Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales, Australia.
J Neurol Neurosurg Psychiatry. 2013 Aug;84(8):931-5. doi: 10.1136/jnnp-2012-304529. Epub 2013 Mar 5.
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.
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.
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.
C9ORF72 六核苷酸重复序列扩展是家族性肌萎缩侧索硬化症（ALS）的常见原因，也是一小部分散发性 ALS 病例的原因。我们试图研究携带 C9ORF72 扩展的家族性和散发性 ALS 的临床和神经生理学特征。
筛选家族性和散发性 ALS 中的 C9ORF72 扩展。描述了扩展阳性病例的临床特征。使用新型阈值跟踪经颅磁刺激技术进行皮质兴奋性研究，通过记录拇短展肌的运动诱发电位来测量。
对大型临床队列的分析确定了 38.5%（72/187）的 ALS 家族和 3.5%（21/606）的散发性 ALS 病例中存在 C9ORF72 扩展。两个扩展阳性家族已知携带报道的 ANG 突变，可能暗示 ALS 的寡基因模型。6%的携带 C9ORF72 扩展的家族性 ALS 病例也被诊断为痴呆症。在男性中，C9ORF72 扩展的 ALS 患病率为 58 岁时为 50%，63 岁时为 63%。在男性中，到 86 岁时观察到 100%的 ALS 患病率，而在 82 岁时，仍有 6%的女性无症状。发病年龄的性别特异性差异明显，男性发病年龄明显更早。重要的是，C9ORF72 相关家族性 ALS 中存在皮质过度兴奋的特征，表现为短程皮质内抑制和皮质静息期缩短，皮质内易化和运动诱发电位幅度增加，表明皮质过度兴奋是 C9ORF72 相关 ALS 的内在过程。
