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Objective: Childhood and Juvenile Absence Epilepsy account for 30% of all genetic generalized epilepsies with a strong genetic contribution. At the current state the genetic background remains to be resolved. The aim of this study was to identify disease associated transcripts pinpointing potential underlying disease mechanisms in patients with CAE and JAE., Methods: We performed gene expression analysis from peripheral blood mononuclear cells (PBMCs) in 30 patients with newly-diagnosed absence epilepsy prior to initiating treatment and 30 healthy age - and gender-matched pediatric controls. In a first group (group 1), 10 patients and controls we performed genome-wide transcriptome analysis using the Affymetrix HG U133 2.0+ microarray. 75 differentially expressed genes were followed up by qRT-PCR in two independent groups of 10 patients and controls (group 2 and 3). Furthermore, we analyzed 18 candidate genes by qRT-PCR in groups 2 and 3, which had previously been considered strong candidates for genetic epilepsies., Results: Genome-wide gene expression analysis in group 1 revealed 601 differentially regulated genes. Independent validation of 75 group 1-derived genes by qRT-PCR in groups 2 and 3 confirmed candidate genes with a consistent, but non-significant pattern of up- or down-regulation across all groups (ATP1B3, CAND1, PRPF6, TRIM8). Previously known genes including GABRA1, GABRB3, GABRG2, and RCN2 showed evidence for up- or down-regulation in individual experiments, but were not reliable across groups either., Discussion: Gene expression analysis in absence epilepsy from PMBCs displayed a high degree of heterogeneity between different patient groups. Our study provides several potentially interesting candidate genes, while demonstrating the limits of using gene expression analysis from blood in the identification of novel pathogenic mechanisms. In particular, we found that gene expression levels vary in response to altered experimental conditions, representing a substantial challenge for the identification of disease-related gene expression signatures for neurological diseases from whole blood., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Recently, mutations and deletions in the GRIN2A gene have been identified to predispose to benign and severe idiopathic focal epilepsies (IFE), revealing a higher incidence of GRIN2A alterations among the more severe phenotypes. This study aimed to explore the phenotypic boundaries of GRIN2A mutations by investigating patients with the two most common epilepsy syndromes: (i) idiopathic generalized epilepsy (IGE) and (ii) temporal lobe epilepsy (TLE). Whole exome sequencing data of 238 patients with IGE as well as Sanger sequencing of 84 patients with TLE were evaluated for GRIN2A sequence alterations. Two additional independent cohorts comprising 1469 IGE and 330 TLE patients were screened for structural deletions (>40kb) involving GRIN2A. Apart from a presumably benign, non-segregating variant in a patient with juvenile absence epilepsy, neither mutations nor deletions were detected in either cohort. These findings suggest that mutations in GRIN2A preferentially are involved in genetic variance of pediatric IFE and do not contribute significantly to either adult focal epilepsies as TLE or generalized epilepsies., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Microdeletions at 15q11.2, 15q13.3 and 16p13.11 are known genetic risk factors for idiopathic generalized epilepsies and other neurodevelopmental disorders. The full phenotypic range of this microdeletion triad in pediatric epilepsies is unknown. We attempted to describe associated phenotypes in a cohort of pediatric epilepsy patients. We screened 570 patients with pediatric epilepsies including idiopathic generalized epilepsies, focal epilepsies and fever-associated epilepsy syndromes for microdeletions at 15q11.2, 15q13.3 and 16p13.11 using quantitative polymerase chain reaction. Identified microdeletions were confirmed using array comparative hybridization. Ten microdeletions in 15q11.2 (n=3), 15q13.3 (n=3) and 16p13.11 (n=4) were identified (1.8%). 9/10 microdeletions were identified in patients with IGE (6/101, 6.0%) or patients with generalized EEG patterns without seizures (3/122, 2.5%). 6/10 microdeletion carriers had various degrees of ID; the frequency of microdeletions in patients with epilepsy and ID was higher (4.6%) compared to patients with normal intellect (0.9%). Iterative phenotyping revealed a wide range of generalized epilepsy phenotypes. In our pediatric cohort, recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 are mainly associated with phenotypes related to idiopathic generalized epilepsies or related EEG patterns. In contrast to previous reports, these recurrent microdeletions are virtually absent in focal epilepsies, FS, FS+ and GEFS+. Microdeletion carriers have a five-fold risk to present with various degrees of ID compared to patients without these risk factors. This microdeletion triad might help delineate a novel spectrum of epilepsy phenotypes classifiable through clinical, electrographic and genetic data., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Early Onset Absence Epilepsy constitutes an Idiopathic Generalized Epilepsy with absences starting before the age of four years. Mutations in SLC2A1, encoding the glucose transporter, account for approximately 10% of EOAE cases. The role of SLC2A1 mutations in absence epilepsies with a later onset has not been assessed. We found two mutation carriers in 26 EOAE patients, while no mutations were found in 124 probands affected by CAE or JAE., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: GRM4 encoding the group III metabotropic glutamate receptor 4 (mGluR4), is located on the chromosomal segment 6p21.3 where tentative susceptibility loci for Juvenile Myoclonic Epilepsy (JME) and Photoparoxysmal Response (PPR) have been mapped. The present candidate gene study examined if variation in GRM4 confers susceptibility to IGE., Patients and Methods: The case-control association sample included 564 unrelated IGE patients and 733 population controls of German descent. Association analysis was carried out for 17 single nucleotide polymorphisms (SNPs) covering the genomic GRM4 sequence for all IGE patients as well as for two common IGE subsyndromes [Juvenile Myoclonic Epilepsy (JME, n=215) and Childhood Absence Epilepsy (CAE, n=175)]. Sequence analysis was performed in 85 IGE and 42 PPR cases and 44 controls., Results: Nominally significant associations were detected between IGE and seven GRM4 SNPs (with P-values ranging from 0.037 to 0.0036), between JME and five SNPs (P=0.042-0.0106), and between CAE and two SNPs (P=0.0466-0.0021). Four novel SNPs were identified by sequence analysis., Conclusions: Our association findings support the hypothesis that GRM4 sequence variants might confer low-risk effects to the etiology of IGE. A minor pathogenetic contribution of the examined variants is possible. These exploratory findings warrant further replication analyses., (Copyright 2010 Elsevier B.V. All rights reserved.)

Purpose: Mutation screening and linkage disequilibrium mapping of the gene encoding the GABA(A) beta(3) subunit (GABRB3) identified a common genetic variant in the exon 1a promoter region (C-allele of rs4906902) which displayed a reduced transcriptional activity and showed a strong allelic association with childhood absence epilepsy (CAE). The present population-based association study tested whether the C-allele of rs4906902 confers susceptibility to CAE or other common syndromes of idiopathic generalized epilepsy (IGE) in a German sample., Methods: Seven hundred and eighty unrelated German IGE patients (250 CAE, 123 juvenile absence epilepsy, 303 juvenile myoclonic epilepsy (JME), 104 epilepsy with generalized tonic-clonic seizures on awakening) and 559 healthy population controls were genotyped for the single nucleotide polymorphism (SNP) rs4906902., Results: The frequency of the risk-conferring C-allele did not differ significantly between CAE patients (f(C)=0.190) and controls (f(C)=0.183; P=0.376, one-tailed). Similarly, no evidence for an allelic association was found for 373 patients with idiopathic absence epilepsy, 303 JME patients, and the entire IGE sample (P>0.77, two-tailed)., Conclusion: Our study failed to replicate an association of the common GABRB3 exon 1a promoter SNP rs4906902 with CAE. Moreover, the present results do not provide evidence that the common functional C-variant confers a substantial epileptogenic effect to a broad spectrum of IGE syndromes in the German population.