Sodium Channels in Human Pain Disorders: Genetics and Pharmacogenomics.

Acute pain is adaptive, but chronic pain is a global challenge. Many chronic pain syndromes are peripheral in origin and reflect hyperactivity of peripheral pain-signaling neurons. Current treatments are ineffective or only partially effective and in some cases can be addictive, underscoring the need for better therapies. Molecular genetic studies have now linked multiple human pain disorders to voltage-gated sodium channels, including disorders characterized by insensitivity or reduced sensitivity to pain and others characterized by exaggerated pain in response to normally innocuous stimuli. Here, we review recent developments that have enhanced our understanding of pathophysiological mechanisms in human pain and advances in targeting sodium channels in peripheral neurons for the treatment of pain using novel and existing sodium channel blockers.

Erythromelalgia caused by the missense mutation p.Arg220Pro in an alternatively spliced exon of SCN9A (NaV1.7).

Erythromelalgia (EM), is a familial pain syndrome characterized by episodic 'burning' pain, warmth, and erythema. EM is caused by monoallelic variants in SCN9A, which encodes the voltage-gated sodium channel (NaV) NaV1.7. Over 25 different SCN9A mutations attributed to EM have been described to date, all identified in the SCN9A transcript utilizing exon 6N. Here we report a novel SCN9A missense variant identified in seven related individuals with stereotypic episodes of bilateral lower limb pain presenting in childhood. The variant, XM_011511617.3:c.659G>C;p.(Arg220Pro), resides in the exon 6A of SCN9A, an exon previously shown to be selectively incorporated by developmentally regulated alternative splicing. The mutation is located in the voltage-sensing S4 segment of domain I, which is important for regulating channel activation. Functional analysis showed the p.Arg220Pro mutation altered voltage-dependent activation and delayed channel inactivation, consistent with a NaV1.7 gain-of-function molecular phenotype. These results demonstrate that alternatively spliced isoforms of SCN9A should be included in all genomic testing of EM.

Erythromelalgia. Part II: Differential diagnoses and management.

The management of erythromelalgia is challenging and requires multidisciplinary effort. Patient education is crucial as unsafe self-administered cooling techniques can lead to significant morbidity, including acral necrosis, infection, and amputation. The goal of management is pain control, reduction of flare frequency, and prevention of complications. This text is focused on the management of erythromelalgia and several other incompletely understood and under-recognized neurovascular disorders such as red scrotum syndrome, red ear syndrome, facial flushing, and complex regional pain syndrome.

Erythromelalgia. Part I: Pathogenesis, clinical features, evaluation, and complications.

Erythromelalgia is a rare pain disorder that is underrecognized and difficult-to-treat. It is characterized by episodes of extremity erythema and pain that can be disabling; it may be genetic, related to an underlying systemic disease, or idiopathic. Considering the prominent cutaneous features characteristic of the condition, dermatologists can play an important role in early recognition and limitation of morbidity. The first article in this 2-part continuing medical education series reviews the epidemiology, pathogenesis, clinical manifestations, evaluation, and complications.

Stem cell-derived sensory neurons modelling inherited erythromelalgia: normalization of excitability.

Effective treatment of pain remains an unmet healthcare need that requires new and effective therapeutic approaches. NaV1.7 has been genetically and functionally validated as a mediator of pain. Preclinical studies of NaV1.7-selective blockers have shown limited success and translation to clinical studies has been limited. The degree of NaV1.7 channel blockade necessary to attenuate neuronal excitability and ameliorate pain is an unanswered question important for drug discovery. Here, we utilize dynamic clamp electrophysiology and induced pluripotent stem cell-derived sensory neurons (iPSC-SNs) to answer this question for inherited erythromelalgia, a pain disorder caused by gain-of-function mutations in Nav1.7. We show that dynamic clamp can produce hyperexcitability in iPSC-SNs associated with two different inherited erythromelalgia mutations, NaV1.7-S241T and NaV1.7-I848T. We further show that blockade of approximately 50% of NaV1.7 currents can reverse neuronal hyperexcitability to baseline levels.

Ih current stabilizes excitability in rodent DRG neurons and reverses hyperexcitability in a nociceptive neuron model of inherited neuropathic pain.

We show here that hyperpolarization-activated current (Ih ) unexpectedly acts to inhibit the activity of dorsal root ganglion (DRG) neurons expressing WT Nav1.7, the largest inward current and primary driver of DRG neuronal firing, and hyperexcitable DRG neurons expressing a gain-of-function Nav1.7 mutation that causes inherited erythromelalgia (IEM), a human genetic model of neuropathic pain. In this study we created a kinetic model of Ih and used it, in combination with dynamic-clamp, to study Ih function in DRG neurons. We show, for the first time, that Ih increases rheobase and reduces the firing probability in small DRG neurons, and demonstrate that the amplitude of subthreshold oscillations is reduced by Ih . Our results show that Ih , due to slow gating, is not deactivated during action potentials (APs) and has a striking damping action, which reverses from depolarizing to hyperpolarizing, close to the threshold for AP generation. Moreover, we show that Ih reverses the hyperexcitability of DRG neurons expressing a gain-of-function Nav1.7 mutation that causes IEM. In the aggregate, our results show that Ih unexpectedly has strikingly different effects in DRG neurons as compared to previously- and well-studied cardiac cells. Within DRG neurons where Nav1.7 is present, Ih reduces depolarizing sodium current inflow due to enhancement of Nav1.7 channel fast inactivation and creates additional damping action by reversal of Ih direction from depolarizing to hyperpolarizing close to the threshold for AP generation. These actions of Ih limit the firing of DRG neurons expressing WT Nav1.7 and reverse the hyperexcitability of DRG neurons expressing a gain-of-function Nav1.7 mutation that causes IEM. KEY POINTS: Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, the molecular determinants of hyperpolarization-activated current (Ih ) have been characterized as a 'pain pacemaker', and thus considered to be a potential molecular target for pain therapeutics. Dorsal root ganglion (DRG) neurons express Nav1.7, a channel that is not present in central neurons or cardiac tissue. Gain-of-function mutations (GOF) of Nav1.7 identified in inherited erythromelalgia (IEM), a human genetic model of neuropathic pain, produce DRG neuron hyperexcitability, which in turn produces severe pain. We found that Ih increases rheobase and reduces firing probability in small DRG neurons expressing WT Nav1.7, and demonstrate that the amplitude of subthreshold oscillations is reduced by Ih . We also demonstrate that Ih reverses the hyperexcitability of DRG neurons expressing a GOF Nav1.7 mutation (L858H) that causes IEM. Our results show that, in contrast to cardiac cells and CNS neurons, Ih acts to stabilize DRG neuron excitability and prevents excessive firing.

Part II: Cutaneous manifestations of peripheral vascular disease.

In this Part 2 of a 2-part continuing medical education series, we review the epidemiology of peripheral vascular disease, its association with cutaneous symptoms, and the diagnosis and evaluation of cutaneous features of vascular disorders. As peripheral vascular disease becomes more prevalent globally, it is essential for dermatologists to become competent at accurately recognizing and diagnosing cutaneous manifestations and directing individuals to receive appropriate care and treatment.

Genetic, electrophysiological, and pathological studies on patients with SCN9A-related pain disorders.

BACKGROUND AND AIMS: Voltage-gated sodium channel Nav1.7, encoded by the SCN9A gene, has been linked to diverse painful peripheral neuropathies, represented by the inherited erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD). The aim of this study was to determine the genetic etiology of patients experiencing neuropathic pain, and shed light on the underlying pathogenesis. METHODS: We enrolled eight patients presenting with early-onset painful peripheral neuropathies, consisting of six cases exhibiting EM/EM-like disorders and two cases clinically diagnosed with PEPD. We conducted a gene-panel sequencing targeting 18 genes associated with hereditary sensory and/or autonomic neuropathy. We introduced novel SCN9A mutation (F1624S) into a GFP-2A-Nav1.7rNS plasmid, and the constructs were then transiently transfected into HEK293 cells. We characterized both wild-type and F1624S Nav1.7 channels using an automated high-throughput patch-clamp system. RESULTS: From two patients displaying EM-like/EM phenotypes, we identified two SCN9A mutations, I136V and P1308L. Among two patients diagnosed with PEPD, we found two additional mutations in SCN9A, F1624S (novel) and A1632E. Patch-clamp analysis of Nav1.7-F1624S revealed depolarizing shifts in both steady-state fast inactivation (17.4 mV, p < .001) and slow inactivation (5.5 mV, p < .001), but no effect on channel activation was observed. INTERPRETATION: Clinical features observed in our patients broaden the phenotypic spectrum of SCN9A-related pain disorders, and the electrophysiological analysis enriches the understanding of genotype-phenotype association caused by Nav1.7 gain-of-function mutations.

[Simultaneous Analysis of Paralepistopsis acromelalga Applied to Cooked and Processed Foods].

The applicability of a method for simultaneous analysis of Acromelic acids A, B, and Clitidine, which are venomous constituents of Paralepistopsis acromelalga, was assessed for three simulations: tempura, chikuzenni, and soy sauce soup. All components were detectable for all cooking methods. No interfering peak affecting the analysis was observed. The findings indicate that samples of leftover cooked products can be used to ascertain causes of food poisoning by Paralepistopsis acromelalga. Additionally, results showed that most of the toxic components were eluted into the soup broth. This property is useful for rapid screening for Paralepistopsis acromelalga in edible mushrooms.

Endoscopic lumbar sympathectomy as a treatment option for primary erythromelalgia - case report and review.

Erythromelalgia is a rare disease, involving pain, edema, redness, and hyperthermia in the limbs. It is extremely refractory to drugs, has no defined treatment, and causes psychological comorbidities in the patient. We describe a case of erythromelalgia involving a 17-year-old boy who had been suffering from the disease for almost 4 years prior to finding an effective treatment. A bilateral endoscopic lumbar sympathectomy was performed, limited to L2 and L3 resections. Four weeks after the procedure, the patient's symptoms were significantly mitigated and at 8 months follow-up he remained almost asymptomatic. Endoscopic lumbar sympathectomy was an effective treatment for primary erythromelalgia in this teenager, with exceptional reduction of his symptoms.

Eritromelalgia é uma doença rara caracterizada por dor, edema, eritema e hipertermia nos membros. É extremamente refratária a medicamentos e não tem um tratamento definido, causando comorbidades psicológicas para o paciente. Descrevemos o caso de um menino de 17 anos que possuía eritromelalgia há quase 4 anos antes de ser submetido a um tratamento efetivo. Foi realizada simpatectomia lombar endoscópica bilateral limitada à ressecção dos gânglios L2 e L3. Após 4 semanas do procedimento, o paciente teve diminuição significativa dos seus sintomas e, com 8 meses de seguimento, permanece praticamente assintomático. A simpatectomia lombar endoscópica foi um tratamento eficaz para eritromelalgia primária em um adolescente, com redução excepcional dos seus sintomas.

Phosphorylation of a chronic pain mutation in the voltage-gated sodium channel Nav1.7 increases voltage sensitivity.

Mutations in voltage-gated sodium channels (Navs) can cause alterations in pain sensation, such as chronic pain diseases like inherited erythromelalgia. The mutation causing inherited erythromelalgia, Nav1.7 p.I848T, is known to induce a hyperpolarized shift in the voltage dependence of activation in Nav1.7. So far, however, the mechanism to explain this increase in voltage sensitivity remains unknown. In the present study, we show that phosphorylation of the newly introduced Thr residue explains the functional change. We expressed wildtype human Nav1.7, the I848T mutant, or other mutations in HEK293T cells and performed whole-cell patch-clamp electrophysiology. As the insertion of a Thr residue potentially creates a novel phosphorylation site for Ser/Thr kinases and because Nav1.7 had been shown in Xenopus oocytes to be affected by protein kinases C and A, we used different nonselective and selective kinase inhibitors and activators to test the effect of phosphorylation on Nav1.7 in a human system. We identify protein kinase C, but not protein kinase A, to be responsible for the phosphorylation of T848 and thereby for the shift in voltage sensitivity. Introducing a negatively charged amino acid instead of the putative phosphorylation site mimics the effect on voltage gating to a lesser extent. 3D modeling using the published cryo-EM structure of human Nav1.7 showed that introduction of this negatively charged site seems to alter the interaction of this residue with the surrounding amino acids and thus to influence channel function. These results could provide new opportunities for the development of novel treatment options for patients with chronic pain.

Clinical and pathologic correlation of cutaneous COVID-19 vaccine reactions including V-REPP: A registry-based study.

BACKGROUND: Cutaneous reactions after COVID-19 vaccination have been commonly reported; however, histopathologic features and clinical correlations have not been well characterized. METHODS: We evaluated for a history of skin biopsy all reports of reactions associated with COVID-19 vaccination identified in an international registry. When histopathology reports were available, we categorized them by reaction patterns. RESULTS: Of 803 vaccine reactions reported, 58 (7%) cases had biopsy reports available for review. The most common histopathologic reaction pattern was spongiotic dermatitis, which clinically ranged from robust papules with overlying crust, to pityriasis rosea-like eruptions, to pink papules with fine scale. We propose the acronym "V-REPP" (vaccine-related eruption of papules and plaques) for this spectrum. Other clinical patterns included bullous pemphigoid-like (n = 12), dermal hypersensitivity (n = 4), herpes zoster (n = 4), lichen planus-like (n = 4), pernio (n = 3), urticarial (n = 2), neutrophilic dermatosis (n = 2), leukocytoclastic vasculitis (n = 2), morbilliform (n = 2), delayed large local reactions (n = 2), erythromelalgia (n = 1), and other (n = 5). LIMITATIONS: Cases in which histopathology was available represented a minority of registry entries. Analysis of registry data cannot measure incidence. CONCLUSION: Clinical and histopathologic correlation allowed for categorization of cutaneous reactions to the COVID-19 vaccine. We propose defining a subset of vaccine-related eruption of papules and plaques, as well as 12 other patterns, following COVID-19 vaccination.

Topical treatments for erythromelalgia.

Erythromelalgia is a rare neurovascular disease that causes episodes of pain, redness, and warmth in the extremities, and can be debilitating. Currently, there is no universally effective treatment for erythromelalgia. As the precise etiology of erythromelalgia remains obscure, presently available treatments are aimed at alleviating erythromelalgia's wide-ranging symptoms. In general, topical therapies for erythromelalgia are preferred for their more limited side effects and for those with contraindications to systemic therapies. This review will summarize the current topical therapies available to treat erythromelalgia and discuss emerging therapies based on our growing understanding of erythromelalgia pathophysiology.

[Isolating Venomous Constituents of Paralepistopsis acromelalgaand Simultaneous Analysis of Its Compounds].

An isolation method for Acromelic acids A, B and Clitidine, which are venomous constituents of Paralepistopsis acromelalga was developed. Highly purified products were obtained from the mushroom extract using silica gel, ODS, ion-exchange column chromatography and preparative TLC. Using those results, we optimized the LC-MS/MS conditions. Finally we developed a method for simultaneous analysis. In recovery tests, the average recovery was 80.8-112.4%, repeatability was 1.4-3.8RSD%. The limits of quantification of the respective compounds were estimated as 0.25 µg/g. Based on the results, this method can reveal causes of food poisoning by Paralepistopsis acromelalga.

Association between systemic sclerosis, palmar fasciitis with polyarthritis, Raynaud's phenomenon and erythromelalgia with underlying malignancy.

The symptoms of a rheumatic disease may also be a sign of a proliferative process. These include conditions that present with skin and vascular changes such as systemic sclerosis and Raynaud's phenomenon with peripheral ischaemia and ulceration. Furthermore, the less common conditions - erythromelalgia or palmar fasciitis with polyarthritis may also accompany cancer. In this article, we discuss the association of diffuse systemic sclerosis with anorectal tumor, palmar fasciitis and polyarthritis with ovarian cancer, erythromelalgia with underlying ovarian malignancy and Raynaud's phenomenon and digital ischemia associated with renal carcinoma. Based on the literature review on this topic we highlighted the importance of recognizing paraneoplastic syndromes at an early stage. This is a crucial point in the adequate management of a patient. Many of the paraneoplastic symptoms of rheumatic and other described conditions may regress with the management of the underlying malignancy.

Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: A registry-based study of 414 cases.

BACKGROUND: Cutaneous reactions after messenger RNA (mRNA)-based COVID-19 vaccines have been reported but are not well characterized. OBJECTIVE: To evaluate the morphology and timing of cutaneous reactions after mRNA COVID-19 vaccines. METHODS: A provider-facing registry-based study collected cases of cutaneous manifestations after COVID-19 vaccination. RESULTS: From December 2020 to February 2021, we recorded 414 cutaneous reactions to mRNA COVID-19 vaccines from Moderna (83%) and Pfizer (17%). Delayed large local reactions were most common, followed by local injection site reactions, urticarial eruptions, and morbilliform eruptions. Forty-three percent of patients with first-dose reactions experienced second-dose recurrence. Additional less common reactions included pernio/chilblains, cosmetic filler reactions, zoster, herpes simplex flares, and pityriasis rosea-like reactions. LIMITATIONS: Registry analysis does not measure incidence. Morphologic misclassification is possible. CONCLUSIONS: We report a spectrum of cutaneous reactions after mRNA COVID-19 vaccines. We observed some dermatologic reactions to Moderna and Pfizer vaccines that mimicked SARS-CoV-2 infection itself, such as pernio/chilblains. Most patients with first-dose reactions did not have a second-dose reaction and serious adverse events did not develop in any of the patients in the registry after the first or second dose. Our data support that cutaneous reactions to COVID-19 vaccination are generally minor and self-limited, and should not discourage vaccination.

Dorsal Root Ganglion Stimulation for Erythromelalgia Related Foot Pain: A Case Report and Review of the Literature.

Erythromelalgia is a rare neurovascular disorder characterized by erythema, warmth, and episodic burning pain, often felt in the face, hands, and feet. Symptoms are typically worse with heat, exercise, stress, and during the overnight hours. Management often requires a multidisciplinary approach, including pain trigger avoidance, cool water baths, and topical and oral neuropathic medications. The use of spinal cord stimulation has been described in multiple case reports with success reported out to 24 months. To our knowledge, the use of dorsal root ganglion (DRG) stimulation for erythromelalgia-related pain has not been described. Herein, we present a case of erythromelalgia-related pain at the bilateral plantar surfaces of the feet, which was treated successfully with bilateral sacral S1 nerve root DRG stimulation.

Small-fiber neuropathy associated with autoinflammatory syndromes in children and adolescents.

INTRODUCTION: Small-fiber neuropathy is rare in children. It has been associated with several autoimmune disorders, but there are no reports of an autoinflammatory etiology. METHODS: The data of four children/adolescents presenting with erythromelalgia and neuropathic pain from 2014 to 2019 were collected retrospectively from the electronic database of a pediatric medical center. RESULTS: Results of clinical and/or electrophysiological evaluation excluded large nerve fiber involvement. Skin biopsy results confirmed small-fiber neuropathy. According to genetic analysis, two patients were heterozygous and one was homozygous for mutations in the familial Mediterranean fever (MEFV) gene. Behcet disease was diagnosed in the fourth patient. Treatment with anti-interleukin-1 agents, intravenous immunoglobulin, and glucocorticoids was beneficial. DISCUSSION: The diagnosis of small-fiber neuropathy should be considered in children/adolescents presenting with erythromelalgia. A thorough investigation is required to reveal the underlying disorder. Clinicians should be alert to the peripheral neurological manifestations of autoinflammatory syndromes because effective treatments are available.

Pediatric Erythromelalgia and SCN9A Mutations: Systematic Review and Single-Center Case Series.

OBJECTIVES: To evaluate the clinical features of erythromelalgia in childhood associated with gain-of-function SCN9A mutations that increase activity of the Nav1.7 voltage-gated sodium channel, we conducted a systematic review of pediatric presentations of erythromelalgia related to SCN9A mutations, and compared pediatric clinical presentations of symptomatic erythromelalgia, with or without SCN9A mutations. STUDY DESIGN: PubMed, Embase, and PsycINFO Databases were searched for reports of inherited erythromelalgia in childhood. Clinical features, management, and genotype were extracted. Case notes of pediatric patients with erythromelalgia from the Great Ormond Street Hospital Pain Service were reviewed for clinical features, patient-reported outcomes, and treatments. Children aged over 10 years were recruited for quantitative sensory testing. RESULTS: Twenty-eight publications described erythromelalgia associated with 15 different SCN9A gene variants in 25 children. Pain was severe and often refractory to multiple treatments, including nonspecific sodium channel blockers. Skin damage or other complications of cold immersion for symptomatic relief were common (60%). SCN9A mutations resulting in greater hyperpolarizing shifts in Nav1.7 sodium channels correlated with symptom onset at younger ages (P = .016). Variability in reporting, and potential publication bias toward severe cases, limit any estimations of overall prevalence. In our case series, symptoms were similar but comorbidities were more common in children with SCN9A mutations. Quantitative sensory testing revealed marked dynamic warm allodynia. CONCLUSIONS: Inherited erythromelalgia in children is associated with difficult-to-manage pain and significant morbidity. Standardized reporting of outcome and management in larger series will strengthen identification of genotype-phenotype relationships. More effective long-term therapies are a significant unmet clinical need.