilepsy diagnosis associated with NaV1.6 mutations has increased significantly (OMIM #600702), with more than 300 patients diagnosed with SCN8A epilepsy mutations and nearly 200 different putative spots of mutations described, totaling over 100 published reports ( Table 4 ). A website developed especially to present SCN8A epilepsy and related diseases (www.scn8a.net) was created to provide information to families, clinicians, and researchers, gathering news and recent publications on the subject in a private forum for family interaction, to answer questions, strengthening the ties between the community and the researchers.

29NaV1.6 is expressed since prenatal, during fetal development. Shortly after birth, expression begins to increase, reaching maximum levels during the first years of life. This channel is widely expressed in the nodes of Ranvier of myelinated axons and in the distal part of the axon initial segments (AIS), although they are also ubiquitously present throughout the central and peripheral nervous systems, in both excitatory and inhibitory neurons. For these reasons, NaV1.6 is one of the most common subtype of voltage-gated sodium channels found in the central nervous system. In humans, the distal AIS is the specialized membrane region in neurons where action potentials are triggered. Overexpression of Nav1.6 in the AIS has been shown to cause an increase in spontaneous and repetitive firing, a possible explanation for why SCN8A mutations in epilepsy patients are predominantly GoF and affect the action potential threshold. On the other hand, the functional importance of Nav1.6 in inhibitory interneurons is not clear yet, but evidence indicates a role for Nav1.6 in establishing synaptic inhibition in the thalamic network, supporting the LoF results caused by missense mutations in the mature protein. These attributes lead to different network effects in distinct nervous system circuits. Mutations in SCN8A are associated with early-infantile epileptic encephalopathy type 13 (EIEE13; OMIM #614558), a phenotypically heterogeneous early onset epilepsy, with seizure onset happening before 18 months of age. Patients typically develop intellectual disability, developmental delay, and movement disorders. Co-occurrence of autism spectrum disorders, severe juvenile osteoporosis, bradyarrhythmia, cortical visual impairment, and gastrointestinal disorders have been reported in rare cases. Sudden unexpected death in epilepsy (SUDEP) has also been linked to SCN8A mutations, described as the most common cause of death in epilepsy patients. Reports have suggested that patients with SCN8A-related epilepsy have increased risk of SUDEP, ranging from 1% to 10%. One possible correlation of SUDEP with SCN8A-related epilepsy is the presence of NaV1.6 in heart muscles and tissues, being broadly expressed within ventricular myocytes. Single mutations may affect heart function, causing failure of the cardiorespiratory system and, consequently, death. Most recently, few cases of SCN8A-related epilepsies with “milder” phenotype were associated with benign familial infantile seizures-5 (BFIS5; OMIM #617080).

30An increase in new described variants made some mutation patterns visible. Wagnon and co-workers observed numerous cases of the same epiletogenic mutation, and suggested that CpG dinucleotides are mutation hotspots that, through enzymatic processing and epigenetic methylation, can convert cytosine to thymine, such as arginine residues 1617 and 1872. The prominent number of new variant cases in Arg850 indicates this residue as a new hotspot, since the arginine codon holds a CpG dinucleotide. In addition to these mutation hotspots, residues I763, I1327, G1475, A1650, and N1877 do not present CpG dinucleotides in their codon; however, they can be considered recurrent mutations in view of its high repetition cases in literature ( Table 4 ).

31The mutation at position c.- 8A>G produces a pathogenic variant, despite not being inside the gene, or promoter regions, transcriptional and translational sites. This mutation was detected in an untranslated region outside of the Kozak consensus sequence. Its role in SCN8A-related epilepsy is still unclear; however, it may change RNA stability, modulate transcriptional factors and promoters, modify the initiation of translation, or work as an enhancer or silencer in the splicing pattern. For all the reasons mentioned above, Nav1.6 variants are predominantly harmful, and the same mutation can lead to different phenotypes, hampering the correlation of genotypes with phenotypes.

32SCN8A mutations can be both GoF and LoF, which will likely require different approaches and targets. Even in patients with the same SCN8A mutation, the response to the same drug treatment can differ. Surprisingly, most SCN8A-related epilepsies respond favorably to channel blockers. Phenytoin and lacosamide are SBCs widely used in SCN8A mutations with GoF effect, while carbamazepine exhibited positive seizure control in a patient with NaV 1.6 mutation and LoF effect.. Phenytoin demonstrated effectiveness in decreasing seizure episodes in several patients with SCN8A-related epilepsies, however, side effects during prolonged use are very common. A recent study of a DS model using zebrafish demonstrated the use of the channel blocking compound MV1312, which is 5–6 fold selectivity of NaV1.6 over NaV1.1–1.7, reduced burst movement phenotype and the number of epileptiform events, activity similar to that described with the use of a selective NaV1.1 activator AA43279. Selective Nav1.6 blockers may represent a new therapeutic strategy for DS patients. In addition, two precise and promising drugs have been described recently: XEN901 and GS967. XEN901 is an arylsulfonamide highly selective and potent NaV1.6 inhibitor that binds specifically in voltage sensor domain IV, avoiding recovery from inactivation. GS967 is a NaV1.6 modulator that inhibits the persistent sodium current and exhibits a protective effect.

33The SCN9A gene encodes for the NaV1.7 channel, located in chromosome 2q24. NaV1.7 is expressed preferably in the PNS, but it is also expressed in the CNS. Consequently, mutations in this channel are generally related to pain disorders; however, current studies have described a correlation between epilepsy and this channel (OMIM #603415).

34Pain disorder mutations with GoF are related with diseases such as erythromelalgia (EMI), small-fiber neuropathy (SFN) and paroxysmal extreme pain disorder (PEPD), and mutations with LoF are related with congenital insensitivity to pain (CIP). Epilepsy studies such as showed mutations with GoF phenotype: W1150R, N641Y, and K655R mutations ( Table 5 ). Being that, after treatment with OXC (120 µmol/L), N641Y and K655R reduced sodium current and decreased the opening time of the channel, while W1150R did not alter that. However, in a study conducted by, one of the patients presented generalized tonic-clonic seizure with fever, treated with sodium valproic acid, and a LoF mutation I1901fs was observed ( Table 5 ).

35Variants of NaV1.7 have been related with febrile seizure or GEFS+ and even as asymptomatic. However, SCN9A can act as a putative modifier of NaV1.1 gene; consequently, it can elevate the severity of patients’ phenotype (; Parihar and Ganesh, 2013). Some NaV1.7 mutations could probably contribute to generate a genetic susceptibility to a known epilepsy disease called Dravet syndrome, in a multifactorial way, as a modifier gene. That said, some rare cases of DS found in patients can be understood. For example, even parents with mild phenotype had children with severe cases.

36The past two decades have enabled remarkable progress in understanding monogenic epilepsies. NaV-related epilepsies are diseases of phenotypic heterogeneity, since sodium channels are found in both the CNS and the PNS, but with different expression ranges. The lack of a clear genotype-phenotype correlation to help guide patient counseling and management by healthcare professionals makes it very complex, and often expensive, to determine a correct diagnosis. Consequently, identify the monogenic mutation in individual patients with epilepsy is important not only for diagnosis and prognosis, but also for a correct treatment approach.

37Susceptibility to specific treatments may be different depending on the disease’s features, diverging even in patients who share the same phenotype and/or mutation. The use of innovative tools that facilitate and prevent diagnostic delay in patients with epilepsy of unknown etiology onset is crucial. WES has proved to be a valuable tool to circumvent the lack of an accurate and fast diagnosis to epilepsies caused by monogenic mutation, and also cheapen and drastically anticipate diagnosis. This genetic diagnostic tool may reduce traditional investigation costs by 55 to 70%, besides avoiding further pre-surgical evaluation and epilepsy surgery. In addition to the financial impact, it can anticipate diagnosis from nearly 3.5 years to 21 days, optimizing management and health care support.

38Effective and safe drugs for the treatment of monogenic epilepsy are still an unmet clinical need. The drugs currently available in the pharmaceutical market are only palliative methods for a temporary control of the disease symptoms, and few patients will benefit from the existing pharmacotherapy, since a great number of patients treated with antiepileptic channel blockers showed no improvement in clinical conditions. Also, most treated patients exhibited manifold side effects, and the prolonged use of these medications proved to be harmful. Several examples of novel and promising candidate compounds to be used in personalized medicine, such as precision therapies, have been suggested. A previously study demonstrated that CBD at 1μM inhibit preferably resurgent currents than transient current in Nav1.6 WT and also inhibit peak resurgent current in Nav1.6 mutant N1768D, with less effect in current density and without alters voltage dependence of activation Possibly the modulation of CBD over mutations in SCN8A that promotes a phenotype with increased resurgent currents would cause a reduction in the causative excitability of epileptic seizures. CBD also showed its ability to preferential inhibit resurgent currents in the NaV1.2 channel. Due the role of Nav1.2 and Nav1.6 in excitatory neurons, preferentially inhibition in resurgent currents by CBD could possibly reduce the excitability in that subset of neurons and decrease the frequency of seizures by a change in threshold of activation and repetitive fire. Peptides derived from scorpion and spider venom are well known modulator tools in neuroscience and showed specific capacity to regulate most NaV subtypes related with monogenic epilepsy, unlike the available promiscuous drugs that generally interact with any NaV channel isoform. Bioengineering tools, like antisense oligonucleotides capable to regulate NaV1.1 channels expression, and the peptide Hm1, that modulates the function of this subtype of sodium channel, are some innovative treatment examples.

39However, there is still a long path toward the development of efficacious treatments for NaV-related epilepsies. Recent studies offered a better understanding of the complexity of the phenotypic and genetic spectrum, which has only just begun to be elucidated. Biomolecular diagnostic tools will drastically reduce the developmental and cognitive effects caused by misdiagnosis and late diagnosis, and maybe, in the upcoming years, the treatment for inherited NaV-related epilepsies will be conducted ideally in utero, during the prenatal stage. Moreover, further functional studies, with greater cohorts of patients, represent an urgent medical need for a better understanding of the correlations between genotype and clinical symptoms, as well as the different NaV-related epilepsies mechanisms. These studies will improve clinical efficacy and promote safety diagnostic strategies, as well as develop prognosis prediction in the near future.

40All authors made an intellectual and direct contribution for this article and approved it for publication.

41This study was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) [407625/2013-5] and the Fundação de Apoio à Pesquisa do Distrito Federal (FAPDF) [grants 193.001.202/2016 and 00193.0000109/2019-17].

42The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.