Bourinaris Thomas, Houlden Henry
Department of Molecular Neuroscience Institute of Neurology, University College London London, WC1N 3BG UK.
Mov Disord Clin Pract. 2018 Nov 8;5(6):575-585. doi: 10.1002/mdc3.12677. eCollection 2018 Nov-Dec.
The C9orf72 hexanucleotide expansion is one of the latest discovered repeat expansion disorders related to neurodegeneration. Its association with the FTD/ALS spectrum disorders is well established, and it is considered to be one of the leading related genes. It has also been reported as a possible cause of several other phenotypes, including parkinsonism and other movement disorders. Its significance, though outside the FTD/ALS spectrum, is not well defined.
A comprehensive search of the literature was performed. All relevant papers, including reviews and case series/reports on movement disorder phenotypes reported with the C9orf72 repeat expansion, were reviewed. Data on frequency, natural history, phenotype, genetics, and possible underlying mechanisms were assessed.
In a number of studies, C9orf72 accounts for a small fraction of typical PD. Atypical parkinsonian syndromes, including CBS, PSP, and MSA have also been reported. Features that increase the probability of positive testing include early cognitive and/or behavioral symptoms, positive family history of ALS or FTD, and the presence of UMN and LMN signs. Furthermore, several studies conclude that C9orf72 is the most common cause of HD-phenocopies. Interestingly, many cases with the parkinsonian phenotype that bear an intermediate range of repeats are also reported, questioning the direct causal role of C9orf72 and suggesting the possibility of being a susceptibility factor, while the presence of the expansion in normal controls questions its clinical significance. Finally, studies on pathology reveal a distinctive broad range of C9orf72-related neurodegeneration that could explain the wide phenotypic variation.
C9orf72六核苷酸重复扩增是最新发现的与神经退行性变相关的重复扩增疾病之一。其与额颞叶痴呆/肌萎缩侧索硬化谱系障碍的关联已得到充分证实，被认为是主要相关基因之一。也有报道称其可能是包括帕金森综合征和其他运动障碍在内的几种其他表型的病因。尽管其在额颞叶痴呆/肌萎缩侧索硬化谱系之外的意义尚不明确。
对文献进行全面检索。对所有相关论文进行了综述，包括关于C9orf72重复扩增所报道的运动障碍表型的综述以及病例系列/报告。评估了频率、自然史、表型、遗传学及可能的潜在机制等方面的数据。
在多项研究中，C9orf72在典型帕金森病中所占比例较小。也有报道称其与包括皮质基底节综合征、进行性核上性麻痹和多系统萎缩在内的非典型帕金森综合征有关。增加检测呈阳性可能性的特征包括早期认知和/或行为症状、肌萎缩侧索硬化或额颞叶痴呆的阳性家族史以及上运动神经元和下运动神经元体征的存在。此外，多项研究得出结论，C9orf72是亨廷顿病样表型最常见的病因。有趣的是，也报道了许多具有中间重复范围的帕金森病表型病例，这对C9orf72的直接因果作用提出了质疑，并提示其可能是一个易感因素，而正常对照中存在该扩增则对其临床意义提出了疑问。最后，病理学研究揭示了一系列独特的与C9orf72相关的神经退行性变，这可以解释广泛的表型变异。
