Familial amyloid polyneuropathy (FAP) caused by a mutation in transthyretin (TTR) gene is an autosomal dominant inherited disorder. The aim of this study is to explore the pathophysiological mechanism of FAP. We prospectively recruited 12 pauci-symptomatic carriers, 18 patients who harbor a TTR mutation, p.A97S, and two-age matched control groups. Data of nerve excitability test (NET) from ulnar motor and sensory axons were collected.NET study of ulnar motor axons of patients shows increased threshold and rheobase, reduced threshold elevation during hyperpolarizing threshold electrotonus (TE), and increased refractoriness. In sensory nerve studies, there are increased threshold reduction in depolarizing TE, lower slope of recovery and delayed time to overshoot after hyperpolarizing TE, increased refractoriness and superexcitability in recovery cycle. NET profiles obtained from the ulnar nerve of carriers show the increase of threshold and rheobase, whereas no significant threshold changes in hyperpolarizing TE and superexcitability. The regression models demonstrate that the increase of refractoriness and prolonged relative refractory period are correlated to the disease progression from carriers to patients. The marked increase of refractoriness at short-width stimulus suggests a defect in sodium current which may represent an early, pre-symptomatic pathophysiological change in TTR-FAP. Focal disruption of basal lamina and myelin may further increase the internodal capacity, manifested by the lower slope of recovery and delayed time to overshoot after hyperpolarization TE as well as the increase of superexcitability. NET could therefore make a pragmatic tool for monitoring disease progress from the very early stage of TTR-FAP.

Familial amyloid polyneuropathy (FAP) is a rare, hereditary peripheral neuropathy commonly caused by mutations in human transthyretin (TTR) gene. Clinically, FAP caused by TTR mutations (TTR-FAP) involves both large and small nerve fibers. Details of early electrophysiological features in TTR-FAP remain unclear. To address this issue, we evaluated nerve excitability (NET) results in motor axons of control mice and two transgenic mouse models carrying V30M (TTRV30M) or A97S (TTRA97S) mutations that simulate clinical features of TTR-FAP. Transgenic TTRV30M and TTRA97S mice demonstrated significant increases in latency in hindlimb withdraw tests, as well as, poor rotarod test performance, compared to TTRORF mice. NET evaluation showed reduced S2 accommodation, and increased TEdundershoot during threshold electrotonus (TE) in motor axons of both TTRV30M and TTRA97S mice, indicating that axonal membranes were in a depolarized state. Decreased rheobase combined with increased refractoriness in the transgenic mice suggested that there were reduced sodium currents. Further immunohistochemical study of the sciatic nerves revealed the significantly decrease of voltage-gated sodium channel expression in the transgenic mice. Moreover, superexcitability during the recovery cycle is significantly increased in transgenic mice compared with control mice, which is attributed to increased internodal capacitance. Finally, the electron microscopy demonstrated the reduced g-ratio in TTRA97S mice may correlate with an atrophic change of axons and/or increase of myelin thickness. In summary, we evaluated NET results in transgenic mice which modeled the clinical features presented in TTR-FAP patients. Reduced sodium channel expression and increased internodal capacitance are factors contributing to the electrophysiological changes in TTR-FAP.

Inherited erythromelalgia (IEM), caused by mutations in Nav1.7 channel is characterized by episodic neuropathic pain triggered especially by warm temperature. However, the mechanism underlying the temperature-dependent episodic attacks of IEM remains elusive. We investigated the electrophysiological effect of temperature changes on Nav1.7 channels with three different mutations, p.I136V, p. I848T, and p.V1316A, both in vitro and in vivo. In vitro biophysical studies of the mutant channels show consistent temperature-dependent enhancement of the relative resurgent currents if normalized to the transient currents, as well as temperature-dependent changes in the time to peak and the kinetics of decay of the resurgent currents, but no congruent temperature-dependent changes in steady-state parameters such as shift of activation/inactivation curves and changes of the absolute size of the window or resurgent currents. In vivo nerve excitability tests (NET) in IEM patients reveal the essentially normal indices of NET at a single stimulus. However, there are evident abnormalities if assessed with preconditioning pulses, such as the decrease of threshold elevation in hyperpolarizing threshold electrotonus (50-100 ms), the increase of inward rectification in current-voltage curve, and the increase of refractoriness at the interpulse interval of 2-6 ms in recovery cycle, probably also implicating derangements in temperature dependence of inactivation and of recovery from inactivation in the mutant channels. The pathogenesis of heat-enhanced pain in IEM could be attributed to deranged temperature dependence of Nav1.7 channels responsible for the genesis of resurgent currents.