von Christoph Jüschke ; Kira Linsel ; Marta Owczarek-Lipska ; Nicola Brandt ; Sarah Zunken ; Janine Altmüller ; Markus N. Preising ; Dennis Kastrati ; Holger Thiele ; Mervyn G. Thomas ; Peter Nürnberg ; Birgit Lorenz ; Ulrich Kellner ; Anja U. Bräuer ; Christoph Korenke ; Irene Gottlob ; John Neidhardt
von Jacqueline E. Taudien ; Diana Bracht ; Heike Olbrich ; Sebastian Swirski ; Fulvio D’Abrusco ; Bert Van der Zwaag ; Maike Möller ; Thomas Lücke ; Norbert Teig ; Ulrika Lindberg ; Kai Wohlgemuth ; Julia Wallmeier ; Anja Blanque ; Christos Gatsogiannis ; Sebastian George ; Christoph Jüschke ; Marta Owczarek-Lipska ; Dorothee Veer ; Hester Y. Kroes ; Enza Maria Valente ; Christoph Korenke ; Heymut Omran ; John Neidhardt
von Frank Martin Brunkhorst ; Michael Adamzik ; Hubertus Axer ; Michael Bauer ; Christian Bode ; Hans-Georg Bone ; Thorsten Brenner ; Michael Bucher ; Sascha Igor David ; Maximilian Dietrich ; Christian Eckmann ; Gunnar Elke ; Torben Esser ; Thomas Felbinger ; Christine Geffers ; Herwig Gerlach ; Beatrice Grabein ; Matthias Gründling ; Ulf Günther ; Stefan Hagel ; Andreas Hecker ; Stefan Henkel ; Babila Janusan ; Stefan John ; Achim Jörres ; Achim Kaasch ; Stefan Kluge ; Matthias Kochanek ; Agnieszka Lajca ; Gernot Marx ; Konstantin Mayer ; Patrick Meybohm ; Onnen Mörer ; Michael Oppert ; Vladimir Patchev ; Mathias Pletz ; Christian Putensen ; Tim Rahmel ; Jenny Rosendahl ; Rolf Rossaint ; Bernd Salzberger ; Michael Sander ; Stefan Schaller ; Christina Scharf-Janssen ; Felix Schmitt ; Matthias Unterberg ; Markus A. Weigand ; Arved Weimann ; Sebastian Weis ; Björn Weiß ; Alexander Wolf ; Alexander Zarbock
von Iris Verbinnen ; Sofia Douzgou Houge ; Tzung-Chien Hsieh ; Hellen Lesmann ; Aron Kirchhoff ; David Geneviève ; Elise Brimble ; Lisa Lenaerts ; Dorien Haesen ; Rebecca J. Levy ; Julien Thevenon ; Laurence Faivre ; Elysa Marco ; Jessica X. Chong ; Mike Bamshad ; Karynne Patterson ; Ghayda M. Mirzaa ; Kimberly Foss ; William Dobyns ; Susan M. White ; Lynn Pais ; Emily O’Heir ; Raphaela Itzikowitz ; Kirsten A. Donald ; Celia Van der Merwe ; Alessandro Mussa ; Raffaela Cervini ; Elisa Giorgio ; Tony Roscioli ; Kerith-Rae Dias ; Carey-Anne Evans ; Natasha J. Brown ; Anna Ruiz ; Juan Pablo Trujillo Quintero ; Rachel Rabin ; John Pappas ; Hai Yuan ; Katherine Lachlan ; Simon Thomas ; Anita Devlin ; Michael Wright ; Richard Martin ; Joanna Karwowska ; Renata Posmyk ; Nicolas Chatron ; Zornitza Stark ; Oliver Heath ; Martin Delatycki ; Rebecca Buchert ; Christoph Korenke ; Keri Ramsey ; Vinodh Narayanan ; Dorothy K. Grange ; Judith L. Weisenberg ; Tobias B. Haack ; Stephanie Karch ; Patricia Kipkemoi ; Moses Mangi ; Karen G. C. B. Bindels de Heus ; Marie-Claire Y. de Wit ; Tahsin Stefan Barakat ; Derek Lim ; Géraldine Van Winckel ; Rebecca C. Spillmann ; Vandana Shashi ; Maureen Jacob ; Antonia M. Stehr ; Peter Krawitz ; Gunnar Douzgos Houge ; Veerle Janssens
Pathogenic variants resulting in protein phosphatase 2A (PP2A) dysfunction result in mild to severe neurodevelopmental delay. PP2A is a trimer of a catalytic (C) subunit, scaffolding (A) subunit, and substrate binding/regulatory (B) subunit, encoded by 19 different genes. De novo missense variants in PPP2R5D (B56δ) or PPP2R1A (Aα) and de novo missense and loss-of-function variants in PPP2CA (Cα) lead to syndromes with overlapping phenotypic features, known as Houge-Janssens syndrome (HJS) types 1, 2, and 3, respectively. Here, we describe an additional condition in the HJS spectrum in 26 individuals with variants in PPP2R5C, encoding the regulatory B56γ subunit. Most changes were de novo and of the missense type. The clinical features were well within the HJS spectrum with strongest resemblance to HJS type 1, caused by B56δ variants. Common features were neurodevelopmental delay and hypotonia, with a high risk of epilepsy, behavioral problems, and mildly dysmorphic facial features. Head circumferences were above average or macrocephalic. The degree of intellectual disability was, on average, milder than in other HJS types. All variants affected either substrate binding (2/19), C-subunit binding (2/19), or both (15/19). Five variants were recurrent. Catalytic activity of the phosphatase was variably affected by the variants. Of note, PPP2R5C total loss-of-function variants could be inherited from a non-symptomatic parent. This implies that a dominant-negative mechanism on substrate dephosphorylation or general PP2A function is the most likely pathogenic mechanism.
The American journal of human genetics New York, NY [u.a.] : Cell Press, 1949 112(2025), 3 vom: März, Seite 554-571
von Dana Pisică ; Victor Volovici ; John K. Yue ; Thomas van Essen ; Hugo F. den Boogert ; Thijs Vande Vyvere ; Iain Haitsma ; Daan Nieboer ; Amy J. Markowitz ; Esther L. Yuh ; Ewout W. Steyerberg ; Wilco C. Peul ; Clemens M. F. Dirven ; David K. Menon ; Geoffrey T. Manley ; Andrew I. Maas ; Hester F. Lingsma ; Renán Sánchez-Porras
von Florian Giesl ; Alexander K. Hartmann ; Patrick Eraerds ; Christian Schubbert ; Hossam Elanzeery ; Stephan John Heise ; Thomas Dalibor ; Jürgen Parisi
von Julie George ; Lukas Maas ; Nima Abedpour ; Maria Cartolano ; Laura Kaiser ; Rieke Nila Fischer ; Andreas H. Scheel ; Jan-Philipp Weber ; Martin Hellmich ; Graziella Bosco ; Caroline Volz ; Christian Müller ; Ilona Dahmen ; Felix John ; Cleidson Padua Alves ; Lisa Werr ; Jens Peter Panse ; Martin Kirschner ; Walburga Engel-Riedel ; Jessica Jürgens ; Erich Stoelben ; Michael Brockmann ; Stefan Grau ; Martin Sebastian ; Jan Alexander Stratmann ; Jens Kern ; Horst-Dieter Hummel ; Balazs Hegedus ; Martin Schuler ; Till Plönes ; Clemens Aigner ; Thomas Elter ; Karin Toepelt ; Yon-Dschun Ko ; Sylke Kurz ; Christian Grohé ; Monika Serke ; Katja Anne Höpker ; Lars Gerd Hagmeyer ; Fabian Doerr ; Khosro Hekmath ; Judith Strapatsas ; Karl-Otto Kambartel ; Geothy Chakupurakal ; Annette Hülsmeyer ; Franz-Georg Bauernfeind ; Frank Griesinger ; Anne Lüers ; Wiebke Dirks ; Rainer Gerhard Wiewrodt ; Andrea Luecke ; Ernst Michael Rodermann ; Andreas Diel ; Volker Hagen ; Kai Severin ; Roland Ullrich ; Christian Reinhardt ; Alexander Quaas ; Magdalena Bogus ; Cornelius Courts ; Peter Nürnberg ; Kerstin Becker ; Viktor Achter ; Reinhard Büttner ; Jürgen Wolf ; Martin Peifer ; Roman Thomas
von Rick J. G. Vreeburg ; Ranjit D. Singh ; Inge A. M. van Erp ; Tommi K. Korhonen ; John K. Yue ; Harry Mee ; Ivan Timofeev ; Angelos Kolias ; Adel Helmy ; Bart Depreitere ; Wouter A. Moojen ; Alexander Younsi ; Peter J. Hutchinson ; Geoffrey T. Manley ; Ewout W. Steyerberg ; Godard C. W. de Ruiter ; Andrew I. Maas ; Wilco C. Peul ; Jeroen T. J. M. van Dijck ; Hugo F. den Boogert ; Jussi P. Posti ; Thomas van Essen ; Renán Sánchez-Porras
CENTER-TBI participants and investigators: Cecilia Åkerlund, Julia Mattern, Oliver Sakowitz, Andreas Unterberg, Alexander Younsi und zahlreiche weitere ; Gesehen am 20.08.2025
Journal of neurosurgery Charlottesville, Va. : American Assoc. of Neurological Surgeons, 1944 141(2024), 4 vom: Okt., Seite 895-907 Online-Ressource
von Thomas van Essen ; Inge A. M. van Erp ; Hester F. Lingsma ; Dana Pisică ; John K. Yue ; Ranjit D. Singh ; Jeroen T. J. M. van Dijck ; Victor Volovici ; Alexander Younsi ; Angelos Kolias ; Lianne D. Peppel ; Majanka Heijenbrok-Kal ; Gerard M. Ribbers ; David K. Menon ; Peter J. A. Hutchinson ; Geoffrey T. Manley ; Bart Depreitere ; Ewout W. Steyerberg ; Andrew I. R. Maas ; Godard C. W. de Ruiter ; Wilco C. Peul ; Renán Sánchez-Porras
Background - Limited evidence existed on the comparative effectiveness of decompressive craniectomy (DC) versus craniotomy for evacuation of traumatic acute subdural hematoma (ASDH) until the recently published randomised clinical trial RESCUE-ASDH. In this study, that ran concurrently, we aimed to determine current practice patterns and compare outcomes of primary DC versus craniotomy. - Methods - We conducted an analysis of centre treatment preference within the prospective, multicentre, observational Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (known as CENTER-TBI) and NeuroTraumatology Quality Registry (known as Net-QuRe) studies, which enrolled patients throughout Europe and Israel (2014-2020). We included patients with an ASDH who underwent acute neurosurgical evacuation. Patients with severe pre-existing neurological disorders were excluded. In an instrumental variable analysis, we compared outcomes between centres according to treatment preference, measured by the case-mix adjusted proportion DC per centre. The primary outcome was functional outcome rated by the 6-months Glasgow Outcome Scale Extended, estimated with ordinal regression as a common odds ratio (OR), adjusted for prespecified confounders. Variation in centre preference was quantified with the median odds ratio (MOR). CENTER-TBI is registered with ClinicalTrials.gov, number NCT02210221, and the Resource Identification Portal (Research Resource Identifier SCR_015582). - Findings - Between December 19, 2014 and December 17, 2017, 4559 patients with traumatic brain injury were enrolled in CENTER-TBI of whom 336 (7%) underwent acute surgery for ASDH evacuation; 91 (27%) underwent DC and 245 (63%) craniotomy. The proportion primary DC within total acute surgery cases ranged from 6 to 67% with an interquartile range (IQR) of 12-26% among 46 centres; the odds of receiving a DC for prognostically similar patients in one centre versus another randomly selected centre were trebled (adjusted median odds ratio 2.7, p < 0.0001). Higher centre preference for DC over craniotomy was not associated with better functional outcome (adjusted common odds ratio (OR) per 14% [IQR increase] more DC in a centre = 0.9 [95% CI 0.7-1.1], n = 200). Primary DC was associated with more follow-on surgeries and complications [secondary cranial surgery 27% vs. 18%; shunts 11 vs. 5%]; and similar odds of in-hospital mortality (adjusted OR per 14% IQR more primary DC 1.3 [95% CI (1.0-3.4), n = 200]). - Interpretation - We found substantial practice variation in the employment of DC over craniotomy for ASDH. This variation in treatment strategy did not result in different functional outcome. These findings suggest that primary DC should be restricted to salvageable patients in whom immediate replacement of the bone flap is not possible due to intraoperative brain swelling. - Funding - Hersenstichting Nederland for the Dutch NeuroTraumatology Quality Registry and the European Union Seventh Framework Program.
Lithium is regarded as the first-line treatment for bipolar disorder (BD), a severe and disabling mental health disorder that affects about 1% of the population worldwide. Nevertheless, lithium is not consistently effective, with only 30% of patients showing a favorable response to treatment. To provide personalized treatment options for bipolar patients, it is essential to identify prediction biomarkers such as polygenic scores. In this study, we developed a polygenic score for lithium treatment response (Li+PGS) in patients with BD. To gain further insights into lithium’s possible molecular mechanism of action, we performed a genome-wide gene-based analysis. Using polygenic score modeling, via methods incorporating Bayesian regression and continuous shrinkage priors, Li+PGS was developed in the International Consortium of Lithium Genetics cohort (ConLi+Gen: N = 2367) and replicated in the combined PsyCourse (N = 89) and BipoLife (N = 102) studies. The associations of Li+PGS and lithium treatment response — defined in a continuous ALDA scale and a categorical outcome (good response vs. poor response) were tested using regression models, each adjusted for the covariates: age, sex, and the first four genetic principal components. Statistical significance was determined at P < 0.05. Li+PGS was positively associated with lithium treatment response in the ConLi+Gen cohort, in both the categorical (P = 9.8 × 10−12, R2 = 1.9%) and continuous (P = 6.4 × 10−9, R2 = 2.6%) outcomes. Compared to bipolar patients in the 1st decile of the risk distribution, individuals in the 10th decile had 3.47-fold (95%CI: 2.22-5.47) higher odds of responding favorably to lithium. The results were replicated in the independent cohorts for the categorical treatment outcome (P = 3.9 × 10−4, R2 = 0.9%), but not for the continuous outcome (P = 0.13). Gene-based analyses revealed 36 candidate genes that are enriched in biological pathways controlled by glutamate and acetylcholine. Li+PGS may be useful in the development of pharmacogenomic testing strategies by enabling a classification of bipolar patients according to their response to treatment.
