Gain-of-function mutations in , which encodes the Nav1.7 voltage-gated sodium channel, are known to cause primary erythromelalgia (PEM). This condition is characterized by recurrent episodes of erythema, burning pain, and warmth in the extremities. These genetic insights have spurred the development of Nav1.7 blockers as a promising therapeutic strategy for PEM. However, translating these findings into effective clinical treatments has remained challenging. In this study, we demonstrate that mepyramine, a compound previously shown to alleviate pain in animal models, effectively targets hNav1.7 channels carrying PEM-associated gain-of-function mutations, providing substantial pain relief in PEM patients. Using voltage-clamp recordings in human embryonic kidney (HEK) 293 cells, we demonstrated that mepyramine inhibits hNav1.7 channels carrying three distinct PEM mutations, I848T, L858F, and L1267V, which differentially affect the gating properties of hNav1.7. Importantly, mepyramine's efficacy was consistent regardless of how these mutations altered channel activation or inactivation properties. To evaluate its clinical potential, we administered a high-dose topical formulation of mepyramine to a group of PEM patients suffering from severe pain that was unresponsive to conventional analgesics, including cases with identified mutations. This treatment rapidly and durably reduced burning pain and erythema, providing meaningful relief for patients who had not responded to, or could not tolerate, previous therapies. These results suggest that mepyramine can inhibit PEM-associated Nav1.7 channel mutants and may offer a new therapeutic approach for PEM patients.
To assess the contribution of large and small nerve fiber alteration in erythromelalgia (EM). Thirty-three EM patients were included and underwent clinical evaluation based on EM severity score, DN4, and Utah Early Neuropathy Scale (UENS) score. Neurophysiological evaluation consisted in nerve conduction studies (NCS) for large nerve fibers and specific tests for small nerve fibers: electrochemical skin conductance, cold and warm detection thresholds, and laser evoked potentials. Finally, the evaluation of vascular changes was based on the presence of clinical feature of microvascular disorders and the measurement of the Toe Pressure Index (TPI). While 28 patients (85%) had vascular alteration on TPI or clinical features, 23 patients (70%) had small-fiber neuropathy on neurophysiological tests, and only 10 patients (30%) had large fiber neuropathy on NCS. Regarding clinical scores, there was no difference between groups (presence or absence of large- or small-fiber neuropathy or microvascular disorder) except for a higher UENS score in patients with large fiber neuropathy. Peripheral neuropathy, mostly involving small nerve fibers, is almost as common as microvascular changes in EM, but remains inconstant and not related to a specific neuropathic pattern or higher clinical severity. The association of neuropathic and vascular factors is not systematic in EM, this syndrome being characterized by different pathophysiological mechanisms leading to a common clinical phenotype.
Olmsted syndrome (OS) is a rare keratinizing disorder characterized by excessive epidermal thickening of the palms and soles, with clinical and genetic heterogeneity. Approximately 50 cases have been reported, with the molecular basis described in only 9. Recently, TRPV3 (transient receptor potential vanilloid 3) mutations were identified in autosomal-dominant OS in 7 sporadic cases and 1 familial case, whereas an MBTPS2 (membrane-bound transcription factor protease, site 2) mutation was reported in X-linked recessive OS. We report a new sporadic case of severe, atypical OS and its underlying genetic basis. Our patient is a young girl with severe nonmutilating (palmo)plantar keratoderma without periorificial keratotic plaques associated with intense acute flares of inflammation, itching, burning pain, vasodilatation, and redness of the extremities consistent with erythromelalgia. Whole exome sequencing of patient DNA identified a novel de novo heterozygous missense mutation within TRPV3, p.Leu673Phe, predicted to be damaging. This case study further implicates TRPV3 in OS pathogenesis. In addition, previous reports of OS have not described erythromelalgia as a clinical feature. Its occurrence in our patient could be a chance event, but, if associated with OS, the features of erythromelalgia may expand the phenotypic spectrum of this rare syndrome.
Chronic pain is usually underestimated in children, due to lack of knowledge and its specific signs. In addition to suffering, chronic pain causes a physical, psychological, emotional, social, and financial burden for the child and his family. Practitioners may find themselves in a situation of failure with depletion of medical resources. Some types of chronic pain are refractory to conventional systemic treatment and may require the use of regional anesthesia. Cancer pain is common in children and its medical management is sometimes insufficient. It is accessible to neuroaxial or peripheral techniques of regional anesthesia if it is limited to an area accessible to one of these techniques and no contraindications (e.g., thrombopenia) are present. Complex regional pain syndrome 1 is not rare in children and adolescents, but it often goes undiagnosed. Regional anesthesia may contribute to the treatment of complex regional pain syndrome 1, mainly in case of recurrence, because it provides rapid effective analgesia and allows rapid implementation of intensive physiotherapy. These techniques have also shown interest in phantom limb pain after limb amputation, but they remain controversial for erythromelalgia pain or chronic abdominopelvic pain. Finally, the treatment of postdural puncture headache due to cerebrospinal fluid leak can be treated by performing an epidural injection of the patient's blood, called a blood-patch. Finally, the management of children with chronic pain should be multidisciplinary (pediatrician, physiotherapist, psychologist, surgeon, anesthesiologist) to support the child and her problem in its entirety.
Congenital insensitivity to pain (CIP) is a rare syndrome with various clinical expressions, characterized by a dramatic impairment of pain perception since birth. In the 1980s, progress in nerve histopathology allowed to demonstrate that CIP was almost always a manifestation of hereditary sensory and autonomic neuropathies (HSAN) involving the small-calibre (A-delta and C) nerve fibres which normally transmit nociceptive inputs along sensory nerves. Identification of the genetic basis of several clinical subtypes has led to a better understanding of the mechanisms involved, emphasizing in particular the crucial role of nerve growth factor (NGF) in the development and survival of nociceptors. Recently, mutations of the gene coding for the sodium channel Nav1.7--a voltage-dependent sodium channel expressed preferentially on peripheral nociceptors and sympathetic ganglia--have been found to be the cause of CIP in patients showing a normal nerve biopsy. This radical impairment of nociception mirrors the hereditary pain syndromes associated with "gain of function" mutations of the same ion channel, such as familial erythromelalgia and paroxysmal extreme pain disorder. Future research with CIP patients may identify other proteins specifically involved in nociception, which might represent potential targets for chronic pain treatment. Moreover, this rare clinical syndrome offers the opportunity to address interesting neuropsychological issues, such as the role of pain experience in the construction of body image and in the empathic representation of others' pain.