Importance: Abnormalities of axonal excitability characterized by upregulation of persistent sodium (Na+) conductances and reduced potassium (K+) currents have been reported in sporadic amyotrophic lateral sclerosis (SALS) phenotypes and linked to the development of clinical features such as fasciculations and neurodegeneration.
Objective: To investigate whether abnormalities of axonal ion channel function, particularly upregulation of persistent Na+ conductances and reduced K+ currents, form the pathophysiological basis of chromosome 9 open reading frame 72 (c9orf72) familial amyotrophic lateral sclerosis (FALS).
Design, setting, and participants: This was a prospective study. Clinical and functional assessment, along with motor-nerve excitability studies, were undertaken in 10 clinically affected patients with c9orf72 FALS, 9 asymptomatic c9orf72 mutation carriers, and 21 patients with SALS from 3 hospitals and 2 outpatient clinics.
Main outcomes and measures: Axonal excitability variables were measured in patients with c9orf72 ALS and results compared with matched patients with SALS and healthy control participants.
Results: Strength-duration time constant (τSD) was significantly increased in the patients with c9orf72 FALS and those with SALS (mean [SD], c9orf72 FALS: 0.50 [0.02] milliseconds; SALS: 0.52 [0.02] milliseconds; P < .01) when compared with control participants (mean [SD], 0.44 [0.01] milliseconds). In contrast, there were no significant changes of τSD in asymptomatic c9orf72 mutation carriers (P = .42). An accompanying increase in depolarizing threshold electrotonus at 90 to 100 milliseconds (TEd 90-100 milliseconds) was also evident in the c9orf72 FALS (P < .05) and SALS (P < .01) cohorts. Mathematical modeling suggested that an increase in persistent Na+ conductances, along with reduced K+ currents, best explained the changes in axonal excitability. Importantly, these abnormalities in axonal excitability correlated with the motor amplitude (τSD: R = -0.38, P < .05 and TEd 90-100 milliseconds: R = -0.44, P < .01), muscle weakness (TEd 90-100 milliseconds: R = -0.32, P < .05), and the ALS Functional Rating Scale (TEd 90-100 milliseconds: R = -0.34, P < .05).
Conclusions and relevance: Findings from the present study establish that upregulation of persistent Na+ conductances and reduced K+ currents were evident in both c9orf72 FALS and SALS cohorts, and these changes in axonal excitability were associated with motor neuron degeneration.