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Gain of function Nav1.7 mutations in idiopathic small fibre neuropathy

Faber et al. (2012)

Annals of Neurology 71: 26–39.

Small nerve fibre neuropathy (SFN) is a relatively common neuropathic pain disorder characterised by reduced intraepidermal nerve fibre density or abnormal quantitative sensory testing (QST), in the absence of large diameter fibre pathology. Disease onset is typically in adulthood. Despite careful and well-defined diagnostic clinical criteria, the etiological basis of SFN in a substantial number of patients (24–93%) remains unknown [1, 2].

Mutations in sodium channel, voltage-gated type 9 alpha subunit (SCN9A) which codes for the voltage-gated sodium channel Nav1.7 have been linked to inherited pain-related disorders. Nav1.7 sodium channels are preferentially expressed on small diameter peripheral axons, in particular dorsal root ganglion (DRG) neurons and sympathetic ganglion neurons, and their activity is a key determinant of the excitability of neurons in which they are expressed. Gain-of-function mutations in SCN9A are associated with the two hereditary pain disorders – paroxysmal extreme pain disorder and inherited erythromelalgia. Loss-of-function mutations in SCN9A, on the other hand, are linked to congenital insensitivity to pain. Given its association with pain disorders, Faber et al. [2] sought to determine whether mutations in SCN9A are present in idiopathic SFN (I-SFN) patients.

The authors assessed 248 patients, 18 years of age and older who have been diagnosed with SFN. Of these, patients were excluded in whom a cause for SFN was identified and those with conditions known to cause SFN such as diabetes mellitus, impaired glucose tolerance, hyperlipidemia, as well as several other SFN-causing conditions. The authors also excluded patients with signs of large nerve involvement. Fourty-four patients met the inclusion/exclusion criteria and underwent skin biopsy and QST for further validation of the diagnosis of I-SFN. In 28 of these who met the stringent criteria for I-SFN, screening for mutations in SCN9A was carried out using exon screening.

Genetic screening of SCN9A identified heterozygous missense mutations in 8 of the 28 I-SFN patients. None of the identified mutations were found in DNA from 100 healthy controls.

Electrophysiology-based functional analysis studies in HEK293 or dorsal root ganglion (DRG) neurons revealed all SCN9A variants identified to be gain-of-function mutations that render DRG neurons hyperexcitable. The enhanced excitability of DRG neurons is a characteristic of other inherited pain disorders caused by mutations in SCN9A, including paroxysmal extreme pain disorder and inherited erythromelalgia, suggesting that the hyperexcitability of DRG neurons caused by the mutations identified in a subset of I-SFN likely underlies SFN-related neuropathy in these patients.

In this study, Fabers et al. clearly show that in almost one third of the patients who meet the strict criteria for I-SFN, gain-of-function missense mutations associated with hyperexcitability of disease-relevant DRG neurons can be identified. The findings indicate that genetic screening of SCN9A in I-SFN patients may result in the identification of similar mutations with strong potential for disease-relevance. Furthermore, the findings suggest that Nav1.7-directed therapies aimed at countering the observed hyperexcitability may confer benefit in SFN patients carrying gain-of-function SCN9A mutations. Finally, while the study by Faber et al. successfully identified genetic lesions in about one third of I-SFN patients, it remains to be seen whether the disease etiology in the remaining two thirds of I-SFN patients could be similarly revealed.

References

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