Laboratory of Neurobiology, Vesalius Research Center, VIB, University of Leuven, Leuven, Belgium.
Curr Opin Neurol. 2013 Oct;26(5):466-72. doi: 10.1097/WCO.0b013e328364c063.
This review examines the clinical implications of recent breakthroughs in amyotrophic lateral sclerosis (ALS).
ALS has been found to be a highly variable condition at the clinical, genetic and mechanistic level. The study of newly discovered genetic causes for ALS has demonstrated that in addition to the effect of toxic mutant proteins, abnormalities of RNA householding contribute to motor neuron degeneration. Furthermore, the classic distinction between gain of function and loss of function may be an oversimplification of the biological reality. The most important clinical breakthrough was the finding of intronic hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) as a common cause of ALS, frontotemporal lobar degeneration (FTLD) and ALS with concomitant FTLD. This provides unambiguous evidence that ALS and FTLD represent the ends of one spectrum of neurodegenerative diseases. The high prevalence of C9orf72 mutations in patients without family history further blurs the distinction between sporadic and familial forms of ALS and FTLD. It also opens opportunities for stratified clinical trials in ALS and for the development of targeted therapies.
ALS is a heterogeneous disorder that overlaps with FTLD. C9orf72 mutations are the most common cause of ALS, and add to the evidence that disturbances in RNA householding contribute to ALS.
本文综述了肌萎缩侧索硬化症 (ALS) 近期突破性研究的临床意义。
ALS 在临床、遗传和机制水平上具有高度变异性。对 ALS 新发现的遗传病因的研究表明，除了毒性突变蛋白的作用外，RNA 稳态异常也导致运动神经元变性。此外，功能获得和功能丧失的经典区分可能过于简化了生物学现实。最重要的临床突破是发现 9 号染色体开放阅读框 72（C9orf72）内含子六核苷酸重复扩展是 ALS、额颞叶变性（FTLD）和伴有 FTLD 的 ALS 的常见原因。这提供了明确的证据，表明 ALS 和 FTLD 代表神经退行性疾病谱的两端。无家族史患者中 C9orf72 突变的高患病率进一步模糊了散发性和家族性 ALS 和 FTLD 之间的区别。它也为 ALS 的分层临床试验和靶向治疗的发展提供了机会。
ALS 是一种具有异质性的疾病，与 FTLD 重叠。C9orf72 突变是 ALS 最常见的原因，这进一步证明了 RNA 稳态紊乱导致 ALS。
