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.
Kalgaard OM, Clausen OP, Mellbye OJ, Hovig T, Kvernebo K
Archives of dermatology •
To report on the histopathologic findings of affected skin in consecutively collected biopsy specimens from 49 patients with erythromelalgia (EM). Skin biopsy specimens were obtained from the foot arch and analyzed by light microscopy, immunofluorescence microscopy, and electron microscopy. Oslo University Hospital-Gaustad, University of Oslo, Oslo, Norway. Thirty-one patients had primary EM, 17 patients had secondary EM, and 1 patient had erythromelalgic syndrome. Evidence of microvascular abnormalities in skin biopsy specimens. Light microscopy showed evidence of capillary proliferation in 10 of 31 patients with primary EM and in 1 of 17 patients with secondary EM. The biopsy specimen from the patient with erythromelalgic syndrome showed numerous capillary nests with endothelial cell defects and a slight perivascular inflammatory reaction. Among the 17 secondary EM cases, sparse perivascular lymphocyte infiltrations were observed in the biopsy specimens from 2 patients with chronic myelogenous leukemia and 1 patient with diabetes mellitus. Eleven patients also had signs of vasculopathy based on findings of immunodeposits of C3 and fibrin. Six of 30 patients with primary EM showed endothelial abnormalities on electron microscopy. All 3 investigations showed unremarkable biopsy results in 16 cases. Histopathologic analysis is not useful as a routine diagnostic tool in EM because no morphological changes are specific to EM. The capillary proliferation and vasculopathy are assumed to be a consequence of intermittent skin hypoxia (vascular hypothesis of pathogenesis). Whether the proliferation is a consequence of EM or a pathogenic factor in the development of the disease is uncertain.