CGG重复序列在FMR1X连锁基因的非编码片段中的扩增与多种表型变化有关。大扩展(>200重复),导致严重的神经发育障碍,脆性X综合征(FXS),是从携带较小的母亲那里传播的,不稳定的扩展范围从55到200重复,称为脆弱的X前突变。这种前突变的女性携带者可能会在其整个生命周期中经历广泛的临床问题,最严重的是称为“脆性X相关震颤共济失调综合征”(FXTAS)的迟发性神经退行性疾病,发生在这些携带者的8%到16%之间。男性前突变携带者,尽管它们不会将扩展的等位基因传递给他们的女儿,患FXTAS的风险要高得多(40-50%)。尽管这种疾病在男性携带者中比女性携带者更普遍和严重,在FXTAS谱的临床表现和进展方面的具体性别差异文献报道甚少.在这里,我们比较了三种运动量表(包括震颤/共济失调(ICARS))的进展模式和速率(每年),震颤(临床震颤评定量表,CRST),和帕金森病(UPDRS),在几项认知和精神病学测试中,在13名女性和9名男性携带者之间,最初至少有一个运动评分≥10。此外,我们记录了21名女性和24名男性前突变携带者的横断面样本中每个临床和认知测量的差异,这些携带者的年龄与FXTAS谱系障碍(FSD)相当,也就是说,显示FXTAS的一个或多个功能。进展评估的结果表明,在CRST量表上,步态共济失调和运动性震颤域的男性携带者的比率是女性携带者的两倍以上,而男性的比率是男性的两倍。相比之下,UPDRS进展速度的性别差异可以忽略不计,和所有的认知测量。总体精神病理学评分(SCL-90),以及焦虑和强迫症/强迫症领域得分,仅在女性样本中显示出显着增加。运动评分进展的性别差异模式与较大,受FSD影响的男性和女性携带者的横截面样本。这些结果与MRIT2白质高信号的性别特定分布一致:所有男性,但没有雌性,显示小脑中柄白质高强度(MCP征),尽管这些高信号在其他大脑区域的分布和严重程度在两种性别之间没有差异。总之,临床记录的运动性能变化和MRI病变分布支持的表现和进展的性别差异的幅度和具体模式,在临床上,某些性别限制因素的可能性,除了第二个可预测的效果之外,女性前突变携带者的正常FMR1等位基因,可能有神经保护作用,特别是关于小脑电路。
Expansions of the CGG repeat in the non-coding segment of the FMR1 X-linked gene are associated with a variety of phenotypic changes. Large expansions (>200 repeats), which cause a severe neurodevelopmental disorder, the fragile x syndrome (FXS), are transmitted from the mothers carrying smaller, unstable expansions ranging from 55 to 200 repeats, termed the fragile X premutation. Female carriers of this premutation may themselves experience a wide range of clinical problems throughout their lifespan, the most severe being the late onset neurodegenerative condition called \"Fragile X-Associated Tremor Ataxia Syndrome\" (FXTAS), occurring between 8 and 16% of these carriers. Male premutation carriers, although they do not transmit expanded alleles to their daughters, have a much higher risk (40-50%) of developing FXTAS. Although this disorder is more prevalent and severe in male than female carriers, specific sex differences in clinical manifestations and progress of the FXTAS spectrum have been poorly documented. Here we compare the pattern and rate of progression (per year) in three motor scales including tremor/ataxia (ICARS), tremor (Clinical Tremor Rating scale, CRST), and parkinsonism (UPDRS), and in several cognitive and psychiatric tests scores, between 13 female and 9 male carriers initially having at least one of the motor scores ≥10. Moreover, we document the differences in each of the clinical and cognitive measures between the cross-sectional samples of 21 female and 24 male premutation carriers of comparable ages with FXTAS spectrum disorder (FSD), that is, who manifest one or more features of FXTAS. The results of progression assessment showed that it was more than twice the rate in male than in female carriers for the ICARS-both gait ataxia and kinetic tremor domains and twice as high in males on the CRST scale. In contrast, sex difference was negligible for the rate of progress in UPDRS, and all the cognitive measures. The overall psychiatric pathology score (SCL-90), as well as Anxiety and Obsessive/Compulsive domain scores, showed a significant increase only in the female sample. The pattern of sex differences for progression in motor scores was consistent with the results of comparison between larger, cross-sectional samples of male and female carriers affected with the FSD. These results were in concert with sex-specific distribution of MRI T2 white matter hyperintensities: all males, but no females, showed the middle cerebellar peduncle white matter hyperintensities (MCP sign), although the distribution and severity of these hyperintensities in the other brain regions were not dissimilar between the two sexes. In conclusion, the magnitude and specific pattern of sex differences in manifestations and progression of clinically recorded changes in motor performance and MRI lesion distribution support, on clinical grounds, the possibility of certain sex-limited factor(s) which, beyond the predictable effect of the second, normal FMR1 alleles in female premutation carriers, may have neuroprotective effects, specifically concerning the cerebellar circuitry.