Department of Clinical Neuroscience, King's College London, Institute of Psychiatry, De Crespigny Park, London, SE5 8AF, UK.
Acta Neuropathol. 2012 Sep;124(3):339-52. doi: 10.1007/s00401-012-1022-4. Epub 2012 Aug 2.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons leading to death from respiratory failure within about 3 years of symptom onset. A family history of ALS is obtained in about 5 % but the distinction between familial and apparently sporadic ALS is artificial and genetic factors play a role in all types. For several years, only one gene was known to have a role in ALS pathogenesis, SOD1. In the last few years there has been a rapid advance in our genetic knowledge of the causes of ALS, and the relationship of the genetic subtypes with pathological subtypes and clinical phenotype. Mutations in the gene for TDP-43 protein, TARDBP, highlight this, with pathology mimicking closely that found in other types of ALS, and a phenotypic spectrum that includes frontotemporal dementia. Mutations in the FUS gene, closely related to TDP-43, lead to a similar clinical phenotype but distinct pathology, so that the three pathological groups represented by SOD1, TARDBP, and FUS are distinct. In this review, we explore the genetic architecture of ALS, highlight some of the genes implicated in pathogenesis, and describe their phenotypic range and overlap with other diseases.
肌萎缩侧索硬化症（ALS）是一种运动神经元退行性疾病，从症状出现到呼吸衰竭导致死亡约需 3 年。约有 5%的患者有 ALS 家族史，但家族性和明显散发性 ALS 的区分是人为的，遗传因素在所有类型中都起作用。几年来，只有一个基因被认为与 ALS 的发病机制有关，即 SOD1。在过去的几年中，我们对 ALS 病因的遗传知识有了迅速的进展，以及遗传亚型与病理亚型和临床表型的关系。TDP-43 蛋白基因 TARDBP 的突变突出了这一点，其病理学与其他类型的 ALS 非常相似，表型谱包括额颞叶痴呆。与 TDP-43 密切相关的 FUS 基因突变导致类似的临床表型，但病理学不同，因此由 SOD1、TARDBP 和 FUS 代表的三个病理组是不同的。在这篇综述中，我们探讨了 ALS 的遗传结构，强调了一些与发病机制有关的基因，并描述了它们的表型范围及其与其他疾病的重叠。
