p.L1612P, a novel voltage-gated sodium channel Nav1.7 mutation inducing a cold sensitive paroxysmal extreme pain disorder

Article Article scientifique Article p.L1612P, a novel voltage-gated sodium channel Nav1.7 mutation inducing a cold sensitive paroxysmal extreme pain disorder eng 2015-02 author Suter Marc R From the Pain Center, Department of Anesthesiology, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland (M.R.S., C.J.L., I.D.); Service of Medical Genetics, Department of Laboratories, Lausanne University Hospital (CHUV), Lausanne, Switzerland (Z.A.B.); Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland (T.K., M.S., M.W.S., C.W.); Department of Clinical Neurosciences, Lausanne University Hospital (CHUV), Lausanne, Switzerland (T.K., C.W.); Department of Pediatrics, Lausanne University Hospital (CHUV), Lausanne, Switzerland (E.R.); Department of Clinical Research, University of Bern, Bern, Switzerland (H.A.); and Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland (I.D.). author Bhuiyan Zahurul A author Laedermann Cédric J author Kuntzer Thierry author Schaller Muriel author Stauffacher Maurice Werner Dominique 0009-0009-8658-8370 412183 Institut de médecine légale (COLEG) author Roulet Eliane author Abriel Hugues author Decosterd Isabelle author Wider Christian 414-423 10.1097/ALN.0000000000000476 25285947 0003-3022 https://journals.lww.com/anesthesiology/fulltext/2015/02000/p_l1612p,_a_novel_voltage_gated_sodium_channel.30.aspx Background: Mutations in the SCN9A 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 SCN9A mutation. Methods: 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. Results: 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 (V1/2 from -61.8 ± 4.5 mV to -30.9 ± 2.2 mV, n = 4 and 7, P < 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. Conclusions: 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. In vitro trials of sodium channel blockers or temperature dependence might help predict treatment efficacy in PEPD. Adolescent Adult Amitriptyline / pharmacology Antidepressive Agents, Tricyclic / pharmacology Cell Line Child Cold Temperature DNA / genetics Female Humans Male Middle Aged Mutation / genetics NAV1.7 Voltage-Gated Sodium Channel / genetics NAV1.7 Voltage-Gated Sodium Channel / metabolism Patch-Clamp Techniques Pedigree Plasmids Somatoform Disorders / genetics Swiss National Science Foundation Novel approaches to the treatment of chronic pain: translating recent discoveries in painrelated neural plasticity to clinical practice- Na+-channel modulators and subtype-selective GABAA receptor ligands 124117 CH Swiss National Science Foundation Novel approaches to the treatment of chronic pain: translating recent discover-ies in pain-related neural plasticity to clinical practice 140339 CH Swiss National Science Foundation Molecular Determinants of Nav1.5 Multiprotein Complexes in Cardiac Cells 147060 CH true Anesthesiology 122 2 6a773256-85cd-4ae4-80a2-c3afbb027e7b Article (Published version) Public pl1612p_a_novel_voltage_gated_sodiu.pdf 709758 application/pdf OA OTHER 251f9625b8f9889950fac759cb71a12c0089b08989addfb328801d22e5ed33f8 openAccess

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