From the Department of Neurology (Y.Y., Z.L., X.H., W.L., J.N., Y.H., P.L., X.H., Q.S., Y.T., B.J., H.J., L.S, B.T., J.W.) and National Clinical Research Center for Geriatric Diseases (H.J., L.S, B.T., J.W.), Xiangya Hospital, Department of Neurology (L.H.), the Third Xiangya Hospital, Laboratory of Medical Genetics (J.X., R.D., H.J., L.S, B.T., J.W.), and Key Laboratory of Hunan Province in Neurodegenerative Disorders (J.H., L.S, B.T., J.W.), Central South University, Changsha, Hunan, PR China.
Neurology. 2020 Dec 15;95(24):e3394-e3405. doi: 10.1212/WNL.0000000000010945. Epub 2020 Sep 28.
To determine whether the GGC repeats in the gene contribute to amyotrophic lateral sclerosis (ALS).
In this study, 545 patients with ALS and 1,305 healthy controls from mainland China were recruited. Several pathogenic mutations in known ALS-causative genes (including and ) and polynucleotide repeat expansions in and genes were excluded. Repeat-primed PCR and GC-rich PCR were performed to determine the GGC repeat size in . Systematic and targeted clinical evaluations and investigations, including skin biopsy and dynamic electrophysiologic studies, were conducted in the genetically affected patients.
GGC repeat expansion was observed in 4 patients (numbers of repeats 44, 54, 96, and 143), accounting for ≈0.73% (4 of 545) of all patients with ALS. A comparison with 1,305 healthy controls revealed that GGC repeat expansion in was associated with ALS (Fisher exact test, 4 of 545 vs 0 of 1,305, = 0.007). Compared to patients with the neuronal intranuclear inclusion disease (NIID) muscle weakness-dominant subtype, patients with ALS phenotype carrying the abnormal repeat expansion tended to have a severe phenotype and rapid deterioration.
Our results suggest that ALS is a specific phenotype of NIID or that GGC expansion in is a factor that modifies ALS. These findings may help clarify the pathogenic mechanism of ALS and may expand the known clinical spectrum of NIID.
确定 基因中的 GGC 重复是否与肌萎缩侧索硬化症（ALS）有关。
本研究纳入了 545 名中国大陆 ALS 患者和 1305 名健康对照者。排除了已知 ALS 致病基因（包括 和 ）中的致病性突变和 及 基因中的多核苷酸重复扩展。采用重复引物 PCR 和 GC 丰富 PCR 检测 中的 GGC 重复大小。对遗传受累患者进行系统和有针对性的临床评估和调查，包括皮肤活检和动态电生理研究。
在 4 名患者（重复次数分别为 44、54、96 和 143）中观察到 GGC 重复扩展，占所有 ALS 患者的 ≈0.73%（4/545）。与 1305 名健康对照者比较， 中的 GGC 重复扩展与 ALS 相关（Fisher 确切检验，4/545 与 0/1305， = 0.007）。与神经元核内包涵体病（NIID）以肌肉无力为主型的患者相比，携带异常重复扩展的 ALS 表型患者的表型往往更严重，病情恶化更快。
我们的结果提示 ALS 是 NIID 的一种特殊表型，或 中的 GGC 扩展是影响 ALS 的一个因素。这些发现可能有助于阐明 ALS 的发病机制，并可能扩大 NIID 的已知临床谱。
