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.