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Abstract：
Currently, there is no effective treatment for the fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. In this pilot study, we evaluated whether allopregnanolone, a natural neurosteroid that exerts beneficial effects in neurodegenerative diseases, nervous system injury, and peripheral neuropathies, could improve lymphocytic bioenergetics and plasma pharmacometabolomics in six males with FXTAS (68 ± 3 years old; FMR1 CGG repeats 94 ± 4; FXTAS stages ranging from 3 to 5) enrolled in a 12-week open-label intervention study conducted at the University of California Davis from December 2015 through July 2016. Plasma pharmacometabolomics and lymphocytic mitochondria function were assessed at baseline (on the day of the first infusion) and at follow-up (within 48 h from the last infusion). In parallel, quantitative measurements of tremor and ataxia and neuropsychological evaluations of mental state, executive function, learning, memory, and psychological symptoms were assessed at the same time points. Allopregnanolone treatment impacted significantly GABA metabolism, oxidative stress, and some of the mitochondria-related outcomes. Notably, the magnitude of the individual metabolic response, as well as the correlation with some of the behavioral tests, was overwhelmingly carrier-specific. Based on this pilot study, allopregnanolone treatment has the potential for improving cognitive and GABA metabolism in FXTAS aligned with the concept of precision medicine.
摘要：
目前,脆性X相关震颤/共济失调综合征（FXTAS）没有有效的治疗方法，迟发性神经退行性疾病.在这项试点研究中，我们评估了别孕烯醇酮，一种在神经退行性疾病中发挥有益作用的天然神经类固醇，神经系统损伤,和周围神经病变，在2015年12月至2016年7月在加利福尼亚大学戴维斯分校进行的为期12周的开放标签干预研究中,可改善6例FXTAS患者(68±3岁;FMR1CGG重复94±4;FXTAS阶段3~5)的淋巴细胞生物能量学和血浆药物代谢组学.血浆药物代谢组学和淋巴细胞线粒体功能在基线（第一次输注当天）和随访时（在最后一次输注后48小时内）进行评估。并行,震颤和共济失调的定量测量和精神状态的神经心理学评估，执行功能，学习,记忆,并在同一时间点评估心理症状。别孕烷醇酮处理显著影响GABA代谢，氧化应激，和一些线粒体相关的结果。值得注意的是,个体代谢反应的大小，以及与一些行为测试的相关性，绝大多数是特定于承运人的。根据这项试点研究，异孕烷醇酮治疗具有改善FXTAS认知和GABA代谢的潜力,符合精准医学的概念.
