Department of Pediatrics and MIND Institute, University of California Davis Health, Sacramento.
Department of Biochemistry and Molecular Medicine, University of California, Davis, School of Medicine, Davis, California, USA.
Curr Opin Neurol. 2021 Aug 1;34(4):541-546. doi: 10.1097/WCO.0000000000000954.
The purpose of this paper is to review the prevalence, pathophysiology, and management of fragile X-associated tremor/ataxia syndrome (FXTAS).
The pathophysiology of FXTAS involves ribonucleic acid (RNA) toxicity due to elevated levels of the premutation-expanded CGG (eoxycytidylate-deoxyguanylate-deoxyguanylate)-repeat FMR1 mRNA, which can sequester a variety of proteins important for neuronal function. A recent analysis of the inclusions in FXTAS demonstrates elevated levels of several proteins, including small ubiquitin-related modifiers 1/2 (SUMO1/2), that target molecules for the proteasome, suggesting that some aspect(s) of proteasomal function may be altered in FXTAS. Recent neuropathological studies show that Parkinson disease and Alzheimer disease can sometimes co-occur with FXTAS. Lewy bodies can be found in 10% of the brains of patients with FXTAS. Microbleeds and iron deposition are also common in the neuropathology, in addition to white matter disease (WMD) and atrophy.
The premutation occurs in 1:200 females and 1:400 males. Penetrance for FXTAS increases with age, though lower in females (16%) compared to over 60% of males by age 70. To diagnose FXTAS, an MRI is essential to document the presence of WMD, a primary component of the diagnostic criteria. Pain can be a significant feature of FXTAS and is seen in approximately 50% of patients.
本文旨在综述脆性 X 相关震颤/共济失调综合征（FXTAS）的流行率、发病机制和治疗方法。
FXTAS 的发病机制涉及 RNA 毒性，原因是前突变扩增的 CGG（胞嘧啶-鸟嘌呤-鸟嘌呤）重复 FMR1 mRNA 水平升高，这可能会隔离多种对神经元功能重要的蛋白质。最近对 FXTAS 包涵体的分析表明，包括小泛素相关修饰物 1/2（SUMO1/2）在内的几种蛋白质的水平升高，这些蛋白质的靶标分子为蛋白酶体，这表明蛋白酶体功能的某些方面可能在 FXTAS 中发生改变。最近的神经病理学研究表明，帕金森病和阿尔茨海默病有时可与 FXTAS 共存。在 FXTAS 患者的大脑中，10%可发现路易体。微出血和铁沉积在神经病理学中也很常见，除了白质疾病（WMD）和萎缩。
前突变在女性中发生率为 1:200，男性中发生率为 1:400。随着年龄的增长，FXTAS 的外显率增加，但女性（16%）低于男性（60%以上），到 70 岁时达到这一比例。为了诊断 FXTAS，MRI 是必需的，以记录 WMD 的存在，WMD 是诊断标准的主要组成部分。疼痛可能是 FXTAS 的一个重要特征，约 50%的患者有疼痛。
