Department of Pediatrics, University of California, Davis, School of Medicine, Sacramento, CA, USA,
J Neurodev Disord. 2011 Sep;3(3):211-24. doi: 10.1007/s11689-011-9084-5. Epub 2011 May 27.
Fragile X syndrome (FXS) is caused by an expanded CGG repeat (>200 repeats) in the 5' un-translated portion of the fragile X mental retardation 1 gene (FMR1) leading to a deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA-binding protein that regulates the translation of a number of other genes that are important for synaptic development and plasticity. Furthermore, many of these genes, when mutated, have been linked to autism in the general population, which may explain the high comorbidity that exists between FXS and autism spectrum disorders (ASD). Additionally, premutation repeat expansions (55 to 200 CGG repeats) may also give rise to ASD through a different molecular mechanism that involves a direct toxic effect of FMR1 mRNA. It is believed that RNA toxicity underlies much of the premutation-related involvement, including developmental concerns like autism, as well as neurodegenerative issues with aging such as the fragile X-associated tremor ataxia syndrome (FXTAS). RNA toxicity can also lead to mitochondrial dysfunction, which is common in older premutation carriers both with and without FXTAS. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in idiopathic autism. Research regarding dysregulation of neurotransmitter systems caused by the lack of FMRP in FXS, including metabotropic glutamate receptor 1/5 (mGluR1/5) pathway and GABA pathways, has led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism.
脆性 X 综合征（FXS）是由脆性 X 智力低下 1 基因（FMR1）5'非翻译区的 CGG 重复扩增（>200 个重复）引起的，导致 FMR1 蛋白（FMRP）缺失或缺乏。FMRP 是一种 RNA 结合蛋白，可调节其他一些对突触发育和可塑性很重要的基因的翻译。此外，这些基因中的许多在普通人群中与自闭症相关突变，这可能解释了 FXS 与自闭症谱系障碍（ASD）之间存在高共病的原因。此外，前突变重复扩增（55 至 200 个 CGG 重复）也可能通过涉及 FMR1 mRNA 直接毒性作用的不同分子机制引起 ASD。人们认为，RNA 毒性是前突变相关参与的基础，包括自闭症等发育问题，以及与衰老相关的神经退行性问题，如脆性 X 相关震颤共济失调综合征（FXTAS）。RNA 毒性也可导致线粒体功能障碍，在前突变携带者中，无论是否存在 FXTAS，这种情况都很常见。前突变和完全突变神经元中细胞调节紊乱的许多问题也与特发性自闭症中记录的细胞异常相平行。关于 FXS 中由于缺乏 FMRP 引起的神经递质系统失调的研究，包括代谢型谷氨酸受体 1/5（mGluR1/5）途径和 GABA 途径，导致了针对 FXS 的新靶向治疗方法。初步证据表明，这些新的靶向治疗方法也将对非脆性 X 形式的自闭症有益。
