Painful peripheral neuropathy often occurs without apparent underlying cause. Gain-of-function variants of sodium channel Na v 1.7 have recently been found in ∼30% of cases of idiopathic painful small-fiber neuropathy. Here, we describe mutations in Na v 1.8, another sodium channel that is specifically expressed in dorsal root ganglion (DRG) neurons and peripheral nerve axons, in patients with painful neuropathy. Seven Na v 1.8 mutations were identified in 9 subjects within a series of 104 patients with painful predominantly small-fiber neuropathy. Three mutations met criteria for potential pathogenicity based on predictive algorithms and were assessed by voltage and current clamp. Functional profiling showed that two of these three Na v 1.8 mutations enhance the channel's response to depolarization and produce hyperexcitability in DRG neurons. These observations suggest that mutations of Na v 1.8 contribute to painful peripheral neuropathy.dorsal root ganglia | patch clamp P ainful peripheral neuropathy involving small-diameter nociceptive nerve fibers represents a significant public health challenge (1); in about one-half of cases, no cause can be identified (1). Faber et al. (2) recently described gain-of-function variants (single amino acid substitutions) in sodium channel Na v 1.7, which is abundantly expressed in spinal sensory [dorsal root ganglion (DRG)] neurons and their axons (3) in nearly 30% of patients with biopsy-confirmed, painful small-fiber neuropathy (SFN) and no other apparent cause. These variants increase the excitability of DRG neurons, providing an explanation for pain in these patients. Molecular substrates for pain in the remaining SFN patients remain unknown. Here, we describe gain-of-function mutations in Na v 1.8, another sodium channel that is specifically expressed in DRG neurons and peripheral nerve axons, in human subjects with painful neuropathy, including a father-son pair. These mutations alter gating properties of the channel in a proexcitatory manner and increase the excitability of DRG neurons. These genetic and functional observations suggest that Na v 1.8 mutations contribute to pain in some peripheral neuropathies.

Itch is a common experience. It can occur in the course of systemic diseases and can be a manifestation of allergies or a consequence of diseases affecting the somatosensory pathway. We describe a kindred characterized by paroxysmal itch caused by a variant in SCN9A gene encoding for the Nav1.7 sodium channel. Patients underwent clinical and somatosensory profile assessment by quantitative sensory testing, nerve conduction study, autonomic cardiovascular reflex, and sympathetic skin response examination, skin biopsy with quantification of intraepidermal nerve fiber density, and SCN9A mutational analysis. The index patient, her mother, and a sister presented with a stereotypical clinical picture characterized by paroxysmal itch attacks involving the shoulders, upper back, and upper limbs, followed by transient burning pain, and triggered by environmental warmth, hot drinks, and spicy food. Somatosensory profile assessment demonstrated a remarkably identical pattern of increased cold and pain thresholds and paradoxical heat sensation. Autonomic tests were negative, whereas skin biopsy revealed decreased intraepidermal nerve fiber density in 2 of the 3 patients. All affected members harbored the 2215A>G I739V substitution in exon 13 of SCN9A gene. Pregabalin treatment reduced itch intensity and attack frequency in all patients. The co-segregation of the I739V variant in the affected members of the family provides evidence, for the first time, that paroxysmal itch can be related to a mutation in sodium channel gene.