Longitudinal progression, metrics, age-dependence, and modifiers of ataxia severity in SCA27B: a multicentre study of 219 patients
Abstract
Background Spinocerebellar Ataxia 27B (SCA27B) is a novel, frequent and likely treatable late-onset autosomal-dominant ataxia caused by GAA repeat-expansions in FGF14 . For understanding disease evolution and imminent trial planning, metrics of the most widely used clinical outcome assessment (Scale for the Assessment and Rating of Ataxia/SARA), longitudinal progression and modifiers thereof are warranted. Methods Multicentre intercontinental observational study (2015–2024) of 661 assessments from 219 patients with SCA27B (age: 68 ± 10 years; SARA: 9 ± 6 points) with item-level distribution-based analyses to characterise SARA metrics relative to ageing-related impairment in 390 healthy controls; and linear mixed-effects modelling to determine longitudinal progression and demographic or genetic modifiers. Findings Ataxia severity in SCA27B as assessed by SARA was primarily attributable to gait, stance, and lower-limb impairment; other ataxia domains scored ≤1 SARA point in 79–94% of patients. Discrimination of SCA27B motor performance from controls decreased with age due to ageing-related motor variability captured by SARA, thus limiting potential metric response windows for symptomatic treatments. Disease progression was faster in the presence of interfering ageing-related comorbidities in 14 (6%) patients. Overall longitudinal progression of SCA27B was 0.54 SARA points/year [95% CI: 0.37–0.71]. Expansions of (GAA) > 180 repeats were frequent also on the shorter allele (n = 18 (8%), range: 196–348 repeats), and associated with faster progression (+1.6 SARA points/year, [95% CI: 0.9–2.2]), including also otherwise less affected ataxia domains speech and sitting. Interpretation Disease progression in SCA27B is characterised by mild progression, ageing-related motor variabilities and comorbidities, and associated with repeat size on both alleles. Funding Else-Kröner-Fresenius-Stiftung, EU, DFG, BMBF, CIHR, NAF, Ataxia-UK, CSC.
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Authors: Andreas Traschütz, R.-D Hilgers, Friedrich Erdlenbruch, Christel Depienne, Thomas Wirth, Clarisse Delvallée, Astrid Nümann, Catherine Ashton, David Pellerin, Elisabetta Indelicato, Felix Heindl, Mathilde Renaud, Max Borsche, Marcus Grobe-Einsler, Jennifer Faber, Thomas Klockgether, Ludger Schöls, Bernard Brais, Mathieu Anheim, Dagmar Timmann, Matthis Synofzik
Institutions: Heinrich Heine University Düsseldorf, Ludwig-Maximilians-Universität München, Inserm, University of Tübingen, RWTH Aachen University, Centre National de la Recherche Scientifique, Université de Lorraine, Université de Strasbourg, Humboldt-Universität zu Berlin, Innsbruck Medical University, Universität Innsbruck, Centre Hospitalier Régional et Universitaire de Nancy, University of Lübeck, McGill University, University Hospital Schleswig-Holstein, Institut de génétique et de biologie moléculaire et cellulaire, University of Duisburg-Essen, German Center for Neurodegenerative Diseases, University Hospital Bonn, Essen University Hospital, Hertie Institute for Clinical Brain Research, Montreal Neurological Institute and Hospital, Sigmund Freud Privatuniversität Wien, Max Delbrück Center, Royal Perth Hospital, Hôpitaux Universitaires de Strasbourg, Nutrition-Génétique et Exposition aux Risques Environnementaux