P.L1612P, a Novel Voltage-gated Sodium Channel Nav1.7 Mutation Inducing a Cold Sensitive Paroxysmal Extreme Pain Disorder. (February 2015)

• Record Type: Journal Article
• Authors: Suter, Marc R.; Bhuiyan, Zahurul A.; Laedermann, Cédric J.; Kuntzer, Thierry; Schaller, Muriel; Stauffacher, Maurice W.; Roulet, Eliane; Abriel, Hugues; Decosterd, Isabelle; Wider, Christian
• Is Part Of: Anesthesiology. Volume 122:Number 2(2015)
• Publication Date: 2015-02
• Subjects: Anesthesiology -- Periodicals; Anesthetics -- Periodicals; Anesthesia -- Periodicals; 617.9605
• DOI: 10.1097/ALN.0000000000000476
• Languages: English
• ISSNs: 0003-3022

Abstract

<abstract> <title> <x xml:space="preserve">Abstract</x> </title> <sec> <title>Background:</title> <p>Mutations in the <italic>SCN9A</italic> gene cause chronic pain and pain insensitivity syndromes. We aimed to study clinical, genetic, and electrophysiological features of paroxysmal extreme pain disorder (PEPD) caused by a novel <italic>SCN9A</italic> mutation.</p> </sec> <sec> <title>Methods:</title> <p>Description of a 4-generation family suffering from PEPD with clinical, genetic and electrophysiological studies including patch clamp experiments assessing response to drug and temperature.</p> </sec> <sec> <title>Results:</title> <p>The family was clinically comparable to those reported previously with the exception of a favorable effect of cold exposure and a lack of drug efficacy including with carbamazepine, a proposed treatment for PEPD. A novel p.L1612P mutation in the Nav1.7 voltage-gated sodium channel was found in the four affected family members tested. Electrophysiologically the mutation substantially depolarized the steady–state inactivation curve (<italic>V</italic><sub>1/2</sub> from −61.8 ± 4.5 mV to −30.9 ± 2.2 mV, n = 4 and 7, <italic>P</italic> < 0.001), significantly increased ramp current (from 1.8% to 3.4%, n = 10 and 12) and shortened recovery from inactivation (from 7.2 ± 5.6 ms to 2.2 ± 1.5 ms, n = 11 and 10). However, there was no persistent current. Cold exposure reduced peak current and prolonged recovery from inactivation in wild-type and mutated channels. Amitriptyline only slightly corrected the steady–state inactivation shift of the mutated channel, which is consistent with the lack of clinical benefit.</p> </sec> <sec> <title>Conclusions:</title> <p>The novel p.L1612P Nav1.7 mutation expands the PEPD spectrum with a unique combination of clinical symptoms and electrophysiological properties. Symptoms are partially responsive to temperature but not to drug therapy. <italic>In vitro</italic> trials of sodium channel blockers or temperature dependence might help predict treatment efficacy in PEPD.</p> </sec> </abstract>