Cancer-related molecular mechanisms research (15)
RNA Research and Splicing (7)
Clostridium difficile and Clostridium perfringens research (6)
Marine Sponges and Natural Products (6)
RNA modifications and cancer (6)
In children, erythromelalgia is a rare but difficult to manage condition that results in bilateral episodic pain and redness in distal extremities. It is heat intolerant and relieved by cooling. Management of erythromelalgia is difficult and requires a complex multidisciplinary approach. We present a case of successful treatment of erythromelalgia with short-term spinal cord stimulation in a 12-year-old girl. The patient had severe burning pain, having undergone trials of multiple medical therapies before presenting to our department. Dual-lead spinal cord stimulator electrodes were successfully implanted without complication, leading to excellent pain control, now 8 months postimplant. This case spurs interest for future research in neuromodulation as part of the multimodal regimen to treat pediatric erythromelalgia.
Inherited erythromelalgia (IEM), caused by mutations in Na1.7 channel is characterized by episodic neuropathic pain triggered especially by warm temperature. However, the mechanism underlying the temperature-dependent episodic attacks of IEM remains elusive. We investigated the electrophysiological effect of temperature changes on Na1.7 channels with three different mutations, p.I136V, p. I848T, and p.V1316A, both in vitro and in vivo. In vitro biophysical studies of the mutant channels show consistent temperature-dependent enhancement of the relative resurgent currents if normalized to the transient currents, as well as temperature-dependent changes in the time to peak and the kinetics of decay of the resurgent currents, but no congruent temperature-dependent changes in steady-state parameters such as shift of activation/inactivation curves and changes of the absolute size of the window or resurgent currents. In vivo nerve excitability tests (NET) in IEM patients reveal the essentially normal indices of NET at a single stimulus. However, there are evident abnormalities if assessed with preconditioning pulses, such as the decrease of threshold elevation in hyperpolarizing threshold electrotonus (50-100 ms), the increase of inward rectification in current-voltage curve, and the increase of refractoriness at the interpulse interval of 2-6 ms in recovery cycle, probably also implicating derangements in temperature dependence of inactivation and of recovery from inactivation in the mutant channels. The pathogenesis of heat-enhanced pain in IEM could be attributed to deranged temperature dependence of Na1.7 channels responsible for the genesis of resurgent currents.
The Nav1.7 channel critically contributes to the excitability of sensory neurons, and gain-of-function mutations of this channel have been shown to cause inherited erythromelalgia (IEM) with neuropathic pain. In this study, we report a case of a severe phenotype of IEM caused by p.V1316A mutation in the Nav1.7 channel. Mechanistically, we first demonstrate that the Navβ4 peptide acts as a gating modifier rather than an open channel blocker competing with the inactivating peptide to give rise to resurgent currents in the Nav1.7 channel. Moreover, there are two distinct open and two corresponding fast inactivated states in the genesis of resurgent Na+ currents. One is responsible for the resurgent route and practically existent only in the presence of Navβ4 peptide, whereas the other is responsible for the "silent" route of recovery from inactivation. In this regard, the p.V1316A mutation makes hyperpolarization shift in the activation curve, and depolarization shift in the inactivation curve, vividly uncoupling inactivation from activation. In terms of molecular gating operation, the most important changes caused by the p.V1316A mutation are both acceleration of the transition from the inactivated states to the activated states and deceleration of the reverse transition, resulting in much larger sustained as well as resurgent Na+ currents. In summary, the genesis of the resurgent currents in the Nav1.7 channel is ascribable to the transient existence of a distinct and novel open state promoted by the Navβ4 peptide. In addition, S4-5 linker in domain III where V1316 is located seems to play a critical role in activation-inactivation coupling, chiefly via direct modulation of the transitional kinetics between the open and the inactivated states. The sustained and resurgent Na+ currents may therefore be correlatively enhanced by specific mutations involving this linker and relevant regions, and thus marked hyperexcitability in corresponding neural tissues as well as IEM symptomatology.
Dozens of epidemic erythromelalgia (EM) outbreaks have been reported in China since the mid-twentieth century, and the most recent happened in Foshan City, Guangdong Province early 2014. This study compared the daily case counts of this recent epidemic EM outbreak from February 11 to March 3 with Baidu search data for the same period. After keyword selection, filtering and composition, the most correlated lag of the EM Search Index was used for comparison and linear regression model development. This study also explored the spatial distribution of epidemic EM in China during this period based on EM Search Index. The EM Search Index at lag 2 was most significantly associated with daily case counts in Foshan (ρ = 0.863, P < 0.001). It captured an upward trend in the outbreak about one week ahead of official report and the linear regression analysis indicated that every 1.071 increase in the EM Search Index reflected a rise of 1 EM cases 2 days earlier. The spatial analysis found that the number of EM Search Indexes increased in the middle of Guangdong Province and South China during the outbreak period. The EM Search Index may be a good early indicator of an epidemic EM outbreak.