Eijkenboom I, Sopacua M, Hoeijmakers JGJ, de Greef BTA, Lindsey P , et al.
Journal of neurology, neurosurgery, and psychiatry •
Neuropathic pain is common in peripheral neuropathy. Recent genetic studies have linked pathogenic voltage-gated sodium channel (VGSC) variants to human pain disorders. Our aims are to determine the frequency of , and variants in patients with pure small fibre neuropathy (SFN), analyse their clinical features and provide a rationale for genetic screening. Between September 2009 and January 2017, 1139 patients diagnosed with pure SFN at our reference centre were screened for , and variants. Pathogenicity of variants was classified according to established guidelines of the Association for Clinical Genetic Science and frequencies were determined. Patients with SFN were grouped according to the VGSC variants detected, and clinical features were compared. Among 1139 patients with SFN, 132 (11.6%) patients harboured 73 different (potentially) pathogenic VGSC variants, of which 50 were novel and 22 were found in ≥ 1 patient. The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for 3.7% (n=42/1139) for and 2.9% (n=33/1139) for . Only erythromelalgia-like symptoms and warmth-induced pain were significantly more common in patients harbouring VGSC variants. (Potentially) pathogenic VGSC variants are present in 11.6% of patients with pure SFN. Therefore, genetic screening of and should be considered in patients with pure SFN, independently of clinical features or underlying conditions.
Kapetis D, Sassone J, Yang Y, Galbardi B, Xenakis MN , et al.
BMC systems biology •
Gain-of-function mutations in SCN9A gene that encodes the voltage-gated sodium channel NaV1.7 have been associated with a wide spectrum of painful syndromes in humans including inherited erythromelalgia, paroxysmal extreme pain disorder and small fibre neuropathy. These mutations change the biophysical properties of NaV1.7 channels leading to hyperexcitability of dorsal root ganglion nociceptors and pain symptoms. There is a need for better understanding of how gain-of-function mutations alter the atomic structure of Nav1.7. We used homology modeling to build an atomic model of NaV1.7 and a network-based theoretical approach, which can predict interatomic interactions and connectivity arrangements, to investigate how pain-related NaV1.7 mutations may alter specific interatomic bonds and cause connectivity rearrangement, compared to benign variants and polymorphisms. For each amino acid substitution, we calculated the topological parameters betweenness centrality (B ), degree (D), clustering coefficient (CC ), closeness (C ), and eccentricity (E ), and calculated their variation (Δ = mutant -WT ). Pathogenic NaV1.7 mutations showed significantly higher variation of |ΔB | compared to benign variants and polymorphisms. Using the cut-off value ±0.26 calculated by receiver operating curve analysis, we found that ΔB correctly differentiated pathogenic NaV1.7 mutations from variants not causing biophysical abnormalities (nABN) and homologous SNPs (hSNPs) with 76% sensitivity and 83% specificity. Our in-silico analyses predict that pain-related pathogenic NaV1.7 mutations may affect the network topological properties of the protein and suggest |ΔB | value as a potential in-silico marker.
Estacion M, Han C, Choi JS, Hoeijmakers JG, Lauria G , et al.
Molecular pain •
Sodium 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. We 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. We 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. Our results demonstrate intra- and interfamily phenotypic diversity in pain syndromes produced by a gain-of-function variant of NaV1.7.