Background: Upregulation of persistent Na+ conductances has been linked to axonal degeneration in sporadic amyotrophic lateral sclerosis and has also been reported in the transgenic superoxide dismutase-1 (SOD-1) mouse model. The mechanisms of ectopic activity (fasciculations and cramp) and axonal degeneration have yet to be clarified in familial ALS (FALS) in humans, and specifically whether there are differences to the processes identified in sporadic patients. Consequently, novel threshold tracking techniques were used to assess whether upregulation of persistent Na+ conductances were a feature linked to axonal degeneration in FALS.
Methods: Axonal excitability studies were undertaken in 6 FALS patients, 13 asymptomatic SOD-1 mutation carriers and 45 SALS patients.
Results: CMAP amplitude was significantly reduced in FALS (6.3±1.3 mV) and SALS (6.0±0.4 mV) compared to controls (10.0±0.4 mV, P<0.05). Mean strength duration time constant (τSD) was significantly increased in FALS (0.55±0.10 ms, P<0.05) and SALS (0.52±0.02 ms, P<0.01) compared to controls (0.41±0.02). There were no differences in τSD between asymptomatic SOD-1 mutation carriers and controls. The increase in τSD correlated with the CMAP amplitude (R= -0.4) and neurophysiological index (R= -0.4). In separate studies that assessed cortical processes, short interval intracortical inhibition (SICI) was significantly reduced (FALS, -2.7±1.3%; controls 13.7±1.3%, P<0.0001) and intracortical facilitation increased (FALS, -5.0±2.2%; controls -0.4±1.1%, P<0.05) in FALS. The reduction in SICI correlated with τSD (R= -0.8).
Conclusions: Taken together, these studies suggest that persistent Na+ conductances are upregulated in FALS and that this upregulation is intrinsically associated with axonal degeneration.