Queen Square Brain Bank, Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Brain. 2011 Sep;134(Pt 9):2548-64. doi: 10.1093/brain/awr160. Epub 2011 Jul 12.
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.
神经元中间丝包涵体病和非典型额颞叶变性是罕见疾病，其特征为泛素阳性包涵体缺乏反式激活反应 DNA 结合蛋白 43 和 tau。最近，融合肉瘤基因的突变已被证明可导致家族性肌萎缩侧索硬化症，随后在神经元中间丝包涵体病和非典型额颞叶变性伴泛素阳性包涵体中发现了融合肉瘤阳性神经元包涵体。在此，我们提供了 14 例融合肉瘤蛋白病的临床、影像学、形态学发现，以及遗传和生化数据。在该队列中，发病年龄各不相同，但包括了早发型疾病。非典型额颞叶变性伴泛素阳性包涵体的患者均表现为行为变异型额颞叶痴呆，而神经元中间丝包涵体病的临床表现更为多样化，包括伴有运动神经元病和锥体外系综合征的病例。神经影像学显示非典型额颞叶变性伴泛素阳性包涵体的病例存在额颞叶前部和尾状核萎缩，但在神经元中间丝包涵体病的病例中更为多样化，疾病早期通常肉眼观察正常。记录了融合肉瘤阳性细胞质包涵体、神经元核内包涵体和神经原纤维的分布和严重程度，并对两个亚组进行了融合肉瘤的生化分析。在海马颗粒细胞层中发现了数量不等的融合肉瘤阳性神经元细胞质和核内包涵体。在神经元中间丝包涵体病中，皮质融合肉瘤阳性神经元细胞质包涵体常呈“Pick 体样”，而在两种情况下均可见环形和新月形包涵体。在所有融合肉瘤阳性病例中，包括可供研究的脑干和脊髓运动神经元的病例（分别为 5 例和 4 例）中，运动神经元均含有数量不等的密集、颗粒状或绞索样细胞质包涵体。在任何病例中均未发现融合肉瘤突变。生化分析发现了两种主要的融合肉瘤物种，并且与神经元中间丝包涵体病相比，它们在非典型额颞叶变性伴泛素阳性包涵体亚组中更不易溶解。两个亚组之间的融合肉瘤阳性病理学有很大的重叠，也有显著的差异，这表明它们可能代表同一疾病的一个谱。在运动神经元和脑外结构中同时存在融合肉瘤阳性包涵体是散发性融合肉瘤蛋白病的一个特征性发现，表明这是一种多系统疾病。
