Rational Small Molecule Treatment for Genetic Epilepsies

Genetic testing has yielded major advances in our understanding of the causes of epilepsy. Seizures remain resistant to treatment in a significant proportion of cases, particularly in severe, childhood-onset epilepsy, the patient population in which an underlying causative genetic variant is most likely to be identified. A genetic diagnosis can be explanatory as to etiology, and, in some cases, might suggest a therapeutic approach; yet, a clear path from genetic diagnosis to treatment remains unclear in most cases. Here, we discuss theoretical considerations behind the attempted use of small molecules for the treatment of genetic epilepsies, which is but one among various approaches currently under development. We explore a few salient examples and consider the future of the small molecule approach for genetic epilepsies. We conclude that significant additional work is required to understand how genetic variation leads to dysfunction of epilepsy-associated protein targets, and how this impacts the function of diverse subtypes of neurons embedded within distributed brain circuits to yield epilepsy and epilepsy-associated comorbidities. A syndrome- or even variant-specific approach may be required to achieve progress. Advances in the field will require improved methods for large-scale target validation, compound identification and optimization, and the development of accurate model systems that reflect the core features of human epilepsy syndromes, as well as novel approaches towards clinical trials of such compounds in small rare disease cohorts.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-021-01110-w.     

酸敏感离子通道功能及其对癫癇的影响

酸敏感离子通道是近年来发现的氢离子门控性钠离子通道,目前共计发现4个基因编码的6种亚型,均于细胞外p H值降低时开放。酸敏感离子通道在炎症、脑缺血、疼痛等病理过程中起重要作用,癫癇发作时细胞外p H值明显降低,使酸敏感离子通道开放;而该通道在终止癫癇发作过程中亦发挥重要作用。目前已发现酸敏感离子通道特异性抑制剂,并可能成为药物研制之新靶点。     

Cacna1g is a genetic modifier of epilepsy in a mouse model of Dravet syndrome

Dravet syndrome, an early onset epileptic encephalopathy, is most often caused by de novo mutation of the neuronal voltage‐gated sodium channel gene SCN1A. Mouse models with deletion of Scn1a recapitulate Dravet syndrome phenotypes, including spontaneous generalized tonic–clonic seizures, susceptibility to seizures induced by elevated body temperature, and elevated risk of sudden unexpected death in epilepsy. Importantly, the epilepsy phenotype of Dravet mouse models is highly strain‐dependent, suggesting a strong influence of genetic modifiers. We previously identified Cacna1g, encoding the Cav3.1 subunit of the T‐type calcium channel family, as an epilepsy modifier in the Scn2a^Q54 transgenic epilepsy mouse model. In this study, we asked whether transgenic alteration of Cacna1g expression modifies severity of the Scn1a^+/? Dravet phenotype. Scn1a^+/? mice with decreased Cacna1g expression showed partial amelioration of disease phenotypes with improved survival and reduced spontaneous seizure frequency. However, reduced Cacna1g expression did not alter susceptibility to hyperthermia‐induced seizures. Transgenic elevation of Cacna1g expression had no effect on the Scn1a^+/? epilepsy phenotype. These results provide support for Cacna1g as a genetic modifier in a mouse model of Dravet syndrome and suggest that Cav3.1 may be a potential molecular target for therapeutic intervention in patients.     

Benign idiopathic partial epilepsy and brain lesion

A 14-year-old girl had severe head trauma from a dog bite at the age of 9 days. This resulted in extensive brain damage, tetraplegia, mental retardation, and epilepsy. The seizures were of rolandic type, and the EEG showed multifocal sharp waves. The course was benign. The initial diagnosis of a pure symptomatic epilepsy was revised after demonstrating typical benign focal sharp waves in the EEG of the healthy sister. Thus a phenocopy of a benign partial epilepsy by the brain lesion could be excluded with sufficient certainty. This observation allows the conclusion that the genetic disposition underlying the sharp-wave trait characteristic of benign partial epilepsies can be involved also in the pathogenesis of seemingly pure symptomatic epilepsies. EEG studies on siblings of such patients are needed to exclude possible phenocopies.     

Evidence for distinct genetic influences on generalized and localization-related epilepsy

PURPOSE: Determining the existence of syndrome-specific genetic factors in epilepsy is essential for phenotype definition in genetic linkage studies, and informs research on basic mechanisms. Analysis of concordance of epilepsy syndromes in families has been used to assess shared versus distinct genetic influences on generalized epilepsy (GE) and localization-related epilepsy (LRE). However, it is unclear how the results should be interpreted in relation to specific genetic hypotheses. METHODS: To assess evidence for distinct genetic influences on GE and LRE, we examined concordance of GE and LRE in 63 families containing multiple individuals with idiopathic or cryptogenic epilepsy, drawn from the Epilepsy Family Study of Columbia University. To control for the number of concordant families expected by chance, we used a permutation test to compare the observed number with the number expected from the distribution of individuals with GE and LRE in the study families. RESULTS: Of the families, 62% were concordant for epilepsy type, and 38% were discordant. In all analyses, the proportion of concordant families was significantly greater than expected. CONCLUSIONS: This suggests that some genetic influences predispose specifically to either GE or LRE. Because of the ascertainment bias resulting from the selection of families containing multiple individuals with epilepsy, we could not test whether there are also shared genetic influences on these two epilepsy subtypes. Population-based studies will be needed to explore these results further.     

全面性癫(癎)伴热性惊厥附加症的临床与分子遗传学研究

目的 探讨全面性癫痫伴热性惊厥附加症（generalized epilepsy with febrile seizures plus，GEFS＋）的临床特点与分子遗传学特征。方法 收集1个GEFS＋家系所有成员的血样标本，选择3种候选基因（SCN1B、SCN1A、GABRG2）附近的11个微卫星标记物D19S414、D19S220、D19S902、D2S156、D2S142、D2S2330、D2S335、D2S364、D5s436、D5S422和D5S400，应用PCR得到扩增产物片段，根据相应产物大小的不同，得到每个样本的基因型；用连锁分析软件的MLINK程序计算每个标记的LOD值，根据两点间的LOD值判断连锁关系，探讨GEFS＋的可能致病基因与染色体19q13．1、2q24以及5q31．1-q33．1区域的连锁关系。连锁分析限定性定位后再进行GABRG2基因突变分析。结果 （1）GEFS＋家系临床特征：家系成员4代共20人。第Ⅱ～Ⅳ代中患者6例（男女各3例）；发作表型为热性惊厥（FS）1例、热性惊厥附加症（FS＋）3例、Fs＋伴失神发作1例，发作类型不详1例，未见严重发作类型。（2）GEFS＋基因连锁分析结果：①D2S335因不能进行基因分型，给予舍弃；②D19S和D2S多个LOD值小于0，在重组率为0．0时D19S220、D19s902、D2S364处的LOD值均小于-2；D19S414、D2S142、D2S156、D2S2330、D5S422处的LOD值小于0，基本可以排除连锁关系；③D5S436、D5$400处的LOD值在重组率为0．0时大于-2，但小于3，既不能排除也不能肯定其连锁关系；该家系致病基因与报道的GEFS＋定位区域19q13．1和2q24区域没有连锁关系；与5q31．1．q33．1区域的连锁关系有待于进一步明确。（3）GABRG2基因的测序结果（先证者）：显示11外显子一处同义突变（c．1420C〉T），未见GABRG2基因致病突变。结论 该GEFS＋家系呈现不同的临床表型，其疾病基因与3种候选基因SCN1A、SCN1B、GABARG2的突变无关；表明GFFS＋具有表型的异质性与遗传的异质性，其病因学有待进一步研究。     

Autism and epilepsy: Historical perspective

Autism spectrum disorders (ASD) and epilepsy co-occur in approximately 30% of individuals with either ASD or epilepsy. While there is no single unifying ASD–epilepsy phenotype, understanding potential commonalities in subgroups of children with an ASD–epilepsy phenotype will help us disentangle the pathophysiology of both ASD and epilepsy. Throughout this brief historical perspective we selectively review critical trends in ASD–epilepsy research and highlight challenges to clinical and research efforts including terminology, heterogeneity of both ASD and epilepsy, and lack of careful characterization of children affected with both ASD and epilepsy. These complex issues continue to burden research on the diagnosis, neurobiology and management of children with ASD and epilepsy. A key concept that has emerged during the past 40 years is the strong association between intellectual disability and a higher prevalence of epilepsy in individuals with ASD. In addition, the two peaks of seizure onset, one in early childhood and one in adolescence and continuing through adulthood may be unique to individuals with ASD. The overlap of language and autistic regression to epilepsy, EEG epileptiform activity, sleep, and to epileptic encephalopathies such as Landau–Kleffner syndrome continue to be controversial areas of research and of clinical interest. An emerging consensus is that shared developmental genetic, molecular and pathophysiological mechanisms exist and account for the common co-occurrence of ASD and epilepsy.     

Genetics of Idiopathic Generalized Epilepsies

Summary:  The idiopathic generalized epilepsies (IGEs) are considered to be primarily genetic in origin. They encompass a number of rare mendelian or monogenic epilepsies and more common forms which are familial but manifest as complex, non-mendelian traits. Recent advances have demonstrated that many monogenic IGEs are ion channelopathies. These include benign familial neonatal convulsions due to mutations in KCNQ2 or KCNQ3 , generalized epilepsy with febrile seizures plus due to mutations in SCN1A , SCN2A , SCN1B , and GABRG2 , autosomal-dominant juvenile myoclonic epilepsy (JME) due to a mutation in GABRA1 and mutations in CLCN2 associated with several IGE sub-types. There has also been progress in understanding the non-mendelian IGEs. A haplotype in the Malic Enzyme 2 gene, ME2 , increases the risk for IGE in the homozygous state. Five missense mutations have been identified in EFHC1 in 6 of 44 families with JME. Rare sequence variants have been identified in CACNA1H in sporadic patients with childhood absence epilepsy in the Chinese Han population. These advances should lead to new approaches to diagnosis and treatment.     

The impact of genetics on the classification of epilepsy syndromes

Recent progress in the genetics of epilepsies may potentially provide important insights into biologic processes underlying epileptogenesis. However, the genetic etiology underlying epilepsy remains largely unknown, and the impact of available genetic data on the nosology of epilepsy is still limited. Therefore, at present, classification of epileptic disorders should be mainly based on electroclinical features. In the future, it is likely that the investigation of familial traits will lead to the definition of novel syndromes and that genotype–phenotype correlations in inherited conditions will shed light on the variable expressivity of epileptic disorders. Moreover, the discovery of new epilepsy genes may allow assessment of whether different phenotypes are etiologically linked.     

离子通道变异与癫痫病

离子通道是神经系统和其它可兴奋组织(肌肉和腺体)产生兴奋和行使功能活动的核心基本物质之一。因编码离子通道基因的突变所导致的各类先天性疾病被称之为通道病因学。临床上常见的先天性癫痫综合征多属于通道病。先天性癫痫占癫痫人群的40％，常见的有以下几种：由N型乙酰胆碱受体CHRNA4或CHRNB亚基突变所致的常染色体显性夜间额叶癫痫：因电压门控钾通道KCNQ2和KCNQ3缺陷所致的良性家族性新生儿惊厥；因电压门控钠通道SCN1B．SCN1A和SCN2A亚基以及GABA受体GABRG2亚基突变诱发的高热抽搐全身型癫痫叠加综合征：南电压门控氯通道(C1C2突变)和GABAA受体或亚基突变所致的几种特发性全身性癫痫：此外，近来还发现了与电压门控钾通道KCNA1有关的另一种与1型共济失调伴发的局限性癫痫。研究分析先天性癫痫家系基因遗传谱及其突变通道的电生理特性，有利于更深入地认识和了解先天性癫痫的通道突变发病机制．制定新的抗癫痫策略，开发针对性抗癫痫新药。本文将对先天性癫痫的通道病因学研究进展作一简要梳理。     

有癫痫发作的脑型血吸虫病的头颅CT检查和临床表现

目的评价头颅ＣＴ对有癫痫发作的脑型血吸虫病的诊断价值。方法选择５４例有癫痫发作并经临床确诊的脑型血吸虫病，其中大发作２６例，局限运动型癫痫２６例，颞叶癫痫２例。全部病例行头颅ＣＴ检查，并与他们的临床表现、分型、治疗和预后进行比较。结果头颅ＣＴ异常４４例，异常ＣＴ随本病分型不同而有差异。结论头颅ＣＴ检查不但有助于脑型血吸虫病致癫痫病人的诊断，而且对本病的鉴别诊断、分型和指导治疗亦有参考价值。     

Impact of severe epilepsy on development: Recovery potential after successful early epilepsy surgery

Purpose: Epilepsy surgery in young children with focal lesions offers a unique opportunity to study the impact of severe seizures on cognitive development during a period of maximal brain plasticity, if immediate control can be obtained. We studied 11 children with early refractory epilepsy (median onset, 7.5 months) due to focal lesion who were rendered seizure‐free after surgery performed before the age of 6 years. Methods: The children were followed prospectively for a median of 5 years with serial neuropsychological assessments correlated with electroencephalography (EEG) and surgery‐related variables. Results: Short‐term follow‐up revealed rapid cognitive gains corresponding to cessation of intense and propagated epileptic activity [two with early catastrophic epilepsy; two with regression and continuous spike‐waves during sleep (CSWS) or frontal seizures]; unchanged or slowed velocity of progress in six children (five with complex partial seizures and frontal or temporal cortical malformations). Longer‐term follow‐up showed stabilization of cognitive levels in the impaired range in most children and slow progress up to borderline level in two with initial gains. Discussion: Cessation of epileptic activity after early surgery can be followed by substantial cognitive gains, but not in all children. In the short term, lack of catch‐up may be explained by loss of retained function in the removed epileptogenic area; in the longer term, by decreased intellectual potential of genetic origin, irreversible epileptic damage to neural networks supporting cognitive functions, or reorganization plasticity after early focal lesions. Cognitive recovery has to be considered as a “bonus,” which can be predicted in some specific circumstances.     

Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage‐gated sodium channel Scn2a

More than 1,200 mutations in neuronal voltage‐gated sodium channel (VGSC) genes have been identified in patients with several epilepsy syndromes. A common feature of genetic epilepsies is variable expressivity among individuals with the same mutation. The Scn2a^Q54 transgenic mouse model has a mutation in Scn2a that results in spontaneous epilepsy. Scn2a^Q54 phenotype severity varies depending on the genetic strain background, making it a useful model for identifying and characterizing epilepsy modifier genes. Scn2a^Q54 mice on the [C57BL/6JxSJL/J]F1 background exhibit earlier seizure onset, elevated spontaneous seizure frequency, and decreased survival compared to Scn2a^Q54 mice congenic on the C57BL/6J strain. Genetic mapping and RNA‐Seq analysis identified Cacna1g as a candidate modifier gene at the Moe1 locus, which influences Scn2a^Q54 phenotype severity. In this study, we evaluated the modifier potential of Cacna1g, encoding the Cav3.1 voltage‐gated calcium channel, by testing whether transgenic alteration of Cacna1g expression modifies severity of the Scn2a^Q54 seizure phenotype. Scn2a^Q54 mice exhibited increased spontaneous seizure frequency with elevated Cacna1g expression and decreased seizure frequency with decreased Cacna1g expression. These results provide support for Cacna1g as an epilepsy modifier gene and suggest that modulation of Cav3.1 may be an effective therapeutic strategy.     

颅脑损伤后早、晚期癫痫

目的：探讨颅脑损伤后早期癫痫（ＥＥｐ）、晚期癫痫（ＬＥｐ）发生的相关因素。方法：通过统计学上数据处理，研究ＥＥｐ、ＬＥｐ与年龄、损伤类型、损伤部位、ＧＣＳ的关系，以及对药物治疗与手术治疗效果进行比较。结果：ＥＥｐ、ＬＥｐ的发生与年龄无显著差异（Ｐ＞００５），与损伤类型、损伤部位及ＧＣＳ有显著性差异（Ｐ＜００１），ＥＥｐ与ＬＥｐ的药物治疗（Ｐ＜００１）及ＬＥｐ的药物疗效与手术疗效（Ｐ＜００１）有显著差异。结论：颅脑损伤后ＥＥｐ、ＬＥｐ与年龄无关，ＬＥｐ与开放型颅脑损伤密切相关，发生率高，额叶后部、顶叶损伤后ＥＥｐ、ＬＥｐ发生均比其它部位高。提出颅脑损伤后应早期抗癫痫治疗，ＬＥｐ药物无效者应施行手术治疗。     

The contribution of in vitro studies to the understanding of epilepsy

The slice technique has turned out to be a valuable tool in the study of fundamental epileptic processes. Intracellular recording from brain tissue in vitro may be maintained for hours. The effect of changes in the perfusion medium may be studied easily without interference from the blood-brain barrier and tissue from different brain regions may be studied in isolation. Generally, brain cells in slices behave as brain cells in vivo in spite of the obvious possibilities for distorted metabolism. The cellular basis of the epileptic process is believed to be large depolarizing potentials. Although similar potentials recorded from cells in slices have been shown to be synaptic potentials, abnormal membrane properties are also induced by epileptogenic substances. The spread of the epileptic process may occur by direct electrical coupling via gap junctions, by local increases in extracellular potassium concentration or by synaptic transmission. Reduced GABA'ergic inhibition, account, at least in part, for epileptic discharges induced by epileptogenic drugs. The role for this mechanism in naturally occurring epilepsy is unknown, but it is probably involved somehow. GABA increases the conductance of the neuronal membrane to Cl. In hippocampal dendrites, it probably in addition increases the conductance to Na because here the induced inhibitory response is depolarizing. The somatic and dendritic membranes are also different in their excitatory responses. In the hippocampus, calcium spikes predominate in the dendrites whereas steady discharges consisting of sodium spikes are characteristic of the soma. The same receptor complex seems to be involved in dendrites and soma in the enhancing effect of benzodiazepines on GABA responses. However, GABA-benzodiazepine receptor complexes in other parts of the brain are probably constituted in different ways. We know of many disturbances in the brain which may be involved in epilepsy. A single critical deviation from normal physiology in naturally occurring epilepsy has not been identified. Possibly, the process may be initiated by any one of several factors, which all take part when the disease is established.