Synofzik M, Otto M, Ludolph A, Weishaupt J H
Abteilung für Neurodegeneration, Zentrum für Neurologie & Hertie-Institut für Klinische Hirnforschung, Universität Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Deutschland.
Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Tübingen, Deutschland.
Nervenarzt. 2017 Jul;88(7):728-735. doi: 10.1007/s00115-017-0349-4.
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) overlap not only clinically, but also with respect to shared neuropathology and genes. A large number of novel genes has recently been identified which underlie both diseases, e. g., C9orf72, TARDBP, GRN, TBK1, UBQLN2, VCP, CHCHD10, or SQSTM1. In contrast, other genes are still largely associated with only one of the two diseases, e. g., SOD1 with ALS or MAPT with FTD. These genetic findings indicate a large number of shared mechanisms, yet along with still a certain cell-specific vulnerability. The recently identified genes are not only key to investigate the pathophysiology underlying ALS and FTD, but also the first step in the development of causal gene- or pathway-specific therapies. Mutations in these genes are also found in a substantial share of seemingly "sporadic" ALS and FTD patients. Given the large genetic heterogeneity with more than >25 genes having been identified for ALS and FTD, genetic diagnostics should - after exclusion of C9orf72 repeat expansions - no longer resort to single gene-diagnostics, but rather use next generation sequencing panels or whole exome sequencing.
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）不仅在临床上存在重叠，在共同的神经病理学和基因方面也有重叠。最近已经鉴定出大量导致这两种疾病的新基因，例如C9orf72、TARDBP、GRN、TBK1、UBQLN2、VCP、CHCHD10或SQSTM1。相比之下，其他基因在很大程度上仍然仅与这两种疾病中的一种相关，例如与ALS相关的SOD1或与FTD相关的MAPT。这些遗传学发现表明存在大量共同机制，但同时也存在一定的细胞特异性易损性。最近鉴定出的基因不仅是研究ALS和FTD潜在病理生理学的关键，也是开发因果基因或途径特异性疗法的第一步。在相当一部分看似“散发性”的ALS和FTD患者中也发现了这些基因的突变。鉴于ALS和FTD已鉴定出超过25种基因的巨大遗传异质性，在排除C9orf72重复扩增后，基因诊断不应再采用单基因诊断，而应使用新一代测序面板或全外显子组测序。
