Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in STXBP1.
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Thalwitzer Kim M, Driedger Jan H, Xian Julie, Saffari Afshin, Zacher Pia, Bölsterli Bigna K, Ruggiero Sarah McKeown, Sullivan Katie Rose, Datta Alexandre N, Kellinghaus Christoph, Althaus Jürgen, Wiemer-Kruel Adelheid, van Baalen Andreas, Pampel Armin, Alber Michael, Braakman Hilde M H, Debus Otfried M, Denecke Jonas, Hobbiebrunken Elke, Breitweg Ina, Diehl Danielle, Eitel Hans, Gburek-Augustat Janina, Preisel Martin, Schlump Jan-Ulrich, Laufs Mirjam, Mammadova Dilbar, Wurst Carsten, Prager Christine, Löhr-Nilles Christa, Martin Peter, Garbade Sven F, Platzer Konrad, Benkel-Herrenbrueck Ira, Egler Kerstin, Fazeli Walid, Lemke Johannes R, Runkel Eva, Klein Barbara, Linden Tobias, Schröter Julian, Steffeck Heike, Thies Bastian, von Deimling Florian, Illsinger Sabine, Borggraefe Ingo, Classen Georg, Wieczorek Dagmar, Ramantani Georgia, Koelker Stefan, Hoffmann Georg F, Ries Markus, Helbig Ingo, Syrbe Steffen
Аннотация
METHODS: We 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.
RESULTS: We 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.
DISCUSSION: We 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.