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Nav1.7-related small fiber neuropathy: impaired slow-inactivation and DRG neuron hyperexcitability.

Abstract：

OBJECTIVES:Although small fiber neuropathy (SFN) often occurs without apparent cause, the molecular etiology of idiopathic SFN (I-SFN) has remained enigmatic. Sodium channel Na(v)1.7 is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons and their small-diameter peripheral axons. We recently reported the presence of Na(v)1.7 variants that produce gain-of-function changes in channel properties in 28% of patients with painful I-SFN and demonstrated impaired slow-inactivation in one of these mutations after expression within HEK293 cells. Here we show that the I739V Na(v)1.7 variant in a patient with biopsy-confirmed I-SFN impairs slow-inactivation within DRG neurons and increases their excitability. METHODS:A patient with SFN symptoms including pain, and no identifiable underlying cause, was evaluated by skin biopsy, quantitative sensory testing, nerve conduction studies, screening of genomic DNA for variants in SCN9A, and functional analysis. RESULTS:Voltage-clamp analysis following expression within DRG neurons revealed that the Na(v)1.7/I739V substitution impairs slow-inactivation, depolarizing the midpoint (V(1/2)) by 5.6 mV, and increasing the noninactivating component at 10 mV from 16.5% to 22.2%. Expression of I739V channels within DRG neurons rendered these cells hyperexcitable, reducing current threshold and increasing the frequency of firing evoked by graded suprathreshold stimuli. CONCLUSIONS:These observations provide support, from a patient with biopsy-confirmed SFN, for the suggestion that functional variants of Na(v)1.7 that impair slow-inactivation can produce DRG neuron hyperexcitability that contributes to pain in SFN. Na(v)1.7 channelopathy-associated SFN should be considered in the differential diagnosis of cases of SFN in which no other cause is found.

journal_name

Neurology

journal_title

Neurology

authors

Han C,Hoeijmakers JG,Ahn HS,Zhao P,Shah P,Lauria G,Gerrits MM,te Morsche RH,Dib-Hajj SD,Drenth JP,Faber CG,Merkies IS,Waxman SG

doi

10.1212/WNL.0b013e3182574f12

subject

Has Abstract

pub_date

2012-05-22 00:00:00

pages

1635-43

issue

eissn

0028-3878

issn

1526-632X

pii

WNL.0b013e3182574f12

journal_volume

pub_type

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Nav1.7-related small fiber neuropathy: impaired slow-inactivation and DRG neuron hyperexcitability.