Genetic aspects of sodium channelopathy in small fiber neuropathy


  • 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 Nav1.9 (Yale holds patent); grants from Pfizer and TransMolecular Inc, C. G. F. reports no disclosures.

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.

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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 NaV1.7, 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 NaV1.7 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.