Phenotypic analysis of catastrophic childhood epilepsy genes.
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ABSTRACT:
SUBMITTER: Griffin A
PROVIDER: S-EPMC8175701 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Childhood absence epilepsy (CAE) is an idiopathic generalised epilepsy characterised by absence seizures manifested by transitory loss of awareness with 2.5-4 Hz spike-wave complexes on ictal EEG. A genetic component to aetiology is established but the mechanism of inheritance and the genes involved are not fully defined. Available evidence suggests that genes encoding brain expressed voltage-gated calcium channels, including CACNG3 on chromosome 16p12-p13.1, may represent susceptibility loci for CAE. The aim of this work was to further evaluate CACNG3 as a susceptibility locus by linkage and association analysis. Assuming locus heterogeneity, a significant HLOD score (HLOD = 3.54, alpha = 0.62) was obtained for markers encompassing CACNG3 in 65 nuclear families with a proband with CAE. The maximum non-parametric linkage score was 2.87 (P < 0.002). Re-sequencing of the coding exons in 59 patients did not identify any putative causal variants. A linkage disequilibrium (LD) map of CACNG3 was constructed using 23 single nucleotide polymorphisms (SNPs). Transmission disequilibrium was sought using individual SNPs and SNP-based haplotypes with the pedigree disequilibrium test in 217 CAE trios and the 65 nuclear pedigrees. Evidence for transmission disequilibrium (P < or = 0.01) was found for SNPs within a approximately 35 kb region of high LD encompassing the 5'UTR, exon 1 and part of intron 1 of CACNG3. Re-sequencing of this interval was undertaken in 24 affected individuals. Seventy-two variants were identified: 45 upstream; two 5'UTR; and 25 intronic SNPs. No coding sequence variants were identified, although four variants are predicted to affect exonic splicing. This evidence supports CACNG3 as a susceptibility locus in a subset of CAE patients.
| S-EPMC2556708 | biostudies-literature
Project description:Background and aimEpilepsy is a neurological disorder in which the altered activity of neurons causes convulsions, periods of unusual behavior and, sometimes, loss of consciousness. The aim of this mini-review is to summarize all the syndromes characterized by epilepsy and for which the associated gene is known.MethodsWe searched those syndromes in PubMed and OMIM database.ResultsGenetic causes underlie epilepsy in about 40% of individuals. Epilepsies are phenotypically and genetically heterogeneous. Inheritance can be autosomal dominant or recessive or X-linked recessive/dominant.ConclusionSince epilepsy has high genetic heterogeneity, in diagnostics, the parallel sequencing of a panel of genes may speed up the determination of the molecular etiology and/or establish a risk of recurrence in family members for the purpose of planning appropriate preventive and/or therapeutic measures.
| S-EPMC8023140 | biostudies-literature
Project description:BackgroundEpilepsy is one of the most common brain disorders worldwide. It is usually hard to be identified properly, and a third of patients are drug-resistant. Genes related to the progression and prognosis of epilepsy are particularly needed to be identified.MethodsIn our study, we downloaded the Gene Expression Omnibus (GEO) microarray expression profiling dataset GSE143272. Differentially expressed genes (DEGs) with a fold change (FC) >1.2 and a P-value <0.05 were identified by GEO2R and grouped in male, female and overlapping DEGs. Functional enrichment analysis and Protein-Protein Interaction (PPI) network analysis were performed.ResultsIn total, 183 DEGs overlapped (77 ups and 106 downs), 302 DEGs (185 ups and 117 downs) in the male dataset, and 750 DEGs (464 ups and 286 downs) in the female dataset were obtained from the GSE143272 dataset. These DEGs were markedly enriched under various Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms. 16 following hub genes were identified based on PPI network analysis: ADCY7, C3AR1, DEGS1, CXCL1 in male-specific DEGs, TOLLIP, ORM1, ELANE, QPCT in female-specific DEGs and FCAR, CD3G, CLEC12A, MOSPD2, CD3D, ALDH3B1, GPR97, PLAUR in overlapping DEGs.ConclusionThis discovery-driven study may be useful to provide a novel insight into the diagnosis and treatment of epilepsy. However, more experiments are needed in the future to study the functional roles of these genes in epilepsy.
| S-EPMC8459949 | biostudies-literature
Project description:To determine optimal second monotherapy for children with childhood absence epilepsy (CAE) experiencing initial treatment failure.Children with CAE experiencing treatment failure during the double-blind phase of a randomized controlled trial comparing ethosuximide, valproic acid, and lamotrigine were randomized to open-label second monotherapy with one of the 2 other study therapies. Primary study outcome was freedom from failure proportion at week 16-20 and month 12 visits after randomization. Secondary study outcome was percentage of participants experiencing attentional dysfunction at these visits.A total of 208 children were enrolled, randomized, and received second therapy. At both week 16-20 visit and month 12 visit, ethosuximide's (63%, 57%) and valproic acid's (65%, 49%) freedom from failure proportions were similar to each other and higher than lamotrigine's (45%, 36%, p = 0.051 and p = 0.062). At both time points, ethosuximide and valproic acid had superior seizure control compared to lamotrigine (p < 0.0001). At both the week 16-20 and month 12 visits, attentional dysfunction was numerically more common with valproic acid than with ethosuximide or lamotrigine. For each medication, second monotherapy freedom from failure proportions demonstrated noninferiority to initial monotherapy freedom from failure proportions.As second monotherapy, ethosuximide and valproic acid, demonstrated higher freedom from failure proportions and greater efficacy than lamotrigine; valproic acid was associated with more attentional dysfunction. Ethosuximide is the optimal second monotherapy for children with CAE not responding to initial therapy with other medications.NCT00088452.This study provides Class III evidence that for children with CAE experiencing initial treatment failure, second monotherapy with ethosuximide or valproic acid is superior to lamotrigine.
| S-EPMC5224720 | biostudies-literature
Project description:Variants in monogenic epilepsy genes can cause phenotypes of varying severity. For example, pathogenic variants in the SCN1A gene can cause the severe, sporadic, and drug-resistant Dravet syndrome or the milder familiar GEFS + syndrome. We hypothesized that coding variants in epilepsy-associated genes could lead to other disease-related phenotypes in the general population. We selected 127 established monogenic epilepsy genes and explored rare loss-of-function (LoF) variant associations with 3700 phenotypes across 281,850 individuals from the UK Biobank with whole-exome sequencing data. For 5.5% of epilepsy genes, we found significant associations of LoF variants with non-epilepsy phenotypes, mostly related to mental health. These findings suggest that LoF variants in epilepsy genes are associated with neurological or psychiatric phenotypes in the general population. The evidence provided may warrant further research and genetic screening of patients with atypical presentation and inform clinical care of comorbid disorders in individuals with monogenic epilepsy forms.
| S-EPMC9905533 | biostudies-literature
Project description:Epilepsy is a severe neurological disorder affecting a large number of individuals, yet the underlying genetic risk factors for epilepsy remain unclear. Recent studies have revealed several recurrent copy number variations (CNVs) that are more likely to be associated with epilepsy. The responsible gene(s) within these regions have yet to be definitively linked to the disorder, and the implications of their interactions are not fully understood. Identification of these genes may contribute to a better pathological understanding of epilepsy, and serve to implicate novel therapeutic targets for further research.In this study, we examined genes within heterozygous deletion regions identified in a recent large-scale study, encompassing a diverse spectrum of epileptic syndromes. By integrating additional protein-protein interaction data, we constructed subnetworks for these CNV-region genes and also those previously studied for epilepsy. We observed 20 genes common to both networks, primarily concentrated within a small molecular network populated by GABA receptor, BDNF/MAPK signaling, and estrogen receptor genes. From among the hundreds of genes in the initial networks, these were designated by convergent evidence for their likely association with epilepsy. Importantly, the identified molecular network was found to contain complex interrelationships, providing further insight into epilepsy's underlying pathology. We further performed pathway enrichment and crosstalk analysis and revealed a functional map which indicates the significant enrichment of closely related neurological, immune, and kinase regulatory pathways.The convergent framework we proposed here provides a unique and powerful approach to screening and identifying promising disease genes out of typically hundreds to thousands of genes in disease-related CNV-regions. Our network and pathway analysis provides important implications for the underlying molecular mechanisms for epilepsy. The strategy can be applied for the study of other complex diseases.
| S-EPMC3044734 | biostudies-literature
Project description:Polymicrogyria (PMG) is an epileptogenic malformation of cortical development. We describe the clinical epilepsy and imaging features of a large cohort with PMG-related epilepsy.Participants were recruited through the Epilepsy Phenome/Genome Project, a multicenter collaborative effort to collect detailed phenotypic data on individuals with epilepsy. We reviewed phenotypic data from participants with epilepsy and PMG.We identified 87 participants, 43 female and 44 male, with PMG and epilepsy. Median age of seizure onset was 3 years (range <1 month to 37 years). Most presented with focal epilepsy (87.4%), some in combination with seizures generalized from onset (23.0%). Focal seizures with dyscognitive features were most common (54.3%). Of those presenting with generalized seizure types, infantile spasms were most prevalent (45.2%). The most common topographic pattern was perisylvian PMG (77.0%), of which the majority was bilateral (56.7%). Generalized PMG presented with an earlier age of seizure onset (median age of 8 months) and an increased prevalence of developmental delay prior to seizure onset (57.1%). Of the unilateral, and asymmetric bilateral groups where PMG was more involved in one hemisphere, the majority (71.4%) of participants had seizures that lateralized to the same hemisphere as the PMG or the hemisphere with greater involvement.Participants with PMG had both focal and generalized onset of seizures. Our data confirm the involvement of known topographic patterns of PMG and suggest that more extensive distributions of PMG present with an earlier age of seizure onset and increased prevalence of developmental delay prior to seizure onset.
| S-EPMC3851304 | biostudies-literature
Project description:To determine seizure semiology in children with newly diagnosed childhood absence epilepsy and to evaluate associations with short-term treatment outcomes.For participants enrolled in a multicenter, randomized, double-blind, comparative-effectiveness trial, semiologic features of pretreatment seizures were analyzed as predictors of treatment outcome at the week 16 to 20 visit.Video of 1,932 electrographic absence seizures from 416 participants was evaluated. Median seizure duration was 10.2 seconds; median time between electrographic seizure onset and clinical manifestation onset was 1.5 seconds. For individual seizures and by participant, the most common semiology features were pause/stare (seizure 95.5%, participant 99.3%), motor automatisms (60.6%, 86.1%), and eye involvement (54.9%, 76.5%). The interrater agreement for motor automatisms and eye involvement was good (72%-84%). Variability of semiology features between seizures even within participants was high. Clustering analyses revealed 4 patterns (involving the presence/absence of eye involvement and motor automatisms superimposed on the nearly ubiquitous pause/stare). Most participants experienced more than one seizure cluster pattern. No individual semiologic feature was individually predictive of short-term outcome. Seizure freedom was half as likely in participants with one or more seizure having the pattern of eye involvement without motor automatisms than in participants without this pattern.Almost all absence seizures are characterized by a pause in activity or staring, but rarely is this the only feature. Semiologic features tend to cluster, resulting in identifiable absence seizure subtypes with significant intraparticipant seizure phenomenologic heterogeneity. One seizure subtype, pause/stare and eye involvement but no motor automatisms, is specifically associated with a worse treatment outcome.
| S-EPMC5562968 | biostudies-literature
Project description:ObjectivesEstimate the causes and risk of death, specifically seizure related, in children followed from onset of epilepsy and to contrast the risk of seizure-related death with other common causes of death in the population.MethodsMortality experiences from 4 pediatric cohorts of newly diagnosed patients were combined. Causes of death were classified as seizure related (including sudden unexpected death [SUDEP]), natural causes, nonnatural causes, and unknown.ResultsOf 2239 subjects followed up for >30?000 person-years, 79 died. Ten subjects with lethal neurometabolic conditions were ultimately excluded. The overall death rate (per 100?000 person-years) was 228; 743 in complicated epilepsy (with associated neurodisability or underlying brain condition) and 36 in uncomplicated epilepsy. Thirteen deaths were seizure-related (10 SUDEP, 3 other), accounting for 19% of all deaths. Seizure-related death rates were 43 overall, 122 for complicated epilepsy, and 14 for uncomplicated epilepsy. Death rates from other natural causes were 159, 561, and 9, respectively. Of 48 deaths from other natural causes, 37 were due to pneumonia or other respiratory complications.ConclusionsMost excess death in young people with epilepsy is not seizure-related. Mortality is significantly higher compared with the general population in children with complicated epilepsy but not uncomplicated epilepsy. The SUDEP rate was similar to or higher than sudden infant death syndrome rates. In uncomplicated epilepsy, sudden and seizure-related death rates were similar to or higher than rates for other common causes of death in young people (eg, accidents, suicides, homicides). Relating the risk of death in epilepsy to familiar risks may facilitate discussions of seizure-related mortality with patients and families.
| S-EPMC3691537 | biostudies-literature
Project description:Epilepsy is a highly prevalent neurological disorder characterized by recurrent seizures. Patients exhibit broad genetic, molecular, and clinical diversity involving mild to severe comorbidities. The factors that contribute to this phenotypic diversity remain unclear. We used publicly available datasets to systematically interrogate the expression pattern of 247 epilepsy-associated genes across human tissues, developmental stages, and central nervous system (CNS) cellular subtypes. We grouped genes based on their curated phenotypes into 3 broad classes: core epilepsy genes (CEG), where seizures are the core syndrome, developmental and epileptic encephalopathy genes (DEEG) that are associated with developmental delay, and seizure-related genes (SRG), which are characterized by developmental delay and gross brain malformations. We find that DEEGs are highly expressed within the CNS, while SRGs are most abundant in non-CNS tissues. DEEGs and CEGs exhibit highly dynamic expression in various brain regions across development, spiking during the prenatal to infancy transition. Lastly, the abundance of CEGs and SRGs is comparable within cellular subtypes in the brain, while the average expression level of DEEGs is significantly higher in GABAergic neurons and non-neuronal cells. Our analysis provides an overview of the expression pattern of epilepsy-associated genes with spatiotemporal resolution and establishes a broad expression-phenotype correlation in epilepsy.
| S-EPMC10274872 | biostudies-literature