Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, One Shields Avenue, Davis, CA, USA.
Transl Neurodegener. 2013 May 21;2(1):10. doi: 10.1186/2047-9158-2-10.
Lack of the fragile X mental retardation protein leads to Fragile X syndrome (FXS) while increased levels of FMR1 mRNA, as those observed in premutation carriers can lead to Fragile X- associated tremor ataxia syndrome (FXTAS). Until recently, FXTAS had been observed only in carriers of an FMR1 premutation (55-200 CGG repeats); however the disorder has now been described in individuals carriers of an intermediate allele (45-54 CGG repeats) as well as in a subject with a full mutation with mosaicism.Here, we report on molecular and clinical data of a male FMR1 mosaic individual with full and premutation alleles. Molecular analysis of FMR1 and FMRP expression in this subject is consistent with a FXS phenotype. We observed reduced expression of FMRP in both peripheral blood and brain leading to the FXS diagnosis. In addition, a dramatic 90% depletion of both FMR1 mRNA and FMRP levels was observed in the blood, as normally observed in FXS cases, and an even greater depletion in the brain. A clinical report of this patient, at age 71, described neurodegenerative signs of parkinsonism that were likely, in retrospect, part of a FXTAS scenario as post-mortem examination shows the presence of intranuclear inclusions, the hallmark pathology of FXTAS.The findings presented in this study indicate co-morbidity for both FXS and FXTAS in this individual carrying both full and premutation FMR1 alleles. In addition, based on symptoms and pathological and molecular evidence, this report suggests the need to redefine the diagnostic criteria of FXTAS.
脆性 X 智力低下蛋白的缺失导致脆性 X 综合征（FXS），而 FMR1 mRNA 水平的增加，如在前突变携带者中观察到的那样，可导致脆性 X 相关震颤共济失调综合征（FXTAS）。直到最近，FXTAS 仅在 FMR1 前突变携带者（55-200 CGG 重复）中观察到；然而，现在已经在中间等位基因（45-54 CGG 重复）携带者以及具有镶嵌性的完全突变个体中描述了该疾病。在这里，我们报告了一个具有完整和前突变等位基因的男性 FMR1 镶嵌个体的分子和临床数据。对该患者的 FMR1 和 FMRP 表达的分子分析与 FXS 表型一致。我们观察到外周血和大脑中 FMRP 的表达减少，导致 FXS 诊断。此外，在血液中观察到 FMR1 mRNA 和 FMRP 水平急剧下降 90%，这在 FXS 病例中是正常的，而在大脑中下降更大。对该患者的临床报告描述了帕金森病的神经退行性迹象，回想起来，这些迹象可能是 FXTAS 情况的一部分，因为尸检显示存在核内包涵体，这是 FXTAS 的标志性病理学。本研究中的发现表明，该个体携带完整和前突变 FMR1 等位基因，同时患有 FXS 和 FXTAS。此外，基于症状和病理及分子证据，本报告表明需要重新定义 FXTAS 的诊断标准。
