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 Table of Contents  
REVIEW ARTICLE
Year : 2017  |  Volume : 1  |  Issue : 4  |  Page : 239-249

Recent progress in identifying genetic and epigenetic contributions to epilepsy


1 Department of Genetics, Institute of Reproduction and Development in Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200438, China
2 Department of Genetics, The State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development in Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200438, China
3 Department of Neurology, Children's Hospital of Fudan University, Shanghai 201102, China

Date of Submission01-Nov-2017
Date of Web Publication7-Feb-2018

Correspondence Address:
Hong-Yan Wang
The State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200438
China
Yi Wang
Children's Hospital of Fudan University, No. 399 Wanyuan Road, Shanghai 201102
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.224912

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  Abstract 


Epilepsy is a serious disorder of the central nervous system characterized by recurrent seizures. There are many known causes of epilepsy, including genetic factors, brain damage, and environmental factors, but the pathogenic mechanisms are largely unknown. Numerous factors, including genetic mutations, brain damage, and environmental insults, have been implicated in the etiology of epilepsy, but the cause for individual epilepsy patients is often unknown. Research on inherited forms of epilepsy has identified mutations in genes encoding ion channels or neurotransmitter receptors. Family-based studies of inherited forms of epilepsy have previously identified mutations in genes encoding ion channels and neurotransmitter receptors. With a deepening understanding of the underlying cellular pathways, researchers have identified epilepsy candidate genes that function in synaptic vesicle trafficking, chromatin remodeling, transcription, and mammalian target of rapamycin (mTOR) signaling. More recently, genes involved in synaptic vesicle transport, chromatin remodeling, and transcription, as well as the mTOR signaling pathway, have also been implicated in inherited forms of the disorder. In addition, recent advances in DNA sequencing and genomic technologies have identified chromosomal copy number variants and epigenetic modifications as possible contributing factors in inherited epilepsy. In this review, we focus on the established and potential contributions of genes, chromosomal abnormalities, and epigenetic modifications to the development of epilepsy.

Keywords: Chromosomal Abnormality; Epigenetic; Epilepsy; Genetic


How to cite this article:
Hu ZY, Wang HY, Wang Y. Recent progress in identifying genetic and epigenetic contributions to epilepsy. Reprod Dev Med 2017;1:239-49

How to cite this URL:
Hu ZY, Wang HY, Wang Y. Recent progress in identifying genetic and epigenetic contributions to epilepsy. Reprod Dev Med [serial online] 2017 [cited 2020 Jun 5];1:239-49. Available from: http://www.repdevmed.org/text.asp?2017/1/4/239/224912




  Introduction Top


Epilepsy is a common neurological disease that is characterized by recurrent and usually unpredictable seizures caused by abnormal electrical activity in the brain. Although epilepsy is estimated to affect approximately 1% of people worldwide, the cause remains unclear for many patients. Many brain insults, including asphyxiation and trauma, infections and immune abnormalities, genetic and metabolic disorders, and cerebral structural malformation, are considered to be causes or contributing factors.[1]


  Genetics Contributes to Epilepsy Top


Genetics has played an important role in the pathogenesis of epilepsy since the first single gene mutation was identified in 1995. Epilepsy is regarded as a highly heritable disease. However, the causes of epilepsy are varied and exhibit genetic heterogeneity.[2],[3] Epidemiological studies of familial epilepsies and twins with epilepsy have provided evidence for a hereditary basis for epilepsy.[4],[5],[6],[7],[8] In one of these studies, the first generation of familial epilepsies with congenital generalized epilepsy was found to exhibit a probability of 8%–12% of having the disease, whereas the incidence in the general population is only approximately 0.5%.[4] Since the important role of genetics was reported in 1980, powerful studies on the cause of familial epilepsy and genetic epilepsy using animal models have supported this notion.[9] The identification of ion channel genes also became a major focus of epilepsy genetic studies. However, only a quarter of genetic epilepsy mouse models are derived from pathological changes in ion channel-related genes.[10] Recent research found that mutations in genes related to multiple pathways could also be associated with epilepsy through whole exome sequencing (WES) or whole genome sequencing in a large number of epilepsy patients. These genes mainly include those involved in synaptic vesicle transport pathways, chromatin remodeling, transcription, and the mammalian target of rapamycin (mTOR) pathway [Table 1].
Table 1: Functional categories of epilepsy genes

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Ion channels and neurotransmitter receptor genes contribute to epilepsy

Researchers first studied the pathogenesis of epilepsy in the nervous system given that abnormal electrical activity in the central nervous system leads to epilepsy. Currently, several studies have confirmed that numerous cases of human idiopathic epilepsy are attributed to “ion channel-related disease,”[11] namely, diseases caused by defects in the translation of ion channel proteins and mutations in ion channel genes. The related ion channels mainly include the voltage-gated ion channels (K +, Na +, Ca 2+, Cl , and HCN) and ligand-gated ion channels (acetylcholine and GABA receptors). Over the past decade, researchers have discovered that numerous genes encoding ion channel proteins are associated with idiopathic epilepsy. Benign familial neonatal infantile seizures (BFNIS) are a rare form of idiopathic generalized epilepsy (IGE). The condition is an autosomal dominant genetic disease. BFNIS can be caused by mutations in the voltage-gated K + channel-related genes KCNQ2 and KCNQ3.[12],[13] In addition, mutations in KCNQ2 are associated with early infantile epileptic encephalopathy (EIEE) and unclassified early-onset encephalopathies.[14],[15],[16] Recently, a mutation in KCNQ2 was also found in a patient with early myoclonic encephalopathy.[17]KCNQ5 also encodes a voltage-gated K + channel. Mutations in KCNQ5 are associated with intellectual disability or epileptic encephalopathy.[18] Mutations in some other genes, such as KCNA2,[19],[20],[21],[22]KCNB1,[19],[23],[24],[25],[26],[27]KCNC1,[28]KCNMA1,[29],[30] and KCNT1,[31],[32],[33] which encode voltage-gated K + channel were also reported to be associated with epileptic encephalopathy.

Generalized epilepsy with febrile seizures plus (GEFS +) is another autosomal dominant IGE. The condition is mainly characterized by febrile seizures (FS) during infancy. FS no longer occur after 6 years of age, and the disease is resolved after puberty. In a study of a GEFS + family, three mutations in sodium channel subunit genes (SCN1B, SCN1A, and SCN2A) and two mutations in GABA receptor genes (GABRG2 and GABRD) were identified.[34],[35],[36],[37],[38] Among these mutations, the SCN1A mutation in infants was closely related to severe myoclonic epilepsy of infancy (SMEI).[39],[40] More than 20 mutations in SCN2A were identified in patients with BFNIS, GEFS +, and SMEI. Most of these mutations are associated with BFNIS. Mutations in another sodium channel gene, SCN8A, were found to be associated with severe epileptic encephalopathy for the first time in 2012.[41] Most SCN8A-mutated epileptic children have similar clinical features, including epileptic seizures with developmental delay and low intelligence.[42],[43],[44],[45] Recent studies in 16 children from three families reported that SCN8A mutations could also be associated with infant seizures and paroxysmal movement disorders.[46]

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is classified as idiopathic focal epilepsy, which is autosomal dominant and exhibits a penetrance of 75%. Its onset age varies among people, and both childhood and adulthood onsets have been noted. Mutations of the acetylcholine receptor genes CHRNA4 and CHRNB2 have been confirmed as key pathogenic factors of ADNFLE.[47] A correlation between GABA receptor subunit genes (GANRA1, GABRB3, GABRG2, and GABRD) and hereditary epilepsy syndrome, including childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME), FS, GEFS +, and SMEI, has been reported.[48],[49],[50],[51],[52],[53] In 2004, Chen et al. identified 12 rare heterozygosis missense mutations relevant to CAE in a Chinese Han population for the first time.[54] To date, >30 mutations in the CACNA1H gene have been identified, demonstrating a connection with IGE.[55] Although mutated, CACNA1H can lead to susceptibility to CAE, JME, FS, juvenile absence epilepsy (JAE), and temporal lobe epilepsy (TLE), but further research failed to provide sufficient evidence to explain their pathogenesis.[54],[55],[56],[57],[58],[59],[60]CLCN2 encodes a voltage-gated chloride ion channel protein. Mutations in CLCN2 may also affect the common types of IGE, including CAE, JAE, JME, and grand mal awake.[61]CLCN4 encodes the 2Cl /H + exchanger ClC-4, which is highly expressed in brain. Recently, CLCN4 mutations have been implicated in X-linked epilepsy and intellectual disability through detailed studies on 52 CLCN4-related cases from 16 families.[62]

Synaptic vesicle translocation genes contribute to epilepsy

EIEE, also named Ohtahara syndrome, is one form of severe early epilepsy, which is associated with STXBP1 mutations. The STXBP1-coding protein is also involved in vesicle release,[63] and the effects of STXBP1 on possible conditions related to epilepsy extend beyond the impact on EIEE. An STXBP1 heterozygous mutation reported in an epilepsy patient with intellectual defects indicates that the effects of STXBP1 are not only restricted to EIEE.[64]SCN1A, SCN1B, and GABRG2 are related to epilepsy-associated/unassociated FSs. STX1B encodessynaptic fusion protein 1b, and its mutations are related to FSs and epilepsy.[65]SNAP25 mutations can give rise to anxiety, ataxia, and seizures in animal models. Primary SNAP25 mutations were identified in a generalized epilepsy child with intellectual defects, but more evidence on whether the SNAP25 mutation can lead to epilepsy still needs to be provided.[66]NECAP1 encodes a grid regulatory protein, and loss-of-function mutations may cause severe infantile epileptic encephalopathy.[67]DNM1 encodes dynein 1, regulates synaptic transmission, and plays an important role in releasing synaptic vesicles. WES of 356 trios of children suffering from epileptic encephalopathy, baby spasms, and Lennox–Gastaut syndrome identified DNM1 primary mutations in five patients. Thus, DNM1 was statistically confirmed as a pathogenic gene of epileptic encephalopathy disease.[68]

Chromatin remodeling and transcription contribute to epilepsy

Chromatin helicase DNA binding protein 2 encoded by CHD2 is a chromatin remodeling factor. To date, more than 20 epilepsy patients have been identified with CHD2 mutations, and most of the mutations are de novo.[69],[70],[71],[72],[73],[74] These patients are mainly characterized by multiple spasm large seizures, muscle cramps, and photosensitivity.[70]

Mammalian target of rapamycin pathway contributes to epilepsy

mTOR is a typical serine/threonine protein kinase, integrating extracellular signals, phosphorylating downstream target protein ribosome kinases, affecting gene transcription and protein translation, and regulating cell growth, cell proliferation, survival, movement, and metabolism. mTOR pathway disorders can cause several diseases, including tuberous sclerosis (TSC1 and TSC2 mutations), giant brain arteriovenous malformation (AKT3, PIK3CA, and MTOR), and focal cortical dysplasia (FCD) (DEPDC5, AKT3, and MTOR).[75],[76] mTOR pathway disorders can also lead to refractory epilepsy, mental retardation, and autism. DEPDC5 is a member of the GATOR1 complex, which is a negative regulator of mTOR pathway signaling. Two research groups have found that DEPDC5 mutations cause focal epilepsy,[77],[78] whereas subsequent studies have also demonstrated that mutations in DEPDC5 increase the risk of sudden death in epilepsy patients.[79]NPRL2 and NPRL3 are two additional genes of the GATOR1 complex. Mutations in these two genes are associated with familial FCD and also contribute to 1%–2% of focal epilepsy cases.[80],[81] Type II cortical dysplasia also exhibits MTOR mutations, thereby triggering refractory epilepsy.[78]

Other functional genes affecting epilepsy

ARX is an X-linked gene that is strongly correlated with brain malformation, cramps, and mental retardation. ARX mutations in West syndrome [82],[83] and Ohtahara syndrome [84],[85] are detected as high rhythm disorders of electroencephalogram (EEG) and explosion suppression. ARX gene mutations also cause spasms without abnormalities (including idiopathic infant spasms, X-linked myoclonic epilepsy, mental retardation-associated epilepsy, and Partington syndrome) and malformation syndromes (such as X-linked no gyrus or hydranencephaly deformity associated with genital abnormalities and Proud syndrome).[86]ARX mutations are common in men, but female cases in which ARX mutations lead to mental diseases with anxiety, depression, schizophrenia, and learning disabilities have also been reported.[87]CDKL5 is located on Xp22 and is a traditional gene related to Rett syndrome-like phenotypes. Mutations in this gene are associated with microcephaly and infantile spasms.[88],[89] Epileptic encephalopathy-associated CDKL5 mutations are also known as CDKL5-related encephalopathy. Bahi-Buisson et al. divided the onset of CDKL5-related encephalopathy into three stages based on the characteristics of numerous cases: (1) frequent epileptic seizures with normal EEG within 3 months after birth, (2) infant spasms with highly disordered EEG, and (3) progression into refractory stiffness or myoclonic epilepsy.[90],[91] Another X-linked gene PCDH19 encodes calcium-dependent members of a cell adhesion protein family. PCDH19 mutations can cause epilepsy and mental retardation limited to females [92] and mosaic males,[93] and mutations in PCDH19 are also associated with Dravet syndrome and multiple types of epilepsy.[94]

Ubiquitin-fold modifier 1 (UFM1) is an ubiquitin-like protein that was identified recently, and its E1 activation enzyme is encoded by UBA5. Biallelic mutations in the UBA5 gene are associated with structural damage in UFM1, resulting in early-onset epileptic encephalopathy (EOEE).[95]MBOAT7 encodes lysophospholipid acyl alcohol acyltransferase 1. Johansen et al. reported that homozygous mutations of MBOAT7 are associated with epilepsy with mental retardation and autism based on an analysis of six consanguineous families.[96] The FARS2 gene located on 6p25.1 encodes the mitochondrial styrene acrylic amide tRNA synthetase. Clinical studies have reported that FARS2 mutations are associated with infant EOEE.[97] The TBC1D24 protein is highly expressed in brain and is the only connection between the TBC and TLDc domains.[98]TBC1D24 mutations are associated with severe early-onset seizures associated with mental retardation,[99],[100],[101],[102],[103] deaf myoclonus,[104],[105],[106],[107] cerebellum atrophy,[108] and DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures) syndrome.[109],[110] Recent studies have demonstrated that skywalker-TBC1D24 lipid combined with pocket mutations affects the phosphoinositide combination, thus causing epilepsy.[111] TBC1D24 mutations are also related to a high risk of sudden unexpected death in epilepsy.[112]


  Effects of Chromosomal Copy Number Variation on Epilepsy Top


Copy number variants (CNVs) refer to the absence or duplication of 1-KB chromosomes. CNVs are an important source of normal genome variation, and numerous CNVs are associated with pathogenic risks. In the field of epilepsy genetics, studies with a large number of congenital epilepsy patients (not associated with autism, intellectual defects, and homogeneous alien syndrome) with abnormal copy numbers of chromosomes have achieved some results. A group from Northern Europe identified that 2% of 1234 congenital general epilepsy cases with genetic microdeletions mainly occurred in 15q11.2 and 16p13.11.[113] Research has also demonstrated that a microdeletion in 15q13.3 in patients with congenital generalized epilepsy is the most severe risk factor for the occurrence of seizures.[114] Microdeletions in 15q11.2 and 16q13.11 were also noted in patients with centralized epilepsy and other types of epilepsy.[115]

Recently, some rare deletions in exons of neuron genes, including NRXN1,[51]RBFOX1,[116] and GPHN,[117] were identified. These deletion mutations increase the onset risk of congenital generalized epilepsy, whereas deficiencies in CHD2 located at 15q26 cause myoclonic epilepsy, photosensitivity, and retardation epileptic encephalopathy.[69],[70] Recent studies have reported that CHD2 deficiencies at 15q26.1-q26.2 are also associated with epilepsy with moderate mental retardation.[118] SLC6A1 is a GABA receptor-associated protein responsible for the reuptake of synaptic GABA, and 4% of astatic myoclonic epilepsy patients exhibit a microdeletion of SLC6A1 in 3q25.[119]


  Relation between Epilepsy and Epigenetics Top


Epigenetics refers to DNA sequences that do not change but cause heritable changes in gene expression and eventually cause phenotypic changes. The epigenetic genome can quickly respond to the environment. Epigenetics represents one of the important internal mechanisms controlling gene expression.[120] Three forms of epigenetics have been implicated in epilepsy: DNA methylation, histone modification, and noncoding RNA. Given that epigenetics is not dependent on the DNA sequences, the genetic material is not lost during cell division and proliferation. Epigenetic effects can lead to gene silencing. A growing number of studies have demonstrated that epigenetics plays an important role in nervous system diseases, including epilepsy.[121] Recently, animal models and human brain tissue research have revealed the occurrence of epilepsy associated with epigenome; thus, epigenetics has become an emerging field of epilepsy research.[122],[123],[124],[125] Currently, epilepsy treatment is ineffective in more than 30% of people with epilepsy. These drugs have no effect on epilepsy complications and cannot prevent the development of epilepsy.[126] It is possible that we can identify a new therapy to cure epilepsy based on epigenetics. Most of the epigenetic studies on epilepsy currently focus on DNA methylation and microRNAs (miRNAs), so we introduced these two aspects in the next section.

Effects of DNA methylation on epilepsy

DNA methylation involves the transfer of a methyl from S-adenosine methionine to carbon atoms at cytosine 5' to form a 5'-methyl-cytosine via the actions of DNA methyltransferase (DNMT). DNA methylation in CpG islands involves covalent binding of methyl groups and CG dinucleotides to prevent gene transcription and is associated with gene silencing.[127],[128] The nonmethylation state is associated with gene activation, whereas demethylation is associated with the reactivation of silent genes.[129] DNA methylation is stable in the brain. However, a limited amount regulated by neurons is dynamic and probably involved in the onset of epilepsy.[130],[131] In addition, enhanced DNA methylation enzyme activity and DNA hypermethylation are associated with human epilepsy and experimental epilepsy.[132],[133],[134],[135],[136]

Recent evidence has revealed that DNA methylation plays a critical role in the onset and development of epilepsy. Abnormal DNA methylation has been examined in the brains of patients with mental disorders, degeneration of nerve tissue, and nervous system diseases, including epilepsy.[132],[137],[138],[139],[140],[141] The methylation hypothesis regarding epileptogenesis indicates that epigenetic changes occur, thus aggravating epileptic seizures.[142] Studies have shown whole-genome DNA methylation changes in the hippocampus of mice with status epilepticus (SE).[143] In addition, there was a significant increase in DNA methylation in a rat model with chronic epilepsy.[144] In the animal hippocampus of SE, hypermethylation was observed in the promoter region of SCN3A and GRIA2 genes.[144],[145] The methyl-CPG-binding proteins MBD1-4 and MeCP2 are associated with DNA methylation. Expression of the MeCP2 gene in the brain plays a specific role in brain development and function. MeCP2 mutations can lead to Rett syndrome,[146] a disease that is associated with mental retardation, seizures, muscle hypotonia, and acquired microcephaly, and that is due to abnormal expression and dysfunction of the methyl-CpG-binding domain.[147],[148] The methyl-binding protein MBD2 could combine with a specific CpG site to lead to upregulation of the gene Scn3a which codes sodium channel protein and induces epilepsy.[145]

In the study of human refractory epilepsy, changes in DNA methylation have been found, and some genes were also regulated by methylation or demethylation.[149] Research on human TLE has revealed that changes in RELN gene methylation result in scattered granulosa cells [132] and an increased level of DNMTs 1 and 3a in the hippocampus.[134] Increased DNMT activity and altered methylation of neurotrophic factors and glutamate receptor subunits encoded by Grin2c in the brain have also been reported in epilepsy experiments.[150] Ras-guanine nucleotide-releasing factor 1 (RASgrf1) is exclusively expressed in the neonatal brain and liver,[151] and its promoter region has a differentially methylated region that can silence gene expression. Downregulation of RASgrf1 was observed in the hippocampus of epileptic animal models and cerebral cortex of epilepsy patients. Moreover, the hypermethylation of RASgrf1 was also associated with epilepsy.[152] Genome-wide DNA methylation analysis has revealed hypomethylation of genes in acute-onset seizures,[143] whereas gene methylation levels are high during the development of epilepsy.[133],[134],[135] However, the mechanism of transformation of the methylation levels remains unclear but is thought to involve initially high activity of the demethylases that are related to the methyltransferase pathways.[137],[153]

Effects of MicroRNA on epileptogenesis

miRNAs are some of the most studied endogenous noncoding RNAs that contain approximately 22 nucleotides. miRNAs are processed from long primary transcripts through a series of nucleic acid shear enzymes and then assembled into the RNA-induced silencing complex, which promotes the degradation or inhibits the transcription of target mRNAs depending on the degree of complementary base pairing. Recent studies have revealed numerous new levels in regulating gene expression associated with epilepsy. These findings will provide new therapeutic targets for epileptogenesis and treatment of acquired epilepsy.[154] Among these therapeutic targets, miRNAs represent one of the important aspects. Histological studies in animal models and epilepsy patients have demonstrated that miRNAs function as a regulator during epileptogenesis [Table 2]. miRNA disorders may promote epileptic seizures, and the adjustment of individual miRNAs can directly affect the brain excitability and pathophysiological characteristics of TLE.[155],[156],[157]
Table 2: MicroRNAs effect on epilepsy

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Downregulation of miR-221 and miR-222 expression is associated with the expression of intercellular adhesion molecule-1 (ICAM1) in TLE cases.[158],[159],[160],[161],[162],[163] Given that ICAM1 is a protein that responds to immunity and inflammation,[164] the miRNA probably functions in the promotion of inflammation during epileptic seizures. Studies of rat models and epilepsy patients have shown that increased expression of miR-146a controls the inflammation responses that are associated with TLE. Increased miR-146a functions as a negative regulator of pro-inflammatory cytokines, potentially representing a compensatory mechanism in epilepsy.[165],[166] And, miR-146a can impair IL1R1/TLR4 signal transduction to contribute to epilepsy.[167] In addition, reduced expression of miR-187 has been noted in studies of the chronic pathogenic progress using animal models and TLE patients, whereas miR-187 expression was found to be anti-inflammatory via inhibition of the production of pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-6, and IL-12p40, via IL-10-dependent mechanisms.[168] MiR-9 is upregulated in TLE.[169],[170],[171] Expression of miR-9 in TLE can promote inflammation by inhibiting the transcription of nuclear factor κ-B1.[172] In immature epileptic-state rats and children with TLE, miR-155 upregulation was noted in the inflammatory response pathway.[161] Recent studies have found that silent rno-miR-155-5p can reduce pathophysiological features and apoptosis by activating setrin-3 in the rat TLE model.[173] Upregulation of mir-134 could reduce the density of dendritic spine and change the occurrence of epilepsy by regulating the LIM structure domain kinase 1.[174] Furthermore, miR-134 could be used as a potential biomarker for the diagnosis of mesial TLE.[175] Recent studies have also found that some miRNAs were related to epilepsy in animal models, such as miR-22-3p,[176] miR-124,[177] miR-199a-5p,[178] and miR-219.[179] Based on genome-wide miRNA expression analysis of tissue obtained via surgical removal in animal models and epileptic patients, numerous additional epilepsy-associated miRNAs have also been identified in studies of cell proliferation, differentiation, and migration, as well as synaptic plasticity and neuronal necrosis during epileptic seizures, but the functions of most miRNAs remain unknown.


  Prospects Top


The etiology and pathogenesis of epilepsy are very complex. Although vast genetic data have been accumulated and numerous epilepsy-related genes have been identified through emerging studies of epilepsy genetics in the past decade, these data are insufficient to explain the mechanism of epileptogenesis. Further exploratory studies involving the pathogenesis of epilepsy should be performed using greater amounts of gene sequences. With the advancement of sequencing technology, applications of next-generation sequencing technology, genome-wide association studies, and massively parallel sequencing provide technical support to discover new genes or epilepsy-associated chromosomal CNVs. After the detection of genetic mutations, research involving pathogenic mutations is necessary to develop precision medicine that is specific for different pathogenic mechanisms. Few studies so far have been focused on the relationship between epigenetics and epilepsy. Only a limited amount of data are available on epilepsy epigenetics, and only a few studies have focused on whether epilepsy is related to specific DNA methylation patterns, nucleosome remodeling, long noncoding RNA, RNA editing, and genetic imprinting. Given that epigenetic modifications can convey information, alter neuronal activity, and affect the expression of various transcription factors, it may also play an important role in epilepsy. Thus, epigenetic studies will also help to further understand the mechanism of epilepsy.

Recent research hot spots of epilepsy mainly focused on the pathogenesis and new treatment strategy of epilepsy. The current antiepileptic therapies mainly function via an overall reduction in neuron excitability, thus enhancing the inhibition of abnormal electrical discharge to control epilepsy. This treatment not only has limited effects but also causes unknown side effects. Recently, researchers have developed new therapeutic methods for different pathogeneses of epilepsy. For example, inhibiting mTOR pathway could prevent seizures in patients with tuberous sclerosis.[180] It has been clinically proven that the inhibition of cytokine IL-1β could prevent refractory epilepsy.[181] The discovery of some gene mutations in epileptics suggests that genetic guidance can be used to treat functional changes that are caused by mutated genes. Gene therapy is the main research direction of many epilepsy animal models. The gene is introduced into brain cells by modifying viral components to produce proteins that can be treated or repaired. Genes have been successfully introduced in brain cells to reduce the frequency, duration, and severity of seizures in some animal models.[182] Cell therapy strategies have also been developed rapidly. In animal model studies, it has been found that some neurons which can produce neurotransmitter GABA that are introduced in the animal hippocampus can effectively control epileptic seizures.[183],[184] However, the therapeutic targets and persistence of gene therapy and cell therapy in patients still need further study, and whether these treatments are deleterious to patients is still controversial. Thus, further exploring the pathogenic genes of epilepsy and the role of epigenetics in epilepsy will contribute to the research of epileptic pathogenesis, thereby promoting the development of effective therapeutic methods for epileptic encephalopathy.

Financial support and sponsorship

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Conflicts of interest

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