Friedreich Ataxia: An (Almost) 30-Year History After Gene Discovery.

IF 3 3区 医学 Q2 CLINICAL NEUROLOGY
Neurology-Genetics Pub Date : 2025-01-13 eCollection Date: 2025-02-01 DOI:10.1212/NXG.0000000000200236
Massimo Pandolfo
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引用次数: 0

Abstract

In the late 1800s, Nikolaus Friedreich first described "degenerative atrophy of the posterior columns of the spinal cord," noting its connection to progressive ataxia, sensory loss, and muscle weakness, now recognized as Friedreich ataxia (FRDA). Renewed interest in the disease in the 1970s and 80s by the Quebec Cooperative Group and by Anita Harding led to the development of clinical diagnostic criteria and insights into associated biochemical abnormalities, although the primary defect remained unknown. In 1988, Susan Chamberlain mapped FRDA's location on chromosome 9. In the early 90s, collaborative research, including work by the author's team, identified a gene, later named FXN, containing an expanded GAA repeat-confirming it as the FRDA mutation. This discovery established a diagnostic foundation for FRDA, advancing genetic testing and opening new research avenues. These new areas of study included the characteristics, origin, and pathogenicity of the GAA repeat expansion; the characterization of frataxin, the encoded protein, including its subcellular localization, structure, and function; the identification of cellular pathways disrupted by frataxin deficiency; and the redefinition of FRDA phenotypes based on genetic testing, along with the study of FRDA's natural history. In addition, efforts focused on the search for biomarkers to reflect diagnosis, disease severity, and progression and, most importantly, the identification and development of therapeutic approaches in both preclinical and clinical settings. The creation of cellular and animal models was crucial to this progress, as was the formation of consortia to collaboratively drive basic and clinical research forward. Now, 28 years after the gene discovery, although much remains to be understood about the disease's mechanisms and the development of effective therapies, the progress is undeniable. A thriving community has emerged, uniting researchers, health care providers, industry professionals, individuals with FRDA, their families, and dedicated volunteers. With this collective effort, a cure is within reach.

弗里德里希共济失调:基因发现后的(近)30年历史。
在19世纪后期,Nikolaus Friedreich首次描述了“脊髓后柱的退行性萎缩”,并指出它与进行性共济失调、感觉丧失和肌肉无力有关,现在被认为是弗里德赖希共济失调(FRDA)。在20世纪70年代和80年代,魁北克合作小组和Anita Harding对这种疾病重新产生了兴趣,导致了临床诊断标准的发展和对相关生化异常的见解,尽管主要缺陷仍然未知。1988年,苏珊·张伯伦绘制了FRDA在9号染色体上的位置。在90年代早期,包括作者团队的工作在内的合作研究发现了一个基因,后来被命名为FXN,包含一个扩展的GAA重复序列,确认它是FRDA突变。这一发现为FRDA的诊断奠定了基础,促进了基因检测的发展,开辟了新的研究途径。这些新的研究领域包括GAA重复扩增的特征、起源和致病性;编码蛋白frataxin的特性,包括其亚细胞定位、结构和功能;鉴定因卵黄蛋白缺乏而中断的细胞通路;以及基于基因检测的FRDA表型的重新定义,以及对FRDA自然史的研究。此外,研究人员还致力于寻找能够反映诊断、疾病严重程度和进展的生物标志物,最重要的是,在临床前和临床环境中确定和开发治疗方法。细胞和动物模型的创建对这一进展至关重要,同时也形成了合作推动基础和临床研究向前发展的联盟。现在,在基因发现28年之后,尽管对这种疾病的机制和有效治疗方法的发展仍有很多有待了解,但进步是不可否认的。一个繁荣的社区已经出现,将研究人员、医疗保健提供者、行业专业人士、FRDA个人、他们的家人和敬业的志愿者团结在一起。有了大家的共同努力,治愈就指日可待了。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Neurology-Genetics
Neurology-Genetics Medicine-Neurology (clinical)
CiteScore
6.30
自引率
3.20%
发文量
107
审稿时长
15 weeks
期刊介绍: Neurology: Genetics is an online open access journal publishing peer-reviewed reports in the field of neurogenetics. Original articles in all areas of neurogenetics will be published including rare and common genetic variation, genotype-phenotype correlations, outlier phenotypes as a result of mutations in known disease-genes, and genetic variations with a putative link to diseases. This will include studies reporting on genetic disease risk and pharmacogenomics. In addition, Neurology: Genetics will publish results of gene-based clinical trials (viral, ASO, etc.). Genetically engineered model systems are not a primary focus of Neurology: Genetics, but studies using model systems for treatment trials are welcome, including well-powered studies reporting negative results.
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