Capturing clinical progression in multisystemic genetic ataxias: lessons from a prospective study of 884 patients with autosomal recessive or early-onset ataxia

Objective The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity and patient-focused outcomes) across a large number of ataxias, and provide first natural history data for several of them. Methods Subitem-level correlation- and distribution-based analysis of 1637 SARA assessments in 884 patients with autosomal-recessive/early-onset ataxia (370 with 2-8 longitudinal assessments), complemented by linear mixed-effects modeling to estimate progression and sample sizes. Results While SARA subitem responsiveness varied between ataxia severities, gait / stance showed a robust granular linear scaling across the broadest range (SARA<25). Responsiveness was diminished by incomplete sub-scale use at intermediate or upper levels, non-transitions (“static periods”), and fluctuating decreases/increases. All subitems -except nose-finger -showed moderate-to-strong correlations to activities of daily living, indicating that metric properties -not content validity-limit SARA responsiveness. SARA captured mild-to-moderate progression in many genotypes, e.g., SYNE1-ataxia: 0.55 points/year, AOA2: 1.14, POLG-ataxia: 1.56; but no change in others (ARSACS, COQ8A-ataxia). While sensitivity to change was optimal in mild ataxia (SARA≤10), it substantially deteriorated in advanced ataxia (SARA>25; 2.7-fold sample size). Use of a novel rank-optimized SARA without subitems finger-chase and nose-finger reduces sample sizes by 20-25%. Interpretation This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported via the European Union Horizon 2020 research and innovation program as part of the innovation project EVIDENCE-RND under the EJP RD COFUND EJP (No. 825575, to RD.H. and M.S.), as part of SolveRD (No 779257, to J.B., M.S., and B.vdW.), and by the DFG under the frame of EJP RD network PROSPAX (No 441409627; M.S., BvDW). The study was further funded by the Federal Ministry of Education and Research, Germany, and through the TreatHSP network (01GM1905 to LS). B.vdW. receives additional research support from ZonMW, Hersenstichting, Gossweiler Foundation, and Radboud university medical centre. L.S., T.Klop., T.Klock., E.B., G.Z., BvdW., and M.S. are members of the European Reference Network for Rare Neurological Diseases, Project ID No 739510. A.T. receives funding from the University of Tuebingen, medical faculty, for the Clinician Scientist Program Grant #439.P.K. receives funding from University of Szeged (Hetenyi Geza: 5S330 A202) and Ministry of Innovation and Technology of Hungary, National Research, Development and Innovation Fund (TKP2021 EGA). JB is supported by a Senior Clinical Researcher mandate of the Research Fund - Flanders (FWO) under grant agreement number 1805021N, is a member of the NEURO Research Centre of Excellence of the University of Antwerp. FMS is supported in part by the Italian Ministry of Health (the EJP RD network PROSPAX; Ricerca Finalizzata RF2016 02361610; RF2019 12370417; Ricerca Corrente, RC 5x1000). Several authors of this publication are member of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO NMD) and of the European Reference Network for Rare Neurological Diseases (ERN RND). We are grateful to Selina Reich for her coordinating support as part of the EOA/PREPARE consortium and to Tanja Heger for monitoring the datasets of the ARCA registry. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The registry and this multicenter study was approved by the IRB Tuebingen Az. 598/2011BO1, and all patients had provided informed consent. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.