A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies
A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies
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DOI：
10.1093/brain/awr160
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发表时间：
2011-09-01
期刊：
影响因子：
14.5
通讯作者：
Revesz, Tamas
中科院分区：
文献类型：
--
作者：
Lashley, Tammaryn;Rohrer, Jonathan D.;Revesz, Tamas
神经元中间丝包涵体病和非典型额颞叶变性是罕见的疾病，其特征是泛素阳性包涵体缺乏反式反应DNA结合蛋白43和tau蛋白。最近，融合肉瘤基因的突变已被证明会导致家族性肌萎缩侧索硬化症，融合肉瘤阳性神经元包涵体随后被证明在神经元中间丝包涵体病和非典型额颞叶变性与泛素化包涵体。在这里，我们提供了14例融合肉瘤蛋白病病例的临床、影像学、形态学表现以及遗传和生化数据。在该队列中，发病年龄可变，但包括非发病性疾病病例。非典型额颞叶变性伴泛素化包涵体的患者均表现为行为变异性额颞叶痴呆，而神经元中间丝包涵体病的临床表现更为异质，包括运动神经元病和锥体外系综合征。神经影像学检查显示，非典型额颞叶变性伴泛素化包涵体的病例中，额叶和前颞叶以及尾状核萎缩，但神经元中间丝包涵体病的病例则更为异质，通常在疾病早期肉眼检查正常。记录肉瘤阳性神经元胞质包涵体、神经元核内包涵体和神经突融合的分布和严重程度，并对两个亚组的肉瘤融合进行生化分析。融合在肉瘤阳性的神经元胞质和核内包涵体中发现在海马颗粒细胞层中的数量不等。皮质融合在肉瘤阳性神经元胞质包涵体往往是“匹克体样”的神经元中间丝包涵体疾病，环形和新月形包涵体中看到这两种情况。运动神经元包含可变数量的紧凑，颗粒状或绞样胞质包涵体在所有融合的肉瘤阳性病例中，脑干和脊髓运动神经元可用于研究（分别为5例和4例）。在所有病例中均未发现肉瘤融合突变。生物化学，两个主要的融合在肉瘤物种被发现，并显示出更不溶于非典型额颞叶变性与泛素化包涵体亚组相比，神经元中间丝包涵体疾病。两个亚组之间的肉瘤阳性病理学融合有相当大的重叠和显著差异，表明它们可能代表同一疾病的谱。运动神经元和运动外大脑结构中融合肉瘤阳性包涵体的共存是散发性融合肉瘤蛋白病的特征性发现，表明多系统疾病。
Neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration are rare diseases characterized by ubiquitin-positive inclusions lacking transactive response DNA-binding protein-43 and tau. Recently, mutations in the fused in sarcoma gene have been shown to cause familial amyotrophic lateral sclerosis and fused in sarcoma-positive neuronal inclusions have subsequently been demonstrated in neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration with ubiquitinated inclusions. Here we provide clinical, imaging, morphological findings, as well as genetic and biochemical data in 14 fused in sarcoma proteinopathy cases. In this cohort, the age of onset was variable but included cases of young-onset disease. Patients with atypical frontotemporal lobar degeneration with ubiquitinated inclusions all presented with behavioural variant frontotemporal dementia, while the clinical presentation in neuronal intermediate filament inclusion disease was more heterogeneous, including cases with motor neuron disease and extrapyramidal syndromes. Neuroimaging revealed atrophy of the frontal and anterior temporal lobes as well as the caudate in the cases with atypical frontotemporal lobar degeneration with ubiquitinated inclusions, but was more heterogeneous in the cases with neuronal intermediate filament inclusion disease, often being normal to visual inspection early on in the disease. The distribution and severity of fused in sarcoma-positive neuronal cytoplasmic inclusions, neuronal intranuclear inclusions and neurites were recorded and fused in sarcoma was biochemically analysed in both subgroups. Fused in sarcoma-positive neuronal cytoplasmic and intranuclear inclusions were found in the hippocampal granule cell layer in variable numbers. Cortical fused in sarcoma-positive neuronal cytoplasmic inclusions were often 'Pick body-like' in neuronal intermediate filament inclusion disease, and annular and crescent-shaped inclusions were seen in both conditions. Motor neurons contained variable numbers of compact, granular or skein-like cytoplasmic inclusions in all fused in sarcoma-positive cases in which brainstem and spinal cord motor neurons were available for study (five and four cases, respectively). No fused in sarcoma mutations were found in any cases. Biochemically, two major fused in sarcoma species were found and shown to be more insoluble in the atypical frontotemporal lobar degeneration with ubiquitinated inclusions subgroup compared with neuronal intermediate filament inclusion disease. There is considerable overlap and also significant differences in fused in sarcoma-positive pathology between the two subgroups, suggesting they may represent a spectrum of the same disease. The co-existence of fused in sarcoma-positive inclusions in both motor neurons and extramotor cerebral structures is a characteristic finding in sporadic fused in sarcoma proteinopathies, indicating a multisystem disorder.