Taken together, a strongly slowed inactivation and thus enhanced persistent current can be induced by either a mutation (like for Nav1.7/I1461T) or cooling temperature (like for Nav1.3) or both, making it a potentially general mechanistic basis for cold aggravated symptoms and a possible explanation for the cold-induced hyperexcitability as potentially observed in patients suffering from PEPD. Here, SCN9A is linked to paroxysmal extreme pain disorder.