Bruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Victorian Clinical Genetics Services, Parkville, Victoria, Australia; Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
Department of Pediatrics, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA; Oklahoma Center for Neuroscience, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
Neurobiol Dis. 2019 Dec;132:104606. doi: 10.1016/j.nbd.2019.104606. Epub 2019 Sep 5.
Friedreich ataxia is the most common of the hereditary ataxias. It is due to homozygous/compound heterozygous mutations in FXN. This gene encodes frataxin, a protein largely localized to mitochondria. In about 96% of affected individuals there is homozygosity for a GAA repeat expansion in intron 1 of the FXN gene. Studies of people with Friedreich ataxia and of animal and cell models, have provided much insight into the pathogenesis of this disorder. The expanded GAA repeat leads to transcriptional deficiency of the FXN gene. The consequent deficiency of frataxin protein leads to reduced iron-sulfur cluster biogenesis and mitochondrial ATP production, elevated mitochondrial iron, and oxidative stress. More recently, a role for inflammation has emerged as being important in the pathogenesis of Friedreich ataxia. These findings have led to a number of potential therapies that have been subjected to clinical trials or are being developed toward human studies. Therapies that have been proposed include pharmaceuticals that increase frataxin levels, protein and gene replacement therapies, antioxidants, iron chelators and modulators of inflammation. Whilst no therapies have yet been approved for Friedreich ataxia, there is much optimism that the advances in the understanding of the pathogenesis of this disorder since the discovery its genetic basis, will result in approved disease modifying therapies in the near future.
弗里德赖希共济失调是遗传性共济失调中最常见的一种。它是由于 FXN 基因的纯合子/复合杂合突变引起的。该基因编码 frataxin，一种主要定位于线粒体的蛋白质。在大约 96%的受影响个体中，FXN 基因内含子 1 中的 GAA 重复扩展呈纯合状态。对弗里德赖希共济失调患者以及动物和细胞模型的研究，为该疾病的发病机制提供了很多深入了解。扩展的 GAA 重复导致 FXN 基因的转录缺陷。随之而来的 frataxin 蛋白缺乏会导致铁硫簇生物合成和线粒体 ATP 产生减少、线粒体铁升高和氧化应激。最近，炎症的作用在弗里德赖希共济失调的发病机制中变得重要。这些发现导致了许多潜在的治疗方法，这些方法已经进行了临床试验或正在开发用于人体研究。已经提出的治疗方法包括增加 frataxin 水平的药物、蛋白质和基因替代疗法、抗氧化剂、铁螯合剂和炎症调节剂。虽然目前还没有批准用于弗里德赖希共济失调的治疗方法，但人们非常乐观地认为，自从发现其遗传基础以来，对这种疾病发病机制的理解的进展，将导致在不久的将来获得批准的疾病修饰治疗方法。
