Alsaloum M, Labau JIR, Liu S, Effraim PR, Waxman SG
Brain : a journal of neurology •
Effective treatment of pain remains an unmet healthcare need that requires new and effective therapeutic approaches. NaV1.7 has been genetically and functionally validated as a mediator of pain. Preclinical studies of NaV1.7-selective blockers have shown limited success and translation to clinical studies has been limited. The degree of NaV1.7 channel blockade necessary to attenuate neuronal excitability and ameliorate pain is an unanswered question important for drug discovery. Here, we utilize dynamic clamp electrophysiology and induced pluripotent stem cell-derived sensory neurons (iPSC-SNs) to answer this question for inherited erythromelalgia, a pain disorder caused by gain-of-function mutations in Nav1.7. We show that dynamic clamp can produce hyperexcitability in iPSC-SNs associated with two different inherited erythromelalgia mutations, NaV1.7-S241T and NaV1.7-I848T. We further show that blockade of approximately 50% of NaV1.7 currents can reverse neuronal hyperexcitability to baseline levels.
Eijkenboom I, Sopacua M, Hoeijmakers JGJ, de Greef BTA, Lindsey P , et al.
Journal of neurology, neurosurgery, and psychiatry •
Neuropathic pain is common in peripheral neuropathy. Recent genetic studies have linked pathogenic voltage-gated sodium channel (VGSC) variants to human pain disorders. Our aims are to determine the frequency of , and variants in patients with pure small fibre neuropathy (SFN), analyse their clinical features and provide a rationale for genetic screening. Between September 2009 and January 2017, 1139 patients diagnosed with pure SFN at our reference centre were screened for , and variants. Pathogenicity of variants was classified according to established guidelines of the Association for Clinical Genetic Science and frequencies were determined. Patients with SFN were grouped according to the VGSC variants detected, and clinical features were compared. Among 1139 patients with SFN, 132 (11.6%) patients harboured 73 different (potentially) pathogenic VGSC variants, of which 50 were novel and 22 were found in ≥ 1 patient. The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for 3.7% (n=42/1139) for and 2.9% (n=33/1139) for . Only erythromelalgia-like symptoms and warmth-induced pain were significantly more common in patients harbouring VGSC variants. (Potentially) pathogenic VGSC variants are present in 11.6% of patients with pure SFN. Therefore, genetic screening of and should be considered in patients with pure SFN, independently of clinical features or underlying conditions.
Secondary erythromelalgia is a rare disease characterized by burning pain, marked erythema, edema, and hyperthermia of the affected limbs. Secondary erythromelalgia can be associated with various systemic diseases. Here, we describe a patient who developed secondary erythromelalgia involving the ears and concomitant clinical and laboratory, probably, indicating the initial stage of a developing lupus erythematosus.
