Longitudinal progression, metrics, age-dependence, and modifiers of ataxia severity in SCA27B: a multicentre study of 219 patients.

IF 11.2 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2026-09-01 Epub Date: 2026-08-15 DOI:10.1016/j.ebiom.2026.106437

Andreas Traschütz, Ralf-Dieter Hilgers, Friedrich Erdlenbruch, Christel Depienne, Thomas Wirth, Clarisse Delvallée, Astrid Nümann, Catherine Ashton, David Pellerin, Elisabetta Indelicato, Felix Heindl, Mathilde Renaud, Max Borsche, Marcus Grobe-Einsler, Jennifer Faber, Thomas Klockgether, Ludger Schöls, Bernard Brais, Mathieu Anheim, Dagmar Timmann, Matthis Synofzik

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引用次数: 0

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.

Funding: Else-Kröner-Fresenius-Stiftung, EU, DFG, BMBF, CIHR, NAF, Ataxia-UK, CSC.

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纵向进展、指标、年龄依赖性和SCA27B共济失调严重程度的改变因素：一项219例患者的多中心研究

背景：脊髓小脑性共济失调27B （SCA27B）是一种由FGF14中GAA重复扩增引起的新型、常见且可能治疗的晚发性常染色体显性共济失调。为了了解疾病演变和即将到来的试验计划，最广泛使用的临床结果评估指标（共济失调/SARA评估和评级量表），纵向进展及其修改是必要的。方法：多中心洲际观察性研究（2015-2024），对219例SCA27B患者（年龄：68±10岁；SARA: 9±6分）的661项评估进行了基于项目水平分布的分析，以表征390名健康对照者与年龄相关损害相关的SARA指标；以及线性混合效应模型，以确定纵向进展和人口统计学或遗传修饰因子。研究结果：通过SARA评估的SCA27B患者共济失调严重程度主要归因于步态、站立和下肢损伤；其他共济失调域评分≤1分的患者占79 ~ 94%。由于SARA捕获的与年龄相关的运动变异性，SCA27B运动性能与对照组的区别随着年龄的增长而下降，从而限制了对症治疗的潜在度量反应窗口。在14例（6%）患者中，存在干扰性衰老相关合并症时，疾病进展更快。SCA27B的总体纵向进展为0.54 SARA点/年[95% CI: 0.37-0.71]。在较短的等位基因上（n = 18(8%)，范围：196-348个重复），（GAA） bbb180重复的扩增也很常见，并且与更快的进展（+1.6 SARA点/年，[95% CI: 0.9-2.2]）相关，也包括较少受影响的言语和坐姿失调域。解释：SCA27B的疾病进展特征为轻度进展、与年龄相关的运动变异性和合并症，并与两个等位基因的重复序列大小相关。资助：Else-Kröner-Fresenius-Stiftung， EU， DFG， BMBF， CIHR， NAF, ataxis - uk， CSC。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.