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 H 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

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskriftArtikelForskningpeer review


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.

Sider (fra-til)e1238-e1249
Udgave nummer11
StatusUdgivet - 12 mar. 2019

Bibliografisk note

Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.


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