Nerve Excitability in Asymptomatic Carriers and Amyotrophic Lateral Sclerosis Patients With C9orf72

Objective: We investigated the effects of C9orf72 mutation carriership on peripheral nerve excitability in asymptomatic individuals from families with a history of C9orf72 amyotrophic lateral sclerosis (ALS) and patients. Methods: We included 47 asymptomatic individuals from families with a history of C9orf72 ALS, of whom 23 were carriers (C9⁺) and 24 were noncarriers (C9⁻). In addition, 11 C9⁺ and 110 C9⁻ ALS patients and 50 healthy controls participated. Nerve excitability tests were conducted on the median nerve. We obtained standard excitability measurements as well as composites of these measurements that reflect various passive and active membrane properties. Data of C9⁺ and C9⁻ asymptomatic individuals were compared, followed by a kinship-adjusted comparison in asymptomatic individuals from the same families. We then compared C9⁺ to C9⁻ ALS patients. Results: In the subset of asymptomatic individuals from the same families, C9⁺ individuals had lower values than C9⁻ individuals on one of the composite excitability measurements (t = −2.15, p = 0.034), corresponding to a hypoexcitable profile consistent with smaller Na⁺-window currents. C9⁺ ALS patients had a hyperexcitable profile with larger refractoriness at 2 ms and relative refractory periods than C9⁻ ALS patients (t = 4.58, p < 0.001; t = 3.43, p = 0.002, respectively), which is in line with slower recovery of the Na⁺-channels from inactivation. Interpretation: Asymptomatic individuals and ALS patients carrying the C9orf72 mutation exhibit a unique electrophysiological phenotype, implicating altered Na⁺-channel characteristics compared to asymptomatic noncarriers and sporadic ALS patients. Monitoring hypoexcitable to hyperexcitable profile transitions in individuals carrying the C9orf72 mutation may be valuable as an early indicator of phenoconversion.