Although small fiber neuropathy (SFN) often occurs without apparent cause, the molecular etiology of idiopathic SFN (I-SFN) has remained enigmatic. Sodium channel Na_v1.7 is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons and their small-diameter peripheral axons. We recently reported the presence of Na_v1.7 variants that produce gain-of-function changes in channel properties in 28% of patients with painful I-SFN and demonstrated impaired slow-inactivation in one of these mutations after expression within HEK293 cells. Here we show that the I739V Na_v1.7 variant in a patient with biopsy-confirmed I-SFN impairs slow-inactivation within DRG neurons and increases their excitability.

A patient with SFN symptoms including pain, and no identifiable underlying cause, was evaluated by skin biopsy, quantitative sensory testing, nerve conduction studies, screening of genomic DNA for variants in SCN9A, and functional analysis.

Voltage-clamp analysis following expression within DRG neurons revealed that the Na_v1.7/I739V substitution impairs slow-inactivation, depolarizing the midpoint (V_1/2) by 5.6 mV, and increasing the noninactivating component at 10 mV from 16.5% to 22.2%. Expression of I739V channels within DRG neurons rendered these cells hyperexcitable, reducing current threshold and increasing the frequency of firing evoked by graded suprathreshold stimuli.

These observations provide support, from a patient with biopsy-confirmed SFN, for the suggestion that functional variants of Na_v1.7 that impair slow-inactivation can produce DRG neuron hyperexcitability that contributes to pain in SFN. Na_v1.7 channelopathy-associated SFN should be considered in the differential diagnosis of cases of SFN in which no other cause is found.