Intra- and interfamily phenotypic diversity in pain syndromes associated with a gain-of-function variant of NaV1.7Report as inadecuate

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Molecular Pain

, 7:92

First Online: 02 December 2011Received: 20 September 2011Accepted: 02 December 2011


BackgroundSodium channel NaV1.7 is preferentially expressed within dorsal root ganglia DRG, trigeminal ganglia and sympathetic ganglion neurons and their fine-diamter axons, where it acts as a threshold channel, amplifying stimuli such as generator potentials in nociceptors. Gain-of-function mutations and variants single amino acid substitutions of NaV1.7 have been linked to three pain syndromes: Inherited Erythromelalgia IEM, Paroxysmal Extreme Pain Disorder PEPD, and Small Fiber Neuropathy SFN. IEM is characterized clinically by burning pain and redness that is usually focused on the distal extremities, precipitated by mild warmth and relieved by cooling, and is caused by mutations that hyperpolarize activation, slow deactivation, and enhance the channel ramp response. PEPD is characterized by perirectal, periocular or perimandibular pain, often triggered by defecation or lower body stimulation, and is caused by mutations that severely impair fast-inactivation. SFN presents a clinical picture dominated by neuropathic pain and autonomic symptoms; gain-of-function variants have been reported to be present in approximately 30% of patients with biopsy-confirmed idiopathic SFN, and functional testing has shown altered fast-inactivation, slow-inactivation or resurgent current. In this paper we describe three patients who house the NaV1.7-I228M variant.

MethodsWe have used clinical assessment of patients, quantitative sensory testing and skin biopsy to study these patients, including two siblings in one family, in whom genomic screening demonstrated the I228M NaV1.7 variant. Electrophysiology voltage-clamp and current-clamp was used to test functional effects of the variant channel.

ResultsWe report three different clinical presentations of the I228M NaV1.7 variant: presentation with severe facial pain, presentation with distal feet, hands pain, and presentation with scalp discomfort in three patients housing this NaV1.7 variant, two of which are from a single family. We also demonstrate that the NaV1.7-I228M variant impairs slow-inactivation, and produces hyperexcitability in both trigeminal ganglion and DRG neurons.

ConclusionOur results demonstrate intra- and interfamily phenotypic diversity in pain syndromes produced by a gain-of-function variant of NaV1.7.

Electronic supplementary materialThe online version of this article doi:10.1186-1744-8069-7-92 contains supplementary material, which is available to authorized users.

Mark Estacion, Chongyang Han, Jin-Sung Choi contributed equally to this work.

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Author: Mark Estacion - Chongyang Han - Jin-Sung Choi - Janneke GJ Hoeijmakers - Giuseppe Lauria - Joost PH Drenth - Monique M G


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