Primary erythromelalgia: a review

Abstract

Primary erythromelalgia (PE ORPHA90026) is a rare autosomal dominant neuropathy characterized by the combination of recurrent burning pain, warmth and redness of the extremities. The incidence rate of PE ranges from 0.36 to 1.1 per 100,000 persons. Gender ratio differs according to different studies and no evidence showed a gender preference. Clinical onset of PE is often in the first decade of life. Burning pain is the most predominant symptom and is usually caused and precipitated by warmth and physical activities. Reported cases of PE contain both inherited and sporadic forms. Genetic etiology of PE is mutations on SCN9A, the encoding gene of a voltage-gated sodium channel subtype Nav1.7. Diagnosis of PE is made upon clinical manifestations and screening for mutations on SCN9A. Exclusion of several other treatable diseases/secondary erythromelalgia is also necessary because of the lack of biomarkers specifically for PE. Differential diagnoses can include Fabry disease, cellulites, Raynaud phenomenon, vasculitis and so on. Diagnostic methods often involve complete blood count, imaging studies and thermograph. Treatment for PE is unsatisfactory and highly individualized. Frequently used pain relieving drugs involve sodium channel blockers such as lidocaine, carbamazepine and mexiletine. Novel drugs such as PF-05089771 and TV-45070 could be promising in ameliorating pain symptoms due to their Nav1.7 selectivity. Patients’ symptoms often worsen over time and many patients develop ulcerations and gangrenes caused by excessive exposure to low temperature in order to relieve pain. This review mainly focuses on PE and the causative gene SCN9A -- its mutations and their effects on Nav1.7 channels’ electrophysiological properties. We propose a genotype-channelopathy-phenotype correlation network underlying PE etiology which could provide guidance for future therapeutics.

Current pain management strategies for patients with erythromelalgia: a critical review

“…Genetic evidence also supports investigative efforts to develop Nav1.7 blockers as a novel therapeutic strategy. These are undergoing clinical trials 2,91. Finally, advancement in electrophysiology, molecular modeling, thermodynamic analysis, and functional analyses profiling is improving our understanding of the molecular mechanisms underlying pain in EM 51.…”

Secondary erythromelalgia: a tryptophan dietary supplement‐induced case associated with elevated 5‐hydroxyindoleacetic acid (5HIAA) urinary levels

“…Symptoms are exacerbated by exposure to heat, exercise, and gravity, and relieved by cooling and elevation . Primary EM is considered a sodium channelopathy caused by mutations of the SCN9A, the encoding gene of a voltage‐gated sodium channel Nav1.7 . Secondary EM can result from myeloproliferative and autoimmune disorders, paraneoplastic conditions, small fiber peripheral neuropathy, mercury poisoning, and medications including verapamil, bromocriptine, nicardipine, and ticlopidine …”

Reduction in pain following treatment with ranolazine in primary erythromelalgia: a case report

“…Dear Editor , Primary erythromelalgia (PE) is a rare autosomal dominant neuropathy characterized by a combination of recurrent burning pain, warmth and redness of the extremities. The genetic aetiology of PE is mutations on SCN9A , the encoding gene of a voltage‐gated sodium channel (VGSC) subtype Na v 1.7 . Patients may go to extreme measures to improve their symptoms, such as going barefoot, cooling affected areas and soaking their feet in cold water for prolonged periods resulting in immersion injury with ulceration and infection due to cutaneous maceration.…”