27 Sodium channel neuropathy Voltage-gated sodium channels are responsible for generation and conduction of action potentials in peripheral nerves. Three types of sodium channels are selectively found on nociceptive small fibers. Mutations in Nav1.7, Nav1.8, Nav1.9, encoded by genes SCN9A, SCN10A and SCN11A, are related with SFN.65,68,69 Approximately 30% of idiopathic SFN patients show a SCN9A mutation.65 Although a correlation between decreased IENFD and sodium channel mutations exists,65,70 IENFD might be normal in patients with Nav mutations and neuropathic small fiber pain symptoms. 8,71 Nav mutations can result in either gain-of-function or loss-of-function. Gain-of-function mutations of Nav1.7 are, amongst others, linked to painful disorders like inherited erythromelalgia (IEM), paroxysmal extreme pain disorder (PEPD) and SFN. Nav1.7 loss-of-function mutations result into congenital insensitivity to pain (CIP).72 Nav1.8 and Nav1.9 mutations are predominantly linked to peripheral painful neuropathy.11,73 Nav mutations may also result in other painful diseases, but these are beyond the scope of this review. Table 3 shows the sodium channels and their corresponding type of nerve fibers in which they are present. This discriminates different kind of symptoms as consequence of specific sodium channel mutations. Indeed, not all mutations are likely to be pathogenic, a good overview is published elsewhere.11 They investigated SCN9A, SCN10A and SCN11A mutations in 1139 patients with pure SFN. In 11.6% of the participants, over seventy different mutations were found. They advise to consider genetic screening for all patients with pure SFN, independently of clinical presentation or underlying pathology. This way, the number of well-characterized variants of Nav channels will increase. Diagnosing sodium channel neuropathy is not yet part of standard care and serves for additional information. For patients with isolated SFN, knowledge about the origin of their symptoms is of great importance. Research is ongoing for the development of specific sodium channel blockers as treatment. Table 3 Type of sodium channels and corresponding type of neurons Sensory neurons Sympathetic neurons Myenteric neurons Nav1.7 Nav1.7 Nav1.7 Nav1.8 Nav1.9 Nav1.9 2 29 2
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