TANK-binding kinase 1 (TBK1) mutations are a recently discovered cause of disorders in the frontotemporal dementia (FTD)-amyotrophic lateral sclerosis (ALS) spectrum. We describe a novel L683∗ mutation, predicted to cause a truncated protein and therefore be pathogenic, in a patient presenting with nonfluent variant primary progressive aphasia at the age of 65 years. Her disease progressed over the following years, leading to her being mute and wheelchair bound seven years into her illness. Brain imaging showed asymmetrical left-sided predominant atrophy affecting the frontal, insular, and temporal cortices as well as the striatum in particular. Review of the literature found 60 different nonsense, frameshift, deletion, or splice site mutations, including the newly described mutation, with data on clinical diagnosis available in 110 people: 58% of the cases presented with an ALS syndrome, 16% with an FTD-ALS overlap, 19% with a cognitive presentation (including behavioral variant FTD and primary progressive aphasia) and 4% with atypical parkinsonism. Age at onset (AAO) data were available in 75 people: mean (standard deviation) AAO was 57.5 (10.3) in those with ALS, which was significantly younger than those with a cognitive presentation (AAO = 65.1 (10.5), p = 0.008), or atypical parkinsonism (AAO = 68.3 (8.7), p = 0.021), with a trend compared with the FTD-ALS group (AAO = 61.9 (7.0), p=0.065); there was no significant difference in AAO between the other groups. In conclusion, clinical syndromes across the whole FTD-ALS-atypical parkinsonism spectrum have been reported in conjunction with mutations in TBK1. It is therefore important to include TBK1 on future gene panels for each of these disorders and to suspect such mutations particularly when there are multiple different phenotypes in the same family.

中文翻译：

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TBK1 突变的可变临床表型：导致原发性进行性失语症的新型突变病例报告及文献复习

TANK 结合激酶 1 (TBK1) 突变是最近发现的额颞叶痴呆 (FTD)-肌萎缩侧索硬化 (ALS) 谱系疾病的原因。我们描述了一个新的 L683∗ 突变，预测会导致截断的蛋白质，因此是致病的，在一个 65 岁时出现非流利变异原发性进行性失语症的患者中。在接下来的几年里，她的病情不断恶化，导致她在患病七年后变得哑巴和坐轮椅。脑成像显示不对称的左侧主要萎缩影响额叶、岛叶和颞叶皮质，尤其是纹状体。查阅文献发现 60 种不同的无义、移码、缺失或剪接位点突变，包括新描述的突变，临床诊断数据可用于 110 人：58% 的病例表现为 ALS 综合征，16% 表现为 FTD-ALS 重叠，19% 表现为认知表现（包括行为变异性 FTD 和原发性进行性失语症），4% 表现为非典型帕金森综合征。75 人的发病年龄 (AAO) 数据可用：ALS 患者的平均（标准差）AAO 为 57.5 (10.3)，明显低于有认知表现的患者 (AAO = 65.1 (10.5)，p = 0.008) )，或非典型帕金森综合征 (AAO = 68.3 (8.7)，p = 0.021)，与 FTD-ALS 组相比有趋势 (AAO = 61.9 (7.0)，p = 0.065)；其他组之间的 AAO 没有显着差异。总之，已经报道了整个 FTD-ALS 非典型帕金森综合征谱中的临床综合征与 TBK1 突变相关。