GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response
GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response
复制标题
DOI：
10.1093/brain/awad157
复制
发表时间：
2023-05-11
期刊：
影响因子：
14.5
通讯作者：
Synofzik, Matthis
中科院分区：
文献类型：
--
作者：
Wilke, Carlo;Pellerin, David;Synofzik, Matthis
由于FGF 14中的常染色体显性内含子GAA重复扩增引起的共济失调[GAA-FGF 14共济失调，脊髓小脑共济失调27 B（SCA 27 B）]最近被鉴定为最常见的遗传性迟发性共济失调之一。我们的目的是描述其表型特征、自然病程进展和4-氨基吡啶（4-AP）治疗反应。我们对50例GAA-FGF 14患者进行了多模式队列研究，包括深入的表型、横断面和纵向进展数据（长达7年）、MRI结果、血清神经丝光（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-FGF 14共济失调始终表现为迟发性[60.0岁（53.5-68.5），中位数（四分位数间距）]全小脑综合征，部分合并传入感觉缺陷（55%）和自主神经功能障碍（28%）。自主神经功能障碍随着时间的推移而增加，而认知障碍仍然罕见，即使在晚期。横断面和纵向评估一致表明共济失调轻度进展[0.29共济失调评估和评级量表（SARA）分/年]，即使在晚期也不超过中度疾病严重程度（最大SARA评分：18分）。功能障碍增加相对缓慢（50%的患者在8年后使用单侧移动辅助器）。与缓慢进展和低小脑外受累相对应，sNfL相对于对照组没有增加。并发的第二种疾病（包括进行性核上性麻痹神经病理学）代表了疾病严重程度的主要个体因素，构成了计划未来GAA-FGF 14试验的重要警告。86%的治疗患者报告了与日常生活相关的4-AP治疗反应。采用开/关设计的一系列三项前瞻性n/1治疗经验显示，4-AP治疗后每日症状时间和症状严重程度显著降低。我们的研究描述了GAA-FGF 14共济失调的表型特征、自然病程进展和4-AP治疗反应。它为大规模自然史研究和4-AP治疗试验铺平了道路，在这个新发现的，可能是最常见的，可治疗的迟发性共济失调。最近已被确定为最常见的遗传原因之一，在FGF 14的内含子GAA重复扩增迟发性共济失调。Wilke等人研究了GAA-FGF 14共济失调的表型演变，提供了其自然史的纵向进展数据，并显示了其对4-氨基吡啶的治疗反应。
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.Intronic GAA repeat expansion in FGF14 has recently been identified as one of the most common genetic causes of late-onset ataxia. Wilke et al. characterise the phenotypic evolution of GAA-FGF14 ataxia, provide longitudinal progression data on its natural history, and show its treatment response to 4-aminopyridine.