Clinical spectrum of STX1B -related epileptic disorders

Stefan Wolking, Patrick May, Davide Mei, Rikke S. Møller, Simona Balestrini, Katherine L. Helbig, Cecilia Desmettre Altuzarra, Nicolas Chatron, Charu Kaiwar, Katharina Stöhr, Peter Widdess-Walsh, Bryce A. Mendelsohn, Adam Numis, Maria R. Cilio, Wim Van Paesschen, Lene L. Svendsen, Stephanie Oates, Elaine Hughes, Sushma Goyal, Kathleen BrownMargarita Sifuentes Saenz, Thomas Dorn, Hiltrud Muhle, Alistair T. Pagnamenta, Dimitris V. Vavoulis, Samantha J.L. Knight, Jenny C. Taylor, Maria Paola Canevini, Francesca Darra, Ralitza M Gavrilova, Zöe Powis, Shan Tang, Justus Marquetand, Martin Armstrong, Duncan McHale, Eric W Klee, Gerhard J. Kluger, Daniel H. Lowenstein, Sarah Weckhuysen, Deb K. Pal, Ingo Helbig, Renzo Guerrini, Rhys H. Thomas, Mark I. Rees, Gaetan Lesca, Sanjay M. Sisodiya, Yvonne G. Weber, Dennis Lal, Carla Marini, Holger Lerche, Julian Schubert

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.MethodsWe 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.ResultsWe 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.ConclusionThese 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.

Original languageEnglish (US)
Pages (from-to)E1238-E1249
JournalNeurology
Volume92
Issue number11
DOIs
StatePublished - Mar 12 2019
Externally publishedYes

Fingerprint

Epilepsy
Syntaxin 1
Febrile Seizures
Seizures
Phenotype
SNARE Proteins
Generalized Epilepsy
Partial Epilepsy
Genetic Association Studies
Neurologic Manifestations
Computer Simulation
Genes
Virulence
Electroencephalography
Fever
Mutation
Research
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Wolking, S., May, P., Mei, D., Møller, R. S., Balestrini, S., Helbig, K. L., ... Schubert, J. (2019). Clinical spectrum of STX1B -related epileptic disorders. Neurology, 92(11), E1238-E1249. https://doi.org/10.1212/WNL.0000000000007089

Clinical spectrum of STX1B -related epileptic disorders. / 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 R.; 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 M; 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.

In: Neurology, Vol. 92, No. 11, 12.03.2019, p. E1238-E1249.

Research output: Contribution to journalArticle

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, RM, 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 & Schubert, J 2019, 'Clinical spectrum of STX1B -related epileptic disorders', Neurology, vol. 92, no. 11, pp. E1238-E1249. https://doi.org/10.1212/WNL.0000000000007089
Wolking S, May P, Mei D, Møller RS, Balestrini S, Helbig KL et al. Clinical spectrum of STX1B -related epileptic disorders. Neurology. 2019 Mar 12;92(11):E1238-E1249. https://doi.org/10.1212/WNL.0000000000007089
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 R. ; 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 M ; 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. / Clinical spectrum of STX1B -related epileptic disorders. In: Neurology. 2019 ; Vol. 92, No. 11. pp. E1238-E1249.
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abstract = "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.MethodsWe 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.ResultsWe 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.ConclusionThese 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.",
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T1 - Clinical spectrum of STX1B -related epileptic disorders

AU - Wolking, Stefan

AU - May, Patrick

AU - Mei, Davide

AU - Møller, Rikke S.

AU - Balestrini, Simona

AU - Helbig, Katherine L.

AU - Altuzarra, Cecilia Desmettre

AU - Chatron, Nicolas

AU - Kaiwar, Charu

AU - Stöhr, Katharina

AU - Widdess-Walsh, Peter

AU - Mendelsohn, Bryce A.

AU - Numis, Adam

AU - Cilio, Maria R.

AU - Van Paesschen, Wim

AU - Svendsen, Lene L.

AU - Oates, Stephanie

AU - Hughes, Elaine

AU - Goyal, Sushma

AU - Brown, Kathleen

AU - Sifuentes Saenz, Margarita

AU - Dorn, Thomas

AU - Muhle, Hiltrud

AU - Pagnamenta, Alistair T.

AU - Vavoulis, Dimitris V.

AU - Knight, Samantha J.L.

AU - Taylor, Jenny C.

AU - Canevini, Maria Paola

AU - Darra, Francesca

AU - Gavrilova, Ralitza M

AU - Powis, Zöe

AU - Tang, Shan

AU - Marquetand, Justus

AU - Armstrong, Martin

AU - McHale, Duncan

AU - Klee, Eric W

AU - Kluger, Gerhard J.

AU - Lowenstein, Daniel H.

AU - Weckhuysen, Sarah

AU - Pal, Deb K.

AU - Helbig, Ingo

AU - Guerrini, Renzo

AU - Thomas, Rhys H.

AU - Rees, Mark I.

AU - Lesca, Gaetan

AU - Sisodiya, Sanjay M.

AU - Weber, Yvonne G.

AU - Lal, Dennis

AU - Marini, Carla

AU - Lerche, Holger

AU - Schubert, Julian

PY - 2019/3/12

Y1 - 2019/3/12

N2 - 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.MethodsWe 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.ResultsWe 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.ConclusionThese 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.

AB - 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.MethodsWe 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.ResultsWe 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.ConclusionThese 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.

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