Background and Clinical Significance: Paroxysmal extreme pain disorder (PEPD) is an extremely rare autosomal dominant sodium channelopathy caused by SCN9A gain-of-function variants. It is characterized by infantile-onset excruciating paroxysmal pain, typically in rectal, ocular, or mandibular regions, triggered by innocuous stimuli and accompanied by autonomic flares. Carbamazepine is dramatically effective in most reported cases. To date, only two genetically confirmed cases have been documented in Chinese patients, and fewer than 20 disease-causing variants are reported worldwide. We report the third Chinese case harboring a novel likely pathogenic SCN9A variant (p.Leu1623Gln), notable for its unusually severe, progressive, and carbamazepine-refractory phenotype, as well as life-threatening psychiatric sequelae, highlighting phenotypic heterogeneity and the devastating impact when standard therapy fails. Case Presentation: A Chinese male proband with positive family history presented with lifelong trigger-induced catastrophic burning and tearing pain in the perineum and lower limbs, associated with erythema, swelling, and occasional non-epileptic seizures. Attacks worsened with age despite escalating polypharmacy, including high-dose opioids, benzodiazepines, topical lidocaine and carbamazepine. Both the proband and his father developed profound psychosocial sequelae including severe depression and suicidal attempts. Next-generation sequencing in the proband revealed a novel heterozygous likely pathogenic variant NM_001365536.1 (SCN9A): c.4868T>A p.(Leu1623Gln). Conclusions: This third reported ethnic Chinese PEPD case expands the genotypic and phenotypic spectrum of SCN9A-related channelopathies, demonstrating that some variants can produce carbamazepine-refractory, progressive, and profoundly disabling disease with high suicidality risk. Early genetic diagnosis is critical in family planning and cascade testing, and has the potential in guiding targeted therapy that is under active research.

Inherited erythromelalgia, small fibre neuropathy and paroxysmal extreme pain disorder are caused by gain-of-function mutations in the voltage-gated sodium channel Nav1.7. It remains unknown how different mutations in the same channel enhancing electrogenesis in sensory neurons results in such distinct disease presentations. Most of the work analysing the impact of these mutations on electrophysiological properties has used overexpression systems in cell lines and rodent sensory neurons, which might differ from the natural context. We have differentiated sensory neurons from induced pluripotent stem cells derived from patient samples that have the Nav1.7 A1632G mutation. This strategy reveals changes in electrophysiological properties, not previously observed in cell lines, that might be important for disease presentation. Furthermore, using CRISPR/Cas9, we corrected this mutation, which reduced the underlying hyperexcitability, providing a path for personalized medicine to treat these disorders, and we introduced the mutation into control induced pluripotent stem cells, which generated hyperexcitability, providing causality. Induced pluripotent stem cell sensory neurons are a robust, scalable and relevant model to study the effects of gain-of-function mutations in ion channels in pain-related disorders.

Chronic pain affects nearly 30% of the global population. Because of significant adverse effects of opioids, alternative therapies are urgently needed. In a drug discovery project, we identified grifolic acid (GA) as a potent NaV1.7 antagonist. Here, we have evaluated its biophysical properties and efficacy in animal pain models. A mechanistic investigation of GA was carried out on dorsal root ganglion (DRG) neurons, and various stable cell lines, using whole-cell patch clamp techniques. Site-directed mutagenesis and molecular docking analyses also were performed to identify the binding pocket of GA on NaV1.7. The antinociceptive efficacy of GA was evaluated in inflammatory pain models. GA exhibited state-dependent blockade of NaV1.7 channels and modulated channel gating kinetics. It suppressed native NaV currents and action potential (AP) firing in DRG neurons. GA inhibited the increase in action potential firing frequency in DRG neurons induced by inflammatory mediators. Mutational and molecular docking studies revealed that GA and bupivacaine targeted anaesthetics binding sites, with their use-dependent properties almost abolished in the F1737A mutant. In formalin and CFA-induced inflammatory pain models in male mice, GA demonstrated analgesic effects comparable to, or exceeding, those of the indomethacin, lidocaine and carbamazepine. GA showed minimal effects on skeletal muscle function but exhibited an inhibitory effect on the CaV2.2 channel. GA is a state-dependent sodium channel and CaV2.2 channel antagonist with potent analgesic effects. These findings support its potential as an antinociceptive agent in the treatment of chronic pain conditions.

Pain is an unpleasant sensory and emotional experience, influenced by various factors. Paroxysmal extreme pain disorder (PEPD) is a rare genetic condition characterized by sudden bouts of pain accompanied by autonomic symptoms. This manuscript presents the case of a 9-year-old boy with paroxysmal extreme pain syndrome and provides a review of the literature. Additionally, a genealogical analysis of the boy's family was conducted to determine the total number of affected family members. The clinical data included an analysis of genetic tests to identify the mutation confirming PEPD. A mutation in the SCN9A gene causes the disease, and due to the small number of patients worldwide (around 500, according to literature reports), an effective method of preventing extreme pain attacks had not been established at the time of writing this manuscript. Based on information from scientific sources and the authors' experiences, it can be firmly stated that various, often difficult-to-identify factors cause paroxysmal extreme pain. This syndrome necessitates further research and the exploration of effective treatment methods.

There has been significant progress in our understanding of the molecular basis by which nociceptors transduce and transmit noxious (tissue damaging) stimuli. This is dependent on ion channels, many of which are selectively expressed in nociceptors. Mutations in such proteins have recently been linked to inherited pain disorders in humans. An exemplar is the voltage-gated sodium channel (VGSC) NaV1.7. Loss of function mutations in NaV1.7 result in congenital inability to experience pain while gain-of-function mutations can cause a number of distinct neuropathic pain disorders, including erythromelalgia, paroxysmal extreme pain disorder, and small-fiber neuropathy. Furthermore, variants in the VGSCs 1.8 and 1.9 have also been linked to human pain disorders. There is a correlation between the impact of mutations on the biophysical properties of the ion channel and the severity of the clinical phenotype. Pain channelopathies are not restricted to VGSCs: a mutation in the ligand-gated ion channel TRPA1, (which responds to environmental irritants) causes a familial episodic pain disorder. Ion channel variants have also been linked to more common neuropathic pain disorders such as painful diabetic neuropathy. Not only do these ion channels present targets for novel analgesics, but stratification based on genotype may improve treatment selection of existing analgesics.