Non-ion Channel Genes Research Articles

Drug-resistant 'Non-Lesional' Visual Sensitive Epilepsies of Childhood - Electroclinical Phenotype-Genotype Associations.

Sporadic nonlesional intractable visual-sensitive epilepsies of childhood represent a challenging subset of epilepsies in terms of management and prognostication given a propensity to evolve as epileptic encephalopathy. To study the genetic heterogeneity of drug-resistant visual sensitive epilepsy of childhood. A retrospective chart review was conducted on patients in the pediatric age group between 2016 and 2018, with drug-resistant epilepsy (DRE) and video electro encephalography (VEEG) documented reflex photosensitivity, eye-condition sensitivity. Those patients who underwent genetic testing with targeted next-generation sequencing using an epilepsy gene panel were selected. During the study period, out of 96 patients who underwent genetic testing, 4 patients (4.17%) with sporadic DRE presented with clinical phenotypes ranging from myoclonic-atonic epilepsy, generalized epilepsy with eyelid myoclonia as well as febrile and unprovoked seizures, along with visual sensitivity. Video EEG documented abnormalities ranged from occipital, posterior-cortex and generalized discharges with "eyes-closed state" triggered, self-induced "smart-phone" triggered, photosensitive focal-onset and generalized myoclonic seizures. Accompanying developmental impairment was noted. These patients who were investigated with clinical exome sequencing were detected to have mutations in not only SCN1A genes (pathogenic exonic and intronic variants) but also CHD2 (pathogenic) and CACNA1H genes (a familial febrile-seizure susceptibility variant of unknown significance). The series highlights the complex genetics of drug-resistant visual-sensitive epilepsy of childhood. Such genotype-phenotype associations throw light on the role of ion-channel and non-ion channel genes on reflex epileptogenesis in this group of patients.

Voltage Gated Sodium Channel Genes in Epilepsy: Mutations, Functional Studies, and Treatment Dimensions.

Genetic epilepsy occurs as a result of mutations in either a single gene or an interplay of different genes. These mutations have been detected in ion channel and non-ion channel genes. A noteworthy class of ion channel genes are the voltage gated sodium channels (VGSCs) that play key roles in the depolarization phase of action potentials in neurons. Of huge significance are SCN1A, SCN1B, SCN2A, SCN3A, and SCN8A genes that are highly expressed in the brain. Genomic studies have revealed inherited and de novo mutations in sodium channels that are linked to different forms of epilepsies. Due to the high frequency of sodium channel mutations in epilepsy, this review discusses the pathogenic mutations in the sodium channel genes that lead to epilepsy. In addition, it explores the functional studies on some known mutations and the clinical significance of VGSC mutations in the medical management of epilepsy. The understanding of these channel mutations may serve as a strong guide in making effective treatment decisions in patient management.

Advance in molecular genetic research on generalized epilepsies

Genetic generalized epilepsies (GGEs) are a group of epilepsy syndromes caused by genetic factors. A few of GGEs conform to the Mendelian patterns, while most of them show polygene inheritance. Researchers initially found that most of the genes associated with GGEs are related to ion channels including voltage-gated sodium channels, potassium channels, calcium channels and chloride channels, and ligand-gated gamma-aminobutyric acid receptor channels. Further researches have shown that certain non-ion channel genes are also related to GGEs, and that de novo mutations and copy number variants also play an important role in the pathogenesis of GGEs. Application of next- and third-generation sequencing promoted delineation of the molecular genetics of the GGEs, but also brought more challenges. Genetic findings have provided an important basis for the elucidation of the pathogenesis, clinical diagnosis and precise treatment of GGEs. This paper provided a review for recent progress made in molecular genetics of GGEs.

Genetic and epigenetic mechanisms of epilepsy: a review.

Epilepsy is a common episodic neurological disorder or condition characterized by recurrent epileptic seizures, and genetics seems to play a key role in its etiology. Early linkage studies have localized multiple loci that may harbor susceptibility genes to epilepsy, and mutational analyses have detected a number of mutations involved in both ion channel and nonion channel genes in patients with idiopathic epilepsy. Genome-wide studies of epilepsy have found copy number variants at 2q24.2-q24.3, 7q11.22, 15q11.2-q13.3, and 16p13.11-p13.2, some of which disrupt multiple genes, such as NRXN1, AUTS2, NLGN1, CNTNAP2, GRIN2A, PRRT2, NIPA2, and BMP5, implicated for neurodevelopmental disorders, including intellectual disability and autism. Unfortunately, only a few common genetic variants have been associated with epilepsy. Recent exome-sequencing studies have found some genetic mutations, most of which are located in nonion channel genes such as the LGI1, PRRT2, EFHC1, PRICKLE, RBFOX1, and DEPDC5 and in probands with rare forms of familial epilepsy, and some of these genes are involved with the neurodevelopment. Since epigenetics plays a role in neuronal function from embryogenesis and early brain development to tissue-specific gene expression, epigenetic regulation may contribute to the genetic mechanism of neurodevelopment through which a gene and the environment interacting with each other affect the development of epilepsy. This review focused on the analytic tools used to identify epilepsy and then provided a summary of recent linkage and association findings, indicating the existence of novel genes on several chromosomes for further understanding of the biology of epilepsy.

The Molecular Biology of Genetic-Based Epilepsies

Epilepsy is one of the most common neurological disorders characterized by abnormal electrical activity in the central nervous system. The clinical features of this disorder are recurrent seizures, difference in age onset, type, and frequency, leading to motor, sensory, cognitive, psychic, or autonomic disturbances. Since the discovery of the first monogenic gene mutation in 1995, it is proposed that genetic factor plays an important role in the mechanism of epilepsy. Genes discovered in idiopathic epilepsies encode for ion channel or neurotransmitter receptor proteins, whereas syndromes with epilepsy as a main feature are caused by genes that are involved in functions such as cortical development, mitochondrial function, and cell metabolism. The identification of these monogenic epilepsy-causing genes provides new insight into the pathogenesis of epilepsies. Although most of the identified gene mutations present a monogenic inheritance, most of idiopathic epilepsies are complex genetic diseases exhibiting a polygenic or oligogenic inheritance. This article reviews recent genetic and molecular progresses in exploring the pathogenesis of epilepsy, with special emphasis on monogenic epilepsy-causing genes, including voltage-gated channels (Na(+), K(+), Ca(2+), Cl(-), and HCN), ligand-gated channels (nicotinic acetylcholine and GABAA receptors), non-ion channel genes as well as the mitochondrial DNA genes. These progresses have improved our understanding of the complex neurological disorder.

Celf Expression In Epilepsy Linked To Sodium Channels

Evaluation of: Sun W, Wagnon JL, Mahaffey CL et al. Aberrant sodium channel activity in the complex seizure disorder of Celf4 mutant mice. J. Physiol. 591(1), 241–255 (2013). The choreographed expression of ion channels is critical for normal brain activity, as evidenced by the range of epilepsy syndromes associated with ion channel genetic variation. As large-scale sequencing efforts, such as Epi4K and EuroEPINOMICS, systematically deconstruct epilepsy genomes, it is likely that further progress will be made in our understanding of how ion channel dysfunction results in epilepsy. By contrast, our knowledge of non-ion channel genes in epilepsy is far less advanced, a problem frequently compounded by the lack of understanding of the basic neurobiology of these genes. Sun et al. address this shortcoming by providing an elegant account of how a key RNA metabolism gene, Celf4, gives rise to seizures by the regulation of axonal ion channels. This has implications for epilepsy genomics, where a priori knowledge of the gene networks that participate in seizure genesis is critical for bioinformatics filtering used to identify diagnostic and prognostic variants. The convergence on an ion channel target affirms their central role in seizure genesis but, more importantly, raises the idea that drugs that target key regulators such as CELF4 could be effective in epilepsy.

Electroclinical characterization of epileptic seizures in leucine-rich, glioma-inactivated 1-deficient mice

Mutations of the LGI1 (leucine-rich, glioma-inactivated 1) gene underlie autosomal dominant lateral temporal lobe epilepsy, a focal idiopathic inherited epilepsy syndrome. The LGI1 gene encodes a protein secreted by neurons, one of the only non-ion channel genes implicated in idiopathic familial epilepsy. While mutations probably result in a loss of function, the role of LGI1 in the pathophysiology of epilepsy remains unclear. Here we generated a germline knockout mouse for LGI1 and examined spontaneous seizure characteristics, changes in threshold for induced seizures and hippocampal pathology. Frequent spontaneous seizures emerged in homozygous LGI1−/− mice during the second postnatal week. Properties of these spontaneous events were examined in a simultaneous video and intracranial electroencephalographic recording. Their mean duration was 120 ± 12 s, and behavioural correlates consisted of an initial immobility, automatisms, sometimes followed by wild running and tonic and/or clonic movements. Electroencephalographic monitoring indicated that seizures originated earlier in the hippocampus than in the cortex. LGI1−/− mice did not survive beyond postnatal day 20, probably due to seizures and failure to feed. While no major developmental abnormalities were observed, after recurrent seizures we detected neuronal loss, mossy fibre sprouting, astrocyte reactivity and granule cell dispersion in the hippocampus of LGI1−/− mice. In contrast, heterozygous LGI1+/− littermates displayed no spontaneous behavioural epileptic seizures, but auditory stimuli induced seizures at a lower threshold, reflecting the human pathology of sound-triggered seizures in some patients. We conclude that LGI1+/− and LGI1−/− mice may provide useful models for lateral temporal lobe epilepsy, and more generally idiopathic focal epilepsy.

Genes associated with idiopathic epilepsies: a current overview

Objective: This article aimed to review the latest genes associated with idiopathic focal and generalized epilepsies.Methods: PubMed and Entrez Gene searches pertaining to this work was conducted using specific keyword search terms related to genes and various listed subtopics related to idiopathic epilepsy syndromes.Results: Mutations in the cholinergic receptor, neuronal nicotinic, α2, α4 and β2 subunit genes have been found in autosomal dominant nocturnal frontal lobe epilepsy. Mutations of potassium voltage-gated channel, KQT-like subfamily, members 2 and 3 genes were identified to be responsible for benign familial neonatal seizures. The voltage-gated sodium channel genes and γ-aminobutyric acid receptor α subunit genes may be involved in the pathogenesis of generalized epilepsy with febrile seizure plus. Mutations of γ-aminobutyric acid receptor α1, γ-aminobutyric acid receptor δ, calcium channel voltage-dependent β4 subunit and chloride channel 2 gene are associated with juvenile myoclonic epilepsy. In addition, mutations of leucine-rich, glioma-inactivated 1 gene leads to genetic abnormalities of familial lateral temporal lobe epilepsy. EF-hand domain (C-terminal)-containing 1 gene can cause some patterns of juvenile myoclonic and juvenile absence epilepsies.Discussion: Genetic factors play an important role in idiopathic epilepsy syndromes. Ion channel genes and some non-ion channel genes contribute to the pathogenesis of idiopathic epilepsies. Based on these findings, genetic diagnosis and new treatment strategies to part of idiopathic epilepsies become possible in the future.

Atrial fibrillation: evidence for genetically determined disease

Atrial fibrillation is traditionally regarded as a sporadic, nongenetic disorder. Nevertheless, recent growing evidence points to an important heritable basis for atrial fibrillation, with significant genetic determinants. This paper reviews recent progress in understanding the role of genetic contributors to the pathogenesis of atrial fibrillation and its familial susceptibility. Population-based studies have demonstrated a significant heritable component in atrial fibrillation, with specific contributors including single-gene mutations and single-nucleotide polymorphisms. Variants in both ion-channel and nonion-channel genes have been identified as potential atrial fibrillation-risk determinants. In addition, studies have pointed to interesting combined roles of genetic and environmental factors in atrial fibrillation pathogenesis, providing insights into gene-environment interactions. Clinical studies suggest that individual genetic profiles may determine the therapeutic response of atrial fibrillation. Rapidly evolving work indicates that there are important genetic determinants of atrial fibrillation, and suggests that understanding these determinants will help us both to appreciate better the underlying pathophysiology and to provide new approaches in diagnosis, prevention and treatment of this common cardiac condition.

Bioinformatic analysis of human CNS-expressed ion channels as candidates for episodic nervous system disorders

As monogenic forms of episodic nervous system disorders are often caused by ion channel mutations, we looked for features of human central nervous system (CNS) expressed ion channels that further our understanding of those phenotypes. To this end, we compared human ion channels with other CNS-expressed genes, which we categorized according to the existence of transmembrane domains. When looking at the phylogenetic distribution of these genes, we observed an increased percentage of ion channels that exist in vertebrate genomes while missing in invertebrate genomes. Because we hypothesized that this pattern may relate to a more specific expression, we searched for characteristics of ion channels that indicate a tighter expression regulation. We found that ion channels have longer intron and protein sequences, features typical of genes with more specific expression. In addition, ion channels have increased human-rodent conservation around their transcription start site, as indicated by a higher fraction of conserved noncoding regions. This points to a high relevance of mutations that regulate ion channel expression. When we finally asked whether vertebrate-specific diversification is also displayed by non-ion channel genes with important roles in the CNS, we found a similar phylogenetic distribution. This concordant phylogenetic pattern suggests that vertebrate-specific adaptations may account for a large part of the shared genetic basis of episodic CNS disorders, including monogenic and genetically complex disease manifestations. Consequently, this phylogenetic pattern may contribute to the prioritization of candidate genes in human genetic studies of episodic CNS disorders.

LGI1: a gene involved in epileptogenesis and glioma progression?

The leucine-rich, glioma inactivated gene 1 (LGI1) gene on human chromosome 10q24 was first identified as a candidate tumor suppressor gene for glioma. Surprisingly, mutations in LGI1 were also shown to cause an idiopathic epilepsy syndrome, autosomal dominant lateral temporal lobe epilepsy (ADLTE). LGI1 is one of the only two currently known non-ion channel genes whose mutations cause idiopathic epilepsy in humans. In this review we summarize the current data on structure and function of the LGI1 protein and discuss clinical aspects of ADLTE and their correlation with LGI1. We also propose that the evidence supporting the tumor suppressor role of LGI1 in malignant gliomas is weak and that further work is necessary to establish LGI1 role in glial cells.

Genetics of the epilepsies.

This article reviews the most significant advances in the field of genetics of the epilepsies during the past year, with emphasis on newly identified genes and functional studies leading to new insights into the pathophysiology of epilepsy. Mutations in the chloride channel gene CLCN2 have been associated with the most common forms of idiopathic generalized epilepsies. A mutation in the ATP1A2 sodium potassium ATPase pump gene has been described in a family in which familial hemiplegic migraine and benign familial infantile convulsions partly co-segregate. The leucine-rich, glioma-inactivated 1 gene (LGI1) (also known as epitempin) was found to be responsible for autosomal-dominant lateral temporal lobe epilepsy in additional families. The serine-threonine kinase 9 gene (STK9) was identified as the second gene associated with X-linked infantile spasms. Mutations in the Aristaless-related homeobox gene (ARX) have been recognized as a cause of X-linked infantile spasms and sporadic cryptogenic infantile spasms. A second gene underlying progressive myoclonus epilepsy of Lafora, NHLRC1, was shown to code for a putative E3 ubiquitin ligase. Genes associated with idiopathic generalized epilepsies remain within the ion channel family. Mutations in non-ion channel genes are responsible for autosomal-dominant lateral temporal lobe epilepsy, a form of idiopathic focal epilepsy, malformations of cortical development, and syndromes that combine X-linked mental retardation and epilepsy. Most genetic epilepsies have a complex mode of inheritance, and genes identified so far account only for a minority of families and sporadic cases. Functional studies are leading to a better understanding of the mechanisms underlying hyperexcitability and seizures.

Channelopathies as a genetic cause of epilepsy

This review describes the significant number of new gene associations with epilepsy syndromes that have emerged during the past year, together with additional mutations and new electrophysiological data relating to previously known gene associations. Autosomal dominant juvenile myoclonic epilepsy was demonstrated to be a channelopathy associated with a GABA(A) receptor, alpha1 subunit mutation. Benign familial neonatal infantile seizures were delineated as another channelopathy of infancy, by molecular characterization of sodium channel, alpha2 subunit defects. A sodium channel, alpha2 subunit defect was previously found to be associated with generalized epilepsy with febrile seizures plus. Similarly, the clinical spectrum associated with potassium channel, KQT-like mutations was extended to include the channelopathy myokymia and neonatal epilepsy. Mutations in the non-ion channel genes, leucine-rich, glioma inactivated 1 gene and Aristaless related homeobox gene, have emerged as important causes of their specific syndromes, with mutations in the latter gene frequently underlying X-linked mental retardation with epilepsy. All but one of the idiopathic epilepsies with a known molecular basis are channelopathies. Where the ion channel defects have been identified, however, they generally account for a minority of families and sporadic cases with the syndrome in question. The data suggest that ion channel mutations of large effect are a common cause of rare monogenic idiopathic epilepsies, but are rare causes of common epilepsies. Additive effects of genetic variation, perhaps within the same ion channel gene families, are likely to underlie the common idiopathic generalized epilepsies with complex inheritance. The genetics of epilepsy is progressing rapidly toward a more detailed molecular dissection and definition of syndromes.

Diagnostic value of computerized EMG analysis in assessment of peripheral neuropathy lesion degree

Three nonion channel genes cause two different adolescent myoclonic epilepsies and solve two mysteries of brain biochemistry and clinical epileptology: Why is glycogen absent in neurons in contrast to other cells of the human body? Why do patients with juvenile myoclonic epilepsy (JME), classified as idiopathic, have areas of brain cortex thicker than normal? The first two genes, Laforin (dual specificity phosphatase) and Malin (E3 ubiquitin ligase), working in concert, purge neurons of glycogen and polyglucosan inclusions by polyubiquitination and proteasome-dependent degradation; thus, there is no glycogen in nerve cells. Mutations in Laforin or Malin, when inherited as a recessive gene, cause insoluble glycogen (polyglucosan) to accumulate in nerve cells, cause cell death, produce stimulus-sensitive myoclonias, grand mal and absence seizures, rapid neurologic deterioration and death. The third nonion channel gene, Myoclonin/EFHC1, causes chronic and lifelong adolescent onset juvenile myoclonic epilepsy. Myoclonin/EFHC1, a developmental gene, prunes branches and leaves of dendrites and modulates dendritic R-type voltage-dependent calcium channels (VDCC). Mutations in Myoclonin/EFHC1, when inherited as a dominant trait, reduce its pruning functions, cause thicker brain cortex, and at the same time alter dendritic R-type VDCC functions, producing myoclonias and grand mal seizures. Unlike fatal Lafora epilepsy, JME has a good prognosis and responds to antiepileptic drugs that work on VDCC.