Nav1.7-related small fiber neuropathy Impaired slow-inactivation and DRG neuron hyperexcitability
Nav1.7-related small fiber neuropathy Impaired slow-inactivation and DRG neuron hyperexcitability
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DOI：
10.1212/wnl.0b013e3182574f12
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发表时间：
2012-05-01
期刊：
影响因子：
9.9
通讯作者：
Waxman, S. G.
中科院分区：
文献类型：
--
作者：
Han, C.;Hoeijmakers, J. G. J.;Waxman, S. G.
目的：虽然小纤维神经病(SFN)的发病原因不明，但特发性SFN(I-SFN)的分子病因至今仍是个谜。钠通道Na(V)1.7优先表达于背根神经节(DRG)和交感神经节神经元及其小直径外周轴突。我们最近报道，在28%的痛性I-SFN患者中，存在Na(V)1.7变异，这些变异导致通道属性的功能增益变化，并在HEK293细胞中表达后，在其中一个突变中表现出缓慢失活。方法：通过皮肤活检、定量感觉测试、神经传导检查、基因组DNA筛查SCN9A变异和功能分析，对一名有包括疼痛在内的SFN症状的患者进行评估。结果：电压钳分析显示，Na(V)1.7/I739V替代抑制了DRG神经元的缓慢失活，使中点(V-1/2)去极化5.6 mV，10 mV时未灭活组分由16.5%提高到22.2%。DRG神经元内I739V通道的表达使这些细胞过度兴奋，降低了电流阈值，增加了刺激阈值以上的放电频率。结论：这些观察结果支持了一名经活检证实的SFN患者的观点，即Na(V)1.7的功能变体可以削弱缓慢失活的Na(V)1.7，从而产生DRG神经元的过度兴奋性，从而导致SFN的疼痛。NA(V)1.7在未发现其他病因的SFN的鉴别诊断中，应考虑与通道病相关的SFN。神经病学(R)2012；78：1635-1643
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. Neurology (R) 2012;78:1635-1643