SCN9A Mutations in Paroxysmal Extreme Pain Disorder: Allelic Variants Underlie Distinct Channel Defects and Phenotypes

Abstract

Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, or OMIM 167400), is an inherited condition characterized by paroxysms of rectal, ocular, or submandibular pain with flushing. A genome-wide linkage search followed by mutational analysis of the candidate gene SCN9A, which encodes hNa(v)1.7, identified eight missense mutations in 11 families and 2 sporadic cases. Functional analysis in vitro of three of these mutant Na(v)1.7 channels revealed a reduction in fast inactivation, leading to persistent sodium current. Other mutations in SCN9A associated with more negative activation thresholds are known to cause primary erythermalgia (PE). Carbamazepine, a drug that is effective in PEPD, but not PE, showed selective block of persistent current associated with PEPD mutants, but did not affect the negative activation threshold of a PE mutant. PEPD and PE are allelic variants with distinct underlying biophysical mechanisms and represent a separate class of peripheral neuronal sodium channelopathy.

Pain insensitivity in a child with a de novo interstitial deletion of the long arm of the chromosome 4: Case report

“…Fertleman CR et al 24 Primary erythermalgia Attacks of neuropathic pain and erithema in the hands and feet triggered by mild warming stimuli…”

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

“…Na v 1.7 is expressed at higher levels in DRG/TG than are other TTX-sensitive isoforms (7,8) and plays an essential role in the modulation of human pain perception. Naturally occurring mutations in SCN9A, the gene encoding Na v 1.7, lead to either congenital insensitivity or severe episodic hypersensitivity to pain (9)(10)(11). In addition, Na v 1.7 and Na v 1.8 gain-offunction mutations in painful peripheral neuropathy syndromes were recently described (12,13).…”

Ion channel therapeutics for pain

“…In addition to this, gain-of-function Nav1.7 mutations have been described in the rare, extreme pain conditions of inherited primary erythromelalgia (IEM) 5 and paroxysmal extreme pain disorder (PEPD). 4 These findings initiated a huge pharmaceutical investment that has delivered a range www.tandfonline.comof reportedly selective Nav 1.7 blockers. A number of these compounds have now entered clinical trials for pain (Fig.…”

“…More recently, evidence for the role of ion channels in pain has come from the study of monogenic pain related diseases caused by mutations that affect the function of specific ion channels. These include studies into both loss and gain of function mutations in the voltage gated sodium channel Nav1.7 mutations, which cause profound pain insensitivity 3 and sensitivity 4,5 respectively, in individuals with such mutations.…”