102 results found
Roncon P, Soukupova M, Binaschi A, et al., 2015, MicroRNA profiles in hippocampal granule cells and plasma of rats with pilocarpine-induced epilepsy - comparison with human epileptic samples, Scientific Reports, Vol: 5, ISSN: 2045-2322
The identification of biomarkers of the transformation of normal to epileptic tissue would help to stratify patients at risk of epilepsy following brain injury, and inform new treatment strategies. MicroRNAs (miRNAs) are an attractive option in this direction. In this study, miRNA microarrays were performed on laser-microdissected hippocampal granule cell layer (GCL) and on plasma, at different time points in the development of pilocarpine-induced epilepsy in the rat: latency, first spontaneous seizure and chronic epileptic phase. Sixty-three miRNAs were differentially expressed in the GCL when considering all time points. Three main clusters were identified that separated the control and chronic phase groups from the latency group and from the first spontaneous seizure group. MiRNAs from rats in the chronic phase were compared to those obtained from the laser-microdissected GCL of epileptic patients, identifying several miRNAs (miR-21-5p, miR-23a-5p, miR-146a-5p and miR-181c-5p) that were up-regulated in both human and rat epileptic tissue. Analysis of plasma samples revealed different levels between control and pilocarpine-treated animals for 27 miRNAs. Two main clusters were identified that segregated controls from all other groups. Those miRNAs that are altered in plasma before the first spontaneous seizure, like miR-9a-3p, may be proposed as putative biomarkers of epileptogenesis.
Epilepsy PhenomeGenome Project & Epi4K Consortium, 2015, Copy number variant analysis from exome data in 349 patients with epileptic encephalopathy, Annals of Neurology, Vol: 78, Pages: 323-328, ISSN: 0364-5134
Infantile spasms (IS) and Lennox–Gastaut syndrome (LGS) are epileptic encephalopathies characterized by early onset, intractable seizures, and poor developmental outcomes. De novo sequence mutations and copy number variants (CNVs) are causative in a subset of cases. We used exome sequence data in 349 trios with IS or LGS to identify putative de novo CNVs. We confirm 18 de novo CNVs in 17 patients (4.8%), 10 of which are likely pathogenic, giving a firm genetic diagnosis for 2.9% of patients. Confirmation of exome-predicted CNVs by array-based methods is still required due to false-positive rates of prediction algorithms. Our exome-based results are consistent with recent array-based studies in similar cohorts and highlight novel candidate genes for IS and LGS.
Dhindsa RS, Bradrick SS, Yao X, et al., 2015, Epileptic encephalopathy-causing mutations in DNM1 impair synaptic vesicle endocytosis, Neurology: Genetics, Vol: 1, ISSN: 2376-7839
OBJECTIVE: To elucidate the functional consequences of epileptic encephalopathy-causing de novo mutations in DNM1 (A177P, K206N, G359A), which encodes a large mechanochemical GTPase essential for neuronal synaptic vesicle endocytosis. METHODS: HeLa and COS-7 cells transfected with wild-type and mutant DNM1 constructs were used for transferrin assays, high-content imaging, colocalization studies, Western blotting, and electron microscopy (EM). EM was also conducted on the brain sections of mice harboring a middle-domain Dnm1 mutation (Dnm1 (Ftfl)). RESULTS: We demonstrate that the expression of each mutant protein decreased endocytosis activity in a dominant-negative manner. One of the G-domain mutations, K206N, decreased protein levels. The G359A mutation, which occurs in the middle domain, disrupted higher-order DNM1 oligomerization. EM of mutant DNM1-transfected HeLa cells and of the Dnm1 (Ftfl) mouse brain revealed vesicle defects, indicating that the mutations likely interfere with DNM1's vesicle scission activity. CONCLUSION: Together, these data suggest that the dysfunction of vesicle scission during synaptic vesicle endocytosis can lead to serious early-onset epilepsies.
Johnson MR, Behmoaras J, Bottolo L, et al., 2015, Systems genetics identifies Sestrin 3 as a regulator of a proconvulsant gene network in human epileptic hippocampus., Nat Commun, Vol: 6
Gene-regulatory network analysis is a powerful approach to elucidate the molecular processes and pathways underlying complex disease. Here we employ systems genetics approaches to characterize the genetic regulation of pathophysiological pathways in human temporal lobe epilepsy (TLE). Using surgically acquired hippocampi from 129 TLE patients, we identify a gene-regulatory network genetically associated with epilepsy that contains a specialized, highly expressed transcriptional module encoding proconvulsive cytokines and Toll-like receptor signalling genes. RNA sequencing analysis in a mouse model of TLE using 100 epileptic and 100 control hippocampi shows the proconvulsive module is preserved across-species, specific to the epileptic hippocampus and upregulated in chronic epilepsy. In the TLE patients, we map the trans-acting genetic control of this proconvulsive module to Sestrin 3 (SESN3), and demonstrate that SESN3 positively regulates the module in macrophages, microglia and neurons. Morpholino-mediated Sesn3 knockdown in zebrafish confirms the regulation of the transcriptional module, and attenuates chemically induced behavioural seizures in vivo.
Rackham OJL, Shihab HA, Johnson MR, et al., 2014, EvoTol: a protein-sequence based evolutionary intolerance framework for disease-gene prioritization, Nucleic Acids Research, Vol: 43, ISSN: 0305-1048
Methods to interpret personal genome sequences are increasingly required. Here, we report a novel framework (EvoTol) to identify disease-causing genes using patient sequence data from within protein coding-regions. EvoTol quantifies a gene's intolerance to mutation using evolutionary conservation of protein sequences and can incorporate tissue-specific gene expression data. We apply this framework to the analysis of whole-exome sequence data in epilepsy and congenital heart disease, and demonstrate EvoTol's ability to identify known disease-causing genes is unmatched by competing methods. Application of EvoTol to the human interactome revealed networks enriched for genes intolerant to protein sequence variation, informing novel polygenic contributions to human disease.
Shazadi K, Petrovski S, Roten A, et al., 2014, Validation of a multigenic model to predict seizure control in newly treated epilepsy, EPILEPSY RESEARCH, Vol: 108, Pages: 1797-1805, ISSN: 0920-1211
Raedisch S, Dickens D, Lang T, et al., 2014, A comprehensive functional and clinical analysis of ABCC2 and its impact on treatment response to carbamazepine, PHARMACOGENOMICS JOURNAL, Vol: 14, Pages: 481-487, ISSN: 1470-269X
Speed D, O'Brien TJ, Palotie A, et al., 2014, Describing the genetic architecture of epilepsy through heritability analysis, Brain, Vol: 137, Pages: 2680-2689, ISSN: 1460-2156
Epilepsy is a disease with substantial missing heritability; despite its high genetic component, genetic association studies have had limited success detecting common variants which influence susceptibility. In this paper, we reassess the role of common variants on epilepsy using extensions of heritability analysis. Our data set consists of 1258 UK patients with epilepsy, of which 958 have focal epilepsy, and 5129 population control subjects, with genotypes recorded for over 4 million common single nucleotide polymorphisms. Firstly, we show that on the liability scale, common variants collectively explain at least 26% (standard deviation 5%) of phenotypic variation for all epilepsy and 27% (standard deviation 5%) for focal epilepsy. Secondly we provide a new method for estimating the number of causal variants for complex traits; when applied to epilepsy, our most optimistic estimate suggests that at least 400 variants influence disease susceptibility, with potentially many thousands. Thirdly, we use bivariate analysis to assess how similar the genetic architecture of focal epilepsy is to that of non-focal epilepsy; we demonstrate both significant differences (P = 0.004) and significant similarities (P = 0.01) between the two subtypes, indicating that although the clinical definition of focal epilepsy does identify a genetically distinct epilepsy subtype, there is also scope to improve the classification of epilepsy by incorporating genotypic information. Lastly, we investigate the potential value in using genetic data to diagnose epilepsy following a single epileptic seizure; we find that a prediction model explaining 10% of phenotypic variation could have clinical utility for deciding which single-seizure individuals are likely to benefit from immediate anti-epileptic drug therapy.
Appenzeller S, Balling R, Barisic N, et al., 2014, De Novo Mutations in Synaptic Transmission Genes Including DNM1 Cause Epileptic Encephalopathies, The American Journal of Human Genetics, Vol: 95, Pages: 360-370, ISSN: 0002-9297
International League Against Epilepsy Consortium on Complex Epilepsies, 2014, Genetic determinants of common epilepsies: a meta-analysis of genome-wide association studies, Lancet Neurology, Vol: 13, Pages: 893-903, ISSN: 1474-4465
BACKGROUND: The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). METHODS: We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1·66 × 10(-8). FINDINGS: We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10(-10)), implicating SCN1A, and at 4p15.1 (p=5·44 × 10(-9)), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10(-9)), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. INTERPRETATION: This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these dis
Matthews PM, Edison P, Geraghty OC, et al., 2014, The emerging agenda of stratified medicine in neurology, NATURE REVIEWS NEUROLOGY, Vol: 10, Pages: 15-26, ISSN: 1759-4758
Speed D, Hoggart C, Petrovski S, et al., 2014, Genome-wide association study and biological pathway analysis of epilepsy prognosis in a prospective cohort of newly treated epilepsy, Human Molecular Genetics
Speed D, Hemani G, Johnson MR, et al., 2013, Response to Lee et al.: SNP-Based Heritability Analysis with Dense Data, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 93, Pages: 1155-1157, ISSN: 0002-9297
Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown1. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox–Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10−3). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10−10 and P = 7.8 × 10−12, respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10−8), as has been reported previously for autism spectrum disorders2.
Schneider SA, Irani SR, Stagg CJ, et al., 2013, Faciobrachial dystonic seizures: the influence ofimmunotherapy on seizure control and preventionof cognitive impairment in a broadening phenotype, Brain, Vol: 136, Pages: 3151-3162, ISSN: 0006-8950
Johnson MR, Perkin GD, 2013, Epilepsy in later Childhood and adulthood, Oxford Textbook of Medicine (5 ed.), Editors: Warrell, Cox, Firth, 2012
Miller TD, Rosenthal CR, Davies AA, et al., 2013, RE-THINKING THE ROLE OF THE HUMAN HIPPOCAMPUS IN RETROGRADE EPISODIC MEMORY, 20th Annual Meeting of the Cognitive-Neuroscience-Society, Publisher: MIT PRESS, Pages: 169-169, ISSN: 0898-929X
Bellos E, Johnson MR, Coin LJ, 2012, cnvHiTSeq: integrative models for high-resolution copy number variation detection and genotyping using population sequencing data, Genome Biology, Vol: 13, ISSN: 1474-7596
Recent advances in sequencing technologies provide the means for identifying copy number variation (CNV) at an unprecedented resolution. A single next-generation sequencing experiment offers several features that can be used to detect CNV, yet current methods do not incorporate all available signatures into a unified model. cnvHiTSeq is an integrative probabilistic method for CNV discovery and genotyping that jointly analyzes multiple features at the population level. By combining evidence from complementary sources, cnvHiTSeq achieves high genotyping accuracy and a substantial improvement in CNV detection sensitivity over existing methods, while maintaining a low false discovery rate. cnvHiTSeq is available at http://sourceforge.net/projects/cnvhitseq
Johnson MR, Craig J, 2012, Reproductive Aspects of Epilepsy, Oxford Textbook of Epilepsy and Epileptic Seizures, Editors: Shorvon, Guerrini, Cook, Lhatoo, Shorvon, Guerrini, Cook, Lhatoo, Publisher: Oxford University Press, ISBN: 9780199659043
Part of the Oxford Textbooks in Clinical Neurology (OTCN) series, this volume covers the scientific basis, clinical diagnosis, and treatment of the reproductive aspects of epilepsy.
The Epi4K Consortium, 2012, Epi4K: gene discovery in 4,000 genomes., Epilepsia, Vol: 53, Pages: 1457-1467, ISSN: 0013-9580
A major challenge in epilepsy research is to unravel the complex genetic mechanisms underlying both common and rare forms of epilepsy, as well as the genetic determinants of response to treatment. To accelerate progress in this area, the National Institute of Neurological Disorders and Stroke (NINDS) recently offered funding for the creation of a “Center without Walls” to focus on the genetics of human epilepsy. This article describes Epi4K, the collaborative study supported through this grant mechanism and having the aim of analyzing the genomes of a minimum 4,000 subjects with highly selected and well‐characterized epilepsy.
Speed D, Hemani G, Johnson MR, et al., 2012, Improved heritability estimation from genome-wide SNP data., American Journal of Human Genetics, Vol: 91
Johnson MR, 2012, A rational approach to prescribing add-on anti-epilepsy drugs. (Invited Speaker)., First Annual Oxford Neurology Course, Oxford, UK
Schneider S, Johnson MR, 2012, Monozygotic twins with LRRK2 mutations: genetically identical but phenotypically discordant., Movement Disorders, Vol: 27, Pages: 1203-1204
Johnson MR, Shorvon SD, 2011, Heredity in epilepsy: Neurodevelopment, comorbidity, and the neurological trait, EPILEPSY & BEHAVIOR, Vol: 22, Pages: 421-427, ISSN: 1525-5050
Johnson MR, Tan NCK, Kwan P, et al., 2011, Newly diagnosed epilepsy and pharmacogenomics research: A step in the right direction?, EPILEPSY & BEHAVIOR, Vol: 22, Pages: 3-8, ISSN: 1525-5050
Leschziner GD, Coffey AJ, Andrew T, et al., 2011, Q8IYL2 is a candidate gene for the familial epilepsy syndrome of Partial Epilepsy with Pericentral Spikes (PEPS), EPILEPSY RESEARCH, Vol: 96, Pages: 109-115, ISSN: 0920-1211
Irani SR, Michell AW, Johnson MR, et al., 2011, Faciobrachial Dystonic Attacks: Seizures or Movement Disorder? Reply, ANNALS OF NEUROLOGY, Vol: 70, Pages: 180-180, ISSN: 0364-5134
McCormack M, Alfirevic A, Bourgeois S, et al., 2011, HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans., N Engl J Med 2011, Vol: 364, Pages: 1134-1143
AbstractBACKGROUND: Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations.METHODS: We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions.RESULTS: The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18).CONCLUSIONS: The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).
Irani SR, Michell AW, Lang B, et al., 2011, Faciobrachial dystonic seizures precede Lgi1 antibody limbic encephalitis, Ann Neurol 2011, Vol: 69, Pages: 892-900
Johnson MR, 2011, Comment on "Blinders, phenotype, and fashionable genetic analysis: A critical examination of the current state of epilepsy genetic studies", EPILEPSIA, Vol: 52, Pages: 191-191, ISSN: 0013-9580
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