Skystad Kvernebo M, Grayson C, Stylianou IM, Woloshen V, Radomski C , et al.
Acta dermato-venereologica •
Gain-of-function variants in the voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, have previously been identified in patients with erythromelalgia, a clinical diagnosis defined by intermittent attacks of painful, hot, swollen, and red skin, predominantly involving the hands and feet. Symptoms are induced or aggravated by warming and relieved by cooling. In primary erythromelalgia there is no known underlying disease. This study investigated the frequency of SCN9A variants in a cohort of primary erythromelalgia patients collected at a single centre, and examined the clinical signs and symptoms associated with identified variants. One hundred patients with possible erythromelalgia were collected prospectively and evaluated by clinical examination. Thirty-five patients fulfilling the clinical criteria of primary erythromelalgia were screened for variants in SCN9A. Five were found to carry likely causal variants, including a variant found in 2 related individuals and a variant not previously described in patients with erythromelalgia. The clinical findings differed significantly between the patients. Overall, in this cohort only 4/34 (11.7%) of unrelated patients had erythromelalgia likely caused by gain-of-function variants in SCN9A. Variants in SCN9A are therefore likely to cause or contribute to primary erythromelalgia in only a small proportion of patients.
Namer B, Ørstavik K, Schmidt R, Kleggetveit IP, Weidner C , et al.
Pain •
Seven patients diagnosed with erythromelalgia (EM) were investigated by microneurography to record from unmyelinated nerve fibers in the peroneal nerve. Two patients had characterized variants of sodium channel Nav1.7 (I848T, I228M), whereas no mutations of coding regions of Navs were found in 5 patients with EM. Irrespective of Nav1.7 mutations, more than 50% of the silent nociceptors in the patients with EM showed spontaneous activity. In the patient with mutation I848T, all nociceptors, but not sympathetic efferents, displayed enhanced early subnormal conduction in the velocity recovery cycles and the expected late subnormality was reversed to supranormal conduction. The larger hyperpolarizing shift of activation might explain the difference to the I228M mutation. Sympathetic fibers that lack Nav1.8 did not show supranormal conduction in the patient carrying the I848T mutation, confirming in human subjects that the presence of Nav1.8 crucially modulates conduction in cells expressing EM mutant channels. The characteristic pattern of changes in conduction velocity observed in the patient with the I848T gain-of function mutation in Nav1.7 could be explained by axonal depolarization and concomitant inactivation of Nav1.7. If this were true, activity-dependent hyperpolarization would reverse inactivation of Nav1.7 and account for the supranormal CV. This mechanism might explain normal pain thresholds under resting conditions.