Neuropathology of FMR1-premutation carriers presenting with dementia and neuropsychiatric symptoms.
Neuropathology of FMR1-premutation carriers presenting with dementia and neuropsychiatric symptoms.
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表现为痴呆和神经精神症状的FMR1前突变携带者的神经病理学
DOI：
10.1093/braincomms/fcab007
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发表时间：
2021
影响因子：
4.8
通讯作者：
Hoozemans JJM
中科院分区：
文献类型：
--
作者：
Dijkstra AA;Haify SN;Verwey NA;Prins ND;van der Toorn EC;Rozemuller AJM;Bugiani M;den Dunnen WFA;Todd PK;Charlet-Berguerand N;Willemsen R;Hukema RK;Hoozemans JJM
FMR 1基因前突变范围（55-200）内的CGG重复扩增可导致脆性X相关震颤/共济失调综合征和脆性X相关神经精神疾病。这些CGG重复被翻译成一种有毒的含聚甘氨酸的蛋白质，FMRpolyG。脆性X相关震颤/共济失调综合征和脆性X相关神经精神障碍的病理学包括FMRpolyG和p62阳性核内包涵体。诊断FMR 1前突变携带者仍然具有挑战性，因为其临床特征与其他神经退行性疾病重叠。在这里，我们描述了两个男性病例与脆性X相关的神经精神障碍相关的症状和轻度运动障碍和新的病理特征，可以归因于可变的表型。肉眼观察，两名供体在MRI上均未显示特征性白色病变;然而，在皮质和皮质下区域发现血管梗死。免疫组织化学分析显示，大量的FMRpolyG核内包涵体在整个大脑，这也是阳性的p62。重要的是，我们发现了一种新的病理性血管表型，在周细胞和内皮细胞中存在包涵体。虽然这些结果需要在更多的病例中得到证实，但我们认为这些脑血管病变可能有助于FMR 1前突变携带者的复杂病理学。总的来说，我们的报告表明，脆性X相关震颤/共济失调综合征和脆性X相关神经精神疾病可能会出现类似于其他类型痴呆的不同临床表现，在没有基因检测的情况下，FMRpolyG可以用于尸检以识别前突变携带者。 FMR 1前突变携带者可在临床上表现出一系列症状，包括神经精神症状。在病理学上，核内含物对FMRpolyG呈阳性，并且在本文讨论的供体中，也存在于脉管系统中。这在以前没有描述过，这一发现可能有助于复杂表型。
CGG repeat expansions within the premutation range (55–200) of the FMR1 gene can lead to Fragile X-associated tremor/ataxia syndrome and Fragile X-associated neuropsychiatric disorders. These CGG repeats are translated into a toxic polyglycine-containing protein, FMRpolyG. Pathology of Fragile X-associated tremor/ataxia syndrome and Fragile X-associated neuropsychiatric disorders comprises FMRpolyG- and p62-positive intranuclear inclusions. Diagnosing a FMR1-premutation carrier remains challenging, as the clinical features overlap with other neurodegenerative diseases. Here, we describe two male cases with Fragile X-associated neuropsychiatric disorders-related symptoms and mild movement disturbances and novel pathological features that can attribute to the variable phenotype. Macroscopically, both donors did not show characteristic white matter lesions on MRI; however, vascular infarcts in cortical- and sub-cortical regions were identified. Immunohistochemistry analyses revealed a high number of FMRpolyG intranuclear inclusions throughout the brain, which were also positive for p62. Importantly, we identified a novel pathological vascular phenotype with inclusions present in pericytes and endothelial cells. Although these results need to be confirmed in more cases, we propose that these vascular lesions in the brain could contribute to the complex symptomology of FMR1-premutation carriers. Overall, our report suggests that Fragile X-associated tremor/ataxia syndrome and Fragile X-associated neuropsychiatric disorders may present diverse clinical involvements resembling other types of dementia, and in the absence of genetic testing, FMRpolyG can be used post-mortem to identify premutation carriers. FMR1-premutation carriers can present clinically with a range of symptoms, including neuropsychiatric symptoms. Pathologically, the nuclear inclusions are positive for FMRpolyG and in the donors discussed here, also present in the vasculature. This has not been described before and this finding possibly contributes to the complex phenotype.
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影响因子：
16.2
作者：
Todd PK;Oh SY;Krans A;He F;Sellier C;Frazer M;Renoux AJ;Chen KC;Scaglione KM;Basrur V;Elenitoba-Johnson K;Vonsattel JP;Louis ED;Sutton MA;Taylor JP;Mills RE;Charlet-Berguerand N;Paulson HL
通讯作者：
Paulson HL
DOI：
10.1080/13854046.2016.1202239
发表时间：
2016-08
期刊：
The Clinical neuropsychologist
影响因子：
--
作者：
Robertson EE;Hall DA;McAsey AR;O'Keefe JA
通讯作者：
O'Keefe JA
影响因子：
2
作者：
Berry-Kravis, Elizabeth;Goetz, Christopher G.;Hagerman, Paul J.
通讯作者：
Hagerman, Paul J.
影响因子：
9.9
作者：
Hall, DA;Berry-Kravis, E;Leehey, MA
通讯作者：
Leehey, MA
影响因子：
8.6
作者：
Grigsby, Jim;Brega, Angela G.;Hagerman, Randi J.
通讯作者：
Hagerman, Randi J.