Axonal ion channel dysfunction in c9orf72 familial amyotrophic lateral sclerosis.
OBJECTIVE
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).


METHODS
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.


METHODS
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
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.
Westmead Clinical School, University of Sydney, Sydney, Australia.
Nimeshan
N
Geevasinga
Westmead Clinical School, University of Sydney, Sydney, Australia.
Parvathi
P
Menon
Brain and Mind Research Institute, University of Sydney, Sydney, Australia.
James
J
Howells
Department of Neurology, Concord Hospital, Central Clinical School, University of Sydney, Sydney, Australia.
Garth A
GA
Nicholson
Brain and Mind Research Institute, University of Sydney, Sydney, Australia.
Matthew C
MC
Kiernan
Westmead Clinical School, University of Sydney, Sydney, Australia.
Steve
S
Vucic
D000200:Action Potentials / Q000235:genetics; D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000503:physiopathology; D001369:Axons / Q000502:physiology*; D000073885:C9orf72 Protein; D015331:Cohort Studies; D004558:Electric Stimulation; D005260:Female; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000502:physiology*; D008297:Male; D008475:Median Nerve / Q000503:physiopathology*; D008875:Middle Aged; D008962:Models, Theoretical; D009154:Mutation / Q000235:genetics*; D011446:Prospective Studies; D011506:Proteins / Q000235:genetics*; D014953:Wrist / Q000294:innervation; D055815:Young Adult
D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D007473:Ion Channels; D011506:Proteins