Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel K_v1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.     

Links between Immune Cells from the Periphery and the Brain in the Pathogenesis of Epilepsy: A Narrative Review

Accumulating evidence has demonstrated that the pathogenesis of epilepsy is linked to neuroinflammation and cerebrovascular dysfunction. Peripheral immune cell invasion into the brain, along with these responses, is implicitly involved in epilepsy. This review explored the current literature on the association between the peripheral and central nervous systems in the pathogenesis of epilepsy, and highlights novel research directions for therapeutic interventions targeting these reactions. Previous experimental and human studies have demonstrated the activation of the innate and adaptive immune responses in the brain. The time required for monocytes (responsible for innate immunity) and T cells (involved in acquired immunity) to invade the central nervous system after a seizure varies. Moreover, the time between the leakage associated with blood–brain barrier (BBB) failure and the infiltration of these cells varies. This suggests that cell infiltration is not merely a secondary disruptive event associated with BBB failure, but also a non-disruptive event facilitated by various mediators produced by the neurovascular unit consisting of neurons, perivascular astrocytes, microglia, pericytes, and endothelial cells. Moreover, genetic manipulation has enabled the differentiation between peripheral monocytes and resident microglia, which was previously considered difficult. Thus, the evidence suggests that peripheral monocytes may contribute to the pathogenesis of seizures.     

基于排列熵和支持向量机的癫痫发作预测研究

针对癫痫发作给病人带来的巨大伤害,为临床治疗留下足够空余时间,提出一个可以预测癫痫发作的系统模型。对21名癫痫病人进行研究,提取具有较低算法复杂度的排列熵构成特征向量,将其输入支持向量机（support vector machine,SVM）训练出学习模型,用来识别发作期样本,利用投票机制充分考虑病人差异来判断所处状态,最终实现癫痫的实时预测。结果表明,其中81%的发作可以提前平均50多分钟预测到,且具有较低的误报率。为癫痫发作预测系统的理论研究打下坚实基础。     

癫痫脑电的递归确定性分析

利用排序递归图的分析方法对癫痫脑电进行了确定性(DET)的分析,得出癫痫头皮脑电(EEG)的DET高于健康EEG。DET特征的差异性在局部导联上更明显,局部导联的DET特征可以作为癫痫疾病的自动诊断特征。通过分析发作阶段和发作间隙皮层脑电(ECoG)的DET,得出整个频带的DET差别不大,而在beta频带,发作阶段的确定性明显高于发作间隙的DET。Beta频带的DET特征可以作为癫痫发作的预测特征。研究结果为癫痫疾病的自动诊断和癫痫发作预测提供了理论依据。     

Classification of focal and nonfocal EEG signals using ANFIS classifier for epilepsy detection

The electroencephalogram (EEG) is the frequently used signal to detect epileptic seizures in the brain. For a successful epilepsy surgery, it is very essential to localize epileptogenic area in the brain. The signals from the epileptogenic area are focal signals and signals from other area of the brain region nonfocal signals. Hence, the classification of focal and nonfocal signals is important for locating the epileptogenic area for epilepsy surgery. In this article, we present a computer aided automatic detection and classification method for focal and nonfocal EEG signal. The EEG signal is decomposed by Dual Tree Complex Wavelet Transform (DT‐CWT) and the features are computed from the decomposed coefficients. These features are trained and classified using Adaptive Neuro Fuzzy Inference System (ANFIS) classifier. The proposed system achieves 98% sensitivity, 100% specificity, and 99% accuracy for EEG signal classification. The experimental results are presented to show the effectiveness of the proposed classification method to classify the focal and nonfocal EEG signals. © 2016 Wiley Periodicals, Inc. Int J Imaging Syst Technol, 26, 277–283, 2016     

应用Simulink模拟耦合神经元的同步活动

癫痫是一组由神经元异常放电所引起的短暂中枢神经系统功能异常为特征的慢性脑部疾病。其发病的原因正是由于神经元集体的异常同步放电行为所致。以FitzHugh-Nagumo神经元为例,使用simulink对耦合神经元的同步活动进行模拟,供相关研究人员进行研究。     

Memory for Visuospatial Location Following Selective Hippocampal Sclerosis: The Use of Different Coordinate Systems.

This study addressed the role of the medial temporal lobe regions and, more specifically, the contribution of the human hippocampus in memory for body-centered (egocentric) and environment-centered (allocentric) spatial location. Twenty-one patients with unilateral atrophy of the hippocampus secondary to long-standing epilepsy (left, n = 7; right, n = 14) and 15 normal control participants underwent 3 tasks measuring recall of egocentric or allocentric spatial location. Patients with left hippocampal sclerosis were consistently impaired in the allocentric conditions of all 3 tasks but not in the egocentric conditions. Patients with right hippocampal sclerosis were impaired to a lesser extent and in only 2 of the 3 tasks. It was concluded that hippocampal structures are crucial for allocentric, but not egocentric, spatial memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Whole Exome Sequencing Identifies a Heterozygous Variant in the Cav1.3 Gene CACNA1D Associated with Familial Sinus Node Dysfunction and Focal Idiopathic Epilepsy

Cav1.3 voltage-gated L-type calcium channels (LTCCs) are involved in cardiac pacemaking, hearing and hormone secretion, but are also expressed postsynaptically in neurons. So far, homozygous loss of function mutations in CACNA1D encoding the Cav1.3 α₁-subunit are described in congenital sinus node dysfunction and deafness. In addition, germline mutations in CACNA1D have been linked to neurodevelopmental syndromes including epileptic seizures, autism, intellectual disability and primary hyperaldosteronism. Here, a three-generation family with a syndromal phenotype of sinus node dysfunction, idiopathic epilepsy and attention deficit hyperactivity disorder (ADHD) is investigated. Whole genome sequencing and functional heterologous expression studies were used to identify the disease-causing mechanisms in this novel syndromal disorder. We identified a heterozygous non-synonymous variant (p.Arg930His) in the CACNA1D gene that cosegregated with the combined clinical phenotype in an autosomal dominant manner. Functional heterologous expression studies showed that the CACNA1D variant induces isoform-specific alterations of Cav1.3 channel gating: a gain of ion channel function was observed in the brain-specific short CACNA1D isoform (Cav1.3_S), whereas a loss of ion channel function was seen in the long (Cav1.3_L) isoform. The combined gain-of-function (GOF) and loss-of-function (LOF) induced by the R930H variant are likely to be associated with the rare combined clinical and syndromal phenotypes in the family. The GOF in the Cav1.3_S variant with high neuronal expression is likely to result in epilepsy, whereas the LOF in the long Cav1.3_L variant results in sinus node dysfunction.     

Variable Expression of GABAA Receptor Subunit Gamma 2 Mutation in a Nuclear Family Displaying Developmental and Encephalopathic Phenotype

Mutations in GABA_A receptor subunit genes (GABRs) are a major etiology for developmental and epileptic encephalopathies (DEEs). This article reports a case of a genetic abnormality in GABRG2 and updates the pathophysiology and treatment development for mutations in DEEs based on recent advances. Mutations in GABRs, especially in GABRA1, GABRB2, GABRB3, and GABRG2, impair GABAergic signaling and are frequently associated with DEEs such as Dravet syndrome and Lennox–Gastaut syndrome, as GABAergic signaling is critical for early brain development. We here present a novel association of a microdeletion of GABRG2 with a diagnosed DEE phenotype. We characterized the clinical phenotype and underlying mechanisms, including molecular genetics, EEGs, and MRI. We then compiled an update of molecular mechanisms of GABR mutations, especially the mutations in GABRB3 and GABRG2 attributed to DEEs. Genetic therapy is also discussed as a new avenue for treatment of DEEs through employing antisense oligonucleotide techniques. There is an urgent need to define treatment targets and explore new treatment paradigms for the DEEs, as early deployment could alleviate long-term disabilities and improve quality of life for patients. This study highlights biomolecular targets for future therapeutic interventions, including via both pharmacological and genetic approaches.