Genetic etiology of Fronto-Temporal Dementia

肌萎缩侧索硬化症（ALS; Lou Gehrigs病）是一种致命的神经退行性疾病，可导致快速进行性瘫痪和呼吸衰竭。ALS是西方世界第三常见的神经退行性疾病，目前尚无有效的治疗方法。额颞叶痴呆（FTD）是65岁以下人群中最常见的痴呆形式。这两种临床上不同的神经系统疾病之间的重叠早已被认识到，但这种交叉的分子基础是未知的。 2011年，神经肌肉疾病研究科（NDRS），国家老龄化研究所神经遗传学实验室的一部分，确定了ALS和FTD的主要遗传原因。为了做到这一点，Traynor博士（NDRU的负责人）组织了一个全球性的财团，将以前是竞争对手的团体聚集在一起，集中精力鉴定这种基因。这是由NIH提供的下一代测序技术实现的。这种创新的方法奏效了，他的团队于2011年9月在Neuron杂志上发表了9号染色体连锁ALS/FTD的原因。在这些情况下，这种疾病是由一个六碱基对的DNA片段引起的，它在病理上反复重复，多达几千次。这种所谓的大六核苷酸重复序列破坏了位于9号染色体上的C9 ORF 72基因。这是迄今为止发现的ALS和FTD的最常见遗传原因，约占欧洲和北美人群中ALS和FTD所有家族性病例的40%。此外，Traynors博士的研究小组表明，这种突变是大约8%缺乏家族史的零星发生的ALS和FTD病例的基础。这是第一次发现这些疾病散发形式的共同遗传原因。在《新英格兰医学杂志》的另一篇文章中，他们还表明，1%的临床诊断为阿尔茨海默病的患者的基础是相同的大六核苷酸重复扩增。AD病例数量减少1%将意味着每年节省约10亿美元的医疗费用。 C9 ORF 72六核苷酸重复扩增的发现是我们理解神经退行性疾病的里程碑式发现。它已经极大地影响了这些疾病的诊断，调查和感知，并提供了两个临床不同的疾病，ALS和FTD之间的机械联系。它还为旨在改善疾病的基因治疗工作提供了一个独特的治疗靶点，这种努力已经在进行中。 总之，我们已成功使用下一代测序鉴定了FTD发病机制中重要的遗传变异。我们的数据还有助于将FTD和ALS统一为一种单一的疾病，包括两种主要的迟发性神经退行性疾病。这两项研究都采用了大量的研究对象，并利用了NIA神经遗传学实验室内可用的测序和基因分型设施。

Amyotrophic lateral sclerosis (ALS; Lou Gehrigs disease) is a fatal neurodegenerative disorder that leads to rapidly progressive paralysis and respiratory failure. ALS is the third most common neurodegenerative disease in the Western World, and there are currently no effective therapies. Frontotemporal dementia (FTD) is the most common form of dementia in the population under the age of 65. An overlap between these two clinically distinct neurological diseases has long been recognized, but the molecular basis of this intersection was unknown. In 2011, the Neuromuscular Diseases Research Section (NDRS), a part of the Laboratory of Neurogenetics at the National Institute on Aging, identified the major genetic cause of both ALS and FTD. To do this, Dr. Traynor (chief of NDRU) organized a worldwide consortium, bringing together groups that had previously been competitors to focus their efforts towards identifying this gene. This was made possible by the next generation sequencing technologies available at the NIH. This innovative approach worked, and his group published the cause of chromosome 9-linked ALS/FTD in the journal Neuron in September 2011. In these cases, the disease is caused by a six base pair segment of DNA that is pathologically repeated over and over again, up to several thousand times. This so-called large hexanucleotide repeat disrupts the C9ORF72 gene located on chromosome 9. This is the most common genetic cause of both ALS and FTD identified to date, accounting for approximately 40% of all familial cases of ALS and FTD in European and North American populations. Further, Dr. Traynors group has shown that this mutation underlies about 8% of cases of sporadically occurring ALS and FTD that lack a family history. This represents the first time that a common genetic cause has been identified for the sporadic form of these diseases. In a separate publication in The New England Journal of Medicine, they have also shown that the same large hexanucleotide repeat expansion underlies 1% of patients clinically diagnosed with Alzheimer's disease. A one percent reduction in the number of AD cases would represent approximately $1 billion in healthcare cost savings annually. The discovery of the C9ORF72 hexanucleotide repeat expansion is a landmark discovery in our understanding of neurodegenerative disease. It has already greatly effected how these diseases are diagnosed, investigated and perceived, and provides a mechanistic link between two clinically distinct disorders, ALS and FTD. It also provides a distinct therapeutic target for gene therapy efforts aimed at ameliorating the disease, and such efforts are already well underway. In summary, we have been successful in identifying genetic variants important in the pathogenesis of FTD using next generation sequencing. Our data also helps to unify FTD and ALS into a single disease rubic that encompasses two of the major late-onset neurodegenerative diseases. Each of the two studies employed large cohorts of research subjects, and utilized the sequencing and genotyping facilities available within the Laboratory of Neurogenetics, NIA.