Painful neuropathies: the emerging role of sodium channelopathies

Brigitte A. Brouwer, Ingemar S. J. Merkies, Monique M. Gerrits, Stephen G. Waxman, Janneke G. J. Hoeijmakers, Catharina G. Faber*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Pain is a frequent debilitating feature reported in peripheral neuropathies with involvement of small nerve (A and C) fibers. Voltage-gated sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where Na(V)1.7, Na(V)1.8, and Na(V)1.9 sodium channels (encoded by SCN9A, SCN10A, and SCN11A) are preferentially expressed. The human genetic pain conditions inherited erythromelalgia and paroxysmal extreme pain disorder were the first to be linked to gain-of-function SCN9A mutations. Recent studies have expanded this spectrum with gain-of-function SCN9A mutations in patients with small fiber neuropathy and in a new syndrome of pain, dysautonomia, and small hands and small feet (acromesomelia). In addition, painful neuropathies have been recently linked to SCN10A mutations. Patch-clamp studies have shown that the effect of SCN9A mutations is dependent upon the cell-type background. The functional effects of a mutation in dorsal root ganglion (DRG) neurons and sympathetic neuron cells may differ per mutation, reflecting the pattern of expression of autonomic symptoms in patients with painful neuropathies who carry the mutation in question. Peripheral neuropathies may not always be length-dependent, as demonstrated in patients with initial facial and scalp pain symptoms with SCN9A mutations showing hyperexcitability in both trigeminal ganglion and DRG neurons. There is some evidence suggesting that gain-of-function SCN9A mutations can lead to degeneration of peripheral axons. This review will focus on the emerging role of sodium channelopathies in painful peripheral neuropathies, which could serve as a basis for novel therapeutic strategies.
Original languageEnglish
Pages (from-to)53-65
JournalJournal of the Peripheral Nervous System
Issue number2
Publication statusPublished - Jun 2014


  • channelopathies
  • neuropathy
  • pain
  • sodium channels


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