13 results on '"Lerche, Holger"'
Search Results
2. Clinical spectrum of -related epileptic disorders
- Author
-
Wolking, Stefan, May, Patrick, Mei, Davide, Møller, Rikke S, Balestrini, Simona, Helbig, Katherine L, Altuzarra, Cecilia Desmettre, Chatron, Nicolas, Kaiwar, Charu, Stöhr, Katharina, Widdess-Walsh, Peter, Mendelsohn, Bryce A, Numis, Adam, Cilio, Maria-Roberta, Van Paesschen, Wim, Svendsen, Lene L, Oates, Stephanie, Hughes, Elaine, Goyal, Sushma, Brown, Kathleen, Sifuentes Saenz, Margarita, Dorn, Thomas, Muhle, Hiltrud, Pagnamenta, Alistair T, Vavoulis, Dimitris V, Knight, Samantha J L, Taylor, Jenny C, Canevini, Maria Paola, Darra, Francesca, Gavrilova, Ralitza H, Powis, Zöe, Tang, Shan, Marquetand, Justus, Armstrong, Martin, McHale, Duncan, Klee, Eric W, Kluger, Gerhard J, Lowenstein, Daniel H, Weckhuysen, Sarah, Pal, Deb K, Helbig, Ingo, Guerrini, Renzo, Thomas, Rhys H, Rees, Mark I, Lesca, Gaetan, Sisodiya, Sanjay M, Weber, Yvonne G, Lal, Dennis, Marini, Carla, Lerche, Holger, Schubert, Julian, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de neurologie pédiatrique
- Subjects
Male ,Drug Resistant Epilepsy ,Adolescent ,Learning Disabilities ,Developmental Disabilities ,Infant, Newborn ,Mutation, Missense ,High-Throughput Nucleotide Sequencing ,Infant ,Syntaxin 1 ,Electroencephalography ,Sequence Analysis, DNA ,Seizures, Febrile ,Young Adult ,Phenotype ,Loss of Function Mutation ,Child, Preschool ,Humans ,Anticonvulsants ,Female ,Epilepsies, Partial ,Child ,Epileptic Syndromes - Abstract
OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.
- Published
- 2019
3. Spectrum of GABAA receptor variants in epilepsy.
- Author
-
Maljevic, Snezana, Møller, Rikke S., Reid, Christopher A., Pérez-Palma, Eduardo, Lal, Dennis, May, Patrick, and Lerche, Holger
- Published
- 2019
- Full Text
- View/download PDF
4. Dementia with Lewy bodies: cerebrospinal fluid suppresses neuronal network activity.
- Author
-
Theiss, Stephan, Maetzler, Walter, Deuschle, Christian, Lerche, Holger, Koche, Henner, and Dihné, Marcel
- Published
- 2017
- Full Text
- View/download PDF
5. Dominant KCNA2 mutation causes episodic ataxia and pharmacoresponsive epilepsy.
- Author
-
Corbett, Mark A., Bellows, Susannah T., Li, Melody, Carroll, Renée, Micallef, Silvana, Carvill, Gemma L., Myers, Candace T., Howell, Katherine B., Maljevic, Snezana, Lerche, Holger, Gazina, Elena V., Mefford, Heather C., Bahlo, Melanie, Berkovic, Samuel F., Petrou, Steven, Scheffer, Ingrid E., and Gecz, Jozef
- Published
- 2016
- Full Text
- View/download PDF
6. A homozygous splice-site mutation in CARS2 is associated with progressive myoclonic epilepsy.
- Author
-
Hallmann, Kerstin, Zsurka, Gábor, Moskau-Hartmann, Susanna, Kirschner, Janbernd, Korinthenberg, Rudolf, Ruppert, Ann-Kathrin, Ozdemir, Ozkan, Weber, Yvonne, Becker, Felicitas, Lerche, Holger, Elger, Christian E, Thiele, Holger, Nürnberg, Peter, Sander, Thomas, and Kunz, Wolfram S
- Published
- 2014
- Full Text
- View/download PDF
7. Heritability of Magnetoencephalography Phenotypes Among Patients With Genetic Generalized Epilepsy and Their Siblings.
- Author
-
Stier, Christina, Elshahabi, Adham, Li Hegner, Yiwen, Hegner, Yiwen Li, Kotikalapudi, Raviteja, Marquetand, Justus, Braun, Christoph, Lerche, Holger, and Focke, Niels K
- Published
- 2021
- Full Text
- View/download PDF
8. Microscopic brain structure revisited in genetic epilepsy.
- Author
-
Lerche, Holger and Novotny Jr, Edward J
- Published
- 2015
- Full Text
- View/download PDF
9. Spectrum of Phenotypic, Genetic, and Functional Characteristics in Patients With Epilepsy With KCNC2 Pathogenic Variants.
- Author
-
Schwarz N, Seiffert S, Pendziwiat M, Rademacher AV, Brünger T, Hedrich UBS, Augustijn PB, Baier H, Bayat A, Bisulli F, Buono RJ, Bruria BZ, Doyle MG, Guerrini R, Heimer G, Iacomino M, Kearney H, Klein KM, Kousiappa I, Kunz WS, Lerche H, Licchetta L, Lohmann E, Minardi R, McDonald M, Montgomery S, Mulahasanovic L, Oegema R, Ortal B, Papacostas SS, Ragona F, Granata T, Reif PS, Rosenow F, Rothschild A, Scudieri P, Striano P, Tinuper P, Tanteles GA, Vetro A, Zahnert F, Goldberg EM, Zara F, Lal D, May P, Muhle H, Helbig I, and Weber Y
- Subjects
- Humans, Phenotype, Seizures genetics, Shaw Potassium Channels genetics, Exome Sequencing, Epilepsy genetics, Epilepsy, Generalized genetics
- Abstract
Background and Objectives: KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants., Methods: Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes., Results: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms., Discussion: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of K
V 3.2 in the regulation of brain excitability., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)- Published
- 2022
- Full Text
- View/download PDF
10. Clinical spectrum of STX1B -related epileptic disorders.
- Author
-
Wolking S, May P, Mei D, Møller RS, Balestrini S, Helbig KL, Altuzarra CD, Chatron N, Kaiwar C, Stöhr K, Widdess-Walsh P, Mendelsohn BA, Numis A, Cilio MR, Van Paesschen W, Svendsen LL, Oates S, Hughes E, Goyal S, Brown K, Sifuentes Saenz M, Dorn T, Muhle H, Pagnamenta AT, Vavoulis DV, Knight SJL, Taylor JC, Canevini MP, Darra F, Gavrilova RH, Powis Z, Tang S, Marquetand J, Armstrong M, McHale D, Klee EW, Kluger GJ, Lowenstein DH, Weckhuysen S, Pal DK, Helbig I, Guerrini R, Thomas RH, Rees MI, Lesca G, Sisodiya SM, Weber YG, Lal D, Marini C, Lerche H, and Schubert J
- Subjects
- Adolescent, Anticonvulsants therapeutic use, Child, Child, Preschool, Developmental Disabilities, Drug Resistant Epilepsy genetics, Electroencephalography, Epilepsies, Partial genetics, Epilepsies, Partial physiopathology, Epileptic Syndromes drug therapy, Epileptic Syndromes physiopathology, Epileptic Syndromes psychology, Female, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Learning Disabilities, Loss of Function Mutation, Male, Mutation, Missense, Phenotype, Seizures, Febrile, Sequence Analysis, DNA, Young Adult, Epileptic Syndromes genetics, Syntaxin 1 genetics
- Abstract
Objective: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B , encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants., Methods: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools., Results: We describe 17 new variants in STX1B , which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes., Conclusion: These data expand the genetic and phenotypic spectrum of STX1B -related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A , the most important gene associated with fever-associated epilepsies., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
- Published
- 2019
- Full Text
- View/download PDF
11. Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent patients.
- Author
-
McCormack M, Gui H, Ingason A, Speed D, Wright GEB, Zhang EJ, Secolin R, Yasuda C, Kwok M, Wolking S, Becker F, Rau S, Avbersek A, Heggeli K, Leu C, Depondt C, Sills GJ, Marson AG, Auce P, Brodie MJ, Francis B, Johnson MR, Koeleman BPC, Striano P, Coppola A, Zara F, Kunz WS, Sander JW, Lerche H, Klein KM, Weckhuysen S, Krenn M, Gudmundsson LJ, Stefánsson K, Krause R, Shear N, Ross CJD, Delanty N, Pirmohamed M, Carleton BC, Cendes F, Lopes-Cendes I, Liao WP, O'Brien TJ, Sisodiya SM, Cherny S, Kwan P, Baum L, and Cavalleri GL
- Subjects
- Humans, Asian People genetics, Carbamazepine adverse effects, Carbamazepine therapeutic use, Case-Control Studies, Complement Factor H genetics, Epilepsy drug therapy, Epilepsy genetics, Genome-Wide Association Study, HLA-A Antigens genetics, Linkage Disequilibrium, Mutation, Missense, Pharmacogenomic Variants, Retrospective Studies, White People genetics, Anticonvulsants adverse effects, Anticonvulsants therapeutic use, Apolipoproteins genetics, Drug Eruptions ethnology, Drug Eruptions etiology, Drug Eruptions genetics, Genetic Variation, Phenytoin adverse effects, Phenytoin therapeutic use
- Abstract
Objective: To characterize, among European and Han Chinese populations, the genetic predictors of maculopapular exanthema (MPE), a cutaneous adverse drug reaction common to antiepileptic drugs., Methods: We conducted a case-control genome-wide association study of autosomal genotypes, including Class I and II human leukocyte antigen (HLA) alleles, in 323 cases and 1,321 drug-tolerant controls from epilepsy cohorts of northern European and Han Chinese descent. Results from each cohort were meta-analyzed., Results: We report an association between a rare variant in the complement factor H-related 4 ( CFHR4 ) gene and phenytoin-induced MPE in Europeans ( p = 4.5 × 10
-11 ; odds ratio [95% confidence interval] 7 [3.2-16]). This variant is in complete linkage disequilibrium with a missense variant (N1050Y) in the complement factor H ( CFH ) gene. In addition, our results reinforce the association between HLA-A*31:01 and carbamazepine hypersensitivity. We did not identify significant genetic associations with MPE among Han Chinese patients., Conclusions: The identification of genetic predictors of MPE in CFHR4 and CFH, members of the complement factor H-related protein family, suggest a new link between regulation of the complement system alternative pathway and phenytoin-induced hypersensitivity in European-ancestral patients., (Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)- Published
- 2018
- Full Text
- View/download PDF
12. Mutations in GABRB3: From febrile seizures to epileptic encephalopathies.
- Author
-
Møller RS, Wuttke TV, Helbig I, Marini C, Johannesen KM, Brilstra EH, Vaher U, Borggraefe I, Talvik I, Talvik T, Kluger G, Francois LL, Lesca G, de Bellescize J, Blichfeldt S, Chatron N, Holert N, Jacobs J, Swinkels M, Betzler C, Syrbe S, Nikanorova M, Myers CT, Larsen LH, Vejzovic S, Pendziwiat M, von Spiczak S, Hopkins S, Dubbs H, Mang Y, Mukhin K, Holthausen H, van Gassen KL, Dahl HA, Tommerup N, Mefford HC, Rubboli G, Guerrini R, Lemke JR, Lerche H, Muhle H, and Maljevic S
- Subjects
- Animals, Automation, Laboratory, Child, Child, Preschool, Cohort Studies, Epilepsy physiopathology, Female, Heterozygote, High-Throughput Nucleotide Sequencing, Humans, Infant, Infant, Newborn, Male, Membrane Potentials physiology, Oocytes, Patch-Clamp Techniques, Phenotype, Receptors, GABA-A metabolism, Xenopus laevis, Epilepsy genetics, Mutation, Receptors, GABA-A genetics
- Abstract
Objective: To examine the role of mutations in GABRB3 encoding the β
3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes., Methods: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs., Results: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant β3 , together with α5 and γ2s subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations., Conclusions: Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism., (© 2017 American Academy of Neurology.)- Published
- 2017
- Full Text
- View/download PDF
13. Phenotypic spectrum of GABRA1: From generalized epilepsies to severe epileptic encephalopathies.
- Author
-
Johannesen K, Marini C, Pfeffer S, Møller RS, Dorn T, Niturad CE, Gardella E, Weber Y, Søndergård M, Hjalgrim H, Nikanorova M, Becker F, Larsen LH, Dahl HA, Maier O, Mei D, Biskup S, Klein KM, Reif PS, Rosenow F, Elias AF, Hudson C, Helbig KL, Schubert-Bast S, Scordo MR, Craiu D, Djémié T, Hoffman-Zacharska D, Caglayan H, Helbig I, Serratosa J, Striano P, De Jonghe P, Weckhuysen S, Suls A, Muru K, Talvik I, Talvik T, Muhle H, Borggraefe I, Rost I, Guerrini R, Lerche H, Lemke JR, Rubboli G, and Maljevic S
- Subjects
- Adolescent, Adult, Animals, Brain physiopathology, Child, Child, Preschool, Cohort Studies, Epilepsy physiopathology, Female, Genetic Association Studies, Humans, Infant, Male, Membrane Potentials physiology, Middle Aged, Oocytes, Phenotype, Receptors, GABA-A metabolism, Xenopus laevis, gamma-Aminobutyric Acid metabolism, Epilepsy genetics, Mutation, Receptors, GABA-A genetics
- Abstract
Objective: To delineate phenotypic heterogeneity, we describe the clinical features of a cohort of patients with GABRA1 gene mutations., Methods: Patients with GABRA1 mutations were ascertained through an international collaboration. Clinical, EEG, and genetic data were collected. Functional analysis of 4 selected mutations was performed using the Xenopus laevis oocyte expression system., Results: The study included 16 novel probands and 3 additional family members with a disease-causing mutation in the GABRA1 gene. The phenotypic spectrum varied from unspecified epilepsy (1), juvenile myoclonic epilepsy (2), photosensitive idiopathic generalized epilepsy (1), and generalized epilepsy with febrile seizures plus (1) to severe epileptic encephalopathies (11). In the epileptic encephalopathy group, the patients had seizures beginning between the first day of life and 15 months, with a mean of 7 months. Predominant seizure types in all patients were tonic-clonic in 9 participants (56%) and myoclonic seizures in 5 (31%). EEG showed a generalized photoparoxysmal response in 6 patients (37%). Four selected mutations studied functionally revealed a loss of function, without a clear genotype-phenotype correlation., Conclusions: GABRA1 mutations make a significant contribution to the genetic etiology of both benign and severe epilepsy syndromes. Myoclonic and tonic-clonic seizures with pathologic response to photic stimulation are common and shared features in both mild and severe phenotypes., (© 2016 American Academy of Neurology.)
- Published
- 2016
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.