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| Item Type: | Article |
|---|---|
| Title: | Longitudinal progression, metrics, age-dependence, and modifiers of ataxia severity in SCA27B: a multicentre study of 219 patients |
| Creators: |
Traschütz, Andreas  ORCID: https://orcid.org/0000-0002-8165-5898, Hilgers, Ralf-Dieter, Erdlenbruch, Friedrich, Depienne, Christel, Wirth, Thomas, Delvallée, Clarisse, Nümann, Astrid, Ashton, Catherine, Pellerin, David, Indelicato, Elisabetta, Heindl, Felix ORCID: https://orcid.org/0009-0000-6478-3313, Renaud, Mathilde, Borsche, Max, Grobe-Einsler, Marcus, Faber, Jennifer, Klockgether, Thomas, Schöls, Ludger, Brais, Bernard, Anheim, Mathieu, Timmann, Dagmar and Synofzik, Matthis ORCID: https://orcid.org/0000-0002-2280-7273
|
| 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. |
| Keywords: | Ataxia, SCA27B, Natural History, Progression, Modifiers, Trials |
| Source: | EBioMedicine |
| ISSN: | 2352-3964 |
| Publisher: | Elsevier |
| Volume: | 131 |
| Page Range: | 106437 |
| Date: | September 2026 |
| Official Publication: | https://doi.org/10.1016/j.ebiom.2026.106437 |
| PubMed: | View item in PubMed |
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