Clin Genet 2012: 82: 351 – 358 Printed in Singapore. All rights reserved  2012 John Wiley & Sons A/S CLINICAL GENETICS doi: 10.1111/j.1399-0004.2012.01937.x Review Genetic aspects of sodium channelopathy in small fiber neuropathy Hoeijmakers JGJ, Merkies ISJ, Gerrits MM, Waxman SG, Faber CG. Genetic aspects of sodium channelopathy in small fiber neuropathy. Clin Genet 2012: 82: 351–358.  John Wiley & Sons A/S, 2012 Small fiber neuropathy (SFN) is a disorder typically dominated by neuropathic pain and autonomic dysfunction, in which the thinly myelinated Aδ-fibers and unmyelinated C-fibers are selectively injured. The diagnosis SFN is based on a reduced intraepidermal nerve fiber density and/or abnormal thermal thresholds in quantitative sensory testing. The etiologies of SFN are diverse, although no apparent cause is frequently seen. Recently, SCN9A-gene variants (single amino acid substitutions) have been found in ∼30% of a cohort of idiopathic SFN patients, producing gain-of-function changes in sodium channel Na V 1.7, which is preferentially expressed in small diameter peripheral axons. Functional testing showed that these variants altered fast inactivation, slow inactivation or resurgent current and rendered dorsal root ganglion neurons hyperexcitable. In this review, we discuss the role of Na V 1.7 in pain and highlight the molecular genetics and pathophysiology of SCN9A-gene variants in SFN. With increasing knowledge regarding the underlying pathophysiology in SFN, the development of specific treatment in these patients seems a logical target for future studies. Conflict of interest J. G. J. H. reports no disclosures. I. S. J. M. served on a scientific advisory board for CSL Behring; has received funding for travel from Talecris Biotherapeutics; and has received research support from the GBS/CIDP International Foundation, the Talents Program foundation, and the Peripheral Nerve Society. M. M. G. reports no disclosures. S. G. W. has consulted for Cardiome Pharm, Bristol Myers Squibb, Vertex Pharmaceuticals, ChromaCell and DaiNippon Sumitomo Pharm; inventor of a patent on sodium channel Na v 1.9 (Yale holds patent); grants from Pfizer and TransMolecular Inc, C. G. F. reports no disclosures. JGJ Hoeijmakers a , ISJ Merkies a,b , MM Gerrits c , SG Waxman d,e and CG Faber a a Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands, b Department of Neurology, Spaarne Hospital, Hoofddorp, The Netherlands, c Department of Clinical Genomics, Maastricht University Medical Center, Maastricht, The Netherlands, d Department of Neurology, Yale University School of Medicine, New Haven, CT, USA, and e Center for Neuroscience and Regeneration Research, Veterans Affairs Medical Center, West Haven, CT, USA Key words: Nav1.7 – SCN9A – small fiber neuropathy – sodium channelopathy Corresponding author: Catharina G. Faber, MD, PhD, Department of Neurology/School of Mental Health and Neuroscience, Maastricht University Medical Center, 6202 AZ, Maastricht, The Netherlands. Tel.: +31 43 3875117; fax: +31 43 3877055; e-mail: c.faber@mumc.nl [PO BOX 5800] Received 20 June 2012, revised and accepted for publication 11 July 2012 Small fiber neuropathy (SFN) is a disorder of the thinly myelinated Aδ-fibers and unmyelinated C-fibers and is typically dominated by neuropathic pain and autonomic dysfunction (1–6). Clinical signs of small-fiber damage include loss of pinprick sensation, thermal sensory loss, allodynia or hyperalgesia. In pure SFN, large diameter fibers are spared, reflected by preservation of muscle strength, tendon reflexes, light touch, proprioceptive and vibratory sense in combination with normal nerve conduction studies (4–7). In addition to the clinical picture, the diagnosis of SFN can be confirmed by demonstration of a reduced intraepidermal nerve fiber density in skin biopsy and/or abnormal thermal thresh- olds in quantitative sensory testing (7, 8). After the diagnosis is made, an underlying cause for SFN has to be searched for, as some of these are potentially treatable. Potential causes for SFN are, among others, diabetes mellitus, impaired glucose tolerance, drugs and 351