Dementia Research Centre, University College London (UCL) Institute of Neurology, London, UK.
Department of Neurodegenerative Disease, University College London (UCL) Institute of Neurology, London, UK.
Lancet Neurol. 2015 Mar;14(3):291-301. doi: 10.1016/S1474-4422(14)70233-9. Epub 2015 Jan 29.
C9orf72 hexanucleotide repeat expansions are the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) worldwide. The clinical presentation is often indistinguishable from classic FTD or ALS, although neuropsychiatric symptoms are more prevalent and, for ALS, behavioural and cognitive symptoms occur more frequently. Pathogenic repeat length is in the hundreds or thousands, but the minimum length that increases risk of disease, and how or whether the repeat size affects phenotype, are unclear. Like in many patients with FTD and ALS, neuronal inclusions that contain TARDBP are seen, but are not universal, and the characteristic pathological finding is of dipeptide repeat (DPR) proteins, formed by unconventional repeat-associated non-ATG translation. Possible mechanisms of neurodegeneration include loss of C9orf72 protein and function, RNA toxicity, and toxicity from the DPR proteins, but which of these is the major pathogenic mechanism is not yet certain.
C9orf72 六核苷酸重复扩增是全球最常见的家族性额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）的病因。其临床表现通常与经典 FTD 或 ALS 无法区分，尽管神经精神症状更为普遍，而且对于 ALS，行为和认知症状更为常见。致病性重复长度为数百或数千，但增加疾病风险的最小重复长度，以及重复大小如何或是否影响表型尚不清楚。与许多 FTD 和 ALS 患者一样，也会出现包含 TARDBP 的神经元包涵体，但并非普遍存在，其特征性病理发现是二肽重复（DPR）蛋白，由非典型重复相关非 ATG 翻译形成。神经退行性变的可能机制包括 C9orf72 蛋白和功能丧失、RNA 毒性以及 DPR 蛋白的毒性，但这些机制中哪一种是主要的致病机制尚不确定。
