Axial Function Reflects Global Severity in Inherited Ataxias: The Upright Stability Score in Ambulatory Friedreich vs. Spinocerebellar Ataxia
Year: 2026
Type: article
Abstract: OBJECTIVE: Inherited ataxias are clinically diverse neurodegenerative diseases, complicating the choice of outcome measures for trials. In spinocerebellar ataxia (SCA), regulatory concerns about the Scale for the Assessment and Rating of Ataxia (SARA) caused a shift toward functional SARA (f-SARA), contributing to pivotal trial failure. We investigated whether the Upright Stability Score (USS), validated in Friedreich ataxia (FRDA), retains its psychometric properties in SCA, and how it compares with SARA, f-SARA, and the Friedreich Ataxia Activities of Daily Living scale (FA-ADL). METHODS: Cross-sectional data from ambulatory participants in two large international natural-history studies (CRC-SCA and UNIFAI) were analyzed with correlation-based psychometric methods, comparing score distributions across scales and genotypes. RESULTS: Data from 406/343 participants in CRC-SCA/UNIFAI were analyzed. In SCA, the USS captured a wider spectrum of balance performance, while in FRDA, early proprioceptive deficits-particularly impaired stance with eyes closed-constrained score variability. USS correlated strongly with SARA, f-SARA, and FA-ADL in both cohorts. SARA showed moderate skew, and f-SARA showed pronounced floor effects in mildly affected SCA, whereas USS and FA-ADL preserved discrimination at the low end. FA-ADL distributions were broadly comparable across genotypes. INTERPRETATION: USS showed cross-sectional convergent validity with established measures across ambulatory FRDA and SCA, reflecting perceived disease burden (FA-ADL) at least as well as SARA. f-SARA is poorly discriminating in ambulatory SCA and is unlikely to work as an outcome measure, in particular in early cohorts. USS showed the potential to serve as a primary outcome assessment in pivotal SCA trials, but longitudinal evidence is required. Limitations include cross-sectional design and a substantial age difference between cohorts.
DOI: 10.1002/acn3.70563
Authors: Christian Rummey, S. H. Subramony, David R. Lynch, Louise A. Corben, Martin B. Delatycki, Jörg B. Schulz, Kathrin Reetz, Massimo Pandolfo, Matthis Synofzik, Theresa Zesiewicz, Antoine Duquette, Matthew Burns, Martin Vyhnálek, Lucie Stovickova, Sinead M. Murphy, Petya Bogdanova‐Mihaylova, Mary Kearney, Richard Walsh, Richard H. Roxburgh, Khalaf Bushara, Marie Y. Davis, Enrico S. Bertini, Gessica Vasco, Shweta Sahni, Mohammed Faruq, Achal K. Srivastava, Bart van de Warrenburg, Elisabetta Indelicato, Sylvia Boesch, Andrew Billnitzer, Tetsuo Ashizawa, Anoopum S. Gupta, Grace Yoon, Georgios Koutsis, Chrysoula Koniari, Zofia Fleszar, Christopher M. Gomez, Andrea Martinuzzi, Gabriella Paparella, Ali G. Hamedani, Puneet Opal, Rizwan S. Akhtar, Caterina Mariotti, Henry Paulson, Peter Todd, Sharan R. Srinivasan, George Wilmot, Ludger Schöls, Susan Perlman, Jeremy D. Schmahmann, Sheng‐Han Kuo, Liana S. Rosenthal, Vikram G. Shakkottai
Institutions: University of Florida Health, University of Florida, Children's Hospital of Philadelphia, The University of Melbourne, Murdoch Children's Research Institute, Jülich Aachen Research Alliance, RWTH Aachen University, McGill University, German Center for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of South Florida, Centre Hospitalier de l’Université de Montréal, Université de Montréal, Charles University, Fakultní nemocnice Motol a Homolka, Trinity College Dublin, Tallaght University Hospital, University of Auckland, University of Minnesota, University of Washington, Bambino Gesù Children's Hospital, Istituti di Ricovero e Cura a Carattere Scientifico, Institute of Genomics and Integrative Biology, Radboud University Medical Center, Innsbruck Medical University, Universität Innsbruck, Houston Methodist Research Institute, Harvard University, Massachusetts General Hospital, University of Toronto, Hospital for Sick Children, National and Kapodistrian University of Athens, Eginition Hospital, University of Tübingen, University of Chicago, University of Pennsylvania, Northwestern University, Fondazione IRCCS Istituto Neurologico Carlo Besta, University of Michigan, Emory University, University of California, Los Angeles, NewYork–Presbyterian Hospital, Columbia University Irving Medical Center, Johns Hopkins University, Johns Hopkins Medicine, The University of Texas Southwestern Medical Center
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,100
Funders: Friedreich's Ataxia Research Alliance, National Ataxia Foundation, Massachusetts General Hospital, Children's Hospital of Philadelphia, University of Pennsylvania, University of Minnesota, Univerzita Karlova v Praze, University of Washington, McGill University, University of South Florida, Murdoch Children's Research Institute, Ospedale Pediatrico Bambino Gesù, European Commission, Trinity College Dublin, Eberhard Karls Universität Tübingen, Else Kröner-Fresenius-Stiftung, University of Toronto, National and Kapodistrian University of Athens, Deutsches Zentrum für Neurodegenerative Erkrankungen, Université de Montréal, Hospital for Sick Children, Radboud Universitair Medisch Centrum, RWTH Aachen University, Perelman School of Medicine, University of Pennsylvania, Houston Methodist Research Institute
OpenAlex ID: W7225348305