Axonal Ion Channel Dysfunction in C9orf72 Familial Amyotrophic Lateral Sclerosis

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 withc9orf72 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 withc9orf72 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 c9orf72mutation 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).

JAMA Neurology 2014