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.

Clinical spectrum of STX1B-related epileptic disorders / S. Wolking, P. May, D. Mei, R.S. Møller, S. Balestrini, K.L. Helbig, C.D. Altuzarra, N. Chatron, C. Kaiwar, K. Stöhr, P. Widdess-Walsh, B.A. Mendelsohn, A. Numis, M.R. Cilio, W. Van Paesschen, L.L. Svendsen, S. Oates, E. Hughes, S. Goyal, K. Brown, M. Sifuentes Saenz, T. Dorn, H. Muhle, A.T. Pagnamenta, D.V. Vavoulis, S.J.L. Knight, J.C. Taylor, M.P. Canevini, F. Darra, R.H. Gavrilova, Z. Powis, S. Tang, J. Marquetand, M. Armstrong, D. Mchale, E.W. Klee, G.J. Kluger, D.H. Lowenstein, S. Weckhuysen, D.K. Pal, I. Helbig, R. Guerrini, R.H. Thomas, M.I. Rees, G. Lesca, S.M. Sisodiya, Y.G. Weber, D. Lal, C. Marini, H. Lerche, J. Schubert. - In: NEUROLOGY. - ISSN 0028-3878. - 92:11(2019 Mar 12), pp. E1238-E1249. [10.1212/WNL.0000000000007089]

Clinical spectrum of STX1B-related epileptic disorders

M.P. Canevini;
2019-03-12

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.
Settore MED/39 - Neuropsichiatria Infantile
8-feb-2019
Article (author)
File in questo prodotto:
File Dimensione Formato  
e1238.full.pdf

accesso aperto

Tipologia: Publisher's version/PDF
Dimensione 706.47 kB
Formato Adobe PDF
706.47 kB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/625859
Citazioni
  • ???jsp.display-item.citation.pmc??? 14
  • Scopus 26
  • ???jsp.display-item.citation.isi??? 26
social impact