Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, 72076 Tübingen, Germany.
German Center for Neurodegenerative Diseases (DZNE), 72076 Tübingen, Germany.
Brain. 2023 Oct 3;146(10):4144-4157. doi: 10.1093/brain/awad157.
Ataxia due to an autosomal dominant intronic GAA repeat expansion in FGF14 [GAA-FGF14 ataxia, spinocerebellar ataxia 27B (SCA27B)] has recently been identified as one of the most common genetic late-onset ataxias. We here aimed to characterize its phenotypic profile, natural history progression, and 4-aminopyridine (4-AP) treatment response. We conducted a multi-modal cohort study of 50 GAA-FGF14 patients, comprising in-depth phenotyping, cross-sectional and longitudinal progression data (up to 7 years), MRI findings, serum neurofilament light (sNfL) levels, neuropathology, and 4-AP treatment response data, including a series of n-of-1 treatment studies. GAA-FGF14 ataxia consistently presented as late-onset [60.0 years (53.5-68.5), median (interquartile range)] pancerebellar syndrome, partly combined with afferent sensory deficits (55%) and dysautonomia (28%). Dysautonomia increased with duration while cognitive impairment remained infrequent, even in advanced stages. Cross-sectional and longitudinal assessments consistently indicated mild progression of ataxia [0.29 Scale for the Assessment and Rating of Ataxia (SARA) points/year], not exceeding a moderate disease severity even in advanced stages (maximum SARA score: 18 points). Functional impairment increased relatively slowly (unilateral mobility aids after 8 years in 50% of patients). Corresponding to slow progression and low extra-cerebellar involvement, sNfL was not increased relative to controls. Concurrent second diseases (including progressive supranuclear palsy neuropathology) represented major individual aggravators of disease severity, constituting important caveats for planning future GAA-FGF14 trials. A treatment response to 4-AP with relevance for everyday living was reported by 86% of treated patients. A series of three prospective n-of-1 treatment experiences with on/off design showed marked reduction in daily symptomatic time and symptom severity on 4-AP. Our study characterizes the phenotypic profile, natural history progression, and 4-AP treatment response of GAA-FGF14 ataxia. It paves the way towards large-scale natural history studies and 4-AP treatment trials in this newly discovered, possibly most frequent, and treatable late-onset ataxia.
由于常染色体显性内含子 GAA 重复扩增导致的共济失调[GAA-FGF14 共济失调，脊髓小脑共济失调 27B（SCA27B）]最近被确定为最常见的遗传性迟发性共济失调之一。我们旨在描述其表型特征、自然病史进展和 4-氨基吡啶（4-AP）治疗反应。我们对 50 名 GAA-FGF14 患者进行了多模态队列研究，包括深入的表型分析、横断面和纵向进展数据（最长 7 年）、MRI 发现、血清神经丝轻链（sNfL）水平、神经病理学和 4-AP 治疗反应数据，包括一系列 n-of-1 治疗研究。GAA-FGF14 共济失调始终表现为迟发性[60.0 岁（53.5-68.5），中位数（四分位距）]全小脑综合征，部分伴有传入感觉缺陷（55%）和自主神经功能障碍（28%）。自主神经功能障碍随时间而增加，而认知障碍即使在晚期也很少发生。横断面和纵向评估一致表明共济失调的轻度进展[每年 0.29 个共济失调评定量表（SARA）评分]，即使在晚期也不超过中度疾病严重程度（最大 SARA 评分：18 分）。功能障碍的增加相对缓慢（50%的患者在 8 年后需要单侧移动辅助）。与缓慢进展和低外小脑受累相对应，sNfL 与对照组相比没有增加。同时发生的第二种疾病（包括进行性核上性麻痹的神经病理学）是疾病严重程度的主要个体加重因素，这为未来 GAA-FGF14 试验的规划构成了重要的注意事项。86%接受治疗的患者报告了对 4-AP 的治疗反应，对日常生活有实际意义。一系列三项前瞻性 n-of-1 治疗经验采用开/关设计，表明 4-AP 可显著减少每日症状时间和症状严重程度。我们的研究描述了 GAA-FGF14 共济失调的表型特征、自然病史进展和 4-AP 治疗反应。它为在这种新发现的、可能最常见的、可治疗的迟发性共济失调中进行大规模自然病史研究和 4-AP 治疗试验铺平了道路。
