• Marc R Suter, Zahurul A Bhuiyan, Cédric J Laedermann, Thierry Kuntzer, Muriel Schaller, Maurice W Stauffacher, Eliane Roulet, Hugues Abriel, Isabelle Decosterd, and Christian Wider.
• 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.).
• Anesthesiology. 2015 Feb 1;122(2):414-23.

BackgroundMutations 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.MethodsDescription of a 4-generation family suffering from PEPD with clinical, genetic and electrophysiological studies including patch clamp experiments assessing response to drug and temperature.ResultsThe 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.ConclusionsThe 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.

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