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To facilitate trial planning, we characterize its responsiveness (including subitem\u2010level relations to ataxia severity and patient\u2010focused outcomes) across a large number of ataxias, and provide first natural history data for several of them.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Subitem\u2010level correlation and distribution\u2010based analysis of 1,637 SARA assessments in 884 patients with autosomal recessive\/early onset ataxia (370 with 2\u20138 longitudinal assessments) were complemented by linear mixed effects modeling to estimate progression and sample sizes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Although SARA subitem responsiveness varied between ataxia severities, <jats:italic>gait\/stance<\/jats:italic> showed a robust granular linear scaling across the broadest range (SARA &lt;\u200925). Responsiveness was diminished by incomplete subscale use at intermediate or upper levels, nontransitions (\u201cstatic periods\u201d), and fluctuating decreases\/increases. All subitems except <jats:italic>nose\u2010finger<\/jats:italic> showed moderate\u2010to\u2010strong correlations to activities of daily living, indicating that metric properties\u2014not content validity\u2014limit SARA responsiveness. SARA captured mild\u2010to\u2010moderate progression in many genotypes (eg, <jats:italic>SYNE1<\/jats:italic>\u2010ataxia: 0.55 points\/yr, ataxia with oculomotor apraxia type 2: 1.14 points\/yr, <jats:italic>POLG<\/jats:italic>\u2010ataxia: 1.56 points\/yr), but no change in others (autosomal recessive spastic ataxia of Charlevoix\u2010Saguenay, <jats:italic>COQ8A<\/jats:italic>\u2010ataxia). Whereas sensitivity to change was optimal in mild ataxia (SARA &lt;\u200910), it substantially deteriorated in advanced ataxia (SARA &gt;\u200925; 2.7\u2010fold sample size). Use of a novel rank\u2010optimized SARA without subitems <jats:italic>finger\u2010chase<\/jats:italic> and <jats:italic>nose\u2010finger<\/jats:italic> reduces sample sizes by 20 to 25%.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>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. ANN NEUROL 2023;94:470\u2013485<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26712","type":"journal-article","created":{"date-parts":[[2023,5,27]],"date-time":"2023-05-27T16:54:19Z","timestamp":1685206459000},"page":"470-485","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Responsiveness of the Scale for the Assessment and Rating of Ataxia and Natural History in 884 Recessive and Early Onset Ataxia Patients"],"prefix":"10.1002","volume":"94","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8165-5898","authenticated-orcid":false,"given":"Andreas","family":"Trasch\u00fctz","sequence":"first","affiliation":[{"name":"Research Division \u201cTranslational Genomics of Neurodegenerative Diseases,\u201d Hertie Institute for Clinical Brain Research and Center of Neurology University of T\u00fcbingen  T\u00fcbingen Germany"},{"name":"German Center for Neurodegenerative Diseases (DZNE)  T\u00fcbingen 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Saguenay\u2013Lac\u2010Saint\u2010Jean, Faculty of Medicine University of Sherbrooke  Quebec Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janina","family":"Gburek\u2010Augustat","sequence":"additional","affiliation":[{"name":"Division of Neuropediatrics, Hospital for Children and Adolescents University of Leipzig  Leipzig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Doss","sequence":"additional","affiliation":[{"name":"Department of Neurology, Charit\u00e9\u2013Universit\u00e4tsmedizin Berlin, corporate member of Free University of Berlin Humboldt University of Berlin  Berlin Germany"},{"name":"Department of Neurological Sciences University of Nebraska Medical Center  Omaha NE USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ha\u015fmet A.","family":"Hana\u011fas\u0131","sequence":"additional","affiliation":[{"name":"Behavioral Neurology and Movement Disorders Unit, Department of 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