Brain Advance Access published online on April 27, 2005
Brain, doi:10.1093/brain/awh520
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1 Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia; Department of Neurology, Prince of Wales Hospital, Sydney, Australia
* To whom correspondence should be addressed. To determine the effect of an established mutation of the
Received February 4, 2005
Revised March 21, 2005
Accepted April 1, 2005
Article
Mutation in the Na+ channel subunit SCN1B produces paradoxical changes in peripheral nerve excitability
2 Prince of Wales Medical Research Institute and Prince of Wales Clinical School, University of New South Wales, Sydney, Australia; Institute of Clinical Neurosciences, University of Sydney and Royal Prince Alfred Hospital, Sydney, Australia
3 Institute of Clinical Neurosciences, University of Sydney and Royal Prince Alfred Hospital, Sydney, Australia
4 Epilepsy Research Centre, University of Melbourne, Austin Health, Victoria, Australia
Matthew C. Kiernan, E-mail: M.Kiernan{at}unsw.edu.au
Abstract 
1 subunit of Na+ channels on nerve excitability, studies were undertaken in patients diagnosed with generalized epilepsy with febrile seizures plus (GEFS+). Multiple nerve excitability measurements were used to investigate the membrane properties of sensory and motor axons in five patients (aged 18-55 years) who were currently experiencing no seizures and were not on anticonvulsants. There was no history of paraesthesiae, fasciculation or cramps to suggest hyperexcitability of peripheral nerve axons. The median nerve was stimulated at the wrist, and compound muscle action potentials (CMAPs) were recorded from abductor pollicis brevis and the antidromic compound sensory nerve action potential (CSAPs) from digit 2. Stimulus-response behaviour, strength-duration time constant, threshold electrotonus, current-threshold relationship and the recovery of excitability following a supramaximal conditioning stimulus were recorded using threshold tracking. Compared with normal controls (n = 29), the axons of patients were of higher threshold. CMAPs and CSAPs were relatively small, although individual values remained within the normal ranges. Refractoriness and relative refractory period (markers of transient Na+ channel function) were significantly reduced in GEFS+ patients with established mutations in SCN1B (P < 0.05), and strength-duration time constants (dependent on persistent Na+ conductances) were reduced. It is suggested that, in peripheral nerve axons, the mutation underlying GEFS+ reduces the number of functioning Na+ channels at the node of Ranvier and that this rather than any change in gating of individual channels dominates axonal excitability in these patients.
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