|Year : 2017 | Volume
| Issue : 4 | Page : 239-249
Recent progress in identifying genetic and epigenetic contributions to epilepsy
Zi-Ying Hu1, Hong-Yan Wang2, Yi Wang3
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 Submission||01-Nov-2017|
|Date of Web Publication||7-Feb-2018|
The State Key Laboratory of Genetic Engineering at School of Life Sciences, Fudan University, 2005 Songhu Road, Shanghai 200438
Children's Hospital of Fudan University, No. 399 Wanyuan Road, Shanghai 201102
Source of Support: None, Conflict of Interest: None
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
| Introduction|| |
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.
| Genetics Contributes to Epilepsy|| |
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., Epidemiological studies of familial epilepsies and twins with epilepsy have provided evidence for a hereditary basis for epilepsy.,,,, 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%. 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. 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. 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].
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,” 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., In addition, mutations in KCNQ2 are associated with early infantile epileptic encephalopathy (EIEE) and unclassified early-onset encephalopathies.,, Recently, a mutation in KCNQ2 was also found in a patient with early myoclonic encephalopathy.KCNQ5 also encodes a voltage-gated K + channel. Mutations in KCNQ5 are associated with intellectual disability or epileptic encephalopathy. Mutations in some other genes, such as KCNA2,,,,KCNB1,,,,,,KCNC1,KCNMA1,, and KCNT1,,, 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.,,,, Among these mutations, the SCN1A mutation in infants was closely related to severe myoclonic epilepsy of infancy (SMEI)., 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. Most SCN8A-mutated epileptic children have similar clinical features, including epileptic seizures with developmental delay and low intelligence.,,, Recent studies in 16 children from three families reported that SCN8A mutations could also be associated with infant seizures and paroxysmal movement disorders.
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. 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.,,,,, In 2004, Chen et al. identified 12 rare heterozygosis missense mutations relevant to CAE in a Chinese Han population for the first time. To date, >30 mutations in the CACNA1H gene have been identified, demonstrating a connection with IGE. 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.,,,,,,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.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.
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, 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.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.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.NECAP1 encodes a grid regulatory protein, and loss-of-function mutations may cause severe infantile epileptic encephalopathy.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.
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.,,,,, These patients are mainly characterized by multiple spasm large seizures, muscle cramps, and photosensitivity.
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)., 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,, whereas subsequent studies have also demonstrated that mutations in DEPDC5 increase the risk of sudden death in epilepsy patients.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., Type II cortical dysplasia also exhibits MTOR mutations, thereby triggering refractory epilepsy.
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 , and Ohtahara syndrome , 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).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.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., 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., 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  and mosaic males, and mutations in PCDH19 are also associated with Dravet syndrome and multiple types of epilepsy.
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).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. 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. The TBC1D24 protein is highly expressed in brain and is the only connection between the TBC and TLDc domains.TBC1D24 mutations are associated with severe early-onset seizures associated with mental retardation,,,,, deaf myoclonus,,,, cerebellum atrophy, and DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures) syndrome., Recent studies have demonstrated that skywalker-TBC1D24 lipid combined with pocket mutations affects the phosphoinositide combination, thus causing epilepsy. TBC1D24 mutations are also related to a high risk of sudden unexpected death in epilepsy.
| Effects of Chromosomal Copy Number Variation on Epilepsy|| |
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. 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. Microdeletions in 15q11.2 and 16q13.11 were also noted in patients with centralized epilepsy and other types of epilepsy.
Recently, some rare deletions in exons of neuron genes, including NRXN1,RBFOX1, and GPHN, 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., Recent studies have reported that CHD2 deficiencies at 15q26.1-q26.2 are also associated with epilepsy with moderate mental retardation. 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.
| Relation between Epilepsy and Epigenetics|| |
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. 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. 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.,,, 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. 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., The nonmethylation state is associated with gene activation, whereas demethylation is associated with the reactivation of silent genes. DNA methylation is stable in the brain. However, a limited amount regulated by neurons is dynamic and probably involved in the onset of epilepsy., In addition, enhanced DNA methylation enzyme activity and DNA hypermethylation are associated with human epilepsy and experimental epilepsy.,,,,
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.,,,,, The methylation hypothesis regarding epileptogenesis indicates that epigenetic changes occur, thus aggravating epileptic seizures. Studies have shown whole-genome DNA methylation changes in the hippocampus of mice with status epilepticus (SE). In addition, there was a significant increase in DNA methylation in a rat model with chronic epilepsy. In the animal hippocampus of SE, hypermethylation was observed in the promoter region of SCN3A and GRIA2 genes., 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, 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., 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.
In the study of human refractory epilepsy, changes in DNA methylation have been found, and some genes were also regulated by methylation or demethylation. Research on human TLE has revealed that changes in RELN gene methylation result in scattered granulosa cells  and an increased level of DNMTs 1 and 3a in the hippocampus. 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. Ras-guanine nucleotide-releasing factor 1 (RASgrf1) is exclusively expressed in the neonatal brain and liver, 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. Genome-wide DNA methylation analysis has revealed hypomethylation of genes in acute-onset seizures, whereas gene methylation levels are high during the development of epilepsy.,, 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.,
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. 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.,,
Downregulation of miR-221 and miR-222 expression is associated with the expression of intercellular adhesion molecule-1 (ICAM1) in TLE cases.,,,,, Given that ICAM1 is a protein that responds to immunity and inflammation, 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., And, miR-146a can impair IL1R1/TLR4 signal transduction to contribute to epilepsy. 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. MiR-9 is upregulated in TLE.,, Expression of miR-9 in TLE can promote inflammation by inhibiting the transcription of nuclear factor κ-B1. In immature epileptic-state rats and children with TLE, miR-155 upregulation was noted in the inflammatory response pathway. 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. 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. Furthermore, miR-134 could be used as a potential biomarker for the diagnosis of mesial TLE. Recent studies have also found that some miRNAs were related to epilepsy in animal models, such as miR-22-3p, miR-124, miR-199a-5p, and miR-219. 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|| |
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. It has been clinically proven that the inhibition of cytokine IL-1β could prevent refractory epilepsy. 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. 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., 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.
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| References|| |
Tian M, Macdonald RL. The intronic GABRG2 mutation, IVS6+2T-> G, associated with childhood absence epilepsy altered subunit mRNA intron splicing, activated nonsense-mediated decay, and produced a stable truncated γ2 subunit. J Neurosci 2012;32:5937-52. doi: 10.1523/JNEUROSCI.5332-11.2012.
Prasad AN, Prasad C. Genetic infuences on the risk for epilepsy. In: Pellock JM, Bourgeois BF, Dodson WE, Nordli. Jr DR, Sankar R, editors. Pediatric Epilepsy. New York: Demos; 2008. p.117-34.
Sigurdardottir L, Poduri A. Inherited epilepsies. In: Lynch DR, editor. Neurogenetics: Scientific and Clinical Advances. New York: Taylor and Francis; 2006. p. 427-67.
Steinlein OK. Genes and mutations in human idiopathic epilepsy. Brain Dev 2004;26:213-8. doi: 10.1016/S0387-7604(03)00149-9.
Berkovic SF, Howell RA, Hay DA, Hopper JL. Epilepsies in twins: Genetics of the major epilepsy syndromes. Ann Neurol 1998;43:435-45. doi: 10.1002/ana.410430405.
Kjeldsen MJ, Kyvik KO, Friis ML, Christensen K. Genetic and environmental factors in febrile seizures: A Danish population-based twin study. Epilepsy Res 2002;51:167-77. doi: 10.1016/S0920-1211(02) 00121-3.
Kjeldsen MJ, Corey LA, Christensen K, Friis ML. Epileptic seizures and syndromes in twins: The importance of genetic factors. Epilepsy Res 2003;55:137-46. doi: 10.1016/S0920-1211(03)00117-7.
Kjeldsen MJ, Corey LA, Solaas MH, Friis ML, Harris JR, Kyvik KO, et al.
Genetic factors in seizures: A population-based study of 47,626 US, Norwegian and Danish twin pairs. Twin Res Hum Genet 2005;8:138-47. doi: 10.1375/1832427053738836.
Newmark ME, Penry JK. Genetics of Epilepsy: A Review. New York: Raven Press; 1980.
Frankel WN. Genetics of complex neurological disease: Challenges and opportunities for modeling epilepsy in mice and rats. Trends Genet 2009;25:361-7. doi: 10.1016/j.tig.2009.07.001.
Lerche H, Jurkat-Rott K, Lehmann-Horn F. Ion channels and epilepsy. Am J Med Genet 2001;106:146-59. doi: 10.1002/ajmg.1582.
Gribkoff VK. The therapeutic potential of neuronal KCNQ channel modulators. Expert Opin Ther Targets 2003;7:737-48. doi: 10.1517/1472818.104.22.1687.
Singh NA, Westenskow P, Charlier C, Pappas C, Leslie J, Dillon J, et al.
KCNQ2 and KCNQ3 potassium channel genes in benign familial neonatal convulsions: Expansion of the functional and mutation spectrum. Brain 2003;126:2726-37. doi: 10.1093/brain/awg286.
Kato M, Yamagata T, Kubota M, Arai H, Yamashita S, Nakagawa T, et al.
Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation. Epilepsia 2013;54:1282-7. doi: 10.1111/epi.12200.
Saitsu H, Kato M, Koide A, Goto T, Fujita T, Nishiyama K, et al.
Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome. Ann Neurol 2012;72:298-300. doi: 10.1002/ana.23620.
Weckhuysen S, Ivanovic V, Hendrickx R, Van Coster R, Hjalgrim H, Møller RS, et al.
Extending the KCNQ2 encephalopathy spectrum: Clinical and neuroimaging findings in 17 patients. Neurology 2013;81:1697-703. doi: 10.1212/01.wnl.0000435296.72400.a1.
Kojima K, Shirai K, Kobayashi M, Miyauchi A, Saitsu H, Matsumoto N, et al.
A patient with early myoclonic encephalopathy (EME) with a de novo
KCNQ2 mutation. Brain Dev 2018;40:69-73. doi: 10.1016/j.braindev.2017.06.004.
Lehman A, Thouta S, Mancini GMS, Naidu S, van Slegtenhorst M, McWalter K, et al.
Loss-of-function and gain-of-function mutations in KCNQ5 cause intellectual disability or epileptic encephalopathy. Am J Hum Genet 2017;101:65-74. doi: 10.1016/j.ajhg.2017.05.016.
Allen NM, Conroy J, Shahwan A, Lynch B, Correa RG, Pena SD, et al.
Unexplained early onset epileptic encephalopathy: Exome screening and phenotype expansion. Epilepsia 2016;57:e12-7. doi: 10.1111/epi.13250.
Corbett MA, Bellows ST, Li M, Carroll R, Micallef S, Carvill GL, et al.
Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy. Neurology 2016;87:1975-84. doi: 10.1212/WNL.0000000000003309.
Hundallah K, Alenizi A, AlHashem A, Tabarki B. Severe early-onset epileptic encephalopathy due to mutations in the KCNA2 gene: Expansion of the genotypic and phenotypic spectrum. Eur J Paediatr Neurol 2016;20:657-60. doi: 10.1016/j.ejpn.2016.03.011.
Masnada S, Hedrich UBS, Gardella E, Schubert J, Kaiwar C, Klee EW, et al.
Clinical spectrum and genotype-phenotype associations of KCNA2-related encephalopathies. Brain 2017;140:2337-54. doi: 10.1093/brain/awx184.
de Kovel CG, Brilstra EH, van Kempen MJ, Van't Slot R, Nijman IJ, Afawi Z, et al.
Targeted sequencing of 351 candidate genes for epileptic encephalopathy in a large cohort of patients. Mol Genet Genomic Med 2016;4:568-80. doi: 10.1002/mgg3.235.
de Kovel CGF, Syrbe S, Brilstra EH, Verbeek N, Kerr B, Dubbs H, et al.
Neurodevelopmental disorders caused by de novo
variants in KCNB1 genotypes and phenotypes. JAMA Neurol 2017;74:1228-36. doi: 10.1001/jamaneurol.2017.1714.
Saitsu H, Akita T, Tohyama J, Goldberg-Stern H, Kobayashi Y, Cohen R, et al. De novo
KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing. Sci Rep 2015;5:15199. doi: 10.1038/srep15199.
Thiffault I, Speca DJ, Austin DC, Cobb MM, Eum KS, Safina NP, et al.
A novel epileptic encephalopathy mutation in KCNB1 disrupts Kv2.1 ion selectivity, expression, and localization. J Gen Physiol 2015;146:399-410.doi: 10.1085/jgp.201511444.
Torkamani A, Bersell K, Jorge BS, Bjork RL Jr., Friedman JR, Bloss CS, et al. De novo
KCNB1 mutations in epileptic encephalopathy. Ann Neurol 2014;76:529-40. doi: 10.1002/ana.24263.
Muona M, Berkovic SF, Dibbens LM, Oliver KL, Maljevic S, Bayly MA, et al.
A recurrent de novo
mutation in KCNC1 causes progressive myoclonus epilepsy. Nat Genet 2015;47:39-46. doi: 10.1038/ng.3144.
Du W, Bautista JF, Yang H, Diez-Sampedro A, You SA, Wang L, et al.
Calcium-sensitive potassium channelopathy in human epilepsy and paroxysmal movement disorder. Nat Genet 2005;37:733-8. doi: 10.1038/ng1585.
Zhang ZB, Tian MQ, Gao K, Jiang YW, Wu Y. De novo
KCNMA1 mutations in children with early-onset paroxysmal dyskinesia and developmental delay. Mov Disord 2015;30:1290-2. doi: 10.1002/mds.26216.
Martin HC, Kim GE, Pagnamenta AT, Murakami Y, Carvill GL, Meyer E, et al.
Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum Mol Genet 2014;23:3200-11. doi: 10.1093/hmg/ddu030.
Fukuoka M, Kuki I, Kawawaki H, Okazaki S, Kim K, Hattori Y, et al.
Quinidine therapy for west syndrome with KCNTI mutation: A case report. Brain Dev 2017;39:80-3. doi: 10.1016/j.braindev.2016.08.002.
Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E, Licchetta L, et al.
Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 2012;44:1188-90. doi: 10.1038/ng.2440.
Wallace RH, Wang DW, Singh R, Scheffer IE, George AL Jr., Phillips HA, et al.
Febrile seizures and generalized epilepsy associated with a mutation in the Na +
-channel beta1 subunit gene SCN1B. Nat Genet 1998;19:366-70. doi: 10.1038/1252.
Escayg A, MacDonald BT, Meisler MH, Baulac S, Huberfeld G, An-Gourfinkel I, et al.
Mutations of SCN1A, encoding a neuronal sodium channel, in two families with GEFS+2. Nat Genet 2000;24:343-5. doi: 10.1038/74159.
Sugawara T, Tsurubuchi Y, Agarwala KL, Ito M, Fukuma G, Mazaki-Miyazaki E, et al.
A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction. Proc Natl Acad Sci U S A 2001;98:6384-9. doi: 10.1073/pnas.111065098.
Baulac S, Huberfeld G, Gourfinkel-An I, Mitropoulou G, Beranger A, Prud'homme JF, et al.
First genetic evidence of GABA(A) receptor dysfunction in epilepsy: A mutation in the gamma2-subunit gene. Nat Genet 2001;28:46-8. doi: 10.1038/88254.
Dibbens LM, Feng HJ, Richards MC, Harkin LA, Hodgson BL, Scott D, et al.
GABRD encoding a protein for extra- or peri-synaptic GABAA receptors is a susceptibility locus for generalized epilepsies. Hum Mol Genet 2004;13:1315-9. doi: 10.1093/hmg/ddh146.
Meisler MH, O'Brien JE, Sharkey LM. Sodium channel gene family: Epilepsy mutations, gene interactions and modifier effects. J Physiol 2010;588:1841-8. doi: 10.1113/jphysiol.2010.188482.
Escayg A, Goldin AL. Sodium channel SCN1A and epilepsy: Mutations and mechanisms. Epilepsia 2010;51:1650-8. doi: 10.1111/j.1528-1167.2010.02640.x.
Veeramah KR, O'Brien JE, Meisler MH, Cheng X, Dib-Hajj SD, Waxman SG, et al. De novo
pathogenic SCN8A mutation identified by whole-genome sequencing of a family quartet affected by infantile epileptic encephalopathy and SUDEP. Am J Hum Genet 2012;90:502-10. doi: 10.1016/j.ajhg.2012.01.006.
Larsen J, Carvill GL, Gardella E, Kluger G, Schmiedel G, Barisic N, et al.
The phenotypic spectrum of SCN8A encephalopathy. Neurology 2015;84:480-9. doi: 10.1212/WNL.0000000000001211.
Ohba C, Kato M, Takahashi S, Lerman-Sagie T, Lev D, Terashima H, et al.
Early onset epileptic encephalopathy caused by de novo
SCN8A mutations. Epilepsia 2014;55:994-1000. doi: 10.1111/epi.12668.
de Kovel CG, Meisler MH, Brilstra EH, van Berkestijn FM, van 't Slot R, van Lieshout S, et al.
Characterization of a de novo
SCN8A mutation in a patient with epileptic encephalopathy. Epilepsy Res 2014;108:1511-8. doi: 10.1016/j.eplepsyres.2014.08.020.
Estacion M, O'Brien JE, Conravey A, Hammer MF, Waxman SG, Dib-Hajj SD, et al.
A novel de novo
mutation of SCN8A (Nav1.6) with enhanced channel activation in a child with epileptic encephalopathy. Neurobiol Dis 2014;69:117-23. doi: 10.1016/j.nbd.2014.05.017.
Gardella E, Becker F, Møller RS, Schubert J, Lemke JR, Larsen LH, et al.
Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Ann Neurol 2016;79:428-36. doi: 10.1002/ana.24580.
De Fusco M, Becchetti A, Patrignani A, Annesi G, Gambardella A, Quattrone A, et al.
The nicotinic receptor beta 2 subunit is mutant in nocturnal frontal lobe epilepsy. Nat Genet 2000;26:275-6. doi: 10.1038/81566.
Maljevic S, Krampfl K, Cobilanschi J, Tilgen N, Beyer S, Weber YG, et al.
A mutation in the GABA(A) receptor alpha(1)-subunit is associated with absence epilepsy. Ann Neurol 2006;59:983-7. doi: 10.1002/ana.20874.
Tanaka M, DeLorey TM, Delgado-Escueta A, Olsen RW. GABRB3, epilepsy, and neurodevelopment. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV, editors. Jasper's Basic Mechanisms of the Epilepsies. 4th
ed. Bethesda: National Center for Biotechnology Information; 2012.
Urak L, Feucht M, Fathi N, Hornik K, Fuchs K. A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity. Hum Mol Genet 2006;15:2533-41. doi: 10.1093/hmg/ddl174.
Tanaka M, Olsen RW, Medina MT, Schwartz E, Alonso ME, Duron RM, et al.
Hyperglycosylation and reduced GABA currents of mutated GABRB3 polypeptide in remitting childhood absence epilepsy. Am J Hum Genet 2008;82:1249-61. doi: 10.1016/j.ajhg.2008.04.020.
Lenzen KP, Heils A, Lorenz S, Hempelmann A, Sander T. Association analysis of the arg220His variation of the human gene encoding the GABA delta subunit with idiopathic generalized epilepsy. Epilepsy Res 2005;65:53-7. doi: 10.1016/j.eplepsyres.2005.04.005.
Wallace RH, Marini C, Petrou S, Harkin LA, Bowser DN, Panchal RG, et al.
Mutant GABA(A) receptor gamma2-subunit in childhood absence epilepsy and febrile seizures. Nat Genet 2001;28:49-52. doi: 10.1038/88259.
Chen Y, Lu J, Pan H, Zhang Y, Wu H, Xu K, et al.
Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol 2003;54:239-43. doi: 10.1002/ana.10607.
Reid CA, Berkovic SF, Petrou S. Mechanisms of human inherited epilepsies. Prog Neurobiol 2009;87:41-57. doi: 10.1016/j.pneurobio.2008.09.016.
Zamponi GW, Lory P, Perez-Reyes E. Role of voltage-gated calcium channels in epilepsy. Pflugers Arch 2010;460:395-403. doi: 10.1007/s00424-009-0772-x.
Khosravani H, Altier C, Simms B, Hamming KS, Snutch TP, Mezeyova J, et al.
Gating effects of mutations in the cav3.2 T-type calcium channel associated with childhood absence epilepsy. J Biol Chem 2004;279:9681-4. doi: 10.1074/jbc.C400006200.
Khosravani H, Bladen C, Parker DB, Snutch TP, McRory JE, Zamponi GW, et al.
Effects of cav3.2 channel mutations linked to idiopathic generalized epilepsy. Ann Neurol 2005;57:745-9. doi: 10.1002/ana.20458.
Heron SE, Phillips HA, Mulley JC, Mazarib A, Neufeld MY, Berkovic SF, et al.
Genetic variation of CACNA1H in idiopathic generalized epilepsy. Ann Neurol 2004;55:595-6. doi: 10.1002/ana.20028.
Heron SE, Khosravani H, Varela D, Bladen C, Williams TC, Newman MR, et al.
Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Ann Neurol 2007;62:560-8. doi: 10.1002/ana.21169.
Niemeyer MI, Cid LP, Sepúlveda FV, Blanz J, Auberson M, Jentsch TJ, et al.
No evidence for a role of CLCN2 variants in idiopathic generalized epilepsy. Nat Genet 2010;42:3. doi: 10.1038/ng0110-3.
Palmer EE, Stuhlmann T, Weinert S, Haan E, Van Esch H, Holvoet M, et al. De novo
and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females. Mol Psychiatry 2018;23:222-30. doi: 10.1038/mp.2016.135.
Saitsu H, Kato M, Mizuguchi T, Hamada K, Osaka H, Tohyama J, et al. De novo
mutations in the gene encoding STXBP1 (MUNC18-1) cause early infantile epileptic encephalopathy. Nat Genet 2008;40:782-8. doi: 10.1038/ng.150.
Hamdan FF, Piton A, Gauthier J, Lortie A, Dubeau F, Dobrzeniecka S, et al. De novo
STXBP1 mutations in mental retardation and nonsyndromic epilepsy. Ann Neurol 2009;65:748-53. doi: 10.1002/ana.21625.
Schubert J, Siekierska A, Langlois M, May P, Huneau C, Becker F, et al.
Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes. Nat Genet 2014;46:1327-32. doi: 10.1038/ng.3130.
Rohena L, Neidich J, Truitt Cho M, Gonzalez KD, Tang S, Devinsky O, et al.
Mutation in SNAP25 as a novel genetic cause of epilepsy and intellectual disability. Rare Dis 2013;1:e26314. doi: 10.4161/rdis.26314.
Alazami AM, Hijazi H, Kentab AY, Alkuraya FS. NECAP1 loss of function leads to a severe infantile epileptic encephalopathy. J Med Genet 2014;51:224-8. doi: 10.1136/jmedgenet-2013-102030.
EuroEPINOMICS-RES Consortium, Epilepsy Phenome/Genome Project, Epi4K Consortium. De novo
mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet 2014;95:360-70. doi: 10.1016/j.ajhg.2014.08.013.
Carvill GL, Heavin SB, Yendle SC, McMahon JM, O'Roak BJ, Cook J, et al.
Targeted resequencing in epileptic encephalopathies identifies de novo
mutations in CHD2 and SYNGAP1. Nat Genet 2013;45:825-30. doi: 10.1038/ng.2646.
Thomas RH, Zhang LM, Carvill GL, Archer JS, Heavin SB, Mandelstam SA, et al.
CHD2 myoclonic encephalopathy is frequently associated with self-induced seizures. Neurology 2015;84:951-8. doi: 10.1212/WNL.0000000000001305.
Suls A, Jaehn JA, Kecskés A, Weber Y, Weckhuysen S, Craiu DC, et al. De novo
loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome. Am J Hum Genet 2013;93:967-75. doi: 10.1016/j.ajhg.2013.09.017.
Lund C, Brodtkorb E, Øye AM, Røsby O, Selmer KK. CHD2 mutations in Lennox-Gastaut syndrome. Epilepsy Behav 2014;33:18-21. doi: 10.1016/j.yebeh.2014.02.005.
Epi4K Consortium, Epilepsy Phenome/Genome Project, Allen AS, Berkovic SF, Cossette P, Delanty N, et al. De novo
mutations in epileptic encephalopathies. Nature 2013;501:217-21. doi: 10.1038/nature12439.
Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A, et al.
Patterns and rates of exonic de novo
mutations in autism spectrum disorders. Nature 2012;485:242-5. doi: 10.1038/nature11011.
Crino PB. MTOR signaling in epilepsy: Insights from malformations of cortical development. Cold Spring Harb Perspect Med 2015;5. pii: a022442. doi: 10.1101/cshperspect.a022442.
Lim JS, Kim WI, Kang HC, Kim SH, Park AH, Park EK, et al.
Brain somatic mutations in MTOR cause focal cortical dysplasia type II leading to intractable epilepsy. Nat Med 2015;21:395-400. doi: 10.1038/nm.3824.
Dibbens LM, de Vries B, Donatello S, Heron SE, Hodgson BL, Chintawar S, et al.
Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet 2013;45:546-51. doi: 10.1038/ng.2599.
Ishida S, Picard F, Rudolf G, Noé E, Achaz G, Thomas P, et al.
Mutations of DEPDC5 cause autosomal dominant focal epilepsies. Nat Genet 2013;45:552-5. doi: 10.1038/ng.2601.
Nascimento FA, Borlot F, Cossette P, Minassian BA, Andrade DM. Two definite cases of sudden unexpected death in epilepsy in a family with a DEPDC5 mutation. Neurol Genet 2015;1:e28. doi: 10.1212/NXG.0000000000000028.
Ricos MG, Hodgson BL, Pippucci T, Saidin A, Ong YS, Heron SE, et al.
Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. Ann Neurol 2016;79:120-31. doi: 10.1002/ana.24547.
Korenke GC, Eggert M, Thiele H, Nürnberg P, Sander T, Steinlein OK, et al.
Nocturnal frontal lobe epilepsy caused by a mutation in the GATOR1 complex gene NPRL3. Epilepsia 2016;57:e60-3. doi: 10.1111/epi.13307.
Kato M, Das S, Petras K, Sawaishi Y, Dobyns WB. Polyalanine expansion of ARX associated with cryptogenic west syndrome. Neurology 2003;61:267-76. doi: 10.1212/01.WNL.0000068012.69928.92.
Strømme P, Mangelsdorf ME, Shaw MA, Lower KM, Lewis SM, Bruyere H, et al.
Mutations in the human ortholog of aristaless cause X-linked mental retardation and epilepsy. Nat Genet 2002;30:441-5. doi: 10.1038/ng862.
Giordano L, Sartori S, Russo S, Accorsi P, Galli J, Tiberti A, et al.
Familial Ohtahara syndrome due to a novel ARX gene mutation. Am J Med Genet A 2010;152A: 3133-7. doi: 10.1002/ajmg.a.33701.
Kato M, Koyama N, Ohta M, Miura K, Hayasaka K. Frameshift mutations of the ARX gene in familial Ohtahara syndrome. Epilepsia 2010;51:1679-84. doi: 10.1111/j.1528-1167.2010.02559.x.
Demos MK, Fullston T, Partington MW, Gécz J, Gibson WT. Clinical study of two brothers with a novel 33 bp duplication in the ARX gene. Am J Med Genet A 2009;149A: 1482-6. doi: 10.1002/ajmg.a.32851.
Ekşioǧlu YZ, Pong AW, Takeoka M. A novel mutation in the aristaless domain of the ARX gene leads to Ohtahara syndrome, global developmental delay, and ambiguous genitalia in males and neuropsychiatric disorders in females. Epilepsia 2011;52:984-92. doi: 10.1111/j.1528-1167.2011.02980.x.
Archer HL, Evans J, Edwards S, Colley J, Newbury-Ecob R, O'Callaghan F, et al.
CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J Med Genet 2006;43:729-34. doi: 10.1136/jmg.2006.041467.
Bahi-Buisson N, Nectoux J, Rosas-Vargas H, Milh M, Boddaert N, Girard B, et al.
Key clinical features to identify girls with CDKL5 mutations. Brain 2008;131:2647-61. doi: 10.1093/brain/awn197.
Bahi-Buisson N, Bienvenu T. CDKL5-related disorders: From clinical description to molecular genetics. Mol Syndromol 2012;2:137-52. doi: 000331333.
Bahi-Buisson N, Kaminska A, Boddaert N, Rio M, Afenjar A, Gérard M, et al.
The three stages of epilepsy in patients with CDKL5 mutations. Epilepsia 2008;49:1027-37. doi: 10.1111/j.1528-1167.2007.01520.x.
Dibbens LM, Tarpey PS, Hynes K, Bayly MA, Scheffer IE, Smith R, et al.
X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment. Nat Genet 2008;40:776-81. doi: 10.1038/ng.149.
de Lange IM, Rump P, Neuteboom RF, Augustijn PB, Hodges K, Kistemaker AI, et al.
Male patients affected by mosaic PCDH19 mutations: Five new cases. Neurogenetics 2017;18:147-53. doi: 10.1007/s10048-017-0517-5.
Depienne C, Trouillard O, Bouteiller D, Gourfinkel-An I, Poirier K, Rivier F, et al.
Mutations and deletions in PCDH19 account for various familial or isolated epilepsies in females. Hum Mutat 2011;32:E1959-75. doi: 10.1002/humu.21373.
Colin E, Daniel J, Ziegler A, Wakim J, Scrivo A, Haack TB, et al.
Biallelic variants in UBA5 reveal that disruption of the UFM1 cascade can result in early-onset encephalopathy. Am J Hum Genet 2016;99:695-703. doi: 10.1016/j.ajhg.2016.06.030.
Johansen A, Rosti RO, Musaev D, Sticca E, Harripaul R, Zaki M, et al.
Mutations in MBOAT7, encoding lysophosphatidylinositol acyltransferase I, lead to intellectual disability accompanied by epilepsy and autistic features. Am J Hum Genet 2016;99:912-6. doi: 10.1016/j.ajhg.2016.07.019.
Raviglione F, Conte G, Ghezzi D, Parazzini C, Righini A, Vergaro R, et al.
Clinical findings in a patient with FARS2 mutations and early-infantile-encephalopathy with epilepsy. Am J Med Genet A 2016;170:3004-7. doi: 10.1002/ajmg.a.37836.
Frasa MA, Koessmeier KT, Ahmadian MR, Braga VM. Illuminating the functional and structural repertoire of human TBC/RABGAPs. Nat Rev Mol Cell Biol 2012;13:67-73. doi: 10.1038/nrm3267.
Corbett MA, Bahlo M, Jolly L, Afawi Z, Gardner AE, Oliver KL, et al.
A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24. Am J Hum Genet 2010;87:371-5. doi: 10.1016/j.ajhg.2010.08.001.
Falace A, Filipello F, La Padula V, Vanni N, Madia F, De Pietri Tonelli D, et al.
TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy. Am J Hum Genet 2010;87:365-70. doi: 10.1016/j.ajhg.2010.07.020.
Guven A, Tolun A. TBC1D24 truncating mutation resulting in severe neurodegeneration. J Med Genet 2013;50:199-202. doi: 10.1136/jmedgenet-2012-101313.
Milh M, Falace A, Villeneuve N, Vanni N, Cacciagli P, Assereto S, et al.
Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy. Hum Mutat 2013;34:869-72. doi: 10.1002/humu.22318.
Poulat AL, Ville D, de Bellescize J, André-Obadia N, Cacciagli P, Milh M, et al.
Homozygous TBC1D24 mutation in two siblings with familial infantile myoclonic epilepsy (FIME) and moderate intellectual disability. Epilepsy Res 2015;111:72-7. doi: 10.1016/j.eplepsyres.2015.01.008.
Azaiez H, Booth KT, Bu F, Huygen P, Shibata SB, Shearer AE, et al.
TBC1D24 mutation causes autosomal-dominant nonsyndromic hearing loss. Hum Mutat 2014;35:819-23. doi: 10.1002/humu.22557.
Bakhchane A, Charif M, Salime S, Boulouiz R, Nahili H, Roky R, et al.
Recessive TBC1D24 mutations are frequent in Moroccan non-syndromic hearing loss pedigrees. PLoS One 2015;10:e0138072. doi: 10.1371/journal.pone.0138072.
Stražišar BG, Neubauer D, Paro Panjan D, Writzl K. Early-onset epileptic encephalopathy with hearing loss in two siblings with TBC1D24 recessive mutations. Eur J Paediatr Neurol 2015;19:251-6. doi: 10.1016/j.ejpn.2014.12.011.
Zhang L, Hu L, Chai Y, Pang X, Yang T, Wu H, et al.
A dominant mutation in the stereocilia-expressing gene TBC1D24 is a probable cause for nonsyndromic hearing impairment. Hum Mutat 2014;35:814-8. doi: 10.1002/humu.22558.
Doummar D, Mignot C, Apartis E, Villard L, Rodriguez D, Chantot-Bastauraud S, et al.
A novel homozygous TBC1D24 mutation causing multifocal myoclonus with cerebellar involvement. Mov Disord 2015;30:1431-2. doi: 10.1002/mds.26303.
Campeau PM, Hennekam RC, DOORS syndrome collaborative group. DOORS syndrome: Phenotype, genotype and comparison with Coffin-Siris syndrome. Am J Med Genet C Semin Med Genet 2014;166C: 327-32. doi: 10.1002/ajmg.c.31412.
Campeau PM, Kasperaviciute D, Lu JT, Burrage LC, Kim C, Hori M, et al.
The genetic basis of DOORS syndrome: An exome-sequencing study. Lancet Neurol 2014;13:44-58. doi: 10.1016/S1474-4422(13) 70265-5.
Fischer B, Lüthy K, Paesmans J, De Koninck C, Maes I, Swerts J, et al.
Skywalker-TBC1D24 has a lipid-binding pocket mutated in epilepsy and required for synaptic function. Nat Struct Mol Biol 2016;23:965-73. doi: 10.1038/nsmb.3297.
Trivisano M, Bellusci M, Terracciano A, De Palma L, Pietrafusa N, Valeriani M, et al.
TBC1D24 gene mutations are associated with high risk of sudden unexpected death. Epilepsy Behav 2017;72:208-9. doi: 10.1016/j.yebeh.2017.04.010.
de Kovel CG, Trucks H, Helbig I, Mefford HC, Baker C, Leu C, et al.
Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies. Brain 2010;133:23-32. doi: 10.1093/brain/awp262.
Dibbens LM, Mullen S, Helbig I, Mefford HC, Bayly MA, Bellows S, et al.
Familial and sporadic 15q13.3 microdeletions in idiopathic generalized epilepsy: Precedent for disorders with complex inheritance. Hum Mol Genet 2009;18:3626-31. doi: 10.1093/hmg/ddp311.
Heinzen EL, Radtke RA, Urban TJ, Cavalleri GL, Depondt C, Need AC, et al.
Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes. Am J Hum Genet 2010;86:707-18. doi: 10.1016/j.ajhg.2010.03.018.
Lal D, Trucks H, Møller RS, Hjalgrim H, Koeleman BP, de Kovel CG, et al.
Rare exonic deletions of the RBFOX1 gene increase risk of idiopathic generalized epilepsy. Epilepsia 2013;54:265-71. doi: 10.1111/epi.12084.
Lionel AC, Vaags AK, Sato D, Gazzellone MJ, Mitchell EB, Chen HY, et al.
Rare exonic deletions implicate the synaptic organizer gephyrin (GPHN) in risk for autism, schizophrenia and seizures. Hum Mol Genet 2013;22:2055-66. doi: 10.1093/hmg/ddt056.
Verhoeven WM, Egger JI, Knegt AC, Zuydam J, Kleefstra T. Absence epilepsy and the CHD2 gene: An adolescent male with moderate intellectual disability, short-lasting psychoses, and an interstitial deletion in 15q26.1-q26.2. Neuropsychiatr Dis Treat 2016;12:1135-9. doi: 10.2147/NDT.S102272.
Carvill GL, McMahon JM, Schneider A, Zemel M, Myers CT, Saykally J, et al.
Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures. Am J Hum Genet 2015;96:808-15. doi: 10.1016/j.ajhg.2015.02.016.
Ma DK, Jang MH, Guo JU, Kitabatake Y, Chang ML, Pow-Anpongkul N, et al.
Neuronal activity-induced gadd45b promotes epigenetic DNA demethylation and adult neurogenesis. Science 2009;323:1074-7. doi: 10.1126/science.1166859.
Jakovcevski M, Akbarian S. Epigenetic mechanisms in neurological disease. Nat Med 2012;18:1194-204. doi: 10.1038/nm.2828.
Qureshi IA, Mehler MF. Understanding neurological disease mechanisms in the era of epigenetics. JAMA Neurol 2013;70:703-10. doi: 10.1001/jamaneurol.2013.1443.
Kobow K, Blümcke I. The emerging role of DNA methylation in epileptogenesis. Epilepsia 2012;53 Suppl 9:11-20. doi: 10.1111/epi.12031.
Lubin FD. Epileptogenesis: Can the science of epigenetics give us answers? Epilepsy Curr 2012;12:105-10. doi: 10.5698/1535-7511-12.3.105.
Henshall DC. MicroRNAs in the pathophysiology and treatment of status epilepticus. Front Mol Neurosci 2013;6:37. doi: 10.3389/fnmol.2013.00037.
Boison D. The biochemistry and epigenetics of epilepsy: Focus on adenosine and glycine. Front Mol Neurosci 2016;9:26. doi: 10.3389/fnmol.2016.00026.
Jaenisch R, Bird A. Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat Genet 2003;33:245-54. doi: 10.1038/ng1089.
Robertson KD. DNA methylation and human disease. Nat Rev Genet 2005;6:597-610. doi: 10.1038/nrg1655.
Choo KB. Epigenetics in disease and cancer. Malays J Pathol 2011;33:61-70.
Martinowich K, Hattori D, Wu H, Fouse S, He F, Hu Y, et al.
DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 2003;302:890-3. doi: 10.1126/science.1090842.
Guo JU, Ma DK, Mo H, Ball MP, Jang MH, Bonaguidi MA, et al.
Neuronal activity modifies the DNA methylation landscape in the adult brain. Nat Neurosci 2011;14:1345-51. doi: 10.1038/nn.2900.
Kobow K, Jeske I, Hildebrandt M, Hauke J, Hahnen E, Buslei R, et al.
Increased reelin promoter methylation is associated with granule cell dispersion in human temporal lobe epilepsy. J Neuropathol Exp Neurol 2009;68:356-64. doi: 10.1097/NEN.0b013e31819ba737.
Kobow K, Kaspi A, Harikrishnan KN, Kiese K, Ziemann M, Khurana I, et al.
Deep sequencing reveals increased DNA methylation in chronic rat epilepsy. Acta Neuropathol 2013;126:741-56. doi: 10.1007/s00401-013-1168-8.
Zhu Q, Wang L, Zhang Y, Zhao FH, Luo J, Xiao Z, et al.
Increased expression of DNA methyltransferase 1 and 3a in human temporal lobe epilepsy. J Mol Neurosci 2012;46:420-6. doi: 10.1007/s12031-011-9602-7.
Williams-Karnesky RL, Sandau US, Lusardi TA, Lytle NK, Farrell JM, Pritchard EM, et al.
Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. J Clin Invest 2013;123:3552-63. doi: 10.1172/JCI65636.
Miller-Delaney SF, Bryan K, Das S, McKiernan RC, Bray IM, Reynolds JP, et al.
Differential DNA methylation profiles of coding and non-coding genes define hippocampal sclerosis in human temporal lobe epilepsy. Brain 2015;138:616-31. doi: 10.1093/brain/awu373.
Feng J, Zhou Y, Campbell SL, Le T, Li E, Sweatt JD, et al.
Dnmt1 and Dnmt3a maintain DNA methylation and regulate synaptic function in adult forebrain neurons. Nat Neurosci 2010;13:423-30. doi: 10.1038/nn.2514.
Martin LJ, Wong M. Aberrant regulation of DNA methylation in amyotrophic lateral sclerosis: A new target of disease mechanisms. Neurotherapeutics 2013;10:722-33. doi: 10.1007/s13311-013-0205-6.
Masliah E, Dumaop W, Galasko D, Desplats P. Distinctive patterns of DNA methylation associated with Parkinson disease: Identification of concordant epigenetic changes in brain and peripheral blood leukocytes. Epigenetics 2013;8:1030-8. doi: 10.4161/epi.25865.
Coppieters N, Dieriks BV, Lill C, Faull RL, Curtis MA, Dragunow M, et al.
Global changes in DNA methylation and hydroxymethylation in Alzheimer's disease human brain. Neurobiol Aging 2014;35:1334-44. doi: 10.1016/j.neurobiolaging.2013.11.031.
Tremolizzo L, Messina P, Conti E, Sala G, Cecchi M, Airoldi L, et al.
Whole-blood global DNA methylation is increased in amyotrophic lateral sclerosis independently of age of onset. Amyotroph Lateral Scler Frontotemporal Degener 2014;15:98-105. doi: 10.3109/21678421.2013.851247.
Kobow K, Blümcke I. The methylation hypothesis: Do epigenetic chromatin modifications play a role in epileptogenesis? Epilepsia 2011;52 Suppl 4:15-9. doi: 10.1111/j.1528-1167.2011.03145.x.
Miller-Delaney SF, Das S, Sano T, Jimenez-Mateos EM, Bryan K, Buckley PG, et al.
Differential DNA methylation patterns define status epilepticus and epileptic tolerance. J Neurosci 2012;32:1577-88. doi: 10.1523/JNEUROSCI.5180-11.2012.
Machnes ZM, Huang TC, Chang PK, Gill R, Reist N, Dezsi G, et al.
DNA methylation mediates persistent epileptiform activity in vitro
and in vivo
. PLoS One 2013;8:e76299. doi: 10.1371/journal.pone.0076299.
Li HJ, Wan RP, Tang LJ, Liu SJ, Zhao QH, Gao MM, et al.
Alteration of scn3a expression is mediated via CpG methylation and MBD2 in mouse hippocampus during postnatal development and seizure condition. Biochim Biophys Acta 2015;1849:1-9. doi: 10.1016/j.bbagrm.2014.11.004.
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY, et al.
Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 1999;23:185-8. doi: 10.1038/13810.
Maxwell SS, Pelka GJ, Tam PP, El-Osta A. Chromatin context and ncRNA highlight targets of meCP2 in brain. RNA Biol 2013;10:1741-57. doi: 10.4161/rna.26921.
Gadalla KK, Bailey ME, Cobb SR. MeCP2 and Rett syndrome: Reversibility and potential avenues for therapy. Biochem J 2011;439:1-4. doi: 10.1042/BJ20110648.
Wang L, Fu X, Peng X, Xiao Z, Li Z, Chen G, et al.
DNA methylation profiling reveals correlation of differential methylation patterns with gene expression in human epilepsy. J Mol Neurosci 2016;59:68-77. doi: 10.1007/s12031-016-0735-6.
Ryley Parrish R, Albertson AJ, Buckingham SC, Hablitz JJ, Mascia KL, Davis Haselden W, et al.
Status epilepticus triggers early and late alterations in brain-derived neurotrophic factor and NMDA glutamate receptor Grin2b DNA methylation levels in the hippocampus. Neuroscience 2013;248:602-19. doi: 10.1016/j.neuroscience.2013.06.029.
Dockery L, Gerfen J, Harview C, Rahn-Lee C, Horton R, Park Y, et al
. Differential methylation persists at the mouse rasgrf1 DMR in tissues displaying monoallelic and biallelic expression. Epigenetics 2009;4:241-7.
Chen X, Peng X, Wang L, Fu X, Zhou JX, Zhu B, et al.
Association of RASgrf1 methylation with epileptic seizures. Oncotarget 2017;8:46286-97. doi: 10.18632/oncotarget.18000.
Henshall DC, Sinclair J, Simon RP. Relationship between seizure-induced transcription of the DNA damage-inducible gene GADD45, DNA fragmentation, and neuronal death in focally evoked limbic epilepsy. J Neurochem 1999;73:1573-83. doi: 10.1046/j.1471-4159.1999.0731573.x.
Henshall DC, Kobow K. Epigenetics and epilepsy. Cold Spring Harb Perspect Med 2015;5. pii: a022731. doi: 10.1101/cshperspect.a022731.
Tao J, Wu H, Lin Q, Wei W, Lu XH, Cantle JP, et al.
Deletion of astroglial dicer causes non-cell-autonomous neuronal dysfunction and degeneration. J Neurosci 2011;31:8306-19. doi: 10.1523/JNEUROSCI.0567-11.2011.
Tan CL, Plotkin JL, Venø MT, von Schimmelmann M, Feinberg P, Mann S, et al.
MicroRNA-128 governs neuronal excitability and motor behavior in mice. Science 2013;342:1254-8. doi: 10.1126/science.1244193.
Jimenez-Mateos EM, Engel T, Merino-Serrais P, McKiernan RC, Tanaka K, Mouri G, et al.
Silencing microRNA-134 produces neuroprotective and prolonged seizure-suppressive effects. Nat Med 2012;18:1087-94. doi: 10.1038/nm.2834.
Roncon P, Soukupovà M, Binaschi A, Falcicchia C, Zucchini S, Ferracin M, et al.
MicroRNA profiles in hippocampal granule cells and plasma of rats with pilocarpine-induced epilepsy – Comparison with human epileptic samples. Sci Rep 2015;5:14143. doi: 10.1038/srep14143.
Kan AA, van Erp S, Derijck AA, de Wit M, Hessel EV, O'Duibhir E, et al.
Genome-wide microRNA profiling of human temporal lobe epilepsy identifies modulators of the immune response. Cell Mol Life Sci 2012;69:3127-45. doi: 10.1007/s00018-012-0992-7.
Risbud RM, Porter BE. Changes in microRNA expression in the whole hippocampus and hippocampal synaptoneurosome fraction following pilocarpine induced status epilepticus. PLoS One 2013;8:e53464. doi: 10.1371/journal.pone.0053464.
Gorter JA, Iyer A, White I, Colzi A, van Vliet EA, Sisodiya S, et al.
Hippocampal subregion-specific microRNA expression during epileptogenesis in experimental temporal lobe epilepsy. Neurobiol Dis 2014;62:508-20. doi: 10.1016/j.nbd.2013.10.026.
Haenisch S, Zhao Y, Chhibber A, Kaiboriboon K, Do LV, Vogelgesang S, et al.
SOX11 identified by target gene evaluation of miRNAs differentially expressed in focal and non-focal brain tissue of therapy-resistant epilepsy patients. Neurobiol Dis 2015;77:127-40. doi: 10.1016/j.nbd.2015.02.025.
Kretschmann A, Danis B, Andonovic L, Abnaof K, van Rikxoort M, Siegel F, et al.
Different microRNA profiles in chronic epilepsy versus acute seizure mouse models. J Mol Neurosci 2015;55:466-79. doi: 10.1007/s12031-014-0368-6.
Dietrich JB. The adhesion molecule ICAM-1 and its regulation in relation with the blood-brain barrier. J Neuroimmunol 2002;128:58-68. doi: 10.1016/S0165-5728(02)00114-5.
Aronica E, Fluiter K, Iyer A, Zurolo E, Vreijling J, van Vliet EA, et al.
Expression pattern of miR-146a, an inflammation-associated microRNA, in experimental and human temporal lobe epilepsy. Eur J Neurosci 2010;31:1100-7. doi: 10.1111/j.1460-9568.2010.07122.x.
Iyer A, Zurolo E, Prabowo A, Fluiter K, Spliet WG, van Rijen PC, et al.
MicroRNA-146a: A key regulator of astrocyte-mediated inflammatory response. PLoS One 2012;7:e44789. doi: 10.1371/journal.pone.0044789.
Iori V, Iyer AM, Ravizza T, Beltrame L, Paracchini L, Marchini S, et al.
Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy. Neurobiol Dis 2017;99:12-23. doi: 10.1016/j.nbd.2016.12.007.
Bot AM, Dębski KJ, Lukasiuk K. Alterations in miRNA levels in the dentate gyrus in epileptic rats. PLoS One 2013;8:e76051. doi: 10.1371/journal.pone.0076051.
McKiernan RC, Jimenez-Mateos EM, Bray I, Engel T, Brennan GP, Sano T, et al.
Reduced mature microRNA levels in association with dicer loss in human temporal lobe epilepsy with hippocampal sclerosis. PLoS One 2012;7:e35921. doi: 10.1371/journal.pone.0035921.
Rossato M, Curtale G, Tamassia N, Castellucci M, Mori L, Gasperini S, et al.
IL-10-induced microRNA-187 negatively regulates TNF-α, IL-6, and IL-12p40 production in TLR4-stimulated monocytes. Proc Natl Acad Sci U S A 2012;109:E3101-10. doi: 10.1073/pnas.1209100109.
Song YJ, Tian XB, Zhang S, Zhang YX, Li X, Li D, et al.
Temporal lobe epilepsy induces differential expression of hippocampal miRNAs including let-7e and miR-23a/b. Brain Res 2011;1387:134-40. doi: 10.1016/j.brainres.2011.02.073.
Bazzoni F, Rossato M, Fabbri M, Gaudiosi D, Mirolo M, Mori L, et al.
Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals. Proc Natl Acad Sci U S A 2009;106:5282-7. doi: 10.1073/pnas.0810909106.
Huang LG, Zou J, Lu QC. Silencing rno-miR-155-5p in rat temporal lobe epilepsy model reduces pathophysiological features and cell apoptosis by activating sestrin-3. Brain Res 2017. pii: S0006-8993(17) 30514-0. doi: 10.1016/j.brainres.2017.11.019.
Sun J, Gao X, Meng D, Xu Y, Wang X, Gu X, et al.
Antagomirs targeting microRNA-134 increase limk1 levels after experimental seizures in vitro
and in vivo
. Cell Physiol Biochem 2017;43:636-43. doi: 10.1159/000480647.
Avansini SH, de Sousa Lima BP, Secolin R, Santos ML, Coan AC, Vieira AS, et al.
MicroRNA hsa-miR-134 is a circulating biomarker for mesial temporal lobe epilepsy. PLoS One 2017;12:e0173060. doi: 10.1371/journal.pone.0173060.
Jimenez-Mateos EM, Arribas-Blazquez M, Sanz-Rodriguez A, Concannon C, Olivos-Ore LA, Reschke CR, et al.
MicroRNA targeting of the P2X7 purinoceptor opposes a contralateral epileptogenic focus in the hippocampus. Sci Rep 2015;5:17486. doi: 10.1038/srep17486.
Wang W, Wang X, Chen L, Zhang Y, Xu Z, Liu J, et al.
The microRNA miR-124 suppresses seizure activity and regulates CREB1 activity. Expert Rev Mol Med 2016;18:e4. doi: 10.1017/erm.2016.3.
Wang D, Li Z, Zhang Y, Wang G, Wei M, Hu Y, et al.
Targeting of microRNA-199a-5p protects against pilocarpine-induced status epilepticus and seizure damage via SIRT1-p53 cascade. Epilepsia 2016;57:706-16. doi: 10.1111/epi.13348.
Zheng H, Tang R, Yao Y, Ji Z, Cao Y, Liu Z, et al.
MiR-219 protects against seizure in the kainic acid model of epilepsy. Mol Neurobiol 2016;53:1-7. doi: 10.1007/s12035-014-8981-5.
Caban C, Khan N, Hasbani DM, Crino PB. Genetics of tuberous sclerosis complex: Implications for clinical practice. Appl Clin Genet 2017;10:1-8. doi: 10.2147/TACG.S90262.
Medel-Matus JS, Cortijo-Palacios LX, Álvarez-Croda DM, Martínez-Quiroz J, López-Meraz ML. Interleukin-1ß, seizures and neuronal cell death. Rev Peru Med Exp Salud Publica 2013;30:262-7.
Kanter-Schlifke I, Georgievska B, Kirik D, Kokaia M. Seizure suppression by GDNF gene therapy in animal models of epilepsy. Mol Ther 2007;15:1106-13. doi: 10.1038/sj.mt.6300148.
Hosford BE, Liska JP, Danzer SC. Ablation of newly generated hippocampal granule cells has disease-modifying effects in epilepsy. J Neurosci 2016;36:11013-23. doi: 10.1523/JNEUROSCI.1371-16.2016.
Shetty AK, Upadhya D. GABA-ergic cell therapy for epilepsy: Advances, limitations and challenges. Neurosci Biobehav Rev 2016;62:35-47. doi: 10.1016/j.neubiorev.2015.12.014.
[Table 1], [Table 2]