Nakamura Masataka, Bieniek Kevin F, Lin Wen-Lang, Graff-Radford Neill R, Murray Melissa E, Castanedes-Casey Monica, Desaro Pamela, Baker Matthew C, Rutherford Nicola J, Robertson Janice, Rademakers Rosa, Dickson Dennis W, Boylan Kevin B
Neuropathology Laboratory, Department of Neuroscience, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL, 32224, USA.
Acta Neuropathol. 2015 Jul;130(1):145-57. doi: 10.1007/s00401-015-1431-2. Epub 2015 Apr 28.
Amyotrophic lateral sclerosis (ALS) is a degenerative disorder affecting upper and lower motor neurons, but it is increasingly recognized to affect other systems, with cognitive impairment resembling frontotemporal dementia (FTD) in some patients. We report clinical and pathologic findings of a family with ALS due to a truncating mutation, p.Gly141X, in copper/zinc superoxide dismutase (SOD1). The proband presented clinically with FTD and later showed progressive motor neuron disease, while all other family members had early-onset and rapidly progressive ALS without significant cognitive deficits. Pathologic examination of both the proband and her daughter revealed degeneration of corticospinal tracts and motor neurons in brain and spinal cord compatible with ALS. On the other hand, the proband also had neocortical and limbic system degeneration with pleomorphic neuronal cytoplasmic inclusions. Extramotor pathology in her daughter was relatively restricted to the hypothalamus and extrapyramidal system, but not the neocortex. The inclusions in the proband and her daughter were immunoreactive for SOD1, but negative for TAR DNA-binding protein of 43 kDa (TDP-43). In the proband, a number of the neocortical inclusions were immunopositive for α-internexin, initially suggesting a diagnosis of atypical FTLD, but there was no evidence of fused in sarcoma (FUS) immunoreactivity, which is often detected in atypical FTLD. Analogous to atypical FTLD, neuronal inclusions had variable co-localization of SOD1 and α-internexin. The current classification of FTLD is based on the major constituent protein: FTLD-tau, FTLD-TDP-43, and FTLD-FUS. The proband in this family indicates that SOD1, while rare, can also be the substrate of FTLD, in addition to the more common presentation of ALS. The explanation for clinical and pathologic heterogeneity of SOD1 mutations, including the p.Gly141X mutation, remains unresolved.
肌萎缩侧索硬化症（ALS）是一种影响上下运动神经元的退行性疾病，但人们越来越认识到它会影响其他系统，在一些患者中会出现类似于额颞叶痴呆（FTD）的认知障碍。我们报告了一个因铜/锌超氧化物歧化酶（SOD1）中的截短突变p.Gly141X导致的ALS家族的临床和病理发现。先证者临床上表现为FTD，随后出现进行性运动神经元病，而所有其他家庭成员均患有早发性且进展迅速的ALS，无明显认知缺陷。对先证者及其女儿进行的病理检查显示，大脑和脊髓中的皮质脊髓束和运动神经元变性，与ALS相符。另一方面，先证者还存在新皮质和边缘系统变性，并伴有多形性神经元胞质内包涵体。她女儿的运动外病理相对局限于下丘脑和锥体外系，而非新皮质。先证者及其女儿的包涵体对SOD1呈免疫反应性，但对43 kDa的TAR DNA结合蛋白（TDP-43）呈阴性。在先证者中，一些新皮质包涵体对α-中间丝蛋白呈免疫阳性，最初提示非典型FTLD的诊断，但未发现融合肉瘤（FUS）免疫反应性的证据，而在非典型FTLD中常可检测到该反应性。与非典型FTLD类似，神经元包涵体中SOD1和α-中间丝蛋白有不同程度的共定位。目前FTLD的分类基于主要组成蛋白：FTLD-tau、FTLD-TDP-43和FTLD-FUS。这个家族中的先证者表明，SOD1虽然罕见，但除了更常见的ALS表现外，也可能是FTLD的底物。包括p.Gly141X突变在内的SOD1突变的临床和病理异质性的解释仍未解决。
