Na _v 1.7-related small fiber neuropathy

Abstract

These observations provide support, from a patient with biopsy-confirmed SFN, for the suggestion that functional variants of Na(v)1.7 that impair slow-inactivation can produce DRG neuron hyperexcitability that contributes to pain in SFN. Na(v)1.7 channelopathy-associated SFN should be considered in the differential diagnosis of cases of SFN in which no other cause is found.

Gain-of-function mutation of a voltage-gated sodium channel NaV1.7 associated with peripheral pain and impaired limb development

“…More than 20 dominant gain-of-function mutations in SCN9A encoding Na V 1.7 have been linked to inherited erythromelalgia (IEM) with the vast majority hyperpolarizing activation, slowing deactivation, slowing rates of closed-state inactivation, and increasing the response to slow ramp depolarizations (7)(8)(9)(10). Gain-of-function Na V 1.7 mutations have also been linked to small-fiber neuropathy (11)(12)(13)(14), which is characterized by neuropathic pain and autonomic dysfunction (15). In contrast, recessive loss-of-function mutations of Na V 1.7 underlie congenital insensitivity to pain (16 -18).…”

p.L1612P, a Novel Voltage-gated Sodium Channel Nav1.7 Mutation Inducing a Cold Sensitive Paroxysmal Extreme Pain Disorder

“…5,6 Other mutations in SCN9A cause disorders such as congenital insensitivity to pain, erythromelalgia, and smallfiber neuropathy and participate in painful not paroxysmal pain syndromes. 7,8 Inherited erythromelalgia (IEM) inducing mutations also increase excitability of sensory neurons but classically through a hyperpolarizing shift of the activation. Typical symptoms of affected patients are peripheral, bilateral severe burning pain of affected extremities associated with erythema, triggered by warmth, stress and exhaustion and often relieved by cooling of the affected sites.…”

“…28 In the I739N and I720K mutations, slow inactivation is modified without impairment of activation and fast-inactivation properties. 7,28 Clinical features in idiopathic small fiber neuropathy patients vary and are different from the prototypical characteristics of PEPD and IEM patients, indicating that the clinical expression of a mutation not only reflects its electrophysiological properties but also other factors, such as epigenetic or environmental changes. 7,28 Amitriptyline is a state-dependent sodium channel blocker which receptor overlaps with the local anesthetic receptor that is known to stabilize the inactivated state.…”

“…7,28 Clinical features in idiopathic small fiber neuropathy patients vary and are different from the prototypical characteristics of PEPD and IEM patients, indicating that the clinical expression of a mutation not only reflects its electrophysiological properties but also other factors, such as epigenetic or environmental changes. 7,28 Amitriptyline is a state-dependent sodium channel blocker which receptor overlaps with the local anesthetic receptor that is known to stabilize the inactivated state. 29 Overall, the effects of amitriptyline were similar in mutant L1612P, a New PEPD Cold Sensitive Nav1.7 Mutation and WT channels and consistent with previous findings.…”

Molecular Architecture of a Sodium Channel S6 Helix

“…The Na V 1.7 channel amplifies subthreshold membrane depolarizations, contributes to the generation of action potentials (3,4), and may facilitate neurotransmitter release at the central terminals of dorsal root ganglia neurons within the spinal cord (5). Loss-of-function Na V 1.7 channel mutations cause congenital indifference to pain (6) whereas gain-of-function missense Na V 1.7 mutations cause several painful disorders including inherited erythromelalgia (7)(8)(9), paroxysmal extreme pain disorder (10,11), and small fiber neuropathy (12)(13)(14). These gain-of-function missense mutations represent experiments of nature that may shed light on the structural basis of sodium channel function.…”