Small-FiberNeuropathyNa v 1.8MutationShiftsActivationto HyperpolarizedPotentialsandIncreasesExcitabilityof DorsalRootGanglionNeurons

Idiopathicsmall-fiberneuropathy(I-SFN),clinicallycharacterizedbyburningpainindistalextremitiesandautonomicdysfunction,isa disorderofsmall-calibernervefibersofunknownetiologywithlimitedtreatmentoptions.Functionalvariantsofvoltage-gatedsodium channelNa v1.7,encodedbySCN9A,havebeenidentifiedinapproximatelyone-thirdofI-SFNpatients.Thesevariantsrenderdorsalroot ganglion(DRG)neuronshyperexcitable.SodiumchannelNav1.8,encodedbySCN10A,ispreferentiallyexpressedinsmall-diameterDRG neurons, and produces most of the current underlying the upstroke of action potentials in these neurons. We previously demonstrated two functional variants of Nav1.8 that either enhance ramp current or shift activation in a hyperpolarizing direction, and render DRG neurons hyperexcitable, in I-SFN patients with no mutations of SCN9A. We have now evaluated additional I-SFN patients with no mutationsinSCN9A,andreportanovelI-SFN-relatedNav1.8mutationI1706VinapatientwithpainfulI-SFN.Whole-cellvoltage-clamp recordings in small DRG neurons demonstrate that the mutation hyperpolarizes activation and the response to slow ramp depolarizations. However, it decreases fractional channels resistant to fast inactivation and reduces persistent currents. Current-clamp studies reveal that mutant channels decrease current threshold and increase the firing frequency of evoked action potentials within small DRG neurons. These observations suggest that the effects of this mutation on activation and ramp current are dominant over the reduced persistentcurrent,andshowthatthesepro-excitatorygatingchangesconferhyperexcitabilityonperipheralsensoryneurons,whichmay contributetopaininthisindividualwithI-SFN.