Ocay DD, Graziano Maloney M, D'Souza G, Brownstein CA, Clinch J , et al.
Pediatric research •
Erythromelalgia is a rare, chronic pain disorder characterized by the triad of intense burning sensation, warmth, and redness, primarily involving the hands and feet, and usually alleviated by cold and worsened by heat. The objective of this scoping review was to: 1) map the existing literature on erythromelalgia in youth, 2) identify knowledge gaps, and 3) inform directions for future research in pediatric erythromelalgia. One hundred and sixty-seven studies reporting 411 cases of childhood-onset erythromelalgia were identified. Variability was found in reporting of clinical symptoms, the clinical presentations and diagnostic criteria used for classification of erythromelagia, the clinical assessments and investigations performed, and the types of interventions and management plans utilised. While factors to aid early recognition and optimize management have been identified, there are also significant gaps for future research to address. Ongoing efforts to develop a multicenter registry of pediatric erythromelalgia cases, with standardized data collection and reporting, will be beneficial to establish consensus recommendations for the diagnosis and management of pediatric erythromelalgia. IMPACT: This scoping review maps the existing literature on pediatric erythromelalgia. Variability was found in reporting of clinical symptoms, the clinical presentations and diagnostic criteria used for classification of erythromelagia, the clinical assessments and investigations performed, and the types of interventions and management plans utilised. The development of an international registry would immensely benefit multidisciplinary experts involved in the care of pediatric erythromelalgia and those with lived experience.
Ocay DD, Halpin M, Ford E, Keighley K, Keighley N , et al.
Children (Basel, Switzerland) •
: Erythromelalgia is a rare condition characterized by burning pain, redness, and warmth primarily in the extremities, usually worsened by heat and alleviated by cold. The objective of this study was to identify the top 10 priorities in pediatric erythromelalgia from multiple perspectives, including clinicians, people with lived experience of childhood-onset erythromelalgia, and their family members. : A modified James Lind Alliance Priority-Setting Process was conducted. The top priorities were identified through four phases: (1) an international online survey to gather priorities, (2) data processing, (3) an interim prioritization online survey, and (4) a virtual workshop to set the final priorities. : In phase 1, 185 potential priorities were submitted by 74 respondents (53% patients, 24% family members, and 23% clinicians) that were developed into 68 unique research questions (phase 2). In phase 3, of the 68 questions, 50 were rated for importance by 58 participants (38% patients, 36% family members, and 26% clinicians), reducing the list to 25 questions. In phase 4, the top 10 was reached through consensus by 12 participants (33% patients, 25% family members, and 42% clinicians) across Canada, South Africa, the United States of America, and the United Kingdom. : The final priorities focused on the treatment of erythromelalgia, understanding underlying mechanisms, the association of erythromelalgia with various body systems, and generating awareness. This list is the first international patient-centered research agenda for childhood-onset erythromelalgia and a call to action from key partners to improve future research and care.
Wisedchaisri G, Gamal El-Din TM, Powell NM, Zheng N, Catterall WA
The Journal of general physiology •
Voltage-gated sodium channels in peripheral nerves conduct nociceptive signals from nerve endings to the spinal cord. Mutations in voltage-gated sodium channel NaV1.7 are responsible for a number of severe inherited pain syndromes, including inherited erythromelalgia (IEM). Here, we describe the negative shifts in the voltage dependence of activation in the bacterial sodium channel NaVAb as a result of the incorporation of four different IEM mutations in the voltage sensor, which recapitulate the gain-of-function effects observed with these mutations in human NaV1.7. Crystal structures of NaVAb with these IEM mutations revealed that a mutation in the S1 segment of the voltage sensor facilitated the outward movement of S4 gating charges by widening the pathway for gating charge translocation. In contrast, mutations in the S4 segments modified hydrophobic interactions with surrounding amino acid side chains or membrane phospholipids that would enhance the outward movement of the gating charges. These results provide key structural insights into the mechanisms by which these IEM mutations in the voltage sensors can facilitate outward movements of the gating charges in the S4 segment and cause hyperexcitability and severe pain in IEM. Our work gives new insights into IEM pathogenesis at the near-atomic level and provides a molecular model for mutation-specific therapy of this debilitating disease.
Wisedchaisri G, Gamal El-Din TM, Zheng N, Catterall WA
Proceedings of the National Academy of Sciences of the United States of America •
Gain-of-function mutations in voltage-gated sodium channel Na1.7 cause severe inherited pain syndromes, including inherited erythromelalgia (IEM). The structural basis of these disease mutations, however, remains elusive. Here, we focused on three mutations that all substitute threonine residues in the alpha-helical S4-S5 intracellular linker that connects the voltage sensor to the pore: Na1.7/I234T, Na1.7/I848T, and Na1.7/S241T in order of their positions in the amino acid sequence within the S4-S5 linkers. Introduction of these IEM mutations into the ancestral bacterial sodium channel NaAb recapitulated the pathogenic gain-of-function of these mutants by inducing a negative shift in the voltage dependence of activation and slowing the kinetics of inactivation. Remarkably, our structural analysis reveals a common mechanism of action among the three mutations, in which the mutant threonine residues create new hydrogen bonds between the S4-S5 linker and the pore-lining S5 or S6 segment in the pore module. Because the S4-S5 linkers couple voltage sensor movements to pore opening, these newly formed hydrogen bonds would stabilize the activated state substantially and thereby promote the 8 to 18 mV negative shift in the voltage dependence of activation that is characteristic of the Na1.7 IEM mutants. Our results provide key structural insights into how IEM mutations in the S4-S5 linkers may cause hyperexcitability of Na1.7 and lead to severe pain in this debilitating disease.
Erythromelalgia (EM) is a rare disorder characterized by erythematous, warm, painful extremities, which is often precipitated by cold conditions. The pathophysiology of EM is incompletely understood. Recent investigations have identified sodium channelopathy as a genetic cause for this pain condition, classified as primary inherited EM. Other subtypes are idiopathic EM and secondary EM. The management of pain in EM is challenging as no single therapy has been found to be effective. There is varying response to pharmacotherapy and significant variability within this clinical population, resulting in a stepwise trial and error approach. Consequently, EM is often associated with poorer health-related quality of life with higher morbidity. There is currently no consensus or guidelines on management of pain in EM. This is a review of the literature on management of pain using pharmacologic, procedural intervention and nonpharmacologic treatment in children and adults with EM.
Inherited erythromelalgia (IEM) is a well-described pain disorder caused by mutations of sodium channel Na1.7, a peripheral channel expressed within dorsal root ganglion and the sympathetic ganglion neurons. Clinically, IEM is characterised by paroxysmal attacks of severe pain, usually in the distal extremities, triggered by warmth or exercise. Pain is not adequately treated by existing pharmacological agents. Individuals with IEM classically cool their limbs for relief, in some cases resulting in tissue injury. We describe a patient from a family with IEM due to the L858F mutation of Na1.7 who presented with refractory hypothermia due to overcooling. This presentation of refractory hypothermia necessitating warming strategies, complicated by severe warmth-induced pain, posed a substantial therapeutic challenge. We report our experience in overcoming hypothermia lasting 3 weeks in a child with IEM, discuss possible pathophysiological mechanisms underlying this unusual complication and suggest potential therapeutic interventions.
The Journal of neuroscience : the official journal of the Society for Neuroscience •
Studies of genetic forms of epilepsy, chronic pain, and migraine caused by mutations in ion channels have given crucial insights into molecular mechanisms, pathogenesis, and therapeutic approaches to complex neurological disorders. Gain-of-function missense mutations in the brain type-I sodium channel Na(V)1.1 are a primary cause of generalized epilepsy with febrile seizures plus. Loss-of-function mutations in Na(V)1.1 channels cause severe myoclonic epilepsy of infancy, an intractable childhood epilepsy. Studies of a mouse model show that this disease is caused by selective loss of sodium current and excitability of GABAergic inhibitory interneurons, which leads to hyperexcitability, epilepsy, and ataxia. Mutations in the peripheral sodium channel Na(V)1.7 cause familial pain syndromes. Gain-of-function mutations cause erythromelalgia and paroxysmal extreme pain disorder as a result of hyperexcitability of sensory neurons, whereas loss-of-function mutations cause congenital indifference to pain because of attenuation of action potential firing. These experiments have defined correlations between genotype and phenotype in chronic pain diseases and focused attention on Na(V)1.7 as a therapeutic target. Familial hemiplegic migraine is caused by mutations in the calcium channel, Ca(V)2.1, which conducts P/Q-type calcium currents that initiate neurotransmitter release. These mutations increase activation at negative membrane potentials and increase evoked neurotransmitter release at cortical glutamatergic synapses. Studies of a mouse genetic model show that these gain-of-function effects lead to cortical spreading depression, aura, and potentially migraine. Overall, these experiments indicate that imbalance in the activity of excitatory and inhibitory neurons is an important underlying cause of these diseases.
