Gain of function Na _V 1.7 mutations in idiopathic small fiber neuropathy

Abstract Objective: Small nerve fiber neuropathy (SFN) often occurs without apparent cause, but no systematic genetic studies have been performed in patients with idiopathic SFN (I‐SFN). We sought to identify a genetic basis for I‐SFN by screening patients with biopsy‐confirmed idiopathic SFN for mutations in the SCN9A gene, encoding voltage‐gated sodium channel Na V 1.7, which is preferentially expressed in small diameter peripheral axons. Methods: Patients referred with possible I‐SFN, who met the criteria of ≥2 SFN‐related symptoms, normal strength, tendon reflexes, vibration sense, and nerve conduction studies, and reduced intraepidermal nerve fiber density (IENFD) plus abnormal quantitative sensory testing (QST) and no underlying etiology for SFN, were assessed clinically and by screening of SCN9A for mutations and functional analyses. Results: Twenty‐eight patients who met stringent criteria for I‐SFN including abnormal IENFD and QST underwent SCN9A gene analyses. Of these 28 patients with biopsy‐confirmed I‐SFN, 8 were found to carry novel mutations in SCN9A . Functional analysis revealed multiple gain of function changes in the mutant channels; each of the mutations rendered dorsal root ganglion neurons hyperexcitable. Interpretation: We show for the first time that gain of function mutations in sodium channel Na V 1.7, which render dorsal root ganglion neurons hyperexcitable, are present in a substantial proportion (28.6%; 8 of 28) of patients meeting strict criteria for I‐SFN. These results point to a broader role of Na V 1.7 mutations in neurological disease than previously considered from studies on rare genetic syndromes, and suggest an etiological basis for I‐SFN, whereby expression of gain of function mutant sodium channels in small diameter peripheral axons may cause these fibers to degenerate. ANN NEUROL 2012;71:26–39