Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in STXBP1

Thalwitzer KM, Driedger JH, Xian J, Saffari A, Zacher P, Bölsterli BK, Ruggiero SM, Sullivan KR, Datta AN, Kellinghaus C, Althaus J, Wiemer-Kruel A, van Baalen A, Pampel A, Alber M, Braakman HM, Debus OM, Denecke J, Hobbiebrunken E, Breitweg I, Diehl D, Eitel H, Gburek-Augustat J, Preisel M, Schlump JU, Laufs M, Mammadova D, Wurst C, Prager C, Löhr-Nilles C, Martin P, Garbade SF, Platzer K, Benkel-Herrenbrück I, Egler K, Fazeli W, Lemke JR, Runkel E, Klein B, Linden T, Schröter J, Steffek H, Thies B, von Deimling F, Illsinger S, Borggräfe I, Classen G, Wieczorek D, Ramantani G, Kölker S, Hoffmann GF, Ries M, Helbig I, Syrbe S (2023)

Publication Language: English

Publication Type: Journal article

Publication year: 2023

Journal

Book Volume: 101

Pages Range: E879-E891

Journal Issue: 9

DOI: 10.1212/WNL.0000000000207550

Abstract

Background and ObjectivesPathogenic variants in STXBP1 are among the major genetic causes of neurodevelopmental disorders. Despite the increasing number of individuals diagnosed without a history of epilepsy, little is known about the natural history and developmental trajectories in this subgroup and endpoints for future therapeutic studies are limited to seizure control.MethodsWe performed a cross-sectional retrospective study using standardized questionnaires for clinicians and caregivers of individuals with STXBP1-related disorders capturing medical histories, genetic findings, and developmental outcomes. Motor and language function were assessed using Gross Motor Function Classification System (GMFCS) scores and a speech impairment score and were compared within and across clinically defined subgroups.ResultsWe collected data of 71 individuals with STXBP1-related disorders, including 44 previously unreported individuals. Median age at inclusion was 5.3 years (interquartile range 3.5-9.3) with the oldest individual aged 43.8 years. Epilepsy was absent in 18/71 (25%) of individuals. The range of developmental outcomes was broad, including 2 individuals presenting with close to age-appropriate motor development. Twenty-nine of 61 individuals (48%) were able to walk unassisted, and 24/69 (35%) were able to speak single words. Individuals without epilepsy presented with a similar onset and spectrum of phenotypic features but had lower GMFCS scores (median 3 vs 4, p < 0.01) than individuals with epilepsy. Individuals with epileptic spasms were less likely to walk unassisted than individuals with other seizure types (6% vs 58%, p < 0.01). Individuals with early epilepsy onset had higher speech impairment scores (p = 0.02) than individuals with later epilepsy onset.DiscussionWe expand the spectrum of STXBP1-related disorders and provide clinical features and developmental trajectories in individuals with and without a history of epilepsy. Individuals with epilepsy, in particular epileptic spasms, and neonatal or early-onset presented with less favorable motor and language functional outcomes compared with individuals without epilepsy. These findings identify children at risk for severe disease and can serve as comparator for future interventional studies in STXBP1-related disorders.

Authors with CRIS profile

Involved external institutions

Universitätsklinikum Heidelberg Germany (DE) Kleinwachau - Sächsisches Epilepsiezentrum Radeberg gGmbH Germany (DE) Universitäts-Kinderspital Zürich Switzerland (CH) Klinikum Oldenburg Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Children's Hospital of Philadelphia United States (USA) (US) Gemeinschaftskrankenhaus Herdecke Germany (DE) Klinikum Osnabrück Germany (DE) Universitätsklinikum Düsseldorf Germany (DE) Epilepsiezentrum Kork Germany (DE) Klinikum Mutterhaus der Borromäerinnen Germany (DE) SRH Zentralklinikum Suhl Germany (DE) Universitätsklinikum Tübingen Germany (DE) Klinikum Wolfsburg Germany (DE) Klinikum Esslingen Germany (DE) Evangelisches Klinikum Bethel Germany (DE) Sozialpädiatrisches Zentrum Coburg Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Universitäts-Kinderspital beider Basel (UKBB) Switzerland (CH) Ruprecht-Karls-Universität Heidelberg Germany (DE) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) Universitätsklinikum Göttingen Germany (DE) Universitätsklinikum Leipzig Germany (DE) Sana Kliniken Düsseldorf Germany (DE) Clemenshospital Germany (DE) Universitätsklinikum Bonn Germany (DE) Universitätsklinikum Gießen und Marburg (UKGM) Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) KJF Klinik St. Elisabeth gGmbH Germany (DE) Klinikum der Universität München (LMU Klinikum) Germany (DE) Klinikum Frankfurt Höchst Germany (DE) Klinikum Aschaffenburg-Alzenau Germany (DE) Johannes Wesling Klinikum Minden Germany (DE) Christophorus-Kliniken Germany (DE) Universitätsklinikum Schleswig-Holstein (UKSH) Germany (DE) Salzburger Landeskliniken (SALK) Austria (AT)

How to cite

APA:

Thalwitzer, K.M., Driedger, J.H., Xian, J., Saffari, A., Zacher, P., Bölsterli, B.K.,... Syrbe, S. (2023). Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in STXBP1. Neurology, 101(9), E879-E891. https://doi.org/10.1212/WNL.0000000000207550

MLA:

Thalwitzer, Kim M., et al. "Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in STXBP1." Neurology 101.9 (2023): E879-E891.

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