Axial Function Reflects Global Severity in Inherited Ataxias: The Upright Stability Score in Ambulatory Friedreich vs. Spinocerebellar Ataxia
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. ShakkottaiABSTRACT
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.