Loesch Danuta Z, Trost Nicholas, Bui Minh Q, Hammersley Eleanor, Lay Sui T, Annesley Sarah J, Sanislav Oana, Allan Claire Y, Tassone Flora, Chen Zhi-Ping, Ngoei Kevin R W, Kemp Bruce E, Francis David, Fisher Paul R, Storey Elsdon
Department of Psychology and Counselling, School of Psychology and Public Health, College of Science Health and Engineering, La Trobe University, Melbourne, VIC, Australia.
Medical Imaging Department, St Vincent's Hospital, Melbourne, VIC, Australia.
Front Genet. 2018 Nov 12;9:531. doi: 10.3389/fgene.2018.00531. eCollection 2018.
The fragile X premutation (PM) allele contains a CGG expansion of 55-200 repeats in the gene's promoter. Male PM carriers have an elevated risk of developing neurological and psychiatric changes, including an approximately 50% risk of the fragile X-associated tremor/ataxia syndrome (FXTAS). The aim of this study was to assess the relationships of regional white matter hyperintensities () semi-quantitative scores, clinical status, motor (UPDRS, ICARS, Tremor) scales, and cognitive impairments, with -specific genetic changes, in a sample of 32 unselected male PM carriers aged 39-81 years. Half of these individuals were affected with FXTAS, while the non-FXTAS group comprised subcategories of non-affected individuals and individuals affected with non-syndromic changes. The dynamics of pathological processes at the cellular level relevant to the clinical status of PM carriers was investigated using the enzyme AMP-activated protein kinase (AMPK), which is a highly sensitive cellular stress-sensing alarm protein. This enzyme, as well as genetic markers - CGG repeat number and the levels of the mRNA - were assessed in blood lymphoblasts. The results showed that the repeat distribution for FXTAS individuals peaked at 85-90 CGGs; non-FXTAS carriers were distributed within the lowest end of the PM repeat range, and non-syndromic carriers assumed an intermediate position. The size of the CGG expansion was significantly correlated, across all three categories, with infratentorial and total and with all motor scores, and the mRNA levels with all the scores, whilst AMPK activity showed considerable elevation in the non-FXTAS combined group, decreasing in the FXTAS group, proportionally to increasing severity of the and tremor/ataxia. We conclude that the size of the CGG expansion relates to the risk for FXTAS, to severity of infratentorial lesions, and to all three motor scale scores. mRNA shows a strong association with the extent of , which is the most sensitive marker of the pathological process. However, the AMPK activity findings - suggestive of a role of this enzyme in the risk of FXTAS - need to be verified and expanded in future studies using larger samples and longitudinal assessment.
脆性X前突变（PM）等位基因在该基因启动子区含有55至200个重复序列的CGG扩增。男性PM携带者发生神经和精神改变的风险升高，包括约50%的脆性X相关震颤/共济失调综合征（FXTAS）风险。本研究的目的是在32名年龄在39至81岁的未经过筛选的男性PM携带者样本中，评估区域白质高信号（WMH）半定量评分、临床状态、运动（统一帕金森病评定量表、国际小脑共济失调评分量表、震颤量表）量表和认知障碍与特定基因变化之间的关系。这些个体中有一半患有FXTAS，而非FXTAS组包括未受影响个体和患有非综合征性改变个体的亚组。使用酶AMP激活蛋白激酶（AMPK）研究了与PM携带者临床状态相关的细胞水平病理过程的动态变化，AMPK是一种高度敏感的细胞应激感应警报蛋白。在血液淋巴细胞中评估了这种酶以及基因标记物——CGG重复数和mRNA水平。结果显示，FXTAS个体的重复序列分布在85至90个CGG处达到峰值；非FXTAS携带者分布在PM重复序列范围的最低端，非综合征性携带者处于中间位置。在所有三个类别中，CGG扩增的大小与幕下和总WMH以及所有运动评分均显著相关，mRNA水平与所有WMH评分相关，而AMPK活性在非FXTAS合并组中显著升高，在FXTAS组中降低，与WMH和震颤/共济失调的严重程度增加成比例。我们得出结论，CGG扩增的大小与FXTAS风险、幕下WMH病变的严重程度以及所有三个运动量表评分相关。mRNA与WMH的程度密切相关，WMH是病理过程中最敏感的标志物。然而，AMPK活性的研究结果——提示该酶在FXTAS风险中的作用——需要在未来使用更大样本和纵向评估的研究中得到验证和扩展。
