Pathophysiological insights into ALS with C9ORF72 expansions
Pathophysiological insights into ALS with C9ORF72 expansions
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DOI：
10.1136/jnnp-2012-304529
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发表时间：
2013-08-01
影响因子：
11
通讯作者：
Nicholson, Garth A.
中科院分区：
文献类型：
--
作者：
Williams, Kelly L.;Fifita, Jennifer A.;Nicholson, Garth A.
目的C9ORF72基因六核苷酸重复序列的扩增是家族性肌萎缩侧索硬化症(ALS)和少数散发性ALS的常见病因。方法对家族性和散发性ALS患者进行C9ORF72扩增筛查，研究其临床和神经生理特征。对扩张阳性病例的临床特点进行了描述。皮质兴奋性研究采用新的阈值跟踪经颅磁刺激技术，运动诱发反应记录在拇展短肌上。结果与结论通过大的临床队列分析，在38.5%(72/187)的ALS家系和3.5%(21/606)的散发性ALS病例中发现了C9ORF72的扩张。已知有两个扩增阳性家系携带已报道的Ang突变，可能涉及ALS的少基因模型。在C9ORF72扩增的家族性ALS患者中，6%的患者还被诊断为痴呆。肌萎缩侧索硬化症的外显率男性为50%，女性为63岁。男性受试者在86岁时观察到100%的ALS外显率，而女性受试者在82岁时仍有6%的人没有症状。发病年龄的性别差异很明显，男性受试者更容易在更年轻的时候患上肌萎缩侧索硬化症。重要的是，在C9ORF72连锁的家族性ALS中，皮质高兴奋性的特征明显，表现为皮质内短间期抑制和皮质静止期持续时间显著缩短，皮质内易化和运动诱发电位幅度增加，表明皮质高兴奋性是C9ORF72连锁ALS的内在过程。
Objective Expansions of a hexanucleotide repeat in C9ORF72 are a common cause of familial amyotrophic lateral sclerosis (ALS) and a small proportion of sporadic ALS cases. We sought to examine clinical and neurophysiological features of familial and sporadic ALS with C9ORF72 expansions.Methods C9ORF72 was screened for expansions in familial and sporadic ALS. Clinical features of expansion positive cases are described. Cortical excitability studies used novel threshold tracking transcranal magnetic stimulation techniques with motor evoked responses recorded over the abductor pollicis brevis.Results and conclusions Analysis of large clinical cohorts identified C9ORF72 expansions in 38.5% (72/ 187) of ALS families and 3.5% (21/606) of sporadic ALS cases. Two expansion positive families were known to carry reported ANG mutations, possibly implicating an oligogenic model of ALS. 6% of familial ALS cases with C9ORF72 expansions were also diagnosed with dementia. The penetrance of ALS was 50% at age 58 years in male subjects and 63 years in female subjects. 100% penetrance of ALS was observed in male subjects by 86 years, while 6% of female subjects remained asymptomatic at age 82 years. Gender specific differences in age of onset were evident, with male subjects significantly more likely to develop ALS at a younger age. Importantly, features of cortical hyperexcitability were apparent in C9ORF72-linked familial ALS as demonstrated by significant reduction in short interval intracortical inhibition and cortical silent period duration along with an increase in intracortical facilitation and motor evoked potential amplitude, indicating that cortical hyperexcitability is an intrinsic process in C9ORF72-linked ALS.