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Voltage-gated sodium channel mutations and painful neuropathy: Nav1.9 joins the family

David L. H. Bennett
DOI: http://dx.doi.org/10.1093/brain/awu105 1574-1576 First published online: 27 April 2014

In its simplest terms neuropathic pain arises as a consequence of hyperexcitability within the somatosensory nervous system. It is not surprising therefore that voltage-gated sodium channels (VGSCs), with their key role in regulating neuronal excitability, have come to the fore as pathophysiological factors in human neuropathic pain states. Not only can mutations in these ion channels lead to altered impulse generation/conduction in sensory neurons but they may also lead to degeneration of axon terminals. The VGSC family of proteins has nine members, of which Nav1.7, Nav1.8 and Nav1.9 (encoded by the genes SCN9A, SCN 10A and SCN 11A, respectively) are preferentially expressed in peripheral neurons (Eijkelkamp et al., 2012). While gain of function variants of Nav1.7 and Nav1.8 have previously been reported in patients with painful peripheral neuropathy, in this issue of Brain, Huang et al. (2014) present the first evidence for a causative role of missense mutations in Nav1.9 in painful neuropathy.

The biophysical properties and distribution of Nav1.7, Nav1.8 and Nav1.9 regulate key aspects of nociceptor function. Nav1.7 is likely to be an important determinant of threshold for excitation in nociceptor terminals and may also regulate neurotransmitter release at the central terminals of nociceptors. Homozygous, loss of function mutations in Nav1.7 result in congenital inability to experience pain and anosmia in man, whereas heterozygous gain of function mutations have been linked to the distinct clinical pain syndromes of inherited erythromelalgia (IEM: pain and erythema exacerbated by warming), paroxysmal extreme pain disorder (PEPD: proximal pain and autonomic features in ocular/mandibular and sacral regions), and small fibre neuropathy [SFN: degeneration of small diameter sensory and autonomic axons usually presenting with severe burning pain in …

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