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Sample records for erythromelalgia

  1. Genetics Home Reference: erythromelalgia

    MedlinePlus

    ... Bennett DL, Wood JN, Kinali M. Novel mutations mapping to the fourth sodium channel domain of Nav1. ... and late-onset inherited erythromelalgia: genotype-phenotype correlation. Brain. 2009 Jul;132(Pt 7):1711-22. doi: ...

  2. Secondary Erythromelalgia - A Case Report -

    PubMed Central

    Kang, Byoung Chan; Nam, Da Jeong; Ahn, Eun Kyoung; Yoon, Duck Mi

    2013-01-01

    Erythromelalgia is a rare neurovascular pain syndrome characterized by a triad of redness, increased temperature, and burning pain primarily in the extremities. Erythromelalgia can present as a primary or secondary form, and secondary erythromelalgia associated with a myeloproliferative disease such as essential thrombocythemia often responds dramatically to aspirin therapy, as in the present case. Herein, we describe a typical case of a 48-year-old woman with secondary erythromelalgia linked to essential thrombocythemia in the unilateral hand. As this case demonstrates, detecting and visualizing the hyperthermal area through infrared thermography of an erythromelalgic patient can assist in diagnosing the patient, assessing the therapeutic results, and understanding the disease course of erythromelalgia. PMID:23862006

  3. Primary erythromelalgia: case report.

    PubMed

    Albuquerque, Lígia Guedes Morais de; França, Emmanuel Rodrigues de; Kozmhinsky, Valter; Querino, Marina Coutinho Domingues; Morais, Amanda Guedes de

    2011-01-01

    Erythromelalgia is a rare clinical syndrome characterized by heat, redness and intermittent pain in the extremities, being most frequent the bilateral development in the lower extremities. Local cooling brings relief to symptoms, while heating, physical exercises and use of stockings/socks intensify the discomfort. This condition can be primary or idiopathic or secondary to haematological disorders and vascular inflammatory and degenerative diseases. It is reported the case of an eighteen-year-old male who presented, at the early age of two, development of the symptoms of erythema ,heat and pain followed by desquamation of hands and feet, in outbreaks, with intervals 4 to 5 years long between the crises.

  4. [Erythromelalgia: Diagnosis and therapeutic approach].

    PubMed

    Miranda, S; Le Besnerais, M; Langlois, V; Benhamou, Y; Lévesque, H

    2017-03-01

    Erythromelalgia is a rare intermittent vascular acrosyndrome characterized by the combination of recurrent burning pain, warmth and redness of the extremities. It is considered in its primary form as an autosomal dominant neuropathy related to mutations of SCN9A, the encoding gene of a voltage-gated sodium channel subtype Nav1.7. Secondary erythromelalgia is associated with myeloproliferative disorders, drugs (bromocriptine, calcium channel blockers), or clinical conditions such as rheumatic diseases or viral infection. Primary familial erythromelalgia include genetics and sporadic forms associated with small fibers neuropathy. Aspirin is a useful treatment of erythromelagia associated with myeloproliferative disorders. Treatment of primary erythromelalgia is difficult, individualized, with sodium channel blockers such as lidocaine, carbamazepine and mexiletine. Copyright © 2016 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  5. [Erythromelalgia: two case reports and literature review].

    PubMed

    Nurowska-Wrzosek, Barbara; Tołodziecka, Lucja; Gaciong, Zbigniew

    2007-07-01

    Erythromelalgia is a rare disease of unclear etiology characterized by recurrent erythema, burning pain and warmth of the affected extremities. In this paper we reported 2 cases of primary familial erythromelalgia and difficulties with achieving a significant improvement with the currently available treatment. Moreover, this paper provides a brief update on pathophysiology, prognosis and treatment of erythromelalgia.

  6. Primary erythromelalgia: a review.

    PubMed

    Tang, Zhaoli; Chen, Zhao; Tang, Beisha; Jiang, Hong

    2015-09-30

    Primary erythromelalgia (PE ORPHA90026) is a rare autosomal dominant neuropathy characterized by the combination of recurrent burning pain, warmth and redness of the extremities. The incidence rate of PE ranges from 0.36 to 1.1 per 100,000 persons. Gender ratio differs according to different studies and no evidence showed a gender preference. Clinical onset of PE is often in the first decade of life. Burning pain is the most predominant symptom and is usually caused and precipitated by warmth and physical activities. Reported cases of PE contain both inherited and sporadic forms. Genetic etiology of PE is mutations on SCN9A, the encoding gene of a voltage-gated sodium channel subtype Nav1.7. Diagnosis of PE is made upon clinical manifestations and screening for mutations on SCN9A. Exclusion of several other treatable diseases/secondary erythromelalgia is also necessary because of the lack of biomarkers specifically for PE. Differential diagnoses can include Fabry disease, cellulites, Raynaud phenomenon, vasculitis and so on. Diagnostic methods often involve complete blood count, imaging studies and thermograph. Treatment for PE is unsatisfactory and highly individualized. Frequently used pain relieving drugs involve sodium channel blockers such as lidocaine, carbamazepine and mexiletine. Novel drugs such as PF-05089771 and TV-45070 could be promising in ameliorating pain symptoms due to their Nav1.7 selectivity. Patients' symptoms often worsen over time and many patients develop ulcerations and gangrenes caused by excessive exposure to low temperature in order to relieve pain. This review mainly focuses on PE and the causative gene SCN9A--its mutations and their effects on Nav1.7 channels' electrophysiological properties. We propose a genotype-channelopathy-phenotype correlation network underlying PE etiology which could provide guidance for future therapeutics.

  7. [Primary familial erythromelalgia. A case report].

    PubMed

    Bouyahyaoui, Y; Meziane, M; Hanaae, Z; Mikou, O; Mernissi, F-Z; Baba Khouya, A; Otmani, S; Hida, M

    2013-04-01

    Erythromelalgia is a rare disease whose etiology is poorly understood. It is characterized by paroxysmal attacks of erythema, pain, and warmth of the extremities and can be primary or secondary. We report a case of primary familial erythromelalgia and stress the difficulties in its therapeutic management. We provide a brief update on the pathophysiology and treatment of primary erythromelalgia. Copyright © 2013. Published by Elsevier SAS.

  8. Erythromelalgia: a case report and literature review.

    PubMed

    Buttaci, Charles J

    2006-01-01

    Erythromelalgia is a rare condition, of uncertain etiology, characterized by episodic erythema, intense burning pain and warmth of the hands and/or feet, and when chronic, associated with significant disability. The diagnosis is based on a thorough history and physical exam during a painful episode along with diagnostic testing to exclude other causes. This paper describes the unique syndrome of erythromelalgia through a case report and literature review. Case presentation and literature review. A 44-year-old male with erythromelalgia. Despite multiple treatment options, erythromelalgia is a challenging disease to effectively manage. Early recognition and treatment may offer patients the best probability of achieving remission or significant improvement.

  9. Erythromelalgia--the role of hypnotherapy.

    PubMed Central

    Chakravarty, K.; Pharoah, P. D.; Scott, D. G.; Barker, S.

    1992-01-01

    Erythromelalgia is an unusual condition characterized by attacks of burning pain in the hands and feet with local congestion and increased skin temperature. We report a case of erythromelalgia, with transient hypertension and elevated urinary catecholamines successfully treated by hypnotherapy. Such an association has not to our knowledge been previously reported in English language publications. PMID:1561190

  10. Erythromelalgia: a rare microvascular disease.

    PubMed

    Latessa, Victoria

    2010-06-01

    Erythromelalgia (EM) is a rare condition of unknown etiology that results in intense, burning pain and redness primarily of the feet, and, even more rarely, in the hands. Most cases are idiopathic (primary EM); others occur secondary to medical conditions, such as autoimmune diseases, and neurological or hematological disorders. Symptoms are episodic and can result in severe disability. Triggers, such as exposure to warmth, pressure or exercise, become apparent to those afflicted with this condition; however, triggers may be unavoidable during the course of daily living. There are no diagnostic tests for EM. Diagnosis is based on history, physical examination during symptomatic episode and the exclusion of other probable causes for the syndrome. Early recognition of the signs and symptoms as well as early treatment offer patients the best hope of remissions and improved quality of life. (c) 2010 Society for Vascular Nursing, Inc. Published by Mosby, Inc. All rights reserved.

  11. Dual Effect of Ziconotide in Primary Erythromelalgia.

    PubMed

    Russo, Rosario; Caroleo, Maria Cristina; Cione, Erika; Perri, Mariarita; Paparo, Maria Teresa; Russo, Antonio

    2015-01-01

    Erythromelalgia (EM) is a rare disabling clinical syndrome more commonly known to affect the lower extremities. There is no single effective treatment for this disease that often requires a multidisciplinary approach. Herein, we report the case of a 31-year-old woman affected by primary erythromelalgia who was successfully treated with intrathecal Ziconotide. We also observed an unexpected result following therapy with Ziconotide. The legs and feet of the patient that at the time of admission were swollen and tumefied dramatically improved after one week of the drug administration.

  12. Dual Effect of Ziconotide in Primary Erythromelalgia

    PubMed Central

    Russo, Rosario; Caroleo, Maria Cristina; Cione, Erika; Perri, Mariarita; Paparo, Maria Teresa; Russo, Antonio

    2015-01-01

    Erythromelalgia (EM) is a rare disabling clinical syndrome more commonly known to affect the lower extremities. There is no single effective treatment for this disease that often requires a multidisciplinary approach. Herein, we report the case of a 31-year-old woman affected by primary erythromelalgia who was successfully treated with intrathecal Ziconotide. We also observed an unexpected result following therapy with Ziconotide. The legs and feet of the patient that at the time of admission were swollen and tumefied dramatically improved after one week of the drug administration. PMID:26609309

  13. Erythromelalgia associated with Clitocybe acromelalga intoxication.

    PubMed

    Nakajima, N; Ueda, M; Higashi, N; Katayama, Y

    2013-06-01

    Erythromelalgia is a rare disorder characterized by reddening, severe burning pain, and swelling of the extremities. Food poisoning by Clitocybe acromelalga, a poisonous mushroom, is known to induce erythromelalgia; however, its treatment protocol remains unclear. We describe here three cases of erythromelalgia following the consumption of C. acromelalga with varying clinical courses. Of the three patients, the first patient presented 22 days after the onset of erythromelalgia; although he was treated with aspirin, numbness in the limbs persisted as sequela. Patient 2 presented at 3 days after the symptomatic onset and was immediately treated with high-dose intravenous nicotinic acid, with a dramatic symptomatic improvement. Patient 3, who had milder symptoms, spontaneously recovered within a week without any treatment. The clinical manifestations and varying clinical courses associated with C. acromelalga toxicity are discussed here, with the pathogenesis of this mycotoxin and a potential treatment. Detailed interviews of such patients are important, particularly because of the remarkably slow course of this mycotoxin as compared with common food poisonings. Treatment with intravenous nicotinic acid was associated with improvement in one patient. We believe that this painful disorder might thus be treatable, although the mechanism underlying the treatment remains unclear.

  14. Auricular erythromelalgia: report of a rare case.

    PubMed

    Messeguer, Francesc; Agusti-Mejias, Anna; Vilata Corell, Juan José; Requena, Celia

    2013-02-15

    Erythromelalgia is a rare disorder characterized by 3 major symptoms: warmth, redness, and burning pain. It involves the feet and, to a lesser extent, the hands, head, and ears. We report the case of a 27-year-old man presenting with a 15-year history of episodes with edema, local hyperthermia, and burning pain of both ears.

  15. Thermoregulatory sweat testing in patients with erythromelalgia.

    PubMed

    Davis, Mark D P; Genebriera, Joseph; Sandroni, Paola; Fealey, Robert D

    2006-12-01

    To examine the results of thermoregulatory sweat testing in patients with erythromelalgia and to compare them with the results of other neurophysiologic tests of small-fiber nerve function. Retrospective study. Tertiary referral center. Thirty-two consecutive patients with erythromelalgia who had thermoregulatory sweat testing in addition to vascular and nerve testing. The following information was abstracted for each patient: demographics, clinical presentation, and results of thermoregulatory sweat testing, vascular (noninvasive) testing, and nerve testing (electromyography and autonomic reflex screen, including quantitative sudomotor axon reflex test). Results of thermoregulatory sweat testing to evaluate small-fiber neuropathy, compared with other tools used to estimate small-fiber neuropathy. Thermoregulatory sweat testing results were abnormal in 28 (88%) of 32 patients, and quantitative sudomotor axon reflex test results were abnormal in 22 patients (69%). Abnormalities noted on thermoregulatory sweat testing varied from local hypohidrosis or anhidrosis to global anhidrosis. Global or almost-global anhidrosis was present in 8 patients (25%); in 19 patients (59%) the anhidrosis was distal, and 1 other patient (3%) had a less specific pattern of anhidrosis (multifocal or regional). The area of anhidrosis generally corresponded to the area that was symptomatic of the erythromelalgia. Small-fiber neuropathy is prevalent in most patients with erythromelalgia. Thermoregulatory sweat testing is a sensitive and useful marker of small-fiber neuropathy in these patients.

  16. Pediatric-isolated auricular erythromelalgia: a case report.

    PubMed

    Grandy, Kelly; Corsten, Gerard; Hong, Paul

    2012-01-01

    Erythromelalgia is a rare disorder that typically affects the skin of the feet, hands, or both, that is characterized by red skin, warmth, and a burning quality of pain. It usually affects both sides of the body, but may manifest unilaterally. Cooling of the affected areas usually results in symptom relief. We report a case of a young boy with erythromelalgia of the ears.

  17. Erythromelalgia: An Uncommon Presentation Precipitated by Aspirin Withdrawal

    PubMed Central

    Khalid, Fatima; Hassan, Syed; Qureshi, Sophia; Qureshi, Waqas; Amer, Syed

    2012-01-01

    Erythromelalgia is a rare disorder frequently associated with myeloproliferative disorders. We describe a case of elderly patient diagnosed with myeloproliferative disorder in remission. The patient was on aspirin for secondary prevention of stroke and was taken off aspirin and developed erythromelalgia within two weeks of withdrawal of aspirin. After restarting aspirin, patient's symptoms improved within 2 weeks. PMID:22844295

  18. A case of secondary erythromelalgia with unusual histological findings.

    PubMed

    Bakkour, Waseem; Motta, Luisa; Stewart, Elizabeth

    2013-06-01

    Erythromelalgia clinically presents with episodic burning, erythema, and warmth of acral sites. It can be divided into primary and secondary associated with myeloproliferative and autoimmune conditions. Histology commonly shows capillary proliferation, swelling of endothelial cells, perivascular edema, and chronic inflammation with sparse lymphocytic infiltrate. We report a case of a 55-year-old man with classical secondary erythromelalgia clinically; however, he had unusual histological findings on biopsy comprising of acute perivascular infiltrate and perivascular mucin. This is the first report of such findings in the context of secondary erythromelalgia.

  19. Subcutaneous panniculitis like T cell lymphoma associated with erythromelalgia.

    PubMed

    Thomas, J; Maramattom, B V; Kuruvilla, P M; Varghese, J

    2014-01-01

    Erythromelalgia is a rare disorder that simulates a small fiber neuropathy and patients often have painful erythematous extremities during episodes. It is of two types: A primary or inherited form that is sometimes associated with a Na channel mutation or a secondary disorder associated with an underlying systemic disorder. We present a 19-year-old boy who presented to us with erythromelalgia and a febrile illness with systemic rash. Detailed work-up revealed another unusual condition: Subcutaneous panniculitis like T cell lymphoma (SPTCL). This is the first report of an association of erythromelalgia with SPTCL.

  20. Red ear syndrome and auricular erythromelalgia: the same condition?

    PubMed

    Brill, T J; Funk, B; Thaçi, D; Kaufmann, R

    2009-12-01

    Several cases of relapsing attacks during which the ear becomes red and patients experience a burning sensation have been reported in the literature. This combination of symptoms has been described as 'red ear syndrome' (RES). We report on a 7-year-old boy who had episodes of reddening, swelling and a burning sensation in one ear with local hyperthermia persisting for 3 years. The differential diagnosis included RES and erythromelalgia, as isolated auricular variants of erythromelalgia have been described and the symptoms are difficult to distinguish from RES. In this report, we discuss the similarities and differences between RES and erythromelalgia.

  1. Secondary erythromelalgia successfully treated with intravenous immunoglobulin.

    PubMed

    Moody, Shadé; Pacheco, Susan; Butler, Ian J; Koenig, Mary Kay

    2012-07-01

    Erythromelalgia is a rare condition characterized by episodic painful erythema and warmth often affecting, but not limited to, the distal extremities. This condition is notoriously difficult to treat. We report a young female patient with seronegative polyarthritis who presented with a 6-year history of recurrent bouts of painful erythema and swelling often triggered by minor trauma. An extensive evaluation was unremarkable. Several medical therapies provided limited and inconsistent relief of her symptoms over many years. Treatment with intravenous immunoglobulin significantly decreased the frequency and severity of her symptoms.

  2. Effectiveness of botulinum toxin A in treatment of refractory erythromelalgia.

    PubMed

    Lin, Kuan-Hsiang; Wang, Shuu-Jiun; Fuh, Jong-Ling; Chen, Shih-Pin

    2013-05-01

    Erythromelalgia is characterized by intense burning pain, erythema, and heat in affected areas after precipitating factors such as warm temperature or stress. It is refractory to treatment in some situations. We describe a woman with adenosquamous cell carcinoma of the lung and medically refractory erythromelalgia. The symptoms of erythromelalgia presented as refractory to any medical treatment. Due to the unresponsive nature of her condition, botulinum toxin type A (onabotulinumtoxin A) was injected over both of her cheeks, periodically for six cycles. Her symptoms responded dramatically to subcutaneous and intradermal injection of botulinum toxin type A. Repetitive injection demonstrated consistent and reproducible responses, and the efficacy was maintained for approximately 1 month. No adverse effects or complications were noted. Botulinum toxin type A might be safe and effective as an alternative treatment for refractory erythromelalgia, but further large-scale studies are required. Copyright © 2013. Published by Elsevier B.V.

  3. A case of erythromelalgia: good response to treatment with gabapentin.

    PubMed

    Ceyhan, Ali Murat; Gurses, Ipek; Yildirim, Mehmet; Akkaya, Vahide Baysal

    2010-05-01

    Erythromelalgia is a rare chronic disorder characterized by intense burning pain, redness, swelling and increased skin temperature. It occurs primarily in the feet, but may also involve the hands, face and ears. Warming of the extremity or placing and maintaining the extremity in a dependent position can exacerbate symptoms. These symptoms are typically refractory to various medications, but are relieved by elevation or exposure to cold. Although a specific therapy is not available for erythromelalgia yet, several treatment modalities may be used as therapeutic options, including: aspirin, indomethacine beta-blockers, calcium channel antagonists, misoprostol, diltiazem, tricyclic antidepressants, serotonin reuptake inhibitors and number of more aggressive procedures--such as intravenous lidocaine, epidural anaesthesia, intrathecal opiates and sympathetic ganglion blockade. There are very few reports in the literature of gabapentin successfully treating erythromelalgia. Here, the authors report a case of primary erythromelalgia in a 20-year-old woman responding to gabapentin therapy.

  4. Refractory erythromelalgia of the ears: response to mexiletine.

    PubMed

    Vivas, Alejandra C; Escandon, Julia; Kirsner, Robert S

    2011-01-01

    Erythromelalgia is a rare condition characterized by burning pain, erythema, swelling, and increased temperature usually in the extremities. We present an unusual presentation of erythromelalgia of the ears in a patient who has been refractory to multiple therapies and in whom relief of symptoms was achieved with the use of mexiletine. A review of clinical presentation, pathophysiology, and therapeutic options are presented. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. Epidermal Nerve Fiber Quantification in Patients With Erythromelalgia.

    PubMed

    Mantyh, William G; Dyck, P James B; Dyck, Peter J; Engelstad, Janean K; Litchy, William J; Sandroni, Paola; Davis, Mark D P

    2016-12-07

    Erythromelalgia is a clinical diagnosis based on intermittent warmth, erythema, and pain in the distal extremities. One problem facing physicians is how to objectively test for this disease. Given that other painful conditions of the distal extremities (ie, neuropathy related to human immunodeficiency virus, diabetes, or Fabry disease) can be evaluated with a skin biopsy to visualize pathologically decreased densities of the small nerve fibers that innervate the epidermis, one hypothesis is that erythromelalgia could similarly be associated with a loss of epidermal nerve fiber density (ENFD). To examine whether erythromelalgia is associated with a structural loss of small fibers using the ENFD technique and to compare this with functional studies of small nerve fibers. In a retrospective study of 52 consecutive patients with erythromelalgia who were seen between September 1, 2010, and September 22, 2015, patients were interviewed and examined and their conditions clinically diagnosed by a board-certified dermatologist at a large tertiary referral center, where ENFD testing became a routine part of evaluating erythromelalgia in 2010. Thus, all 52 consecutive patients were included solely based on their clinical diagnosis of erythromelalgia. For quantification of ENFD, observers were masked to all patient information except for name and clinic number. The hypothesis that patients with erythromelalgia would have decreased ENFD was formulated before data collection. Epidermal nerve fiber density, the primary outcome, is a measurement of the density of small nerve fibers within the epidermis. Secondary measures included functional small fiber evaluation, such as autonomic (heart rate, blood pressure, and sweat testing) and subjective testing of pain. In this cohort study, 52 consecutively seen patients were identified (female, 42 [80%]; median age, 44 years; age range, 13-82 years). Whereas only 5 of 52 patients (10%) had ENFD at or below the fifth percentile of healthy

  6. The Complexity of Pain Management in Patients with Erythromelalgia.

    PubMed

    Patel, Neha; Chen, Emily; Cucchiaro, Giovanni

    2015-11-01

    A 15-year-old girl diagnosed with erythromelalgia was admitted to the hospital with severe pain in her feet associated with burning, pruritus, erythema, and swelling. She had not responded to conventional management and received some relief only from cold bath immersions, which resulted in chronic blistering and multiple episodes of superinfection. After a successful trial of spinal cord stimulation, she had a permanent implantation procedure. The spinal cord stimulator relieved her pain and improved function but not the sensation of burning pain. However, this pain resolved after she started daily mexiletine. This case demonstrates that erythromelalgia sometimes can be managed successfully with a combination of pharmacologic and interventional procedures.

  7. A refractory case of erythromelalgia involving the ears.

    PubMed

    Ramirez, Claudia C; Kirsner, Robert S

    2004-01-01

    Erythromelalgia is a rare syndrome that is characterized by episodic attacks of burning pain, erythema, and increased temperature usually affecting the extremities, which is aggravated by warmth or exercise. We describe a patient with a 3-year history of refractory burning pain and red ears. A review of clinical features, disease classification, associated diseases, and treatment of this disease is presented.

  8. A case of secondary erythromelalgia with perivascular and intramural mucin.

    PubMed

    Blake, Tristan; Mortimore, Rohan; De Ambrosis, Kathryn

    2016-02-01

    We present a 49-year-old man with type I erythromelalgia, demonstrating a newly reported histological feature of striking perivascular mucin. There is a single previously reported case in the literature describing these histological features. This patient had a comorbid history of primary myelofibrosis diagnosed 2 years prior to his presentation. © 2014 The Australasian College of Dermatologists.

  9. The use of capsaicin cream in a case of erythromelalgia.

    PubMed Central

    Muhiddin, K. A.; Gallen, I. W.; Harries, S.; Pearce, V. R.

    1994-01-01

    We present a case of erythromelalgia in a 68 year old lady who responded, within 48 hours, to a twice daily topical application of capsaicin cream 0.025%. Capsaicin cream was stopped after 2 months, and 6 months later the patient continued to have the symptomatic relief she experienced initially. Images Figure 1 PMID:7824425

  10. Localized secondary erythromelalgia in an 11-year-old boy.

    PubMed

    Wu, Hui-Hui; Wang, Ming-Jun; Luo, Di-Qing; Lin, Qing

    2013-01-01

    We report an 11-year-old boy with localized secondary erythromelalgia on his left medial thigh. The episodes responded well to indomethacin and prednisone but recurred after the medications were stopped. The disease was stable after being treated for 5 months. © 2012 Wiley Periodicals, Inc.

  11. Erythromelalgia of the ears: an unusual variant and response to therapy.

    PubMed

    Berk, David R; Eisen, Arthur Z

    2008-03-01

    Erythromelalgia is characterized by episodes of erythematous, warm, burning acral skin, which is exacerbated by heat and relieved by cold. Erythromelalgia usually affects the feet and/or hands but, although rare, erythromelalgia may affect the ears. The authors present a 65-year-old woman with erythromelalgia of the ears with disabling symptoms whose diagnosis was delayed for 6 years. The patient failed to respond to numerous therapies before rapidly improving with oral amitriptyline and amitriptyline 1% to 2% and ketamine 0.5% to 1% topical gel.

  12. Burning pain: axonal dysfunction in erythromelalgia.

    PubMed

    Farrar, Michelle A; Lee, Ming-Jen; Howells, James; Andrews, Peter I; Lin, Cindy S-Y

    2017-05-01

    Erythromelalgia (EM) is a rare neurovascular disorder characterized by intermittent severe burning pain, erythema, and warmth in the extremities on heat stimuli. To investigate the underlying pathophysiology, peripheral axonal excitability studies were performed and changes with heating and therapy explored. Multiple excitability indices (stimulus-response curve, strength-duration time constant (SDTC), threshold electrotonus, and recovery cycle) were investigated in 23 (9 EMSCN9A+ and 14 EMSCN9A-) genetically characterized patients with EM stimulating median motor and sensory axons at the wrist. At rest, patients with EM showed a higher threshold and rheobase (P < 0.001) compared with controls. Threshold electrotonus and current-voltage relationships demonstrated greater changes of thresholds in both depolarizing and hyperpolarizing preconditioning electrotonus in both EM cohorts compared with controls in sensory axons (P < 0.005). When average temperature was raised from 31.5°C to 36.3°C in EMSCN9A+ patients, excitability changes showed depolarization, specifically SDTC significantly increased, in contrast to the effects of temperature previously established in healthy subjects (P < 0.05). With treatment, 4 EMSCN9A+ patients (4/9) reported improvement with mexiletine, associated with reduction in SDTC in motor and sensory axons. This is the first study of primary EM using threshold tracking techniques to demonstrate alterations in peripheral axonal membrane function. Taken together, these changes may be attributed to systemic neurovascular abnormalities in EM, with chronic postischaemic resting membrane potential hyperpolarization due to Na/K pump overactivity. With heating, a trigger of acute symptoms, axonal depolarization developed, corresponding to acute axonal ischaemia. This study has provided novel insights into EM pathophysiology.

  13. Burning pain: axonal dysfunction in erythromelalgia

    PubMed Central

    Farrar, Michelle A.; Lee, Ming-Jen; Howells, James; Andrews, Peter I.; Lin, Cindy S.-Y.

    2017-01-01

    Abstract Erythromelalgia (EM) is a rare neurovascular disorder characterized by intermittent severe burning pain, erythema, and warmth in the extremities on heat stimuli. To investigate the underlying pathophysiology, peripheral axonal excitability studies were performed and changes with heating and therapy explored. Multiple excitability indices (stimulus–response curve, strength–duration time constant (SDTC), threshold electrotonus, and recovery cycle) were investigated in 23 (9 EMSCN9A+ and 14 EMSCN9A−) genetically characterized patients with EM stimulating median motor and sensory axons at the wrist. At rest, patients with EM showed a higher threshold and rheobase (P < 0.001) compared with controls. Threshold electrotonus and current–voltage relationships demonstrated greater changes of thresholds in both depolarizing and hyperpolarizing preconditioning electrotonus in both EM cohorts compared with controls in sensory axons (P < 0.005). When average temperature was raised from 31.5°C to 36.3°C in EMSCN9A+ patients, excitability changes showed depolarization, specifically SDTC significantly increased, in contrast to the effects of temperature previously established in healthy subjects (P < 0.05). With treatment, 4 EMSCN9A+ patients (4/9) reported improvement with mexiletine, associated with reduction in SDTC in motor and sensory axons. This is the first study of primary EM using threshold tracking techniques to demonstrate alterations in peripheral axonal membrane function. Taken together, these changes may be attributed to systemic neurovascular abnormalities in EM, with chronic postischaemic resting membrane potential hyperpolarization due to Na+/K+ pump overactivity. With heating, a trigger of acute symptoms, axonal depolarization developed, corresponding to acute axonal ischaemia. This study has provided novel insights into EM pathophysiology. PMID:28134657

  14. Experience with oral mexiletine in primary erythromelalgia in children

    PubMed Central

    Iqbal, Javeed; Bhat, Mushtaq I.; Charoo, Bashir A.; Syed, Wajid A.; Sheikh, Mushtaq A.; Bhat, Imtiyaz N.

    2009-01-01

    Primary erythromelalgia is characterized by burning pain, redness, and warmth in the extremities. We present two cases of primary erythromelalgia both of whom presented with a history of several months of severe burning pain in both hands and feet. Both patients had received multiple pain medications with no improvement in symptoms. Pain was relieved by putting affected parts in ice cold water, which resulted in immersion injury of the affected parts. Both patients stopped taking part in school and social activities. We tried oral mexiletine, a class Ib antiarrythmic agent, in view of its reported role in various chronic painful conditions. Dramatic improvement was observed with its use. Both patients improved after several weeks of use, and there were fewer soaking episodes. We observed no adverse effects with mexilitine therapy. PMID:19584578

  15. Pain in primary erythromelalgia--a neuropathic component?

    PubMed

    Orstavik, Kristin; Mørk, Cato; Kvernebo, Knut; Jørum, Ellen

    2004-08-01

    Erythromelalgia is a condition characterized by attacks of red, hot, painful extremities with relief of symptoms by cooling and aggravation by warmth. Although the main emphasis has been on pathophysiological mechanisms related to circulatory changes, recent reports have focused on an involvement of efferent small nerve fibers indicating a neuropathic component. Since the symptoms resemble those described in neuropathic pain, we wanted to investigate the possible affection of afferent nerve fibers. Twenty-five patients with primary erythromelalgia were examined by neurological testing, neurography and quantitative sensory testing. Thresholds for heat, cold, heat-pain and cold-pain detection were compared with those of a group of 29 healthy controls. The patients had significantly higher median heat (39.5 (36.1-40.8) and cold (29.3 (27.1-30.8)-detection thresholds at the dorsal aspects of their feet compared to the controls (37.0 (35.4-37.7) and 31.2 (30.3-31.5) respectively). These findings show an impaired small fiber function inside or close to the symptomatic area in this group of erythromelalgia patients. Seven patients had brush-evoked allodynia and fourteen had punctate hyperalgesia inside or close to the symptomatic areas in their feet. When comparing the individual results, there is a tendency to clustering of patients in two separate groups; reduced small fiber input/no hyperalgesia and normal thermal thresholds/hyperalgesia. Our results showing an affection of afferent small nerve fibers together with the nature of the symptoms, suggest that the pain experienced by erythromelalgia patients could have a neuropathic component.

  16. Erythromelalgia: Identification of a corticosteroid-responsive subset.

    PubMed

    Pagani-Estévez, Gabriel L; Sandroni, Paola; Davis, Mark D; Watson, James C

    2017-03-01

    Corticosteroids (CS) may benefit certain patients with erythromelalgia. Our objective was to determine clinical predictors of corticosteroid-responsive erythromelalgia. Patients with erythromelalgia who received CS were identified and stratified into corticosteroid nonresponders (NRs), partial corticosteroid responders (PSRs), complete corticosteroid responders (CSRs), and steroid responders (SRs = PSRs + CSRs). In the study variable analysis, P < .05 was considered statistically significant. The median (interquartile range) age of the 31-patient cohort was 47 years (26-57 years), and 22 (71%) were female. Fourteen (45%) were NRs, 17 (55%) SRs, 8 (26%) PSRs, and 9 (29%) CSRs. A subacute temporal profile to disease zenith (<21 days) was described in 15 (48%) patients, of whom 13 (87%) were SRs (P = .003; odds ratio [OR] = 0.069 [95% confidence interval {CI}, 0.011-0.431]). Six (67%) CSRs reported a disease precipitant (eg, surgery, trauma, or infection; P = .007; OR = 12.667 [95% CI, 2-80.142]). SR patients received CS sooner than NR at 3 (3-12) versus 24 (17-45) months (P = .003). A high-dose CS trial (≥200 mg prednisone cumulatively) was administered to 17 (55%) patients, of whom 13 (76%) were SRs (P = .012; OR = 8.125 [95% CI, 1.612-40.752]). This was a retrospective case series. An infectious, traumatic, or surgical precipitant and subacute presentation may portend CR erythromelalgia. A transient "golden window" where CS intervention is useful may exist before irreversible nociceptive remodeling and central sensitization occurs. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  17. Autonomic dysfunction in SCN9A-associated primary erythromelalgia.

    PubMed

    Kim, Min-Kyeong; Yuk, Ji-Won; Kim, Hyang-Sook; Park, Ki-Jong; Kim, Dae-Seong

    2013-04-01

    Primary erythromelalgia (EM) is an autosomal dominant disorder caused by mutations of SCN9A. It is clinically characterized by reddish discoloration and episodic burning sensation of distal extremities triggered by warmth. We report a 49-year-old male with primary EM caused by SCN9A mutation (p.F216S), in whom an autonomic reflex screening test revealed a mild sudomotor dysfunction.

  18. Spinal Cord Stimulation for Treatment of Neuropathic Pain Associated With Erythromelalgia.

    PubMed

    Matzke, Laura L; Lamer, Tim J; Gazelka, Halena M

    2016-01-01

    Erythromelalgia is a rare disorder associated with neuropathic pain that commonly affects the lower extremities. This pain is often refractory to multimodal treatment. Both pharmacologic management and interventional anesthetic blocks have been used with varying and often limited success. To date, little experience has been gained with the use of spinal cord stimulation in treating pain associated with erythromelalgia. We present a case of successful treatment of pain secondary to erythromelalgia with a spinal cord stimulator in an 80-year-old woman. This patient had severe pain and debility secondary to erythromelalgia, having undergone trials of multiple medical therapies before presenting to our clinic. Dual-lead percutaneous spinal cord stimulation was successfully implanted without complication, leading to excellent pain control, now 18 months postimplant. Spinal cord stimulation may be a promising treatment of neuropathic pain associated with erythromelalgia.

  19. Incidence of erythromelalgia: a population-based study in Olmsted County, Minnesota.

    PubMed

    Reed, K B; Davis, M D P

    2009-01-01

    To estimate the population-based incidence of erythromelalgia. Background Only one report describing the incidence of erythromelalgia has been published previously. A population-based analysis of data from the Rochester Epidemiology Project. Tertiary care medical centre in Olmsted County, Minnesota (a rural county in the south-eastern portion of the state). Thirty-three residents of Olmsted County with a diagnosis of erythromelalgia during the study period. Age- and sex-specific incidence rates of erythromelalgia were determined. None. Population-based incidence rate. The overall age- and sex-adjusted incidence rate (95% confidence interval, 95% CI) was 1.3 (0.8-1.7) per 100,000 people per year. The incidence of primary and secondary erythromelalgia was 1.1 (0.7-1.5) and 0.2 (0.02-0.4) per 100,000 people per year, respectively. The age-adjusted incidence rates (95% CI) were 2.0 (1.2-2.7) per 100,000 women and 0.6 (0.1-1.1) per 100,000 men. The study was limited by the small sample size and potential variability in recognition of erythromelalgia. The population-based incidence of erythromelalgia has increased with each decade in Olmsted County over the past three decades; overall incidence was 1.3 per 100,000 people per year, approximately 5 times higher than previously reported.

  20. Incidence of Erythromelalgia: A Population-Based Study in Olmsted County, Minnesota

    PubMed Central

    Reed, Kurtis B.; Davis, Mark D. P.

    2009-01-01

    Objective To estimate the population-based incidence of erythromelalgia. Background Only one report describing the incidence of erythromelalgia has been published previously. Study Design A population-based analysis of data from the Rochester Epidemiology Project. Setting Tertiary care medical center in Olmsted County, Minnesota (a rural county in the southeastern portion of the state). Patients Thirty-three residents of Olmsted County with a diagnosis of erythromelalgia during the study period. Methods Age- and sex-specific incidence rates of erythromelalgia were determined. Intervention None. Main Outcome Population-based incidence rate. Results The overall age- and sex-adjusted incidence rate (95% confidence interval) was 1.3 (0.8-1.7) per 100,000 people per year. The incidence of primary and secondary erythromelalgia was 1.1 (0.7-1.5) and 0.2 (0.02-0.4) per 100,000 people per year, respectively. The age-adjusted incidence rates (95% confidence interval) were 2.0 (1.2-2.7) per 100,000 women and 0.6 (0.1-1.1) per 100,000 men. The study was limited by the small sample size and potential variability in recognition of erythromelalgia. Conclusion The population-based incidence of erythromelalgia has increased with each decade in Olmsted County over the past 3 decades; overall incidence was 1.3 per 100,000 people per year. PMID:18713229

  1. Results of computer-assisted sensory evaluation in 41 patients with erythromelalgia.

    PubMed

    Genebriera, J; Michaels, J D; Sandroni, P; Davis, M D P

    2012-06-01

    Erythromelalgia is a rare disorder characterized by the clinical syndrome of burning pain, warmth and redness of the limbs. Neurological abnormalities (both large- and small-fibre neuropathy) are common. There have been few published reports on the sensory status of patients with erythromelalgia. To investigate the results of quantitative sensation testing in erythromelalgia using computer-assisted sensory evaluation, including vibratory detection threshold, cool detection threshold and heat-pain threshold (HPT). Patients who underwent dermatological or neurological evaluation of suspected erythromelalgia at our institution and received a final diagnosis of erythromelalgia were identified from a master diagnosis index covering the period January 1994 to June 2008. A retrospective chart review was performed. Main outcome measures were sensory abnormalities (e.g. pain, burning sensation, tingling) in response to heat, cooling and vibration during computer-assisted sensory testing. In total, 41 patients with erythromelalgia were enrolled in the study and underwent computer-assisted sensory evaluation. Of these, 34 patients (82.9%) had abnormal results. The commonest abnormality was isolated HPT: 11 patients (26.8%) had heat hypoalgesia and 18 (43.9%) had heat hyperalgesia, whereas only 2 (4.9%) of the healthy control patients had hyperalgesia on testing. Multiple sensory modalities were found to be abnormal in patients with erythromelalgia, with the commonest clinical abnormality being isolated heat-pain abnormality. These findings lend support to the notion that neuropathy underlies the clinical diagnosis of erythromelalgia. Future studies will explore the nature of the relationship between these sensory abnormalities and the clinical features of erythromelalgia. © Mayo Foundation for Medical Education and Research. CED © 2012 British Association of Dermatologists.

  2. Lumbar Sympathetic Pulsed Radiofrequency Treatment for Primary Erythromelalgia: A Case Report.

    PubMed

    Lee, Jin Young; Sim, Woo Seog; Kang, Ryung A; Lee, Eun Kyung; Yang, Jae Young; Kim, Dae Yoon

    2017-01-01

    Erythromelalgia is often refractory and resistant to many forms of treatment. Numerous therapeutic options have been tried, but effective treatment remains elusive. The sympathetic nervous system has been involved in various painful conditions of neuropathic, vascular, and visceral origin. Sympathetic block is helpful in making a diagnosis and managing pain. We report a case of excellent pain relief after lumbar sympathetic pulsed radiofrequency treatment in a patient with primary erythromelalgia of the lower extremities. This case suggests the viability of pulsed radiofrequency treatment in patients with erythromelalgia. © 2016 Wiley Periodicals, Inc.

  3. Childhood steroid-responsive acute erythromelalgia with axonal neuropathy of large myelinated fibers: a dysimmune neuropathy?

    PubMed

    Pfund, Zoltan; Stankovics, Jozsef; Decsi, Tamas; Illes, Zsolt

    2009-01-01

    A 12-year-old girl developed acute erythromelalgia of distal extremities. Physical, imaging and laboratory examinations failed to find an infective, systemic autoimmune, metabolic, endocrine, and vascular origin. The severe pain and allodynia indicated small-fiber neuropathy but muscle weakness suggested an involvement of large myelinated nerve fibers. This was confirmed by electrophysiological testing. High-dose then slowly tapered methylprednisolone resulted in rapid remission of painful erythromelalgia and complete electrophysiological recovery. Our case may suggest an additional variant to recently described steroid-responsive erythromelalgia with small-fiber axonopathy and may denote a transitory variant to Guillain-Barré syndrome or chronic dysimmune neuropathies.

  4. Hansen's disease associated with erythromelalgia mimicking Lupus erythematosus.

    PubMed

    Damodar, Shenoi Shrutakirthi; Smitha, Prabhu; Nirmal, Balakrishnan; Sudhir, Nayak U K; Ballambat, Pai Sathish

    2014-01-01

    Hansen's disease, though considered to be at the verge of elimination in many countries including India, still continues to surprise patients and dermatologists alike. This is mainly due to its varying and unconventional presentations which may lead to initial misdiagnosis and prolongation of treatment. Here we describe an unusual case presenting with erythematous photosensitive facial lesions associated with erythromelalgia of the finger tips, provisionally diagnosed as SLE. A subsequent histopathology examination proved it to be Hansens' disease Borderline Tuberculoid variety. Hansen's disease can be termed as the modern great imitator, displacing the traditional great imitator, syphilis.

  5. Erythromelalgia with a linear pattern in a 12-year-old girl.

    PubMed

    Huh, Seokwon; Jung, Mo Kyung; Eun, Lucy Youngmin; Jung, Jo Won; Choi, Jae Young

    2015-08-01

    Erythromelalgia is a rare clinical syndrome characterized by erythema, increased temperature, and severe burning pain that can be aggravated by warmth or relieved by cold. Erythromelalgia occurs either as a primary, idiopathic form, or secondary to a number of diseases and conditions. Although fairly well studied in adults, the characteristics, pathogenesis, and natural history are poorly characterized in the pediatric age group. Different therapeutic options have been tried, but no optimal treatment has been suggested for erythromelalgia. We report a rare case of linear erythromelalgia in a 12-year-old girl involving her central body from the peripheral extremities, which seemed to be secondary due to vasculitis. Clinical progress waxed and waned on maintenance aspirin and propranolol. © 2015 Japan Pediatric Society.

  6. [A case of primary erythromelalgia successfully treated with high-dose intravenous immunoglobulin therapy].

    PubMed

    Kuroda, Takeshi; Sugimoto, Azusa; Ishigaki, Seiichirou; Murakami, Hidetomo; Kawamura, Mitsuru

    2014-02-01

    Erythromelalgia is a rare condition characterized by constant or paroxysmal burning pain, erythema, and the elevation of skin temperature in the extremities. Recently, the impairment of C-fiber function due to autoimmune system involvement is considered as the primary cause of erythromelalgia. However, a successful treatment has yet not been established. We report a case of a 39-year-old woman with primary erythromelalgia accompanied by high cerebrospinal fluid protein concentration and axonal neuropathy. She received various antiepileptic and anti-inflammatory drugs, but failed to improve. She finally underwent high-dose intravenous immunoglobulin therapy, which dramatically improved her symptoms and normalized cerebrospinal fluid protein concentration. This result demonstrates the effectiveness of high-dose intravenous immunoglobulin therapy for the treatment of primary erythromelalgia and the possibility of autoimmune system involvement.

  7. Erythromelalgia as a manifestation of autonomic nervous system involvement in multiple sclerosis.

    PubMed

    Adamec, Ivan; Lakoš Jukić, Ines; Habek, Mario

    2016-07-01

    Erythromelalgia is a rare condition characterized by burning pain, erythema and increased temperature of the hands or the feet. Its etiology is not completely understood but it is believed that the underlying cause is a peripheral vascular dysfunction that leads to simultaneous tissue hypoxia and hyperemia. We present a rare co-occurrence of erythromelalgia and multiple sclerosis in a patient with autonomic nervous system dysfunction and propose a causative interconnection. Copyright © 2016 Elsevier B.V. All rights reserved.

  8. Functional vascular diseases: Raynaud's syndrome, acrocyanosis and erythromelalgia.

    PubMed

    Heidrich, H

    2010-02-01

    Raynauds syndrome, acrocyanosis and erythromelalgia are functional vascular diseases that differ with respect to prevalence, clinical picture, therapy, prognosis, and impairment of quality of life. Raynauds syndrome occurs in 5 to 20 % of the population in Europe, is observed four times more often in women than in men and appears first at the age of 40 (3 to 80), on the average. Raynauds attacks are characterized by a paroxysmal white-blue-red or just white and blue discoloration of the fingers and toes; the attacks are induced by cold or stress, usually, cease after no more than some minutes (average 23 min.), but can also persist for hours. A distinction must be made between primary (aetiology unknown), secondary (aetiology known) and suspected secondary Raynauds syndromes (causal underlying disease suspected). There are several different therapy options, but not all of them have been substantiated by evidence. Acrocyanosis is rarer than Raynauds syndrome, and contrary to the latter, is characterized by nonparoxysmal, in most cases persistent, painless bluish-red symmetrical discolorations of the hands, feet and knees. It is more frequent in women than in men and becomes manifest before the 25th year of age, on the average (15th to 70th year of age). A distinction is made between primary acrocyanosis without detectable underlying disease and secondary acrocyanosis with a specific underlying disease. No effective therapy for primary acrocyanosis is known, but secondary forms can sometimes be treated. Patients with primary and secondary erythromelalgia, a very rare condition, sustain paroxysmal burning pain with marked reddening of the legs, feet and less often the hands. The attacks are triggered by warmth. Women are affected more often than men. The age of first manifestation is 40 to 55 years, but the first attacks may just as well occur during childhood. There are different therapeutic approaches with occasional success, but no general recommendations.

  9. Severe case and literature review of primary erythromelalgia: novel SCN9A gene mutation.

    PubMed

    Skeik, Nedaa; Rooke, Thom W; Davis, Mark Denis P; Davis, Dawn Marie R; Kalsi, Henna; Kurth, Ingo; Richardson, Randal C

    2012-02-01

    Erythromelalgia is a rare clinical syndrome characterized by intermittent heat, redness, swelling and pain more commonly affecting the lower extremities. Symptoms are mostly aggravated by warmth and are eased by a cold temperature. In some cases, symptoms can be very severe and disabling. Erythromelalgia can be classified as either familial or sporadic, with the familial form inherited in an autosomal dominant manner. Recently, there has been a lot of progress in studying Na(v)1.7 sodium channels (expressed mostly in the sympathetic and nociceptive small-diameter sensory neurons of the dorsal root ganglion) and different mutations affecting the encoding SCN9A gene that leads to channelopathies responsible for some disorders, including primary erythromelalgia. We present a severe case of progressive primary erythromelalgia caused by a new de novo heterozygous missense mutation (c.2623C>G) of the SCN9A gene which substitutes glutamine 875 by glutamic acid (p.Q875E). To our knowledge, this mutation has not been previously reported in the literature. We also provided a short literature review about erythromelalgia and Na(v) sodium channelopathies.

  10. Massage Therapy Techniques as Pain Management for Erythromelalgia: A Case Report

    PubMed Central

    Dicks, Krista; Rizek, Philippe

    2010-01-01

    Background Erythromelalgia is characterized by temperature-dependent redness, pain, and warmth in one or more extremities. It may be a primary disease, or it may occur secondarily because of underlying illness. It is a chronic, debilitating condition often resistant to medical treatment. Purpose The present report evaluates massage as a complementary therapy to reduce pain and other symptoms associated with erythromelalgia. Participant A 31-year-old female with a long-standing history of erythromelalgia bilaterally in the lower extremities presented with complaints of acute pain exacerbation, anxiety, decreased quality of sleep, and difficulty with activities of daily living for prolonged periods of time. She had no previous experience with massage therapy or any other complementary therapies. Intervention Massage therapy was introduced over the course of 9 treatments, each 1 hour in duration, using various massage therapy techniques, remedial exercise, and recommended home care. Results In this patient with erythromelalgia, effleurage and petrissage as massage therapy techniques provided temporary pain relief in the lower extremities and long-term benefits that relieved anxiety, which improved restorative sleep and increased the patient’s participation in activities of daily living. Conclusions For this treatment protocol, therapist observation and patient feedback suggest that massage therapy may lead to a state of increased relaxation, decreased stress, decreased muscle tension, and improved sleep. These positive effects may have an indirect role in the ability of the patient to cope with erythromelalgia day to day. PMID:21589683

  11. Defining a treatable cause of erythromelalgia: acute adolescent autoimmune small-fiber axonopathy.

    PubMed

    Paticoff, Joshua; Valovska, Assia; Nedeljkovic, Srdjan S; Oaklander, Anne Louise

    2007-02-01

    Conditions described as "erythromelalgia" and "erythermalgia" are being formally specified by etiological diagnoses that enable the use of disease-modifying as well as symptomatic treatments. We describe an otherwise healthy 20-year-old man with acute-onset erythromelalgia. Severe bilateral distal limb pain and vasodilation persisted despite the use of many antihyperalgesics. Pathological examination of cutaneous nerve endings revealed severe small-fiber predominant axonopathy. Treatment of his apparent autoimmune polyneuropathy with high dose corticosteroids, 4 days of lidocaine infusion, and a prednisone taper cured him. Similarities to other cases allowed us to tentatively characterize a new treatable cause of erythromelalgia; acute adolescent autoimmune small-fiber axonopathy. In this report we evaluate various options for diagnosis and treatment.

  12. Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia.

    PubMed

    Klein, Christopher J; Wu, Yanhong; Kilfoyle, Dean H; Sandroni, Paola; Davis, Mark D; Gavrilova, Ralitza H; Low, Phillip A; Dyck, Peter J

    2013-04-01

    Mutations in SCN9A have been reported in (1) congenital insensitivity to pain (CIP); (2) primary erythromelalgia; (3) paroxysmal extreme pain disorder; (4) febrile seizures and recently (5) small fibre sensory neuropathy. We sought to investigate for SCN9A mutations in a clinically well-characterised cohort of patients with CIP and erythromelalgia. We sequenced all exons of SCN9A in 19 clinically well-studied cases including 6 CIP and 13 erythromelalgia (9 with family history, 10 with small-fibre neuropathy). The identified variants were assessed in dbSNP135, 1K genome, NHLBI-Exome Sequencing Project (5400-exomes) databases, and 768 normal chromosomes. In erythromelalgia case 7, we identified a novel Q10>K mutation. In CIP case 6, we identified a novel, de novo splicing mutation (IVS8-2A>G); this splicing mutation compounded with a nonsense mutation (R523>X) and abolished SCN9A mRNA expression almost completely compared with his unaffected father. In CIP case 5, we found a variant (P610>T) previously considered causal for erythromelalgia, supporting recently raised doubt on its causal nature. We also found a splicing junction variant (IVS24-7delGTTT) in all 19 patients, this splicing variant was previously considered casual for CIP, but IVS24-7delGTTT was in fact the major allele in Caucasian populations. Two novel SCN9A mutations were identified, but frequently polymorphism variants are found which may provide susceptibility factors in pain modulation. CIP and erythromelalgia are defined as genetically heterogeneous, and some SCN9A variants previously considered causal may only be modifying factors.

  13. Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia

    PubMed Central

    Klein, Christopher J; Wu, Yanhong; Kilfoyle, Dean H; Sandroni, Paola; Davis, Mark D; Gavrilova, Ralitza H; Low, Phillip A; Dyck, Peter J

    2013-01-01

    Objective Mutations in SCN9A have been reported in (1) congenital insensitivity to pain (CIP); (2) primary erythromelalgia; (3) paroxysmal extreme pain disorder; (4) febrile seizures and recently (5) small fibre sensory neuropathy. We sought to investigate for SCN9A mutations in a clinically well-characterised cohort of patients with CIP and erythromelalgia. Methods We sequenced all exons of SCN9A in 19 clinically well-studied cases including 6 CIP and 13 erythromelalgia (9 with family history, 10 with small-fibre neuropathy). The identified variants were assessed in dbSNP135, 1K genome, NHLBI-Exome Sequencing Project (5400-exomes) databases, and 768 normal chromosomes. Results In erythromelalgia case 7, we identified a novel Q10>K mutation. In CIP case 6, we identified a novel, de novo splicing mutation (IVS8-2A>G); this splicing mutation compounded with a nonsense mutation (R523>X) and abolished SCN9A mRNA expression almost completely compared with his unaffected father. In CIP case 5, we found a variant (P610>T) previously considered causal for erythromelalgia, supporting recently raised doubt on its causal nature. We also found a splicing junction variant (IVS24-7delGTTT) in all 19 patients, this splicing variant was previously considered casual for CIP, but IVS24-7delGTTT was in fact the major allele in Caucasian populations. Conclusions Two novel SCN9A mutations were identified, but frequently polymorphism variants are found which may provide susceptibility factors in pain modulation. CIP and erythromelalgia are defined as genetically heterogeneous, and some SCN9A variants previously considered causal may only be modifying factors. PMID:23129781

  14. Burning feet in polycythemia vera - peripheral sensorimotor axonal neuropathy with erythromelalgia.

    PubMed

    Wollina, Uwe

    2015-01-01

    Polycythemia vera is a rare myeloproliferative disease. Cutaneous symptoms are uncommon. We report about a 72-year-old female patient with JAK2(V617F) -positive polycythemia who developed peripheral sensorimotor axonal neuropathy and erythromelalgia. Possible causes and treatment are discussed.

  15. Erythromelalgia-like presentation of chronic acquired demyelinating polyneuropathy in a setting of past alcohol abuse.

    PubMed

    Chuquilin, Miguel; Dhand, Upinder K

    2016-02-01

    Erythromelalgia may be primary or secondary to an underlying medical condition. Association with small fiber neuropathy and axonal large fiber peripheral neuropathy has been described. Erythromelalgia in the setting of acquired demyelinating neuropathy has not been reported. We report a 52-year-old woman with severe erythromelalgia, pain and burning, progressive weakness, hyporeflexia and distal pan-sensory deficits. Cerebrospinal fluid protein was 219 mg/dL. Nerve conduction study revealed extreme (ten-fold) prolongation of distal motor latencies, markedly slow motor nerve conduction, reduced terminal latency index, reduced distal compound muscle action potential (CMAP) amplitude, possible conduction blocks, and distal denervation. Treatment with intravenous immunoglobulin, prednisone and azathioprine resulted in marked clinical and electrophysiological improvement. Our patient fulfills the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP); however, the unique electrodiagnostic features and presentation with erythromelalgia may represent a CIDP variant or a novel dysimmune neuropathy, or may partly be related to neurotoxic effects of prior alcohol abuse. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Patient education and self-advocacy: queries and responses on pain management; erythromelalgia.

    PubMed

    Tokarz, Kyle A

    2009-01-01

    Questions from patients concerning a disease process known as erythromelalgia, its diagnosis, symptoms, and treatments are answered to help patients and caregivers understand the disease and its treatment. The responses from the author are intended to educate patients about their disease and make them more effective self-advocates.

  17. Temperature dependence of erythromelalgia mutation L858F in sodium channel Nav1.7.

    PubMed

    Han, Chongyang; Lampert, Angelika; Rush, Anthony M; Dib-Hajj, Sulayman D; Wang, Xiaoliang; Yang, Yong; Waxman, Stephen G

    2007-01-19

    The disabling chronic pain syndrome erythromelalgia (also termed erythermalgia) is characterized by attacks of burning pain in the extremities induced by warmth. Pharmacological treatment is often ineffective, but the pain can be alleviated by cooling of the limbs. Inherited erythromelalgia has recently been linked to mutations in the gene SCN9A, which encodes the voltage-gated sodium channel Nav1.7. Nav1.7 is preferentially expressed in most nociceptive DRG neurons and in sympathetic ganglion neurons. It has recently been shown that several disease-causing erythromelalgia mutations alter channel-gating behavior in a manner that increases DRG neuron excitability. Here we tested the effects of temperature on gating properties of wild type Nav1.7 and mutant L858F channels. Whole-cell voltage-clamp measurements on wild type or L858F channels expressed in HEK293 cells revealed that cooling decreases current density, slows deactivation and increases ramp currents for both mutant and wild type channels. However, cooling differentially shifts the midpoint of steady-state activation in a depolarizing direction for L858F but not for wild type channels. The cooling-dependent shift of the activation midpoint of L858F to more positive potentials brings the threshold of activation of the mutant channels closer to that of wild type Nav1.7 at lower temperatures, and is likely to contribute to the alleviation of painful symptoms upon cooling in affected limbs in patients with this erythromelalgia mutation.

  18. Early- and late-onset inherited erythromelalgia: genotype-phenotype correlation.

    PubMed

    Han, Chongyang; Dib-Hajj, Sulayman D; Lin, Zhimiao; Li, Yan; Eastman, Emmanuella M; Tyrrell, Lynda; Cao, Xianwei; Yang, Yong; Waxman, Stephen G

    2009-07-01

    Inherited erythromelalgia (IEM), an autosomal dominant disorder characterized by severe burning pain in response to mild warmth, has been shown to be caused by gain-of-function mutations of sodium channel Na(v)1.7 which is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons. Almost all physiologically characterized cases of IEM have been associated with onset in early childhood. Here, we report the voltage-clamp and current-clamp analysis of a new Na(v)1.7 mutation, Q10R, in a patient with clinical onset of erythromelalgia in the second decade. We show that the mutation in this patient hyperpolarizes activation by only -5.3 mV, a smaller shift than seen with early-onset erythromelalgia mutations, but similar to that of I136V, another mutation that is linked to delayed-onset IEM. Using current-clamp, we show that the expression of Q10R induces hyperexcitability in DRG neurons, but produces an increase in excitability that is smaller than the change produced by I848T, an early-onset erythromelalgia mutation. Our analysis suggests a genotype-phenotype relationship at three levels (clinical, cellular and molecular/ion channel), with mutations that produce smaller effects on sodium channel activation being associated with a smaller degree of DRG neuron excitability and later onset of clinical signs.

  19. Recurrent facial erythema with burning sensation and increased temperature: a variant of erythromelalgia or a new entity?

    PubMed

    Luo, Di-Qing; Zhao, Yu-Kun; Xu, Qing-Fang; He, Xiang-Qun; Wu, Liang-Cai

    2014-06-01

    Erythromelalgia is a rare clinical syndrome characterized by episodic attacks of burning pain, erythema, and increased temperature, primarily affecting the extremities, and in rare instances, involving the ear, face, neck, and the scrotum. The dermatoscopic features of erythromelalgia in a case with solely facial involvement have never been described previously. We describe a 14-year-old female who presented with erythema, burning sensation, and warmth on her face only, which mimic the features of erythromelalgia. Physical examination showed higher temperature on the involved cheeks than on axillas during the episode, while the temperature on both areas was the same between episodes. Dermatoscope showed more dilated vessels inside the erythema during the episodes than between the episodes. The symptoms had excellent response to the combination treatment of gabapentin, indomethacin, and topical lidocaine compounds. The present case is considered to be a variant of erythromelalgia. Its erythema may be resulted from the dilated vessels. Combination of modalities may provide effective management for erythromelalgia. "Erythermalgia" may be better than "erythromelalgia" to describe such conditions. Wiley Periodicals, Inc.

  20. Erythromelalgia presenting with premature exfoliation of primary teeth: a diagnostic dilemma.

    PubMed

    Prabhu, Neeta; Alexander, Sherene; Wong, Peter; Cameron, Angus

    2012-01-01

    Erythromelalgia is an extremely rare neurovascular disorder, characterized by symptoms of red, hot, and painful extremities. There is considerable confusion regarding the etiology and pathogenesis of this condition, and the diagnosis is essentially a clinical one. This condition may occur in isolation or in association with other myeloproliferative disorders. Unfortunately, no therapy is effective consistently in managing the symptoms, although early diagnosis can aid in psychological counseling and minimizing the frequency and severity of the attacks. The purpose of this report was to describe the case of a child presenting with premature loss of primary teeth and the difficulties in determining the final diagnosis of erythromelalgia, which responded positively to low-grade aspirin therapy.

  1. Temperature dependence of erythromelalgia mutation L858F in sodium channel Nav1.7

    PubMed Central

    Han, Chongyang; Lampert, Angelika; Rush, Anthony M; Dib-Hajj, Sulayman D; Wang, Xiaoliang; Yang, Yong; Waxman, Stephen G

    2007-01-01

    Background The disabling chronic pain syndrome erythromelalgia (also termed erythermalgia) is characterized by attacks of burning pain in the extremities induced by warmth. Pharmacological treatment is often ineffective, but the pain can be alleviated by cooling of the limbs. Inherited erythromelalgia has recently been linked to mutations in the gene SCN9A, which encodes the voltage-gated sodium channel Nav1.7. Nav1.7 is preferentially expressed in most nociceptive DRG neurons and in sympathetic ganglion neurons. It has recently been shown that several disease-causing erythromelalgia mutations alter channel-gating behavior in a manner that increases DRG neuron excitability. Results Here we tested the effects of temperature on gating properties of wild type Nav1.7 and mutant L858F channels. Whole-cell voltage-clamp measurements on wild type or L858F channels expressed in HEK293 cells revealed that cooling decreases current density, slows deactivation and increases ramp currents for both mutant and wild type channels. However, cooling differentially shifts the midpoint of steady-state activation in a depolarizing direction for L858F but not for wild type channels. Conclusion The cooling-dependent shift of the activation midpoint of L858F to more positive potentials brings the threshold of activation of the mutant channels closer to that of wild type Nav1.7 at lower temperatures, and is likely to contribute to the alleviation of painful symptoms upon cooling in affected limbs in patients with this erythromelalgia mutation. PMID:17239250

  2. [Metanephric adenoma of the kidney associated with polycythemia and erythromelalgia: report of one case].

    PubMed

    Zambrano, Norman; Vivaldi, Bruno; Espinoza, Ricardo

    2012-05-01

    We report a 21-year-old male, presenting with erythromelalgia and polycythemia. A solid renal mass of the lower pole of the right kidney was discovered. The patient was subjected to a right open partial nephrectomy. The pathological study of the surgical specimen showed a metanephric adenoma of the kidney. The patient had an uneventful postoperative evolution. Currently the patient is in good health without evidence of recurrence of the tumor and normal hematological parameters.

  3. Intervention for erythromelalgia, a chronic pain syndrome: comprehensive pain rehabilitation center, Mayo Clinic.

    PubMed

    Durosaro, Olayemi; Davis, Mark D P; Hooten, W Michael; Kerkvliet, Jennifer L

    2008-12-01

    To describe the response in patients with erythromelalgia to the pain rehabilitation program at Mayo Clinic, Rochester, Minnesota. Retrospective case series. Comprehensive Pain Rehabilitation Center at a tertiary referral medical center. Patients Eight patients with erythromelalgia admitted to the pain rehabilitation program from January 1, 2002, through June 30, 2007. The Multidimensional Pain Inventory, the 36-Item Short Form Health Survey, the Pain Catastrophizing Scale, and the Center for Epidemiologic Studies Depression Scale were administered at admission and dismissal from the program. Mean differences in scores were compared using 2-sided paired t tests. Scores for the life interference, life control, and general activity subscales of the Multidimensional Pain Inventory showed significant improvement from admission to dismissal (all P < .05). Similarly, the scores of the Pain Catastrophizing Scale, the Center for Epidemiologic Studies Depression Scale, and the physical functioning and emotional role limitation subscales of the 36-Item Short Form Health Survey were significantly improved after intervention (all P < .01). Conclusion The results of our study indicate that pain rehabilitation is a useful method for managing pain-related impairment in physical and emotional functioning in patients with erythromelalgia.

  4. SCN10A Mutation in a Patient with Erythromelalgia Enhances C-Fiber Activity Dependent Slowing.

    PubMed

    Kist, Andreas M; Sagafos, Dagrun; Rush, Anthony M; Neacsu, Cristian; Eberhardt, Esther; Schmidt, Roland; Lunden, Lars Kristian; Ørstavik, Kristin; Kaluza, Luisa; Meents, Jannis; Zhang, Zhiping; Carr, Thomas Hedley; Salter, Hugh; Malinowsky, David; Wollberg, Patrik; Krupp, Johannes; Kleggetveit, Inge Petter; Schmelz, Martin; Jørum, Ellen; Lampert, Angelika; Namer, Barbara

    2016-01-01

    Gain-of-function mutations in the tetrodotoxin (TTX) sensitive voltage-gated sodium channel (Nav) Nav1.7 have been identified as a key mechanism underlying chronic pain in inherited erythromelalgia. Mutations in TTX resistant channels, such as Nav1.8 or Nav1.9, were recently connected with inherited chronic pain syndromes. Here, we investigated the effects of the p.M650K mutation in Nav1.8 in a 53 year old patient with erythromelalgia by microneurography and patch-clamp techniques. Recordings of the patient's peripheral nerve fibers showed increased activity dependent slowing (ADS) in CMi and less spontaneous firing compared to a control group of erythromelalgia patients without Nav mutations. To evaluate the impact of the p.M650K mutation on neuronal firing and channel gating, we performed current and voltage-clamp recordings on transfected sensory neurons (DRGs) and neuroblastoma cells. The p.M650K mutation shifted steady-state fast inactivation of Nav1.8 to more hyperpolarized potentials and did not significantly alter any other tested gating behaviors. The AP half-width was significantly broader and the stimulated action potential firing rate was reduced for M650K transfected DRGs compared to WT. We discuss the potential link between enhanced steady state fast inactivation, broader action potential width and the potential physiological consequences.

  5. A new TRPV3 missense mutation in a patient with Olmsted syndrome and erythromelalgia.

    PubMed

    Duchatelet, Sabine; Pruvost, Solenn; de Veer, Simon; Fraitag, Sylvie; Nitschké, Patrick; Bole-Feysot, Christine; Bodemer, Christine; Hovnanian, Alain

    2014-03-01

    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.

  6. SCN10A Mutation in a Patient with Erythromelalgia Enhances C-Fiber Activity Dependent Slowing

    PubMed Central

    Neacsu, Cristian; Eberhardt, Esther; Schmidt, Roland; Lunden, Lars Kristian; Ørstavik, Kristin; Kaluza, Luisa; Meents, Jannis; Zhang, Zhiping; Carr, Thomas Hedley; Salter, Hugh; Malinowsky, David; Wollberg, Patrik; Krupp, Johannes; Kleggetveit, Inge Petter; Schmelz, Martin; Jørum, Ellen; Namer, Barbara

    2016-01-01

    Gain-of-function mutations in the tetrodotoxin (TTX) sensitive voltage-gated sodium channel (Nav) Nav1.7 have been identified as a key mechanism underlying chronic pain in inherited erythromelalgia. Mutations in TTX resistant channels, such as Nav1.8 or Nav1.9, were recently connected with inherited chronic pain syndromes. Here, we investigated the effects of the p.M650K mutation in Nav1.8 in a 53 year old patient with erythromelalgia by microneurography and patch-clamp techniques. Recordings of the patient’s peripheral nerve fibers showed increased activity dependent slowing (ADS) in CMi and less spontaneous firing compared to a control group of erythromelalgia patients without Nav mutations. To evaluate the impact of the p.M650K mutation on neuronal firing and channel gating, we performed current and voltage-clamp recordings on transfected sensory neurons (DRGs) and neuroblastoma cells. The p.M650K mutation shifted steady-state fast inactivation of Nav1.8 to more hyperpolarized potentials and did not significantly alter any other tested gating behaviors. The AP half-width was significantly broader and the stimulated action potential firing rate was reduced for M650K transfected DRGs compared to WT. We discuss the potential link between enhanced steady state fast inactivation, broader action potential width and the potential physiological consequences. PMID:27598514

  7. A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity.

    PubMed

    Sheets, Patrick L; Jackson, James O; Waxman, Stephen G; Dib-Hajj, Sulayman D; Cummins, Theodore R

    2007-06-15

    Mutations in the TTX-sensitive voltage-gated sodium channel subtype Nav1.7 have been implicated in the painful inherited neuropathy, hereditary erythromelalgia. Hereditary erythromelalgia can be difficult to treat and, although sodium channels are targeted by local anaesthetics such as lidocaine (lignocaine), some patients do not respond to treatment with local anaesthetics. This study examined electrophysiological differences in Nav1.7 caused by a hereditary erythromelalgia mutation (N395K) that lies within the local anaesthetic binding site of the channel. The N395K mutation produced a hyperpolarized voltage dependence of activation, slower kinetics of deactivation, and impaired steady-state slow inactivation. Computer simulations indicate that the shift in activation is the major determinant of the hyperexcitability induced by erythromelalgia mutations in sensory neurons, but that changes in slow inactivation can modulate the overall impact on excitability. This study also investigated lidocaine inhibition of the Nav1.7-N395K channel. We show that the N395K mutation attenuates the inhibitory effects of lidocaine on both resting and inactivated Nav1.7. The IC50 for lidocaine was estimated at 500 microM for inactivated wild-type Nav1.7 and 2.8 mM for inactivated Nav1.7-N395K. The N395K mutation also significantly reduced use-dependent inhibition of lidocaine on Nav1.7 current. In contrast, a different hereditary erythromelalgia mutation (F216S), not located in the local anaesthetic binding site, had no effect on lidocaine inhibition of Nav1.7 current. Our observation of reduced lidocaine inhibition on Nav1.7-N395K shows that the residue N395 is critical for lidocaine binding to Nav1.7 and suggests that the response of individuals with hereditary erythromelalgia to lidocaine treatment may be determined, at least in part, by their specific genotype.

  8. A Nav1.7 channel mutation associated with hereditary erythromelalgia contributes to neuronal hyperexcitability and displays reduced lidocaine sensitivity

    PubMed Central

    Sheets, Patrick L; Jackson, James O; Waxman, Stephen G; Dib-Hajj, Sulayman D; Cummins, Theodore R

    2007-01-01

    Mutations in the TTX-sensitive voltage-gated sodium channel subtype Nav1.7 have been implicated in the painful inherited neuropathy, hereditary erythromelalgia. Hereditary erythromelalgia can be difficult to treat and, although sodium channels are targeted by local anaesthetics such as lidocaine (lignocaine), some patients do not respond to treatment with local anaesthetics. This study examined electrophysiological differences in Nav1.7 caused by a hereditary erythromelalgia mutation (N395K) that lies within the local anaesthetic binding site of the channel. The N395K mutation produced a hyperpolarized voltage dependence of activation, slower kinetics of deactivation, and impaired steady-state slow inactivation. Computer simulations indicate that the shift in activation is the major determinant of the hyperexcitability induced by erythromelalgia mutations in sensory neurons, but that changes in slow inactivation can modulate the overall impact on excitability. This study also investigated lidocaine inhibition of the Nav1.7-N395K channel. We show that the N395K mutation attenuates the inhibitory effects of lidocaine on both resting and inactivated Nav1.7. The IC50 for lidocaine was estimated at 500 μm for inactivated wild-type Nav1.7 and 2.8 mm for inactivated Nav1.7-N395K. The N395K mutation also significantly reduced use-dependent inhibition of lidocaine on Nav1.7 current. In contrast, a different hereditary erythromelalgia mutation (F216S), not located in the local anaesthetic binding site, had no effect on lidocaine inhibition of Nav1.7 current. Our observation of reduced lidocaine inhibition on Nav1.7-N395K shows that the residue N395 is critical for lidocaine binding to Nav1.7 and suggests that the response of individuals with hereditary erythromelalgia to lidocaine treatment may be determined, at least in part, by their specific genotype. PMID:17430993

  9. A novel Nav1.7 mutation producing carbamazepine-responsive erythromelalgia.

    PubMed

    Fischer, Tanya Z; Gilmore, Elaine S; Estacion, Mark; Eastman, Emmanuella; Taylor, Sean; Melanson, Michel; Dib-Hajj, Sulayman D; Waxman, Stephen G

    2009-06-01

    Human and animal studies have shown that Na(v)1.7 sodium channels, which are preferentially expressed within nociceptors and sympathetic neurons, play a major role in inflammatory and neuropathic pain. Inherited erythromelalgia (IEM) has been linked to gain-of-function mutations of Na(v)1.7. We now report a novel mutation (V400M) in a three-generation Canadian family in which pain is relieved by carbamazepine (CBZ). We extracted genomic DNA from blood samples of eight members of the family, and the sequence of SCN9A coding exons was compared with the reference Na(v)1.7 complementary DNA. Wild-type Na(v)1.7 and V400M cell lines were then analyzed using whole-cell patch-clamp recording for changes in activation, deactivation, steady-state inactivation, and ramp currents. Whole-cell patch-clamp studies of V400M demonstrate changes in activation, deactivation, steady-state inactivation, and ramp currents that can produce dorsal root ganglia neuron hyperexcitability that underlies pain in these patients. We show that CBZ, at concentrations in the human therapeutic range, normalizes the voltage dependence of activation and inactivation of this inherited erythromelalgia mutation in Na(v)1.7 but does not affect these parameters in wild-type Na(v)1.7. Our results demonstrate a normalizing effect of CBZ on mutant Na(v)1.7 channels in this kindred with CBZ-responsive inherited erythromelalgia. The selective effect of CBZ on the mutant Na(v)1.7 channel appears to explain the ameliorative response to treatment in this kindred. Our results suggest that functional expression and pharmacological studies may provide mechanistic insights into hereditary painful disorders.

  10. A Novel Nav1.7 Mutation Producing Carbamazepine-Responsive Erythromelalgia

    PubMed Central

    Fischer, Tanya Z.; Gilmore, Elaine S.; Estacion, Mark; Eastman, Emmanuella; Taylor, Sean; Melanson, Michel; Dib-Hajj, Sulayman D.; Waxman, Stephen G.

    2014-01-01

    Objective Human and animal studies have shown that Nav1.7 sodium channels, which are preferentially expressed within nociceptors and sympathetic neurons, play a major role in inflammatory and neuropathic pain. Inherited erythromelalgia (IEM) has been linked to gain-of-function mutations of Nav1.7. We now report a novel mutation (V400M) in a three-generation Canadian family in which pain is relieved by carbamazepine (CBZ). Methods We extracted genomic DNA from blood samples of eight members of the family, and the sequence of SCN9A coding exons was compared with the reference Nav1.7 complementary DNA. Wild-type Nav1.7 and V400M cell lines were then analyzed using whole-cell patch-clamp recording for changes in activation, deactivation, steady-state inactivation, and ramp currents. Results Whole-cell patch-clamp studies of V400M demonstrate changes in activation, deactivation, steady-state inactivation, and ramp currents that can produce dorsal root ganglia neuron hyperexcitability that underlies pain in these patients. We show that CBZ, at concentrations in the human therapeutic range, normalizes the voltage dependence of activation and inactivation of this inherited erythromelalgia mutation in Nav1.7 but does not affect these parameters in wild-type Nav1.7. Interpretation Our results demonstrate a normalizing effect of CBZ on mutant Nav1.7 channels in this kindred with CBZ-responsive inherited erythromelalgia. The selective effect of CBZ on the mutant Nav1.7 channel appears to explain the ameliorative response to treatment in this kindred. Our results suggest that functional expression and pharmacological studies may provide mechanistic insights into hereditary painful disorders. PMID:19557861

  11. Topical amitriptyline combined with ketamine for the treatment of erythromelalgia: a retrospective study of 36 patients at Mayo Clinic.

    PubMed

    Poterucha, Timothy J; Weiss, William T; Warndahl, Roger A; Rho, Richard H; Sandroni, Paola; Davis, Mark D P; Murphy, Sinead L

    2013-03-01

    Erythromelalgia is an uncommon neurovascular disorder characterized by redness, increased skin temperature, and pain that usually occurs in the extremities. Treatment remains challenging because of its varying response to medical therapy. The objective of this study was to assess the response of erythromelalgia to compounded topical amitriptyline-ketamine. We retrospectively evaluated 36 patients with erythromelalgia who were treated with compounded topical amitriptyline-ketamine from January 1, 2004, through January 31, 2011. Thirty-two patients (89%) were female. Mean (standard deviation) age was 44.7 (15.8) years (range, 5-74 years). Patients applied the medication 1 to 6 times per day (median, 5 times). One patient (3%) had complete relief from symptoms, 14 (39%) had substantial relief, 12 (33%) had some relief, 7 (19%) had no relief, and 2 (6%) had local worsening of symptoms. No patients had systemic adverse effects. A majority of patients with erythromelalgia (75%) reported improvement in pain with topical application of a compounded amitriptyline-ketamine formulation. The medication was well tolerated.

  12. Pediatric erythromelalgia: a retrospective review of 32 cases evaluated at Mayo Clinic over a 37-year period.

    PubMed

    Cook-Norris, Robert H; Tollefson, Megha M; Cruz-Inigo, Andres E; Sandroni, Paola; Davis, Mark D P; Davis, Dawn M R

    2012-03-01

    Erythromelalgia has not been well characterized in the pediatric population. We sought to review our experience of erythromelalgia in the pediatric age group. We conducted a retrospective review of patients 18 years of age and younger with a diagnosis of erythromelalgia who were examined at Mayo Clinic in Rochester, MN, from 1970 to 2007. The records of 32 patients (girls, 22 [69%]) were evaluated. Mean age was 14.1 years (range, 5-18 years) and mean time to diagnosis was 5.2 years. Seven patients (22%) had a first-degree relative with erythromelalgia; 4 were from the same family. Physical activity was limited because of discomfort in 21 patients (66%) and school attendance was affected in 11 patients (34%). Noninvasive vascular studies, which compared temperature, laser Doppler flow, and transcutaneous oximetry in the toes, identified vascular abnormalities in 13 (93%) of 14 patients. Neurophysiologic studies with autonomic reflex screening (including quantitative sudomotor axon reflex test and thermoregulatory sweat testing) showed evidence of a small-fiber neuropathy involving the skin in 10 (59%) of 17 patients studied; there was no evidence of large-fiber neuropathy in 20 patients in whom electromyographic and nerve conduction studies were performed. Topical lidocaine was the most commonly prescribed treatment (44%). Fifteen patients were monitored for an average of 9.1 years (median, 5.0 years; range, 0.4-23.7 years). At last follow-up, 5 patients had stable disease, 4 showed improvement, two had resolution, one reported worsening of symptoms, and 3 had died (one suicide). Conclusions are limited because this was a retrospective chart review. Erythromelalgia in pediatric patients is associated with substantial morbidity and even death. The majority of cases are not inherited. Most patients studied have associated small-fiber neuropathy. The disease course is variable. A reliable and safe treatment has not been determined. Copyright © 2011 American Academy of

  13. Clinical features and management of erythromelalgia: long term follow-up of 46 cases.

    PubMed

    Parker, Louise K; Ponte, Cristina; Howell, Kevin J; Ong, Voon H; Denton, Christopher P; Schreiber, Benjamin E

    2017-01-01

    To review our clinical experience of this rare condition and describe the clinical features and response to therapy in a cohort of patients with erythromelalgia (EM), a rare condition, characterised by paroxysmal hyperthermia of the extremities with erythema, pain and intense burning. A review was made of the electronic and paper medical records of patients with the diagnosis of EM, with a telephone interview to verify and complete clinical information relating treatment and outcome. 46 patients (41 females) were included in this study. Mean age was 57 years and mean duration of symptoms was 16 years. Raynaud's phenomenon was present in 36 patients (80%) and 4 patients (9%) had systemic sclerosis. Smoking (current or previous) was identified as a possible risk factor in 26 cases and exposure to chronic vibration in 3 cases. Overall, the effect on quality of life was mild in 15% of cases, moderate in 30% and severe in 48%. The most common symptoms were burning (96%), heat (93%), pain (87%), and redness (83%). Symptoms affected the lower limbs in 98% of cases, upper limbs in 76%, face in 20% and trunk in 11%. Triggers included heat (85%), exercise (78%) and time of day (76%). Various medications were tried, showing poor effect in most cases. Intravenous iloprost was given to 27 patients, with benefit in 17 patients (63%). Erythromelalgia is a rare chronic debilitating condition. Exercise, heat and night time are common triggers. Current medical therapies are seldom effective and further research is sorely needed.

  14. Inherited erythromelalgia due to mutations in SCN9A: natural history, clinical phenotype and somatosensory profile.

    PubMed

    McDonnell, Aoibhinn; Schulman, Betsy; Ali, Zahid; Dib-Hajj, Sulayman D; Brock, Fiona; Cobain, Sonia; Mainka, Tina; Vollert, Jan; Tarabar, Sanela; Waxman, Stephen G

    2016-04-01

    Inherited erythromelalgia, the first human pain syndrome linked to voltage-gated sodium channels, is widely regarded as a genetic model of human pain. Because inherited erythromelalgia was linked to gain-of-function changes of sodium channel Na(v)1.7 only a decade ago, the literature has mainly consisted of reports of genetic and/or clinical characterization of individual patients. This paper describes the pattern of pain, natural history, somatosensory profile, psychosocial status and olfactory testing of 13 subjects with primary inherited erythromelalgia with mutations of SCN9A, the gene encoding Na(v)1.7. Subjects were clinically profiled using questionnaires, quantitative sensory testing and olfaction testing during the in-clinic phase of the study. In addition, a detailed pain phenotype for each subject was obtained over a 3-month period at home using diaries, enabling subjects to self-report pain attacks, potential triggers, duration and severity of pain. All subjects reported pain and heat in the extremities (usually feet and/or hands), with pain attacks triggered by heat or exercise and relieved mainly by non-pharmacological manoeuvres such as cooling. A large proportion of pain attacks (355/1099; 32%) did not involve a specific trigger. There was considerable variability in the number, duration and severity of pain attacks between subjects, even those carrying the same mutation within a family, and within individuals over the 12-13 week observation period. Most subjects (11/13) had pain between attacks. For these subjects, mean pain severity between pain attacks was usually lower than that during an attack. Olfaction testing using the Sniffin'T test did not demonstrate hyperosmia. One subject had evidence of orthostatic hypotension. Overall, there was a statistically significant correlation between total Hospital Anxiety and Depression Scale scores (P= 0.005) and pain between attacks and for Hospital Anxiety and Depression Scale Depression scores and pain

  15. An Egyptian child with erythromelalgia responding to a new line of treatment: a case report and review of the literature

    PubMed Central

    2014-01-01

    Introduction Erythromelalgia is a rare clinical syndrome characterized by episodic erythema, warmth and intense burning pain, which commonly involves the extremities. For those affected, this disorder may lead to significant long-term morbidity. Unfortunately, to date, no definitive therapy is available. This case report describes an Egyptian child with primary erythromelalgia that manifested at an early age and showed partial response to therapy with cetirizine hydrochloride. This anecdotal case report may have a diagnostic value for clinicians who have not seen this disorder. Case presentation A 34-month-old previously healthy right-handed Hamitic boy without any significant past medical history presented at the age of 2 years with episodic bilateral pain in his feet. His mother reported associated warmth and erythema localized to his feet that never extended beyond his ankle joints. This pain is triggered by exertion and/or warm temperature exposure and is relieved by cooling measures. The diagnosis of erythromelalgia was made based on the patient’s medical history and a thorough physical examination during the episodes. No evidence of local or systemic infection was present. Other causes for the symptoms were excluded by a negative extensive diagnostic work-up. Our patient did not respond to ibuprofen (15mg/kg/dose) three times a day but partial improvement with the oral non-sedating antihistaminic cetirizine hydrochloride (2.5mg/kg/once daily) was observed. When the child stopped cetirizine hydrochloride for 1 month as a test, the symptoms became aggravated and were relieved when cetirizine therapy was restarted. Cetirizine hydrochloride had not previously been reported to have this effect in children with erythromelalgia. Conclusions Erythromelalgia is a clinical syndrome of which the etiology, diagnosis and management are controversial. We describe a case of a 34-month-old Egyptian child with primary erythromelalgia that manifested at an early age. We

  16. Erythromelalgia in the pediatric patient: role of computed-tomography-guided lumbar sympathetic blockade

    PubMed Central

    Kundu, Anjana; Rafiq, Mahmood; Warren, Patrick S; Tobias, Joseph D

    2016-01-01

    Erythromelalgia (EM) is an uncommon condition characterized by erythema, increased skin temperature, and burning pain, most frequently occurring in the lower extremities. The pain is generally very severe and treatment can be extremely challenging, especially in the pediatric and adolescent population. We report a series of three cases of primary EM in pediatric patients involving the lower extremities, refractory to medical treatment that responded favorably to computed-tomography-guided lumbar sympathetic blockade. There was a significant improvement in pain scores, quality of life, and overall function as well as decreased analgesic requirements. Lumbar sympathetic blockade should be considered as a therapeutic modality in pediatric and adolescent patients with EM who are refractory to other treatments. PMID:27799815

  17. Primary erythromelalgia with leukonychia combined with ulcerations and infection by Monilia guilliermondii.

    PubMed

    Yuan, Zhengyong; He, Changxiao

    2011-03-01

    An 8-year-old girl presented with recurrent redness, warming, and pain of the lower extremities for more than 4 years, with exacerbation and accompanying swelling for the past 1 year and ulcers for 1 month. The episodes were triggered by exertion and heat. Her family history revealed that her mother had experienced similar symptoms. Physical examination showed proximal white nails and the distal border in normal color. There was some ulceration in the dorsum of the feet with thick, yellowish secretions, covered by some crusted lesions. Laboratory culture result showed that there were many Monilia guilliermondii in the ulcer specimen. Finally, she was diagnosed with juvenile onset of primary erythromelalgia and was given symptomatic treatment for neuropathic pain and pedal ulcers. Copyright © 2011 Elsevier Taiwan LLC. All rights reserved.

  18. Genome Sequence of Erythromelalgia-Related Poxvirus Identifies it as an Ectromelia Virus Strain

    PubMed Central

    Mendez-Rios, Jorge D.; Martens, Craig A.; Bruno, Daniel P.; Porcella, Stephen F.; Zheng, Zhi-Ming; Moss, Bernard

    2012-01-01

    Erythromelagia is a condition characterized by attacks of burning pain and inflammation in the extremeties. An epidemic form of this syndrome occurs in secondary students in rural China and a virus referred to as erythromelalgia-associated poxvirus (ERPV) was reported to have been recovered from throat swabs in 1987. Studies performed at the time suggested that ERPV belongs to the orthopoxvirus genus and has similarities with ectromelia virus, the causative agent of mousepox. We have determined the complete genome sequence of ERPV and demonstrated that it has 99.8% identity to the Naval strain of ectromelia virus and a slighly lower identity to the Moscow strain. Small DNA deletions in the Naval genome that are absent from ERPV may suggest that the sequenced strain of Naval was not the immediate progenitor of ERPV. PMID:22558090

  19. Genome sequence of erythromelalgia-related poxvirus identifies it as an ectromelia virus strain.

    PubMed

    Mendez-Rios, Jorge D; Martens, Craig A; Bruno, Daniel P; Porcella, Stephen F; Zheng, Zhi-Ming; Moss, Bernard

    2012-01-01

    Erythromelagia is a condition characterized by attacks of burning pain and inflammation in the extremeties. An epidemic form of this syndrome occurs in secondary students in rural China and a virus referred to as erythromelalgia-associated poxvirus (ERPV) was reported to have been recovered from throat swabs in 1987. Studies performed at the time suggested that ERPV belongs to the orthopoxvirus genus and has similarities with ectromelia virus, the causative agent of mousepox. We have determined the complete genome sequence of ERPV and demonstrated that it has 99.8% identity to the Naval strain of ectromelia virus and a slighly lower identity to the Moscow strain. Small DNA deletions in the Naval genome that are absent from ERPV may suggest that the sequenced strain of Naval was not the immediate progenitor of ERPV.

  20. Erythromelalgia: Incidence and clinical experience in a single centre in Sweden.

    PubMed

    Alhadad, Alaa; Wollmer, Per; Svensson, Ake; Eriksson, Karl-Fredrik

    2012-01-01

    Erythromelalgia (EM) incidence has not been well studied and there are only two studies published on this subject as far as we know. The aims are to study the incidence of this rare condition in the south of Sweden, to report the clinical experience from a single centre including characterisation of comorbidity and to report on prognosis. Retrospective study of a population-based analysis of data from the southernmost part of Sweden corresponding to the median age of the patients (Statistics Sweden). The diagnosis of EM is based on the medical record reflecting the triad of redness, burning pain and increased temperature of the feet or hands or both. We evaluated the presence or absence of EM triad by recording the history, physical examination, laboratory analysis, cold provocation test and laser Doppler imaging, and by searching for any confounding disease in cases of suspected EM. During a 10.5 year period we clinically identified 27 patients with EM. Median age was 49 [IQR (34 - 68)] years, 19 (70 %) were women. The mean delay from the onset of the symptoms to the time of diagnosis was 4.5 (SD ± 3.9) years. Gender and age adjusted incidence of EM for our region was calculated to be 0.36 per 100 000 persons per year. Three patients developed intraabdominal cancer during the follow up, but there was no mortality directed related to EM. The overall population-based incidence of erythromelalgia was 0.36 per 100 000 which is identical with a previous report in a Scandinavian population.

  1. Pain disorders and erythromelalgia caused by voltage-gated sodium channel mutations.

    PubMed

    Dabby, Ron

    2012-02-01

    Voltage-gated sodium channels play a pivotal role in pain transmission. They are widely expressed in nociceptive neurons, and participate in the generation of action potentials. Alteration in ionic conduction of these channels causes abnormal electrical firing, thus renders neurons hyperexcitable. So far, mutations in the Na(v)1.7 sodium channel, which is expressed in the dorsal root ganglia cells and sympathetic neurons, have been described to cause perturbations in pain sensation. Until recently, gain-of-function Na(v)1.7 mutations were known to cause two neuropathic pain syndromes: inherited erythromelalgia and paroxysmal extreme pain syndrome. These syndromes are inherited in a dominant trait; they usually begin in childhood or infancy, and are characterized by attacks of severe neuropathic pain accompanied with autonomic symptoms. Recently, small fiber neuropathy and chronic nonparoxysmal pain have been described in patients harboring gain-of-function mutations in Na(v)1.7 channel. Loss-of-function mutations in Na(v)1.7 are extremely rare, and invariably cause congenital inability to perceive pain.

  2. Microneurographic findings of relevance to pain in patients with erythromelalgia and patients with diabetic neuropathy.

    PubMed

    Orstavik, Kristin; Jørum, Ellen

    2010-02-19

    Mechanisms responsible for neuropathic pain are still unclear. By using microneurography we have been able to record from single C-nociceptive and sympathetic fibers in patients and attempted to uncover possible abnormal functional properties of these fibers of relevance for pain. In two previously published studies conducted on patients with erythromelalgia and patients with diabetic neuropathy, some of the major findings were: (1) spontaneous activity in nociceptive fibers, (2) sensitization of mechano-insensitive C-fibers, and (3) an altered distribution of C-afferent nerve fibers with a reversal of the proportion of the two main subtypes of C-nociceptive fibers, indicating a loss of function of polymodal nociceptors. Although some degree of spontaneous activity and sensitization also was found in patients without pain, these mechanisms may still be of importance for the development and maintenance of neuropathic pain. A change in the distribution of C-nociceptive fibers in the skin as shown in the patients with diabetic neuropathy may help to reveal mechanisms responsible for small-fiber dysfunction.

  3. A large temperature fluctuation may trigger an epidemic erythromelalgia outbreak in China.

    PubMed

    Liu, Tao; Zhang, Yonghui; Lin, Hualiang; Lv, Xiaojuan; Xiao, Jianpeng; Zeng, Weilin; Gu, Yuzhou; Rutherford, Shannon; Tong, Shilu; Ma, Wenjun

    2015-03-30

    Although erythromelalgia (EM) has been documented in the literature for almost 150 years, it is still poorly understood. To overcome this limitation, we examined the spatial distribution of epidemic EM, and explored the association between temperature fluctuation and epidemic EM outbreaks in China. We searched all peer-reviewed literature on primary epidemic EM outbreaks in China. A two-stage model was used to characterize the relationship between temperature fluctuation and epidemic EM outbreaks. We observed that epidemic EM outbreaks were reported from 13 provinces during 1960-2014 and they mainly occurred between February and March in southern China. The majority of EM cases were middle school students, with a higher incidence rate in female and resident students. The major clinical characteristics of EM cases included burning, sharp, tingling and/or stinging pain in toes, soles and/or dorsum of feet, fever, erythema and swelling. A large "V"-shaped fluctuation of daily average temperature (TM) observed during the epidemic EM outbreaks was significantly associated with the number of daily EM cases (β = 1.22, 95%CI: 0.66 ~ 1.79), which indicated that this "V"-shaped fluctuation of TM probably triggered the epidemic EM outbreaks.

  4. A large temperature fluctuation may trigger an epidemic erythromelalgia outbreak in China

    NASA Astrophysics Data System (ADS)

    Liu, Tao; Zhang, Yonghui; Lin, Hualiang; Lv, Xiaojuan; Xiao, Jianpeng; Zeng, Weilin; Gu, Yuzhou; Rutherford, Shannon; Tong, Shilu; Ma, Wenjun

    2015-03-01

    Although erythromelalgia (EM) has been documented in the literature for almost 150 years, it is still poorly understood. To overcome this limitation, we examined the spatial distribution of epidemic EM, and explored the association between temperature fluctuation and epidemic EM outbreaks in China. We searched all peer-reviewed literature on primary epidemic EM outbreaks in China. A two-stage model was used to characterize the relationship between temperature fluctuation and epidemic EM outbreaks. We observed that epidemic EM outbreaks were reported from 13 provinces during 1960-2014 and they mainly occurred between February and March in southern China. The majority of EM cases were middle school students, with a higher incidence rate in female and resident students. The major clinical characteristics of EM cases included burning, sharp, tingling and/or stinging pain in toes, soles and/or dorsum of feet, fever, erythema and swelling. A large ``V''-shaped fluctuation of daily average temperature (TM) observed during the epidemic EM outbreaks was significantly associated with the number of daily EM cases (β = 1.22, 95%CI: 0.66 ~ 1.79), which indicated that this ``V''-shaped fluctuation of TM probably triggered the epidemic EM outbreaks.

  5. Alternative splicing may contribute to time-dependent manifestation of inherited erythromelalgia.

    PubMed

    Choi, Jin-Sung; Cheng, Xiaoyang; Foster, Edmund; Leffler, Andreas; Tyrrell, Lynda; Te Morsche, Rene H M; Eastman, Emmanuella M; Jansen, Henry J; Huehne, Kathrin; Nau, Carla; Dib-Hajj, Sulayman D; Drenth, Joost P H; Waxman, Stephen G

    2010-06-01

    The Na(v)1.7 sodium channel is preferentially expressed in nocioceptive dorsal root ganglion and sympathetic ganglion neurons. Gain-of-function mutations in Na(v)1.7 produce the nocioceptor hyperexcitability underlying inherited erythromelalgia, characterized in most kindreds by early-age onset of severe pain. Here we describe a mutation (Na(v)1.7-G616R) in a pedigree with adult-onset of pain in some family members. The mutation shifts the voltage-dependence of channel fast-inactivation in a depolarizing direction in the adult-long, but not in the neonatal-short splicing isoform of Na(v)1.7 in dorsal root ganglion neurons. Altered inactivation does not depend on the age of the dorsal root ganglion neurons in which the mutant is expressed. Expression of the mutant adult-long, but not the mutant neonatal-short, isoform of Na(v)1.7 renders dorsal root ganglion neurons hyperexcitable, reducing the current threshold for generation of action potentials, increasing spontaneous activity and increasing the frequency of firing in response to graded suprathreshold stimuli. This study shows that a change in relative expression of splice isoforms can contribute to time-dependent manifestation of the functional phenotype of a sodium channelopathy.

  6. Erythromelalgia mutation Q875E Stabilizes the activated state of sodium channel Nav1.7.

    PubMed

    Stadler, Theresa; O'Reilly, Andrias O; Lampert, Angelika

    2015-03-06

    The human voltage-gated sodium channel Nav1.7 plays a crucial role in transmission of noxious stimuli. The inherited pain disorder erythromelalgia (IEM) has been linked to Nav1.7 gain-of-function mutations. Here we show that the IEM-associated Q875E mutation located on the pore module of Nav1.7 produces a large hyperpolarizing shift (-18 mV) in the voltage dependence of activation. Three-dimensional homology modeling indicates that the side chains of Gln-875 and the gating charge Arg-214 of the domain I voltage sensor are spatially close in the activated conformation of the channel. We verified this proximity by using an engineered disulfide bridge approach. The Q875E mutation introduces a negative charge that may modify the local electrical field experienced by the voltage sensor and, upon activation, interact directly via a salt bridge with the Arg-214 gating charge residue. Together these processes could promote transition to, and stabilization of, the domain I voltage sensor in the activated conformation and thus produce the observed gain of function. In support of this hypothesis, an increase in the extracellular concentration of Ca(2+) or Mg(2+) reverted the voltage dependence of activation of the IEM mutant to near WT values, suggesting a cation-mediated electrostatic screening of the proposed interaction between Q875E and Arg-214. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  7. A large temperature fluctuation may trigger an epidemic erythromelalgia outbreak in China

    PubMed Central

    Liu, Tao; Zhang, Yonghui; Lin, Hualiang; Lv, Xiaojuan; Xiao, Jianpeng; Zeng, Weilin; Gu, Yuzhou; Rutherford, Shannon; Tong, Shilu; Ma, Wenjun

    2015-01-01

    Although erythromelalgia (EM) has been documented in the literature for almost 150 years, it is still poorly understood. To overcome this limitation, we examined the spatial distribution of epidemic EM, and explored the association between temperature fluctuation and epidemic EM outbreaks in China. We searched all peer-reviewed literature on primary epidemic EM outbreaks in China. A two-stage model was used to characterize the relationship between temperature fluctuation and epidemic EM outbreaks. We observed that epidemic EM outbreaks were reported from 13 provinces during 1960–2014 and they mainly occurred between February and March in southern China. The majority of EM cases were middle school students, with a higher incidence rate in female and resident students. The major clinical characteristics of EM cases included burning, sharp, tingling and/or stinging pain in toes, soles and/or dorsum of feet, fever, erythema and swelling. A large “V”-shaped fluctuation of daily average temperature (TM) observed during the epidemic EM outbreaks was significantly associated with the number of daily EM cases (β = 1.22, 95%CI: 0.66 ~ 1.79), which indicated that this “V”-shaped fluctuation of TM probably triggered the epidemic EM outbreaks. PMID:25820221

  8. Erythromelalgia Mutation Q875E Stabilizes the Activated State of Sodium Channel Nav1.7*

    PubMed Central

    Stadler, Theresa; O'Reilly, Andrias O.; Lampert, Angelika

    2015-01-01

    The human voltage-gated sodium channel Nav1.7 plays a crucial role in transmission of noxious stimuli. The inherited pain disorder erythromelalgia (IEM) has been linked to Nav1.7 gain-of-function mutations. Here we show that the IEM-associated Q875E mutation located on the pore module of Nav1.7 produces a large hyperpolarizing shift (−18 mV) in the voltage dependence of activation. Three-dimensional homology modeling indicates that the side chains of Gln-875 and the gating charge Arg-214 of the domain I voltage sensor are spatially close in the activated conformation of the channel. We verified this proximity by using an engineered disulfide bridge approach. The Q875E mutation introduces a negative charge that may modify the local electrical field experienced by the voltage sensor and, upon activation, interact directly via a salt bridge with the Arg-214 gating charge residue. Together these processes could promote transition to, and stabilization of, the domain I voltage sensor in the activated conformation and thus produce the observed gain of function. In support of this hypothesis, an increase in the extracellular concentration of Ca2+ or Mg2+ reverted the voltage dependence of activation of the IEM mutant to near WT values, suggesting a cation-mediated electrostatic screening of the proposed interaction between Q875E and Arg-214. PMID:25575597

  9. Early detection of an epidemic erythromelalgia outbreak using Baidu search data.

    PubMed

    Gu, Yuzhou; Chen, Fengling; Liu, Tao; Lv, Xiaojuan; Shao, Zhaoming; Lin, Hualiang; Liang, Chaobin; Zeng, Weilin; Xiao, Jianpeng; Zhang, Yonghui; Huang, Cunrui; Rutherford, Shannon; Ma, Wenjun

    2015-07-28

    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.

  10. Early detection of an epidemic erythromelalgia outbreak using Baidu search data

    PubMed Central

    Gu, Yuzhou; Chen, Fengling; Liu, Tao; Lv, Xiaojuan; Shao, Zhaoming; Lin, Hualiang; Liang, Chaobin; Zeng, Weilin; Xiao, Jianpeng; Zhang, Yonghui; Huang, Cunrui; Rutherford, Shannon; Ma, Wenjun

    2015-01-01

    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. PMID:26218589

  11. Bilateral congenital corneal anesthesia in a patient with SCN9A mutation, confirmed primary erythromelalgia, and paroxysmal extreme pain disorder.

    PubMed

    Kim, David Ta; Rossignol, Elsa; Najem, Kinda; Ospina, Luis H

    2015-10-01

    The SCN9A gene codes for the sodium voltage-gated channel NaV 1.7. Gain of function mutations cause pain disorders such as primary erythromelalgia, paroxysmal extreme pain disorder, and small fiber neuropathy. Loss of function mutations lead to congenital insensitivity to pain. We report the case of a 6-year-old girl with a SCN9A mutation who presented with both gain of function and loss of function phenotypes, including congenital corneal anesthesia. Copyright © 2015 American Association for Pediatric Ophthalmology and Strabismus. Published by Elsevier Inc. All rights reserved.

  12. Erythromelalgia mutation L823R shifts activation and inactivation of threshold sodium channel Nav1.7 to hyperpolarized potentials.

    PubMed

    Lampert, Angelika; Dib-Hajj, Sulayman D; Eastman, Emmanuella M; Tyrrell, Lynda; Lin, Zhimiao; Yang, Yong; Waxman, Stephen G

    2009-12-11

    Erythromelalgia (also termed erythermalgia) is a neuropathic pain syndrome, characterized by severe burning pain combined with redness in the extremities, triggered by mild warmth. The inherited form of erythromelalgia (IEM) has recently been linked to mutations in voltage-gated sodium channel Nav1.7, which is expressed in peripheral nociceptors. Here, we used whole-cell voltage-clamp recordings in HEK293 cells to characterize the IEM mutation L823R, which introduces an additional positive charge into the S4 voltage sensor of domain II. The L823R mutation produces an approximately 15mV hyperpolarizing shift in the midpoint of activation and also affects the activation slope factor. Closing of the channel from the open state (deactivation) is slowed, increasing the likelihood of the channel remaining in the open state. The L823R mutation induces a approximately 10mV hyperpolarizing shift in fast-inactivation. L823R is the only naturally-occurring IEM mutation studied thus far to shift fast-inactivation to more negative potentials. We conclude that introduction of an additional charge into the S4 segment of domain II of Nav1.7 leads to a pronounced hyperpolarizing shift of activation, a change that is expected to increase nociceptor excitability despite the hyperpolarizing shift in fast-inactivation, which is unique among the IEM mutations.

  13. Deletion mutation of sodium channel Na(V)1.7 in inherited erythromelalgia: enhanced slow inactivation modulates dorsal root ganglion neuron hyperexcitability.

    PubMed

    Cheng, Xiaoyang; Dib-Hajj, Sulayman D; Tyrrell, Lynda; Te Morsche, Rene H; Drenth, Joost P H; Waxman, Stephen G

    2011-07-01

    Gain-of-function missense mutations of voltage-gated sodium channel Na(V)1.7 have been linked to the painful disorder inherited erythromelalgia. These mutations hyperpolarize activation, slow deactivation and enhance currents evoked by slow ramp stimuli (ramp currents). A correlation has recently been suggested between the age of onset of inherited erythromelalgia and the extent of hyperpolarizing shifts in mutant Na(V)1.7 channel activation; mutations causing large activation shifts have been linked to early age of onset inherited erythromelalgia, while mutations causing small activation shifts have been linked to age of onset within the second decade of life. Here, we report a family with inherited erythromelalgia with an in-frame deletion of a single residue--leucine 955 (Del-L955) in DII/S6. The proband did not show symptoms until the age of 15 years, and her affected mother only experienced mild symptoms during adolescence, which disappeared at the age of 38 years. Del-L955 shows no effect on Na(V)1.7 current density and fast inactivation, but causes an approximately -24 mV shift in activation, together with increases in amplitude of persistent currents and ramp currents. The mutation also produces an approximately -40 mV shift in slow inactivation, which reduces channel availability. Comparison of the effects of the Del-L955 mutation on dorsal root ganglion neuron hyperexcitability with those produced by another inherited erythromelalgia mutation (L858F) that does not enhance slow inactivation suggests that a delayed age of onset and milder symptoms in association with a large shift of channel activation, enhanced persistent and enhanced ramp currents may be related to the approximately -40 mV shift in slow inactivation for Del-L955, the largest shift thus far demonstrated in mutant Na(V)1.7 channels. Our results suggest that despite the pivotal role of activation shift in inherited erythromelalgia development, slow inactivation may regulate clinical

  14. Imaging the neural correlates of neuropathic pain and pleasurable relief associated with inherited erythromelalgia in a single subject with quantitative arterial spin labelling

    PubMed Central

    Segerdahl, Andrew R.; Xie, Jingyi; Paterson, Kathryn; Ramirez, Juan D.; Tracey, Irene; Bennett, David L.H.

    2012-01-01

    We identified a patient with severe inherited erythromelalgia secondary to an L858F mutation in the voltage-gated sodium channel Nav1.7. The patient reported severe ongoing foot pain, which was exquisitely sensitive to limb cooling. We confirmed this heat hypersensitivity using quantitative sensory testing. Additionally, we employed a novel perfusion imaging technique in a simple block design to assess her baseline erythromelalgia pain vs cooling relief. Robust activations of key pain, pain-affect, and reward-related centres were observed. This combined approach allowed us to confirm the presence of a temperature-sensitive channelopathy of peripheral neurons and to investigate the neural correlates of tonic neuropathic pain and relief in a single subject. PMID:22365309

  15. Primary erythromelalgia in a 12-year-old boy: positive response to sodium channel blockers despite negative SCN9A mutations.

    PubMed

    Jakob, A; Creutzfeldt, R; Staszewski, O; Winterpacht, A; Berner, R; Hufnagel, M

    2012-09-01

    Erythromelalgia is a rare disorder characterized by recurrent pain attacks, swelling and redness in the distal extremities. The primary forms of the disorder are caused by mutations in voltage-gated sodium channels. Treatment is difficult and controlled therapeutic studies offer little to no guidance. We report on a 12-year-old boy and his first occurrence of primary erythromelalgia. Genetic findings for mutations in the SCN9A gene, which encodes for the α-subunit of sodium channel NaV1.7, were negative. Although initial treatment with sodium nitroprusside was ineffective, subsequent medication with lidocaine and mexiletine, in combination with gabapentin, was successful. Despite negative findings for mutations in the sodium channels, the use of sodium channel blockers should be considered in these patients. © Georg Thieme Verlag KG Stuttgart · New York.

  16. Imaging the neural correlates of neuropathic pain and pleasurable relief associated with inherited erythromelalgia in a single subject with quantitative arterial spin labelling.

    PubMed

    Segerdahl, Andrew R; Xie, Jingyi; Paterson, Kathryn; Ramirez, Juan D; Tracey, Irene; Bennett, David L H

    2012-05-01

    We identified a patient with severe inherited erythromelalgia secondary to an L858F mutation in the voltage-gated sodium channel Na(v)1.7. The patient reported severe ongoing foot pain, which was exquisitely sensitive to limb cooling. We confirmed this heat hypersensitivity using quantitative sensory testing. Additionally, we employed a novel perfusion imaging technique in a simple block design to assess her baseline erythromelalgia pain vs cooling relief. Robust activations of key pain, pain-affect, and reward-related centres were observed. This combined approach allowed us to confirm the presence of a temperature-sensitive channelopathy of peripheral neurons and to investigate the neural correlates of tonic neuropathic pain and relief in a single subject. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  17. A novel mutation of α-galactosidase A gene causes Fabry disease mimicking primary erythromelalgia in a Chinese family.

    PubMed

    Ge, Wei; Wei, Bin; Zhu, Hao; Miao, Zhigang; Zhang, Weimin; Leng, Cuihua; Li, Jizhen; Zhang, Dan; Sun, Miao; Xu, Xingshun

    2017-05-01

    Fabry disease is an X-linked genetic disorder caused by the mutations of α-galactosidase A (GLA, MIM 300644) gene presenting with various clinical symptoms including small-fiber peripheral neuropathy and limb burning pain. Here, we reported a Chinese pedigree with the initial diagnosis of primary erythromelalgia in an autosomal dominant (AD)-inherited pattern. Mutation analysis of SCN9A and GLA genes by direct sequencing and functional analysis of a novel mutation of GLA in cells were performed. Our data did not show any pathological mutations in SCN9A gene; however, a novel missense mutation c.139T>C (p.W47R) of GLA was identified in a male proband as well as two female carriers in this family. Enzyme assay of α-galactosidase A activity showed deficient enzyme activity in male patients and female carriers, further confirming the diagnosis of Fabry disease. Finally, a functional analysis indicated that the replacement of the 47th amino acid tryptophan (W47) with arginine (W47R) or glycine (W47G) led to reduced activity of α-galactosidase A in 293T cells. Therefore, these findings demonstrated that the novel mutation p.W47R of GLA is the cause of Fabry disease. Because Fabry disease and primary erythromelalgia share similar symptoms, it is a good strategy for clinical physicians to perform genetic mutation screenings on both SCN9A and GLA genes in those patients with limb burning pain but without a clear inheritant pattern.

  18. Pharmacotherapy for Pain in a Family With Inherited Erythromelalgia Guided by Genomic Analysis and Functional Profiling.

    PubMed

    Geha, Paul; Yang, Yang; Estacion, Mark; Schulman, Betsy R; Tokuno, Hajime; Apkarian, A Vania; Dib-Hajj, Sulayman D; Waxman, Stephen G

    2016-06-01

    There is a need for more effective pharmacotherapy for chronic pain, including pain in inherited erythromelalgia (IEM) in which gain-of-function mutations of sodium channel NaV1.7 make dorsal root ganglion (DRG) neurons hyperexcitable. To determine whether pain in IEM can be attenuated via pharmacotherapy guided by genomic analysis and functional profiling. Pain in 2 patients with IEM due to the NaV1.7 S241T mutation, predicted by structural modeling and functional analysis to be responsive to carbamazepine, was assessed in a double-blind, placebo-controlled study conducted from September 2014 to April 21, 2015. Functional magnetic resonance imaging assessed patterns of brain activity associated with pain during treatment with placebo or carbamazepine. Multielectrode array technology was used to assess the effect of carbamazepine on firing of DRG neurons carrying S241T mutant channels. Behavioral assessment of pain; functional magnetic resonance imaging; and assessment of firing in DRG neurons carrying S241T mutant channels. This study included 2 patients from the same family with IEM and the S241T NaV1.7 mutation. We showed that, as predicted by molecular modeling, thermodynamic analysis, and functional profiling, carbamazepine attenuated pain in patients with IEM due to the S241T NaV1.7 mutation. Patient 1 reported a reduction in mean time in pain (TIP) per day during the 15-day maintenance period, from 424 minutes while taking placebo to 231.9 minutes while taking carbamazepine (400 mg/day), and a reduction in total TIP over the 15-day maintenance period, from 6360 minutes while taking placebo to 3015 minutes while taking carbamazepine. Patient 2 reported a reduction in mean TIP per day during the maintenance period, from 61 minutes while taking placebo to 9.1 minutes while taking carbamazepine (400 mg then 200 mg/day), and a reduction in total TIP, from 915 minutes while taking placebo over the 15-day maintenance period to 136 minutes while taking carbamazepine

  19. Mutation I136V alters electrophysiological properties of the Na(v)1.7 channel in a family with onset of erythromelalgia in the second decade.

    PubMed

    Cheng, Xiaoyang; Dib-Hajj, Sulayman D; Tyrrell, Lynda; Waxman, Stephen G

    2008-01-02

    Primary erythromelalgia is an autosomal dominant pain disorder characterized by burning pain and skin redness in the extremities, with onset of symptoms during the first decade in the families whose mutations have been physiologically studied to date. Several mutations of voltage-gated Na+ channel NaV1.7 have been linked with primary erythromelalgia. Recently, a new substitution Na(v)1.7/I136V has been reported in a Taiwanese family, in which pain appeared at later ages (9-22 years, with onset at 17 years of age or later in 5 of 7 family members), with relatively slow progression (8-10 years) to involvement of the hands. The proband reported onset of symptoms first in his feet at the age of 11, which then progressed to his hands at the age of 19. The new mutation is located in transmembrane segment 1 (S1) of domain I (DI) in contrast to all Na(v)1.7 mutations reported to date, which have been localized in the voltage sensor S4, the linker joining segments S4 and S5 or pore-lining segments S5 and S6 in DI, II and III. In this study, we characterized the gating and kinetic properties of I136V mutant channels in HEK293 cells using whole-cell patch clamp. I136V shifts the voltage-dependence of activation by -5.7 mV, a smaller shift in activation than the other erythromelalgia mutations that have been characterized. I136V also decreases the deactivation rate, and generates larger ramp currents. The I136V substitution in Na(v)1.7 alters channel gating and kinetic properties. Each of these changes may contribute to increased excitability of nociceptive dorsal root ganglion neurons, which underlies pain in erythromelalgia. The smaller shift in voltage-dependence of activation of Na(v)1.7, compared to the other reported cases of inherited erythromelalgia, may contribute to the later age of onset and slower progression of the symptoms reported in association with this mutation.

  20. Mutation I136V alters electrophysiological properties of the NaV1.7 channel in a family with onset of erythromelalgia in the second decade

    PubMed Central

    Cheng, Xiaoyang; Dib-Hajj, Sulayman D; Tyrrell, Lynda; Waxman, Stephen G

    2008-01-01

    Background Primary erythromelalgia is an autosomal dominant pain disorder characterized by burning pain and skin redness in the extremities, with onset of symptoms during the first decade in the families whose mutations have been physiologically studied to date. Several mutations of voltage-gated Na+ channel NaV1.7 have been linked with primary erythromelalgia. Recently, a new substitution NaV1.7/I136V has been reported in a Taiwanese family, in which pain appeared at later ages (9–22 years, with onset at 17 years of age or later in 5 of 7 family members), with relatively slow progression (8–10 years) to involvement of the hands. The proband reported onset of symptoms first in his feet at the age of 11, which then progressed to his hands at the age of 19. The new mutation is located in transmembrane segment 1 (S1) of domain I (DI) in contrast to all NaV1.7 mutations reported to date, which have been localized in the voltage sensor S4, the linker joining segments S4 and S5 or pore-lining segments S5 and S6 in DI, II and III. Results In this study, we characterized the gating and kinetic properties of I136V mutant channels in HEK293 cells using whole-cell patch clamp. I136V shifts the voltage-dependence of activation by -5.7 mV, a smaller shift in activation than the other erythromelalgia mutations that have been characterized. I136V also decreases the deactivation rate, and generates larger ramp currents. Conclusion The I136V substitution in NaV1.7 alters channel gating and kinetic properties. Each of these changes may contribute to increased excitability of nociceptive dorsal root ganglion neurons, which underlies pain in erythromelalgia. The smaller shift in voltage-dependence of activation of NaV1.7, compared to the other reported cases of inherited erythromelalgia, may contribute to the later age of onset and slower progression of the symptoms reported in association with this mutation. PMID:18171466

  1. Pharmacological reversal of a pain phenotype in iPSC-derived sensory neurons and patients with inherited erythromelalgia.

    PubMed

    Cao, Lishuang; McDonnell, Aoibhinn; Nitzsche, Anja; Alexandrou, Aristos; Saintot, Pierre-Philippe; Loucif, Alexandre J C; Brown, Adam R; Young, Gareth; Mis, Malgorzata; Randall, Andrew; Waxman, Stephen G; Stanley, Philip; Kirby, Simon; Tarabar, Sanela; Gutteridge, Alex; Butt, Richard; McKernan, Ruth M; Whiting, Paul; Ali, Zahid; Bilsland, James; Stevens, Edward B

    2016-04-20

    In common with other chronic pain conditions, there is an unmet clinical need in the treatment of inherited erythromelalgia (IEM). TheSCN9Agene encoding the sodium channel Nav1.7 expressed in the peripheral nervous system plays a critical role in IEM. A gain-of-function mutation in this sodium channel leads to aberrant sensory neuronal activity and extreme pain, particularly in response to heat. Five patients with IEM were treated with a new potent and selective compound that blocked the Nav1.7 sodium channel resulting in a decrease in heat-induced pain in most of the patients. We derived induced pluripotent stem cell (iPSC) lines from four of five subjects and produced sensory neurons that emulated the clinical phenotype of hyperexcitability and aberrant responses to heat stimuli. When we compared the severity of the clinical phenotype with the hyperexcitability of the iPSC-derived sensory neurons, we saw a trend toward a correlation for individual mutations. The in vitro IEM phenotype was sensitive to Nav1.7 blockers, including the clinical test agent. Given the importance of peripherally expressed sodium channels in many pain conditions, our approach may have broader utility for a wide range of pain and sensory conditions.

  2. Aspirin-responsive, migraine-like transient cerebral and ocular ischemic attacks and erythromelalgia in JAK2-positive essential thrombocythemia and polycythemia vera.

    PubMed

    Michiels, Jan Jacques; Berneman, Zwi; Gadisseur, Alain; Lam, King H; De Raeve, Hendrik; Schroyens, Wilfried

    2015-01-01

    Migraine-like cerebral transient ischemic attacks (MIAs) and ocular ischemic manifestations were the main presenting features in 10 JAK2(V617F)-positive patients studied, with essential thrombocythemia (ET) in 6 and polycythemia vera (PV) in 4. Symptoms varied and included cerebral ischemic attacks, mental concentration disturbances followed by throbbing headaches, nausea, vomiting, syncope or even seizures. MIAs were frequently preceded or followed by ocular ischemic events of blurred vision, scotomas, transient flashing of the eyes, and sudden transient partial blindness preceded or followed erythromelalgia in the toes or fingers. The time lapse between the first symptoms of aspirin-responsive MIAs and the diagnosis of ET in 5 patients ranged from 4 to 12 years. At the time of erythromelalgia and MIAs, shortened platelet survival, an increase in the levels of the platelet activation markers β-thromboglobulin and platelet factor 4 and also in urinary thromboxane B2 were clearly indicative of the spontaneous in vivo platelet activation of constitutively JAK2(V617F)-activated thrombocythemic platelets. Aspirin relieves the peripheral, cerebral and ocular ischemic disturbances by irreversible inhibition of platelet cyclo-oxygenase (COX-1) activity and aggregation ex vivo. Vitamin K antagonist, dipyridamole, ticlopidine, sulfinpyrazone and sodium salicylate have no effect on platelet COX-1 activity and are ineffective in the treatment of thrombocythemia-specific manifestations of erythromelalgia and atypical MIAs. If not treated with aspirin, ET and PV patients are at a high risk of major arterial thrombosis including stroke, myocardial infarction and digital gangrene. © 2014 S. Karger AG, Basel.

  3. Treatment of Na(v)1.7-mediated pain in inherited erythromelalgia using a novel sodium channel blocker.

    PubMed

    Goldberg, Yigal Paul; Price, Nicola; Namdari, Rostam; Cohen, Charles Jay; Lamers, Mieke H; Winters, Conrad; Price, James; Young, Clint E; Verschoof, Henry; Sherrington, Robin; Pimstone, Simon Neil; Hayden, Michael Reuben

    2012-01-01

    Mutations in the SCN9A gene leading to deficiency of its protein product, Na(v)1.7, cause congenital indifference to pain (CIP). CIP is characterized by the absence of the ability to sense pain associated with noxious stimuli. In contrast, the opposite phenotype to CIP, inherited erythromelalgia (IEM), is a disorder of spontaneous pain caused by missense mutations resulting in gain-of-function in Na(v)1.7 that promote neuronal hyperexcitability. The primary aim of this study was to demonstrate that Na(v)1.7 antagonism could alleviate the pain of IEM, thereby demonstrating the utility of this opposite phenotype model as a tool for rapid proof-of-concept for novel analgesics. An exploratory, randomized, double-blind, 2-period crossover study was conducted in 4 SCN9A mutation-proven IEM patients. In each treatment period (2days), separated by a 2-day washout period, patients were orally administered XEN402 (400mg twice daily) or matching placebo. In 3 patients, pain was induced by heat or exercise during each treatment arm. A fourth patient, in constant severe pain, required no induction. Patient-reported outcomes of pain intensity and/or relief were recorded, and the time taken to induce pain was measured. The ability to induce pain in IEM patients was significantly attenuated by XEN402 compared with placebo. XEN402 increased the time to maximal pain induction and significantly reduced the amount of pain (42% less) after induction (P=.014). This pilot study showed that XEN402 blocks Na(v)1.7-mediated pain associated with IEM, thereby demonstrating target engagement in humans and underscoring the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of-concept. Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  4. Dynamic-clamp analysis of wild-type human Nav1.7 and erythromelalgia mutant channel L858H.

    PubMed

    Vasylyev, Dmytro V; Han, Chongyang; Zhao, Peng; Dib-Hajj, Sulayman; Waxman, Stephen G

    2014-04-01

    The link between sodium channel Nav1.7 and pain has been strengthened by identification of gain-of-function mutations in patients with inherited erythromelalgia (IEM), a genetic model of neuropathic pain in humans. A firm mechanistic link to nociceptor dysfunction has been precluded because assessments of the effect of the mutations on nociceptor function have thus far depended on electrophysiological recordings from dorsal root ganglia (DRG) neurons transfected with wild-type (WT) or mutant Nav1.7 channels, which do not permit accurate calibration of the level of Nav1.7 channel expression. Here, we report an analysis of the function of WT Nav1.7 and IEM L858H mutation within small DRG neurons using dynamic-clamp. We describe the functional relationship between current threshold for action potential generation and the level of WT Nav1.7 conductance in primary nociceptive neurons and demonstrate the basis for hyperexcitability at physiologically relevant levels of L858H channel conductance. We demonstrate that the L858H mutation, when modeled using dynamic-clamp at physiological levels within DRG neurons, produces a dramatically enhanced persistent current, resulting in 27-fold amplification of net sodium influx during subthreshold depolarizations and even greater amplification during interspike intervals, which provide a mechanistic basis for reduced current threshold and enhanced action potential firing probability. These results show, for the first time, a linear correlation between the level of Nav1.7 conductance and current threshold in DRG neurons. Our observations demonstrate changes in sodium influx that provide a mechanistic link between the altered biophysical properties of a mutant Nav1.7 channel and nociceptor hyperexcitability underlying the pain phenotype in IEM.

  5. Kinetic modeling of Nav1.7 provides insight into erythromelalgia-associated F1449V mutation.

    PubMed

    Gurkiewicz, Meron; Korngreen, Alon; Waxman, Stephen G; Lampert, Angelika

    2011-04-01

    Gain-of-function mutations of the voltage-gated sodium channel (VGSC) Na(v)1.7 have been linked to human pain disorders. The mutation F1449V, located at the intracellular end of transmembrane helix S6 of domain III, induces the inherited pain syndrome erythromelalgia. A kinetic model of wild-type (WT) and F1449V Na(v)1.7 may provide a basis for predicting putative intraprotein interactions. We semiautomatically constrained a Markov model using stochastic search algorithms and whole cell patch-clamp recordings from human embryonic kidney cells transfected with Na(v)1.7 and its F1449V mutation. The best models obtained simulated known differences in action potential thresholds and firing patterns in spinal sensory neurons expressing WT and F1449V. The most suitable Markov model consisted of three closed, one open, and two inactivated states. The model predicted that the F1449V mutation shifts occupancy of the closed states closer to the open state, making it easier for the channel pore to open. It also predicted that F1449V's second inactivated state is more than four times more likely to be occupied than the equivalent state in WT at hyperpolarized potentials, although the mutation still lowered the firing threshold of action potentials. The differences between WT and F1449V were not limited to a single transition. Thus a point mutation in position F1449, while phenotypically most probably affecting the activation gate, may also modify channel functions mediated by structures in more distant areas of the channel protein.

  6. A novel SCN9A mutation responsible for primary erythromelalgia and is resistant to the treatment of sodium channel blockers.

    PubMed

    Wu, Min-Tzu; Huang, Po-Yuan; Yen, Chen-Tung; Chen, Chih-Cheng; Lee, Ming-Jen

    2013-01-01

    Primary erythromelalgia (PE) is an autosomal dominant neurological disorder characterized by severe burning pain and erythema in the extremities upon heat stimuli or exercise. Mutations in human SCN9A gene, encoding the α-subunit of the voltage-gated sodium channel, Na(v)1.7, were found to be responsible for PE. Three missense mutations of SCN9A gene have recently been identified in Taiwanese patients including a familial (I136V) and two sporadic mutations (I848T, V1316A). V1316A is a novel mutation and has not been characterized yet. Topologically, I136V is located in DI/S1 segment and both I848T and V1316A are located in S4-S5 linker region of DII and DIII domains, respectively. To characterize the elelctrophysiological manifestations, the channel conductance with whole-cell patch clamp was recorded on the over-expressed Chinese hamster overy cells. As compared with wild type, the mutant channels showed a significant hyperpolarizing shift in voltage dependent activation and a depolarizing shift in steady-state fast inactivation. The recovery time from channel inactivation is faster in the mutant than in the wild type channels. Since warmth can trigger and exacerbate symptoms, we then examine the influence of tempearture on the sodium channel conduction. At 35°C, I136V and V1316A mutant channels exhibit a further hyperpolarizing shift at activation as compared with wild type channel, even though wild type channel also produced a significant hyperpolarizing shift compared to that of 25°C. High temperature caused a significant depolarizing shift in steady-state fast inactivation in all three mutant channels. These findings may confer to the hyperexcitability of sensory neurons, especially at high temperature. In order to identifying an effective treatment, we tested the IC₅₀ values of selective sodium channel blockers, lidocaine and mexiletine. The IC₅₀ for mexiletine is lower for I848T mutant channel as compared to that of the wild type and other two

  7. A Novel SCN9A Mutation Responsible for Primary Erythromelalgia and Is Resistant to the Treatment of Sodium Channel Blockers

    PubMed Central

    Yen, Chen-Tung; Chen, Chih-Cheng; Lee, Ming-Jen

    2013-01-01

    Primary erythromelalgia (PE) is an autosomal dominant neurological disorder characterized by severe burning pain and erythema in the extremities upon heat stimuli or exercise. Mutations in human SCN9A gene, encoding the α–subunit of the voltage-gated sodium channel, Nav1.7, were found to be responsible for PE. Three missense mutations of SCN9A gene have recently been identified in Taiwanese patients including a familial (I136V) and two sporadic mutations (I848T, V1316A). V1316A is a novel mutation and has not been characterized yet. Topologically, I136V is located in DI/S1 segment and both I848T and V1316A are located in S4-S5 linker region of DII and DIII domains, respectively. To characterize the elelctrophysiological manifestations, the channel conductance with whole-cell patch clamp was recorded on the over-expressed Chinese hamster overy cells. As compared with wild type, the mutant channels showed a significant hyperpolarizing shift in voltage dependent activation and a depolarizing shift in steady-state fast inactivation. The recovery time from channel inactivation is faster in the mutant than in the wild type channels. Since warmth can trigger and exacerbate symptoms, we then examine the influence of tempearture on the sodium channel conduction. At 35°C, I136V and V1316A mutant channels exhibit a further hyperpolarizing shift at activation as compared with wild type channel, even though wild type channel also produced a significant hyperpolarizing shift compared to that of 25°C. High temperature caused a significant depolarizing shift in steady-state fast inactivation in all three mutant channels. These findings may confer to the hyperexcitability of sensory neurons, especially at high temperature. In order to identifying an effective treatment, we tested the IC50 values of selective sodium channel blockers, lidocaine and mexiletine. The IC50 for mexiletine is lower for I848T mutant channel as compared to that of the wild type and other two mutants

  8. Secondary erythromelalgia successfully treated with patient-controlled epidural analgesia and interferon α-2b: A case report and review of the literature

    PubMed Central

    LI, XINGZHI; LI, YAOMIN; QU, YAO; LU, LAIJIN

    2016-01-01

    Erythromelalgia (EM) is a debilitating neurovascular disease that is refractory to numerous treatment modalities. The present study reported the case of a 72-year-old woman diagnosed with EM secondary to polycythemia vera (PV), who was effectively treated with the use of patient-controlled epidural analgesia (PCEA) and interferon α-2b therapy. The study aimed to provide clinical information on this condition based on the findings of the present case and previously-reported cases. PCEA containing local anesthetics and dexamethasone or fentanyl resulted in nearly complete relief of symptoms. Furthermore, continuous use of interferon α-2b for the treatment of the PV completely relieved the EM symptoms. In conclusion, PCEA and interferon α-2b may be promising treatments for EM secondary to PV. PMID:27168811

  9. Mexiletine-responsive erythromelalgia due to a new Na(v)1.7 mutation showing use-dependent current fall-off.

    PubMed

    Choi, Jin-Sung; Zhang, Lili; Dib-Hajj, Sulayman D; Han, Chongyang; Tyrrell, Lynda; Lin, Zhimiao; Wang, Xiaoliang; Yang, Yong; Waxman, Stephen G

    2009-04-01

    Inherited erythromelalgia (IEM), characterized by episodic burning pain and erythema of the extremities, is produced by gain-of-function mutations in sodium channel Na(v)1.7, which is preferentially expressed in nociceptive and sympathetic neurons. Most patients do not respond to pharmacotherapy, although occasional reports document patients as showing partial relief with lidocaine or mexiletine. A 7-year-old girl, with a two-year history of symmetric burning pain and erythema in her hands and feet, was diagnosed with erythromelalgia. Treatment with mexiletine reduced the number and severity of pain episodes. We report here a new IEM Na(v)1.7 mutation in this patient, and its response to mexiletine. SCN9A exons from the proband were amplified and sequenced. We identified a single nucleotide substitution (T2616G) in exon 15, not present in 200 ethnically-matched control alleles, which substitutes valine 872 by glycine (V872G) within DII/S5. Whole-cell patch-clamp analysis of wild-type and mutant Na(v)1.7 channels in mammalian cells show that V872G shifts activation by -10 mV, slows deactivation, and generates larger ramp currents. We observed a stronger use-dependent fall-off in current following exposure to mexiletine for V872G compared to wild-type channels. These observations suggest that some patients with IEM may show a favorable response to mexiletine due to a use-dependent effect on mutant Na(v)1.7 channels. Continued relief from pain, even after mexiletine was discontinued in this patient, might suggest that early treatment may slow the progression of the disease.

  10. Inherited pain: sodium channel Nav1.7 A1632T mutation causes erythromelalgia due to a shift of fast inactivation.

    PubMed

    Eberhardt, Mirjam; Nakajima, Julika; Klinger, Alexandra B; Neacsu, Cristian; Hühne, Kathrin; O'Reilly, Andrias O; Kist, Andreas M; Lampe, Anne K; Fischer, Kerstin; Gibson, Jane; Nau, Carla; Winterpacht, Andreas; Lampert, Angelika

    2014-01-24

    Inherited erythromelalgia (IEM) causes debilitating episodic neuropathic pain characterized by burning in the extremities. Inherited "paroxysmal extreme pain disorder" (PEPD) differs in its clinical picture and affects proximal body areas like the rectal, ocular, or jaw regions. Both pain syndromes have been linked to mutations in the voltage-gated sodium channel Nav1.7. Electrophysiological characterization shows that IEM-causing mutations generally enhance activation, whereas mutations leading to PEPD alter fast inactivation. Previously, an A1632E mutation of a patient with overlapping symptoms of IEM and PEPD was reported (Estacion, M., Dib-Hajj, S. D., Benke, P. J., Te Morsche, R. H., Eastman, E. M., Macala, L. J., Drenth, J. P., and Waxman, S. G. (2008) NaV1.7 Gain-of-function mutations as a continuum. A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders. J. Neurosci. 28, 11079-11088), displaying a shift of both activation and fast inactivation. Here, we characterize a new mutation of Nav1.7, A1632T, found in a patient suffering from IEM. Although transfection of A1632T in sensory neurons resulted in hyperexcitability and spontaneous firing of dorsal root ganglia (DRG) neurons, whole-cell patch clamp of transfected HEK cells revealed that Nav1.7 activation was unaltered by the A1632T mutation but that steady-state fast inactivation was shifted to more depolarized potentials. This is a characteristic normally attributed to PEPD-causing mutations. In contrast to the IEM/PEPD crossover mutation A1632E, A1632T failed to slow current decay (i.e. open-state inactivation) and did not increase resurgent currents, which have been suggested to contribute to high-frequency firing in physiological and pathological conditions. Reduced fast inactivation without increased resurgent currents induces symptoms of IEM, not PEPD, in the new Nav1.7 mutation, A1632T. Therefore

  11. Nav1.7 mutations associated with paroxysmal extreme pain disorder, but not erythromelalgia, enhance Navbeta4 peptide-mediated resurgent sodium currents.

    PubMed

    Theile, Jonathan W; Jarecki, Brian W; Piekarz, Andrew D; Cummins, Theodore R

    2011-02-01

    Abnormal pain sensitivity associated with inherited and acquired pain disorders occurs through increased excitability of peripheral sensory neurons in part due to changes in the properties of voltage-gated sodium channels (Navs). Resurgent sodium currents (I(NaR)) are atypical currents believed to be associated with increased excitability of neurons and may have implications in pain. Mutations in Nav1.7 (peripheral Nav isoform) associated with two genetic pain disorders, inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD), enhance Nav1.7 function via distinct mechanisms. We show that changes in Nav1.7 function due to mutations associated with PEPD, but not IEM, are important in I(NaR) generation, suggesting that I(NaR) may play a role in pain associated with PEPD. This knowledge provides us with a better understanding of the mechanism of I(NaR) generation and may lead to the development of specialized treatment for pain disorders associated with I(NaR).

  12. Treatment with carbamazepine and gabapentin of a patient with primary erythermalgia (erythromelalgia) identified to have a mutation in the SCN9A gene, encoding a voltage-gated sodium channel.

    PubMed

    Natkunarajah, J; Atherton, D; Elmslie, F; Mansour, S; Mortimer, P

    2009-12-01

    Primary erythermalgia (erythromelalgia) is a rare autosomal dominant condition characterized by intermittent attacks of erythema, increased skin temperature and severe burning pain in the extremities, in a bilateral symmetrical distribution. Mutations in the SCN9A gene, which encodes a voltage-gated sodium channel have been shown to cause this disease. We report a family identified to have a mutation in the SCN9A gene, in which one severely affected family member has responded to the therapeutic combination of gabapentin and carbamazepine treatment.

  13. Nav1.7-A1632G Mutation from a Family with Inherited Erythromelalgia: Enhanced Firing of Dorsal Root Ganglia Neurons Evoked by Thermal Stimuli.

    PubMed

    Yang, Yang; Huang, Jianying; Mis, Malgorzata A; Estacion, Mark; Macala, Lawrence; Shah, Palak; Schulman, Betsy R; Horton, Daniel B; Dib-Hajj, Sulayman D; Waxman, Stephen G

    2016-07-13

    Voltage-gated sodium channel Nav1.7 is a central player in human pain. Mutations in Nav1.7 produce several pain syndromes, including inherited erythromelalgia (IEM), a disorder in which gain-of-function mutations render dorsal root ganglia (DRG) neurons hyperexcitable. Although patients with IEM suffer from episodes of intense burning pain triggered by warmth, the effects of increased temperature on DRG neurons expressing mutant Nav1.7 channels have not been well documented. Here, using structural modeling, voltage-clamp, current-clamp, and multielectrode array recordings, we have studied a newly identified Nav1.7 mutation, Ala1632Gly, from a multigeneration family with IEM. Structural modeling suggests that Ala1632 is a molecular hinge and that the Ala1632Gly mutation may affect channel gating. Voltage-clamp recordings revealed that the Nav1.7-A1632G mutation hyperpolarizes activation and depolarizes fast-inactivation, both gain-of-function attributes at the channel level. Whole-cell current-clamp recordings demonstrated increased spontaneous firing, lower current threshold, and enhanced evoked firing in rat DRG neurons expressing Nav1.7-A1632G mutant channels. Multielectrode array recordings further revealed that intact rat DRG neurons expressing Nav1.7-A1632G mutant channels are more active than those expressing Nav1.7 WT channels. We also showed that physiologically relevant thermal stimuli markedly increase the mean firing frequencies and the number of active rat DRG neurons expressing Nav1.7-A1632G mutant channels, whereas the same thermal stimuli only increase these parameters slightly in rat DRG neurons expressing Nav1.7 WT channels. The response of DRG neurons expressing Nav1.7-A1632G mutant channels upon increase in temperature suggests a cellular basis for warmth-triggered pain in IEM. Inherited erythromelalgia (IEM), a severe pain syndrome characterized by episodes of intense burning pain triggered by warmth, is caused by mutations in sodium channel Nav

  14. Novel mutations mapping to the fourth sodium channel domain of Nav1.7 result in variable clinical manifestations of primary erythromelalgia.

    PubMed

    Cregg, Roman; Laguda, Bisola; Werdehausen, Robert; Cox, James J; Linley, John E; Ramirez, Juan D; Bodi, Istvan; Markiewicz, Michael; Howell, Kevin J; Chen, Ya-Chun; Agnew, Karen; Houlden, Henry; Lunn, Michael P; Bennett, David L H; Wood, John N; Kinali, Maria

    2013-06-01

    We identified and clinically investigated two patients with primary erythromelalgia mutations (PEM), which are the first reported to map to the fourth domain of Nav1.7 (DIV). The identified mutations (A1746G and W1538R) were cloned and transfected to cell cultures followed by electrophysiological analysis in whole-cell configuration. The investigated patients presented with PEM, while age of onset was very different (3 vs. 61 years of age). Electrophysiological characterization revealed that the early onset A1746G mutation leads to a marked hyperpolarizing shift in voltage dependence of steady-state activation, larger window currents, faster activation kinetics (time-to-peak current) and recovery from steady-state inactivation compared to wild-type Nav1.7, indicating a pronounced gain-of-function. Furthermore, we found a hyperpolarizing shift in voltage dependence of slow inactivation, which is another feature commonly found in Nav1.7 mutations associated with PEM. In silico neuron simulation revealed reduced firing thresholds and increased repetitive firing, both indicating hyperexcitability. The late-onset W1538R mutation also revealed gain-of-function properties, although to a lesser extent. Our findings demonstrate that mutations encoding for DIV of Nav1.7 can not only be linked to congenital insensitivity to pain or paroxysmal extreme pain disorder but can also be causative of PEM, if voltage dependency of channel activation is affected. This supports the view that the degree of biophysical property changes caused by a mutation may have an impact on age of clinical manifestation of PEM. In summary, these findings extent the genotype-phenotype correlation profile for SCN9A and highlight a new region of Nav1.7 that is implicated in PEM.

  15. Mexiletine as a treatment for primary erythromelalgia: normalization of biophysical properties of mutant L858F NaV1.7 sodium channels

    PubMed Central

    Cregg, R; Cox, J J; Bennett, D L H; Wood, J N; Werdehausen, R

    2014-01-01

    Background and Purpose The non-selective sodium channel inhibitor mexiletine has been found to be effective in several animal models of chronic pain and has become popular in the clinical setting as an orally available alternative to lidocaine. It remains unclear why patients with monogenic pain disorders secondary to gain-of-function SCN9a mutations benefit from a low systemic concentration of mexiletine, which does not usually induce adverse neurological side effects. The aim of this study was, therefore, to investigate the biophysical effects of mexiletine on the L858F primary erythromelalgia NaV1.7 mutation in vitro. Experimental Approach Human wild-type and L858F-mutated NaV1.7 channels were expressed in HEK293A cells. Whole-cell currents were recorded by voltage-clamp techniques to characterize the effect of mexiletine on channel gating properties. Key Results While the concentration-dependent tonic block of peak currents by mexiletine was similar in wild-type and L858F channels, phasic block was more pronounced in cells transfected with the L858F mutation. Moreover, mexiletine substantially shifted the pathologically-hyperpolarized voltage-dependence of steady-state activation in L858F-mutated channels towards wild-type values and the voltage-dependence of steady-state fast inactivation was shifted to more hyperpolarized potentials, leading to an overall reduction in window currents. Conclusion and Implications Mexiletine has a normalizing effect on the pathological gating properties of the L858F gain-of-function mutation in NaV1.7, which, in part, might explain the beneficial effects of systemic treatment with mexiletine in patients with gain-of-function sodium channel disorders. PMID:24866741

  16. Nav1.7 mutations associated with paroxysmal extreme pain disorder, but not erythromelalgia, enhance Navβ4 peptide-mediated resurgent sodium currents

    PubMed Central

    Theile, Jonathan W; Jarecki, Brian W; Piekarz, Andrew D; Cummins, Theodore R

    2011-01-01

    Inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD) are inherited pain syndromes predominantly caused by missense mutations in the peripheral neuronal voltage-gated sodium channel (Nav) isoform Nav1.7. While both IEM and PEPD mutations increase neuronal excitability, IEM mutations primarily enhance activation and PEPD mutations impair inactivation. In addition, one PEPD mutation, Nav1.7-I1461T, has been shown to increase resurgent sodium currents in dorsal root ganglion (DRG) neurons. Because resurgent currents have been implicated in increased neuronal excitability, we asked whether (1) additional PEPD mutations located within the putative inactivation gate and docking sites and (2) IEM mutations might also increase these unusual currents. Resurgent currents are generated following open-channel block at positive potentials by an endogenous blocking particle and subsequent expulsion of this blocker upon repolarization to moderately negative potentials. Here we used a mimetic of the putative blocking particle, the Navβ4 peptide, to determine if enhanced resurgent currents are induced by three distinct PEPD mutations and two IEM mutations in stably transfected HEK293 cells. We demonstrate that (1) Nav1.7-mediated resurgent currents are observed in HEK293 cells with the Navβ4 peptide in the recording pipette, (2) while the PEPD mutants M1627K, T1464I and V1299F exhibit enhanced resurgent current amplitudes compared to wild-type, the IEM mutants I848T and L858H do not, and (3) there is a strong correlation between the decay time constant of open-channel fast inactivation and resurgent current amplitude. These data suggest that resurgent currents may play a role in the neuronal hyperexcitability associated with PEPD, but not IEM, mutations. PMID:21115638

  17. Mexiletine as a treatment for primary erythromelalgia: normalization of biophysical properties of mutant L858F NaV 1.7 sodium channels.

    PubMed

    Cregg, R; Cox, J J; Bennett, D L H; Wood, J N; Werdehausen, R

    2014-10-01

    The non-selective sodium channel inhibitor mexiletine has been found to be effective in several animal models of chronic pain and has become popular in the clinical setting as an orally available alternative to lidocaine. It remains unclear why patients with monogenic pain disorders secondary to gain-of-function SCN9a mutations benefit from a low systemic concentration of mexiletine, which does not usually induce adverse neurological side effects. The aim of this study was, therefore, to investigate the biophysical effects of mexiletine on the L858F primary erythromelalgia NaV 1.7 mutation in vitro. Human wild-type and L858F-mutated NaV 1.7 channels were expressed in HEK293A cells. Whole-cell currents were recorded by voltage-clamp techniques to characterize the effect of mexiletine on channel gating properties. While the concentration-dependent tonic block of peak currents by mexiletine was similar in wild-type and L858F channels, phasic block was more pronounced in cells transfected with the L858F mutation. Moreover, mexiletine substantially shifted the pathologically-hyperpolarized voltage-dependence of steady-state activation in L858F-mutated channels towards wild-type values and the voltage-dependence of steady-state fast inactivation was shifted to more hyperpolarized potentials, leading to an overall reduction in window currents. Mexiletine has a normalizing effect on the pathological gating properties of the L858F gain-of-function mutation in NaV 1.7, which, in part, might explain the beneficial effects of systemic treatment with mexiletine in patients with gain-of-function sodium channel disorders. © 2014 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

  18. The Biophysical Basis Underlying Gating Changes in the p.V1316A Mutant Nav1.7 Channel and the Molecular Pathogenesis of Inherited Erythromelalgia.

    PubMed

    Huang, Chiung-Wei; Lai, Hsing-Jung; Huang, Po-Yuan; Lee, Ming-Jen; Kuo, Chung-Chin

    2016-09-01

    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

  19. The Biophysical Basis Underlying Gating Changes in the p.V1316A Mutant Nav1.7 Channel and the Molecular Pathogenesis of Inherited Erythromelalgia

    PubMed Central

    Huang, Chiung-Wei; Huang, Po-Yuan; Lee, Ming-Jen; Kuo, Chung-Chin

    2016-01-01

    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

  20. Specific changes in conduction velocity recovery cycles of single nociceptors in a patient with erythromelalgia with the I848T gain-of-function mutation of Nav1.7.

    PubMed

    Namer, Barbara; Ørstavik, Kristin; Schmidt, Roland; Kleggetveit, Inge-Petter; Weidner, Christian; Mørk, Cato; Kvernebo, Mari Skylstad; Kvernebo, Knut; Salter, Hugh; Carr, Thomas Hedley; Segerdahl, Märta; Quiding, Hans; Waxman, Stephen George; Handwerker, Hermann Otto; Torebjörk, Hans Erik; Jørum, Ellen; Schmelz, Martin

    2015-09-01

    Seven patients diagnosed with erythromelalgia (EM) were investigated by microneurography to record from unmyelinated nerve fibers in the peroneal nerve. Two patients had characterized variants of sodium channel Nav1.7 (I848T, I228M), whereas no mutations of coding regions of Navs were found in 5 patients with EM. Irrespective of Nav1.7 mutations, more than 50% of the silent nociceptors in the patients with EM showed spontaneous activity. In the patient with mutation I848T, all nociceptors, but not sympathetic efferents, displayed enhanced early subnormal conduction in the velocity recovery cycles and the expected late subnormality was reversed to supranormal conduction. The larger hyperpolarizing shift of activation might explain the difference to the I228M mutation. Sympathetic fibers that lack Nav1.8 did not show supranormal conduction in the patient carrying the I848T mutation, confirming in human subjects that the presence of Nav1.8 crucially modulates conduction in cells expressing EM mutant channels. The characteristic pattern of changes in conduction velocity observed in the patient with the I848T gain-of function mutation in Nav1.7 could be explained by axonal depolarization and concomitant inactivation of Nav1.7. If this were true, activity-dependent hyperpolarization would reverse inactivation of Nav1.7 and account for the supranormal CV. This mechanism might explain normal pain thresholds under resting conditions.

  1. A Pore-blocking Hydrophobic Motif at the Cytoplasmic Aperture of the Closed-state Nav1.7 Channel Is Disrupted by the Erythromelalgia-associated F1449V Mutation*

    PubMed Central

    Lampert, Angelika; O'Reilly, Andrias O.; Dib-Hajj, Sulayman D.; Tyrrell, Lynda; Wallace, B. A.; Waxman, Stephen G.

    2008-01-01

    Sodium channel Nav1.7 has recently elicited considerable interest as a key contributor to human pain. Gain-of-function mutations of Nav1.7 produce painful disorders, whereas loss-of-function Nav1.7 mutations produce insensitivity to pain. The inherited erythromelalgia Nav1.7/F1449V mutation, within the C terminus of domain III/transmembrane helix S6, shifts channel activation by -7.2 mV and accelerates time to peak, leading to nociceptor hyperexcitability. We constructed a homology model of Nav1.7, based on the KcsA potassium channel crystal structure, which identifies four phylogenetically conserved aromatic residues that correspond to DIII/F1449 at the C-terminal end of each of the four S6 helices. The model predicted that changes in side-chain size of residue 1449 alter the pore's cytoplasmic aperture diameter and reshape inter-domain contact surfaces that contribute to closed state stabilization. To test this hypothesis, we compared activation of wild-type and mutant Nav1.7 channels F1449V/L/Y/W by whole cell patch clamp analysis. All but the F1449V mutation conserve the voltage dependence of activation. Compared with wild type, time to peak was shorter in F1449V, similar in F1449L, but longer for F1449Y and F1449W, suggesting that a bulky, hydrophobic residue is necessary for normal activation. We also substituted the corresponding aromatic residue of S6 in each domain individually with valine, to mimic the naturally occurring Nav1.7 mutation. We show that DII/F960V and DIII/F1449V, but not DI/Y405V or DIV/F1752V, regulate Nav1.7 activation, consistent with well established conformational changes in DII and DIII. We propose that the four aromatic residues contribute to the gate at the cytoplasmic pore aperture, and that their ring side chains form a hydrophobic plug which stabilizes the closed state of Nav1.7. PMID:18550534

  2. A new Nav1.7 mutation in an erythromelalgia patient.

    PubMed

    Estacion, Mark; Yang, Yang; Dib-Hajj, Sulayman D; Tyrrell, Lynda; Lin, Zhimiao; Yang, Yong; Waxman, Stephen G

    2013-03-01

    Gain-of-function missense mutations of SCN9A gene, which encodes voltage-gated sodium channel Nav1.7, alter channel's biophysical properties causing painful disorders which are refractory to pharmacotherapy in the vast majority of patients. Here we report a novel SCN9A mutation (ca.T3947C) in exon 20 in a 9 year old patient, not present in 200 ethnically-matched control alleles; the mutation substitutes the invariant valine 1316 residue within DIII/S5 by alanine (V1316A). Voltage-clamp studies show that Nav1.7 V1316A mutation hyperpolarizes activation (-9 mV), and enhances response to ramp stimuli (3-fold), changes that are predicted to cause hyperexcitability of DRG neurons. V1316A also hyperpolarizes steady-state slow-inactivation (-9.9 mV), which is predicted to attenuate the effect of this mutation on DRG neuron firing. These changes are consistent with previously characterized Erytheromelalgia associated mutations of Nav1.7. Copyright © 2013 Elsevier Inc. All rights reserved.

  3. Painful Na-channelopathies: an expanding universe.

    PubMed

    Waxman, Stephen G

    2013-07-01

    The universe of painful Na-channelopathies--human disorders caused by mutations in voltage-gated sodium channels--has recently expanded in three dimensions. We now know that mutations of sodium channels cause not only rare genetic 'model disorders' such as inherited erythromelalgia and channelopathy-associated insensitivity to pain but also common painful neuropathies. We have learned that mutations of NaV1.8, as well as mutations of NaV1.7, can cause painful Na-channelopathies. Moreover, recent studies combining atomic level structural models and pharmacogenomics suggest that the goal of genomically guided pain therapy may not be unrealistic.

  4. Idiopathic erythermalgia: a congenital disorder.

    PubMed

    Michiels, J J; van Joost, T; Vuzevski, V D

    1989-11-01

    Idiopathic erythermalgia during early childhood and adolescence is characterized by red, congested, burning pain of the lower extremities provoked by exercise or exposure to warmth. The clinical symptoms of idiopathic erythermalgia in a young woman and her mother are described. Histopathologic and immunofluorescence findings in biopsy specimens of affected areas of skin were consistent with a nonspecific inflammatory process. The condition was completely refractory to any treatment. Even the long-lasting relief of pain with one low dose of aspirin, which is a prerequisite for the diagnosis of thrombocytemic erythromelalgia, was lacking. Idiopathic erythermalgia appears to be a separate clinical entity and congenital disorder.

  5. Breast Cancer Presenting as Paraneoplastic Erythroderma: An Extremely Rare Case

    PubMed Central

    Katsantonis, Ioannis; Roussos, Nikolaos; Manoludaki, Kassiani; Antonopoulos, Stavros

    2014-01-01

    The skin may exhibit the first clinical evidence of a systemic disease and may provide the first clues to a diagnosis in malignancies. Erythroderma is defined as generalized redness and scaling and it is a clinical manifestation of a variety of underlying diseases including, rarely, solid tumors. Breast cancer is associated with a variety of skin paraneoplastic manifestations like acanthosis nigricans, erythromelalgia, thrombotic thrombocytopenic purpura, acrokeratosis paraneoplastica, dermatomyositis, systemic sclerosis, and scleroderma. However, in the literature, the correlation of erythroderma with breast cancer is quite infrequent. Here, we describe a case of a 76-year-old woman who presented with a paraneoplastic manifestation of erythroderma due to breast cancer. PMID:25295062

  6. Small Fiber Neuropathy in Children: Two Case Reports Illustrating the Importance of Recognition.

    PubMed

    Hoeijmakers, Janneke G J; Faber, Catharina G; Miedema, Carien J; Merkies, Ingemar S J; Vles, Johan S H

    2016-10-01

    Small fiber neuropathy (SFN) is a debilitating condition that often leads to pain and autonomic dysfunction. In the last few decades, SFN has been gaining more attention, particularly in adults. However, literature about SFN in children remains limited. The present article reports the cases of 2 adolescent girls diagnosed with SFN. The first patient (14 years of age) complained about painful itch and tingling in her legs, as well as dysautonomia symptoms for years. She also reported a red/purple-type discoloration of her legs aggravated by warmth and standing, compatible with erythromelalgia. The diagnosis of SFN was confirmed by a reduced intraepidermal nerve fiber density (IENFD) in skin biopsy sample. No underlying conditions were found. Symptomatic neuropathic pain treatment was started with moderate effect. The second patient (16 years of age) developed painful sensations in both feet and hands 6 weeks after an ICU admission for diabetic ketoacidosis, which included dysautonomia symptoms. She also exhibited some signs of erythromelalgia. The patient was diagnosed with predominant SFN (abnormal IENFD and quantitative sensory testing) as well as minor large nerve fiber involvement. Treatment with duloxetine, combined with a rehabilitation program, resulted in a marked improvement in her daily functioning. Although the SFN diagnosis in these 2 cases could be established according to the definition of SFN used in adults, additional diagnostic tools are needed that may be more appropriate for children. Additional information about the course of SFN in children may result in better treatment options. Copyright © 2016 by the American Academy of Pediatrics.

  7. Toxicological profiles of poisonous, edible, and medicinal mushrooms.

    PubMed

    Jo, Woo-Sik; Hossain, Md Akil; Park, Seung-Chun

    2014-09-01

    Mushrooms are a recognized component of the human diet, with versatile medicinal properties. Some mushrooms are popular worldwide for their nutritional and therapeutic properties. However, some species are dangerous because they cause toxicity. There are many reports explaining the medicinal and/or toxic effects of these fungal species. Cases of serious human poisoning generally caused by the improper identification of toxic mushroom species are reported every year. Different substances responsible for the fatal signs and symptoms of mushroom toxicity have been identified from various poisonous mushrooms. Toxicity studies of mushroom species have demonstrated that mushroom poisoning can cause adverse effects such as liver failure, bradycardia, chest pain, seizures, gastroenteritis, intestinal fibrosis, renal failure, erythromelalgia, and rhabdomyolysis. Correct categorization and better understanding are essential for the safe and healthy consumption of mushrooms as functional foods as well as for their medicinal use.

  8. [Diagnosis and treatment of polycythaemia vera: state of the art].

    PubMed

    Marton, Imelda; Simon, Zsófia; Borbényi, Zita

    2016-10-01

    Polycythaemia vera (PV), a condition characterized by blood hyperviscosity due to the expansion of the erythrocyte mass is the most common entity among all Philadelphia chromosome-negative myeloproliferative neoplasms. Arterial and venous thrombotic events are leading determinants of morbidity and mortality but impairment of quality of life due to vasomotor symptoms (erythromelalgia, pruritus) and disease-associated symptoms (tiredness, fatigue, pruritus, night sweats, vision problems, headache, concentration loss, abdominal discomfort, early satiety, fever, weight loss) are also present. The review of polycythaemia vera is actual as the updated WHO 2016 classification of myeloid neoplasms has changed the diagnostic criteria and a new second-line treatment option - JAK1/JAK2 inhibitor ruxolitinib - has been approved for patients who had an inadequate response to or are intolerant of hydroxyurea, which represents a breakthrough in the treatment of this patient population. Orv. Hetil., 2016, 157(44), 1743-1751.

  9. Toxicological Profiles of Poisonous, Edible, and Medicinal Mushrooms

    PubMed Central

    Jo, Woo-Sik; Hossain, Md. Akil

    2014-01-01

    Mushrooms are a recognized component of the human diet, with versatile medicinal properties. Some mushrooms are popular worldwide for their nutritional and therapeutic properties. However, some species are dangerous because they cause toxicity. There are many reports explaining the medicinal and/or toxic effects of these fungal species. Cases of serious human poisoning generally caused by the improper identification of toxic mushroom species are reported every year. Different substances responsible for the fatal signs and symptoms of mushroom toxicity have been identified from various poisonous mushrooms. Toxicity studies of mushroom species have demonstrated that mushroom poisoning can cause adverse effects such as liver failure, bradycardia, chest pain, seizures, gastroenteritis, intestinal fibrosis, renal failure, erythromelalgia, and rhabdomyolysis. Correct categorization and better understanding are essential for the safe and healthy consumption of mushrooms as functional foods as well as for their medicinal use. PMID:25346597

  10. Off-Pump Myocardial Revascularization in a High-Risk Patient with Essential Thrombocythemia

    PubMed Central

    Darwazah, Ahmad K.; Madi, Hamad; Zagha, Rami; Hawash, Yahia

    2014-01-01

    Essential thrombocythemia is a rare type of myeloproliferative disorder. Cerebral, myocardial, and peripheral thrombosis are all frequent complications of the disease. A 71-year-old man presented with severe coronary artery disease, associated with cerebral vascular ischemic changes and erythromelalgia. His platelet count was 1,486 ×103/μL. The patient underwent successful myocardial revascularization by means of an off-pump technique after his platelet count had been reduced by hydroxycarbamide administration. We conclude that the use of off-pump cardiopulmonary bypass in high-risk patients with essential thrombocythemia is safe. Reducing platelet count via the administration of hydroxycarbamide and the careful balancing of antiplatelets and anticoagulants is crucial in determining the outcome of surgery. PMID:25425991

  11. [Neuropathic pain associated with Nav1.7 mutations: clinical picture and treatment].

    PubMed

    Doppler, K; Sommer, C

    2013-12-01

    Voltage-gated sodium channels are essential for electrogenesis in excitable cells. The isoform Nav1.7 is primarily expressed in nociceptors. Mutations of the SCN9A gene, which codes for the α-subunit of Nav1.7, are the cause of primary erythromelalgia and paroxysmal extreme pain disorder, two rare neuropathic pain conditions. Recent studies have shown that mutations in the SCN9A gene are the cause of a subgroup of idiopathic small fiber neuropathies and that polymorphisms of SCN9A are associated with an increase in susceptibility to pain. These findings not only contribute to the understanding of the pathophysiology of neuropathic pain but also offer targets for a more specific pain therapy.

  12. Inherited Pain

    PubMed Central

    Eberhardt, Mirjam; Nakajima, Julika; Klinger, Alexandra B.; Neacsu, Cristian; Hühne, Kathrin; O'Reilly, Andrias O.; Kist, Andreas M.; Lampe, Anne K.; Fischer, Kerstin; Gibson, Jane; Nau, Carla; Winterpacht, Andreas; Lampert, Angelika

    2014-01-01

    Inherited erythromelalgia (IEM) causes debilitating episodic neuropathic pain characterized by burning in the extremities. Inherited “paroxysmal extreme pain disorder” (PEPD) differs in its clinical picture and affects proximal body areas like the rectal, ocular, or jaw regions. Both pain syndromes have been linked to mutations in the voltage-gated sodium channel Nav1.7. Electrophysiological characterization shows that IEM-causing mutations generally enhance activation, whereas mutations leading to PEPD alter fast inactivation. Previously, an A1632E mutation of a patient with overlapping symptoms of IEM and PEPD was reported (Estacion, M., Dib-Hajj, S. D., Benke, P. J., Te Morsche, R. H., Eastman, E. M., Macala, L. J., Drenth, J. P., and Waxman, S. G. (2008) NaV1.7 Gain-of-function mutations as a continuum. A1632E displays physiological changes associated with erythromelalgia and paroxysmal extreme pain disorder mutations and produces symptoms of both disorders. J. Neurosci. 28, 11079–11088), displaying a shift of both activation and fast inactivation. Here, we characterize a new mutation of Nav1.7, A1632T, found in a patient suffering from IEM. Although transfection of A1632T in sensory neurons resulted in hyperexcitability and spontaneous firing of dorsal root ganglia (DRG) neurons, whole-cell patch clamp of transfected HEK cells revealed that Nav1.7 activation was unaltered by the A1632T mutation but that steady-state fast inactivation was shifted to more depolarized potentials. This is a characteristic normally attributed to PEPD-causing mutations. In contrast to the IEM/PEPD crossover mutation A1632E, A1632T failed to slow current decay (i.e. open-state inactivation) and did not increase resurgent currents, which have been suggested to contribute to high-frequency firing in physiological and pathological conditions. Reduced fast inactivation without increased resurgent currents induces symptoms of IEM, not PEPD, in the new Nav1.7 mutation, A1632T

  13. [Small fiber neuropathy].

    PubMed

    Langlois, V; Bedat Millet, A-L; Lebesnerais, M; Miranda, S; Marguet, F; Benhamou, Y; Marcorelles, P; Lévesque, H

    2017-04-11

    Small fiber neuropathy (SFN) is still unknown. Characterised by neuropathic pain, it typically begins by burning feet, but could take many other expression. SFN affects the thinly myelinated Aδ and unmyelinated C-fibers, by an inherited or acquired mechanism, which could lead to paresthesia, thermoalgic disorder or autonomic dysfunction. Recent studies suggest the preponderant role of ion channels such as Nav1.7. Furthermore, erythromelalgia or burning mouth syndrome are now recognized as real SFN. Various aetiologies of SFN are described. It could be isolated or associated with diabetes, impaired glucose metabolism, vitamin deficiency, alcohol, auto-immune disease, sarcoidosis etc. Several mutations have recently been identified, like Nav1.7 channel leading to channelopathies. Diagnostic management is based primarily on clinical examination and demonstration of small fiber dysfunction. Laser evoked potentials, Sudoscan(®), cutaneous biopsy are the main test, but had a difficult access. Treatment is based on multidisciplinary management, combining symptomatic treatment, psychological management and treatment of an associated etiology. Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  14. Sex Differences in the Incidence of Skin and Skin-Related Diseases in Olmsted County, Minnesota, United States, and a Comparison With Other Rates Published Worldwide

    PubMed Central

    Andersen, Louise K.; Davis, Mark D. P.

    2016-01-01

    Many skin and skin-related diseases affect the sexes unequally, with attendant implications for public health and resource allocation. To better evaluate the incidence of skin and skin-related diseases affecting males versus females, we reviewed published population-based epidemiology studies of skin disorders performed utilizing Rochester Epidemiology Project (REP) data. Females had a higher incidence of the following diseases: connective tissue diseases (scleroderma, morphea, dermatomyositis, primary Sjögren syndrome, systemic lupus erythematosus [not in all studies]), pityriasis rosea, herpes progenitalis, condyloma acuminatum, hidradenitis suppurativa, herpes zoster (except in children), erythromelalgia, venous stasis syndrome, and venous ulcers. Males had a higher incidence of psoriasis and psoriatic arthritis, basal cell carcinoma (exception, females aged ≤40 years), squamous cell carcinoma, and lentigo maligna. Incidence rates were equal in males and females for cutaneous malignant melanoma (exception, higher in females aged 18–39 years), lower-extremity cellulitis, cutaneous nontuberculous mycobacterial infection, Behçet disease, delusional infestation, alopecia areata, and bullous pemphigoid. Many of the population-based sex-specific incidence rates of skin and skin-related diseases derived from the Rochester Epidemiology Project are strikingly different from those estimated elsewhere. In general, females are more commonly affected by skin and skin-related diseases. The reasons for this imbalance remain to be determined and are likely multifactorial. PMID:27009931

  15. Persistent genital arousal and restless genitalia: sexual dysfunction or subtype of vulvodynia?

    PubMed

    Markos, A R; Dinsmore, Wallace

    2013-11-01

    We conducted a literature review of patients' conditions described under persistent genital arousal disorder and restless genital syndrome, vulvodynia and male genital skin pain of unknown aetiology (penoscrotodynia). Our aim is to improve the understanding of the condition, unify nomenclature and promote evidence-based practice. The most prominent symptom in persistent genital arousal disorder and restless genital syndrome is a spontaneous, unwelcomed, intrusive and distressing vulval sensation. There are similarities between the clinical presentation of vulvodynia, penoscrotodynia, persistent genital arousal disorder and restless genital syndrome patients. The aetiology of persistent genital arousal disorder and restless genital syndrome, similar to vulvodynia, could be better explained in terms of neuro-vascular dysfunction, genital peripheral neuropathy and/or dysfunctional micro-vascular arterio-venous shunting. Erythromelalgia lends itself to explain some cases of restless genital syndrome, who have concurrent restless legs syndrome; and therefore draw parallels with the red scrotum syndrome. The published literature supports the concept of classifying restless genital syndrome as a sub-type of vulvodynia rather than sexual dysfunction.

  16. Regulation of Nav1.7: A Conserved SCN9A Natural Antisense Transcript Expressed in Dorsal Root Ganglia.

    PubMed

    Koenig, Jennifer; Werdehausen, Robert; Linley, John E; Habib, Abdella M; Vernon, Jeffrey; Lolignier, Stephane; Eijkelkamp, Niels; Zhao, Jing; Okorokov, Andrei L; Woods, C Geoffrey; Wood, John N; Cox, James J

    2015-01-01

    The Nav1.7 voltage-gated sodium channel, encoded by SCN9A, is critical for human pain perception yet the transcriptional and post-transcriptional mechanisms that regulate this gene are still incompletely understood. Here, we describe a novel natural antisense transcript (NAT) for SCN9A that is conserved in humans and mice. The NAT has a similar tissue expression pattern to the sense gene and is alternatively spliced within dorsal root ganglia. The human and mouse NATs exist in cis with the sense gene in a tail-to-tail orientation and both share sequences that are complementary to the terminal exon of SCN9A/Scn9a. Overexpression analyses of the human NAT in human embryonic kidney (HEK293A) and human neuroblastoma (SH-SY5Y) cell lines show that it can function to downregulate Nav1.7 mRNA, protein levels and currents. The NAT may play an important role in regulating human pain thresholds and is a potential candidate gene for individuals with chronic pain disorders that map to the SCN9A locus, such as Inherited Primary Erythromelalgia, Paroxysmal Extreme Pain Disorder and Painful Small Fibre Neuropathy, but who do not contain mutations in the sense gene. Our results strongly suggest the SCN9A NAT as a prime candidate for new therapies based upon augmentation of existing antisense RNAs in the treatment of chronic pain conditions in man.

  17. Thoracic sympathectomy: a review of current indications.

    PubMed

    Hashmonai, Moshe; Cameron, Alan E P; Licht, Peter B; Hensman, Chris; Schick, Christoph H

    2016-04-01

    Thoracic sympathetic ablation was introduced over a century ago. While some of the early indications have become obsolete, new ones have emerged. Sympathetic ablation is being still performed for some odd indications thus prompting the present study, which reviews the evidence base for current practice. The literature was reviewed using the PubMed/Medline Database, and pertinent articles regarding the indications for thoracic sympathectomy were retrieved and evaluated. Old, historical articles were also reviewed as required. Currently, thoracic sympathetic ablation is indicated mainly for primary hyperhidrosis, especially affecting the palm, and to a lesser degree, axilla and face, and for facial blushing. Despite modern pharmaceutical, endovascular and surgical treatments, sympathetic ablation has still a place in the treatment of very selected cases of angina, arrhythmias and cardiomyopathy. Thoracic sympathetic ablation is indicated in several painful conditions: the early stages of complex regional pain syndrome, erythromelalgia, and some pancreatic and other painful abdominal pathologies. Although ischaemia was historically the major indication for sympathetic ablation, its use has declined to a few selected cases of thromboangiitis obliterans (Buerger's disease), microemboli, primary Raynaud's phenomenon and Raynaud's phenomenon secondary to collagen diseases, paraneoplastic syndrome, frostbite and vibration syndrome. Thoracic sympathetic ablation for hypertension is obsolete, and direct endovascular renal sympathectomy still requires adequate clinical trials. There are rare publications of sympathetic ablation for primary phobias, but there is no scientific basis to support sympathetic surgery for any psychiatric indication.

  18. [Congenital insensitivity to pain].

    PubMed

    Danziger, N; Willer, J-C

    2009-02-01

    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.

  19. Nonlinear effects of hyperpolarizing shifts in activation of mutant NaV1.7 channels on resting membrane potential.

    PubMed

    Estacion, Mark; Waxman, Stephen G

    2017-02-01

    The Nav1.7 sodium channel is preferentially expressed within dorsal root ganglion (DRG) and sympathetic ganglion neurons. Gain-of-function mutations that cause the painful disorder inherited erythromelalgia (IEM) shift channel activation in a hyperpolarizing direction. When expressed within DRG neurons, these mutations produce a depolarization of resting membrane potential (RMP). The biophysical basis for the depolarized RMP has to date not been established. To explore the effect on RMP of the shift in activation associated with a prototypical IEM mutation (L858H), we used dynamic clamp models that represent graded shifts that fractionate the effect of the mutation on activation voltage-dependence. Dynamic clamp recording from DRG neurons using a before-and-after protocol for each cell made it possible, even in the presence of cell-to-cell variation in starting RMP, to assess the effects of these graded mutant models. Our results demonstrate a non-linear, progressively larger effect on RMP as the shift in activation voltage-dependence becomes more hyperpolarized. The observed differences in RMP were predicted by the "late" current of each mutant model. Since the depolarization of RMP imposed by IEM mutant channels is known, in itself, to produce hyperexcitability of DRG neurons, the development of pharmacological agents that normalize or partially normalize activation voltage-dependence of IEM mutant channels merits further study.

  20. A sodium channel gene SCN9A polymorphism that increases nociceptor excitability.

    PubMed

    Estacion, Mark; Harty, T Patrick; Choi, Jin-Sung; Tyrrell, Lynda; Dib-Hajj, Sulayman D; Waxman, Stephen G

    2009-12-01

    Sodium channel Na(V)1.7, encoded by the SCN9A gene, is preferentially expressed in nociceptive primary sensory neurons, where it amplifies small depolarizations. In studies on a family with inherited erythromelalgia associated with Na(V)1.7 gain-of-function mutation A863P, we identified a nonsynonymous single-nucleotide polymorphism within SCN9A in the affected proband and several unaffected family members; this polymorphism (c. 3448C&T, Single Nucleotide Polymorphisms database rs6746030, which produces the amino acid substitution R1150W in human Na(V)1.7 [hNa(V)1.7]) is present in 1.1 to 12.7% of control chromosomes, depending on ethnicity. In this study, we examined the effect of the R1150W substitution on function of the hNa(V)1.7 channel, and on the firing of dorsal root ganglion (DRG) neurons in which this channel is normally expressed. We show that this polymorphism depolarizes activation (7.9-11mV in different assays). Current-clamp analysis shows that the 1150W allele depolarizes (6mV) resting membrane potential and increases ( approximately 2-fold) the firing frequency in response to depolarization in DRG neurons in which it is present. Our results suggest that polymorphisms in the Na(V)1.7 channel may influence susceptibility to pain.

  1. Human Mendelian pain disorders: a key to discovery and validation of novel analgesics.

    PubMed

    Goldberg, Y P; Pimstone, S N; Namdari, R; Price, N; Cohen, C; Sherrington, R P; Hayden, M R

    2012-10-01

    We have utilized a novel application of human genetics, illuminating the important role that rare genetic disorders can play in the development of novel drugs that may be of relevance for the treatment of both rare and common diseases. By studying a very rare Mendelian disorder of absent pain perception, congenital indifference to pain, we have defined Nav1.7 (endocded by SCN9A) as a critical and novel target for analgesic development. Strong human validation has emerged with SCN9A gain-of-function mutations causing inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder, both Mendelian disorder of spontaneous or easily evoked pain. Furthermore, variations in the Nav1.7 channel also modulate pain perception in healthy subjects as well as in painful conditions such as osteoarthritis and Parkinson disease. On the basis of this, we have developed a novel compound (XEN402) that exhibits potent, voltage-dependent block of Nav1.7. In a small pilot study, we showed that XEN402 blocks Nav1.7 mediated pain associated with IEM thereby demonstrating the use of rare genetic disorders with mutant target channels as a novel approach to rapid proof-of-concept. Our approach underscores the critical role that human genetics can play by illuminating novel and critical pathways pertinent for drug discovery.

  2. Sodium channel slow inactivation interferes with open channel block

    PubMed Central

    Hampl, Martin; Eberhardt, Esther; O’Reilly, Andrias O.; Lampert, Angelika

    2016-01-01

    Mutations in the voltage-gated sodium channel Nav1.7 are linked to inherited pain syndromes such as erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). PEPD mutations impair Nav1.7 fast inactivation and increase persistent currents. PEPD mutations also increase resurgent currents, which involve the voltage-dependent release of an open channel blocker. In contrast, IEM mutations, whenever tested, leave resurgent currents unchanged. Accordingly, the IEM deletion mutation L955 (ΔL955) fails to produce resurgent currents despite enhanced persistent currents, which have hitherto been considered a prerequisite for resurgent currents. Additionally, ΔL955 exhibits a prominent enhancement of slow inactivation (SI). We introduced mutations into Nav1.7 and Nav1.6 that either enhance or impair SI in order to investigate their effects on resurgent currents. Our results show that enhanced SI is accompanied by impaired resurgent currents, which suggests that SI may interfere with open-channel block. PMID:27174182

  3. Postcoital generalised pruritus as a first symptom of polycythaemia vera.

    PubMed

    Patidar, O P; Patidar, Rekha; Patidar, R P

    2013-01-01

    Ploycythaemia vera (PV) is most common of chronic myeloproliferative disorder that involves the multipotent haemaotopoietic progenitor cells. PV has indolent course and recognised either by incidental discovery of high haemoglobin or haemtocrit. PV may present with aquagenic pruritus (AP) for years together without any other sign and symptoms. So advice of simple complete bood count as a routine in every case of pruritus can be helpful to diagnose it timely thereby dreaded complications of PV, related to hyperviscosity of blood like thrombosis both arterial and venous can be managed antecedently. A 50-year-old male doctor diagnosed as a case of PV presented to us with postcoital generalised pruritus (PCP) as a first, rarest symptoms and he remained undiagnosed for 10 years till he developed other features of PV like aquagenic pruritus, headache, red congestion in eyes and erythromelalgia symptoms complex erythema, burning pain and warmness of lower extremities. Then he was investigated and was found to have high haemoglobin or haemtocrit, JAK 2 genetic mutation changes were present, bone marrow biopsy and other biochemical investigations confirmed the diagnosis of PV. Initially he was managed with repeated phlebotomy to bring down high haemtocrit value in acceptable range (approximately 45%). Simultaneously he was put on hydroxyurea 500 mg twice daily doses. Since then his symptoms improved and monthly blood count was done to monitor the haemtocrit. So advice of simple blood count is highly informative in every case of generalised pruritus.

  4. [Paraneoplastic rheumatic syndromes].

    PubMed

    Gracia-Ramos, Abraham Edgar; Vera-Lastra, Olga Lidia

    2012-01-01

    Paraneoplastic rheumatic syndromes are defined as those events associated with cancer that occur away from the primary tumor or its metastases and are induced by the presence of the tumor through biological products like hormones, peptides, autocrine or paracrine mediators, antibodies or cytotoxic lymphocytes. Of these, hypertrophic osteoarthropathy, carcinomatous polyarthritis, dermatomyositis/polymyositis, and paraneoplastic vasculitis are the most frequently recognized. Other less known associations are based upon a smaller number of case reports, and include palmar fasciitis, panniculitis, erythema nodosum, Raynaud¥s phenomenon, erythromelalgia and Lupus-like syndrome. Usually the clinical course of rheumatic paraneoplastic syndrome and cancer parallels the resolution of the tumor usually leads to resolution of this syndrome. It is difficult make the distinction between idiopathic rheumatic syndromes from those that result from cancer. Still, there are several clinical data that can guide us to the presence of an occult malignancy, and should be identified as the detection of cancer can lead to early treatment and better prognosis.

  5. Sex differences in the incidence of skin and skin-related diseases in Olmsted County, Minnesota, United States, and a comparison with other rates published worldwide.

    PubMed

    Andersen, Louise K; Davis, Mark D P

    2016-09-01

    Many skin and skin-related diseases affect the sexes unequally, with attendant implications for public health and resource allocation. To evaluate better the incidence of skin and skin-related diseases affecting males vs. females, we reviewed published population-based epidemiology studies of skin disorders performed utilizing Rochester Epidemiology Project data. Females had a higher incidence of the following diseases: connective tissue diseases (scleroderma, morphea, dermatomyositis, primary Sjögren syndrome, systemic lupus erythematosus [not in all studies]), pityriasis rosea, herpes progenitalis, condyloma acuminatum, hidradenitis suppurativa, herpes zoster (except in children), erythromelalgia, venous stasis syndrome, and venous ulcers. Males had a higher incidence of psoriasis and psoriatic arthritis, basal cell carcinoma (exception, females aged ≤40 years), squamous cell carcinoma, and lentigo maligna. Incidence rates were equal in males and females for cutaneous malignant melanoma (exception, higher in females aged 18-39 years), lower-extremity cellulitis, cutaneous nontuberculous mycobacterial infection, Behçet disease, delusional infestation, alopecia areata, and bullous pemphigoid. Many of the population-based sex-specific incidence rates of skin and skin-related diseases derived from the Rochester Epidemiology Project are strikingly different from those estimated elsewhere. In general, females are more commonly affected by skin and skin-related diseases. The reasons for this imbalance remain to be determined and are likely multifactorial.

  6. Fractal Dimension Characterization of in-vivo Laser Doppler Flowmetry signals

    NASA Astrophysics Data System (ADS)

    Srinivasan, Gayathri; Sujatha, N.

    Laser Doppler Blood Flow meter uses tissue backscattered light to non-invasively assess the blood flow rate. qualitatively. As there is large spatial variability and the temporal heterogeneity in tissue microvasculature, the measured blood flow rate is expressed in relative units. A non-linear approach in order to understand the dynamics of the microcirculation led to the fractal characterization of the blood flow signals. The study presented in the paper aims to analyze the fractal behavior of Laser Doppler Flow (LDF) signals and to quantitatively estimate the fractal dimension of waveforms using Box-Counting method. The measured Fractal dimension is an estimate of temporal variability of tissue perfusion. The rate at which fractal dimension varies as a function of location between individuals, exhibits a weak correlation with time. Further studies with a larger number of subjects are necessary to test the generality of the findings and if changes in dimension are reproducible in given individuals. In conclusion, the fractal dimension determined by Box-counting method may be useful for characterizing LDF time series signals. Future experiments evaluating whether the technique can be used to quantify microvascular dysfunction, as commonly occurring in conditions such as Diabetes, Raynaud's phenomenon, Erythromelalgia and Achenbach syndrome needs to be evaluated.

  7. Evidence of Small-Fiber Polyneuropathy in Unexplained, Juvenile-Onset, Widespread Pain Syndromes

    PubMed Central

    Klein, Max M.

    2013-01-01

    OBJECTIVE: We tested the hypothesis that acquired small-fiber polyneuropathy (SFPN), previously uncharacterized in children, contributes to unexplained pediatric widespread pain syndromes. METHODS: Forty-one consecutive patients evaluated for unexplained widespread pain beginning before age 21 had medical records comprehensively analyzed regarding objective diagnostic testing for SFPN (neurodiagnostic skin biopsy, nerve biopsy, and autonomic function testing), plus histories, symptoms, signs, other tests, and treatments. Healthy, demographically matched volunteers provided normal controls for SFPN tests. RESULTS: Age at illness onset averaged 12.3 ± 5.7 years; 73% among this poly-ethnic sample were female (P = .001). Sixty-eight percent were chronically disabled, and 68% had hospitalizations. Objective testing diagnosed definite SFPN in 59%, probable SFPN in 17%, and possible SFPN in 22%. Only 1 of 41 had entirely normal SFPN test results. Ninety-eight percent of patients had other somatic complaints consistent with SFPN dysautonomia (90% cardiovascular, 82% gastrointestinal, and 34% urologic), 83% reported chronic fatigue, and 63% had chronic headache. Neurologic examinations identified reduced sensation in 68% and vasomotor abnormalities in 55%, including 23% with erythromelalgia. Exhaustive investigations for SFPN causality identified only history of autoimmune illnesses in 33% and serologic markers of disordered immunity in 89%. Treatment with corticosteroids and/or intravenous immune globulin objectively and subjectively benefited 80% of patients (12/15). CONCLUSIONS: More than half among a large series of patients with childhood-onset, unexplained chronic widespread pain met rigorous, multitest, diagnostic criteria for SFPN, which extends the age range of acquired SFPN into early childhood. Some cases appeared immune-mediated and improved with immunomodulatory therapies. PMID:23478869

  8. Novel SCN9A mutations underlying extreme pain phenotypes: unexpected electrophysiological and clinical phenotype correlations.

    PubMed

    Emery, Edward C; Habib, Abdella M; Cox, James J; Nicholas, Adeline K; Gribble, Fiona M; Woods, C Geoffrey; Reimann, Frank

    2015-05-20

    The importance of NaV1.7 (encoded by SCN9A) in the regulation of pain sensing is exemplified by the heterogeneity of clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been associated with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is usually caused by enhanced NaV1.7 channel activation, whereas mutations that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional mutations in SCN9A are known to underlie congenital insensitivity to pain (CIP). Although well documented, the correlation between SCN9A genotypes and clinical phenotypes is still unclear. Here we report three families with novel SCN9A mutations. In a multiaffected dominant family with IEM, we found the heterozygous change L245 V. Electrophysiological characterization showed that this mutation did not affect channel activation but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, characteristics more commonly associated with PEPD. In two compound heterozygous CIP patients, we found mutations that still retained functionality of the channels, with two C-terminal mutations (W1775R and L1831X) exhibiting a depolarizing shift in channel activation. Two mutations (A1236E and L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation. To our knowledge, these are the first descriptions of mutations with some retained channel function causing CIP. This study emphasizes the complex genotype-phenotype correlations that exist for SCN9A and highlights the C-terminal cytoplasmic region of NaV1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies.

  9. Genetics and molecular pathophysiology of Na(v)1.7-related pain syndromes.

    PubMed

    Dib-Hajj, Sulayman D; Yang, Yong; Waxman, Stephen G

    2008-01-01

    SCN9A, the gene which encodes voltage-gated sodium channel Na(v)1.7, is located on human chromosome 2 within a cluster of other members of this gene family. Na(v)1.7 is present at high levels in most peripheral nociceptive neurons in dorsal root ganglion (DRG) and in sympathetic neurons. In addition to its focal tissue-specific expression, Na(v)1.7 is distinguished by its ability to amplify small depolarizations, thus acting as a threshold channel and modulating excitability. Dominantly inherited gain-of-function mutations in SCN9A have been linked to two familial painful disorders: inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). One set of mutations leads to severe episodes of pain in the feet and hands in patients with IEM, and a different set of mutations causes pain in a perirectal, periocular, and mandibular distribution in patients with PEPD. These mutations allow mutant channels to activate in response to weaker stimuli, or to remain open longer in response to stimulation. The introduction of mutant channels into DRG neurons alters electrogenesis and renders these primary sensory neurons hyperexcitable. Mutant Na(v)1.7 channels lower the threshold for single action potentials and increase the number of action potentials that neurons fire in response to suprathreshold stimuli. In contrast, recessively inherited loss-of-function mutations in SCN9A, which cause a loss of function of Na(v)1.7 in patients, lead to indifference to pain with sparing of motor and cognitive abilities. The central role of Na(v)1.7 in these disorders, and the apparently limited consequences of loss of this channel in humans make it an attractive target for treatment of pain.

  10. Painful neuropathies: the emerging role of sodium channelopathies.

    PubMed

    Brouwer, Brigitte A; Merkies, Ingemar S J; Gerrits, Monique M; Waxman, Stephen G; Hoeijmakers, Janneke G J; Faber, Catharina G

    2014-06-01

    Pain is a frequent debilitating feature reported in peripheral neuropathies with involvement of small nerve (Aδ and C) fibers. Voltage-gated sodium channels are responsible for the generation and conduction of action potentials in the peripheral nociceptive neuronal pathway where NaV 1.7, NaV 1.8, and NaV 1.9 sodium channels (encoded by SCN9A, SCN10A, and SCN11A) are preferentially expressed. The human genetic pain conditions inherited erythromelalgia and paroxysmal extreme pain disorder were the first to be linked to gain-of-function SCN9A mutations. Recent studies have expanded this spectrum with gain-of-function SCN9A mutations in patients with small fiber neuropathy and in a new syndrome of pain, dysautonomia, and small hands and small feet (acromesomelia). In addition, painful neuropathies have been recently linked to SCN10A mutations. Patch-clamp studies have shown that the effect of SCN9A mutations is dependent upon the cell-type background. The functional effects of a mutation in dorsal root ganglion (DRG) neurons and sympathetic neuron cells may differ per mutation, reflecting the pattern of expression of autonomic symptoms in patients with painful neuropathies who carry the mutation in question. Peripheral neuropathies may not always be length-dependent, as demonstrated in patients with initial facial and scalp pain symptoms with SCN9A mutations showing hyperexcitability in both trigeminal ganglion and DRG neurons. There is some evidence suggesting that gain-of-function SCN9A mutations can lead to degeneration of peripheral axons. This review will focus on the emerging role of sodium channelopathies in painful peripheral neuropathies, which could serve as a basis for novel therapeutic strategies.

  11. Can robots patch-clamp as well as humans? Characterization of a novel sodium channel mutation.

    PubMed

    Estacion, M; Choi, J S; Eastman, E M; Lin, Z; Li, Y; Tyrrell, L; Yang, Y; Dib-Hajj, S D; Waxman, S G

    2010-06-01

    Ion channel missense mutations cause disorders of excitability by changing channel biophysical properties. As an increasing number of new naturally occurring mutations have been identified, and the number of other mutations produced by molecular approaches such as in situ mutagenesis has increased, the need for functional analysis by patch-clamp has become rate limiting. Here we compare a patch-clamp robot using planar-chip technology with human patch-clamp in a functional assessment of a previously undescribed Nav1.7 sodium channel mutation, S211P, which causes erythromelalgia. This robotic patch-clamp device can increase throughput (the number of cells analysed per day) by 3- to 10-fold. Both modes of analysis show that the mutation hyperpolarizes activation voltage dependence (8 mV by manual profiling, 11 mV by robotic profiling), alters steady-state fast inactivation so that it requires an additional Boltzmann function for a second fraction of total current (approximately 20% manual, approximately 40% robotic), and enhances slow inactivation (hyperpolarizing shift--15 mV by human,--13 mV robotic). Manual patch-clamping demonstrated slower deactivation and enhanced (approximately 2-fold) ramp response for the mutant channel while robotic recording did not, possibly due to increased temperature and reduced signal-to-noise ratio on the robotic platform. If robotic profiling is used to screen ion channel mutations, we recommend that each measurement or protocol be validated by initial comparison to manual recording. With this caveat, we suggest that, if results are interpreted cautiously, robotic patch-clamp can be used with supervision and subsequent confirmation from human physiologists to facilitate the initial profiling of a variety of electrophysiological parameters of ion channel mutations.

  12. Differential effect of D623N variant and wild-type Na(v)1.7 sodium channels on resting potential and interspike membrane potential of dorsal root ganglion neurons.

    PubMed

    Ahn, Hye-Sook; Vasylyev, Dmytro V; Estacion, Mark; Macala, Lawrence J; Shah, Palak; Faber, Catharina G; Merkies, Ingemar S J; Dib-Hajj, Sulayman D; Waxman, Stephen G

    2013-09-05

    Sodium channel NaV1.7 is preferentially expressed in dorsal root ganglion (DRG) and sympathetic ganglion neurons. Gain-of-function NaV1.7 mutations/variants have been identified in the painful disorders inherited erythromelalgia and small-fiber neuropathy (SFN). DRG neurons transfected with these channel variants display depolarized resting potential, reduced current-threshold, increased firing-frequency and spontaneous firing. Whether the depolarizing shift in resting potential and enhanced spontaneous firing are due to persistent activity of variant channels, or to compensatory changes in other conductance(s) in response to expression of the variant channel, as shown in model systems, has not been studied. We examined the effect of wild-type NaV1.7 and a NaV1.7 mutant channel, D623N, associated with SFN, on resting potential and membrane potential during interspike intervals in DRG neurons. Resting potential in DRG neurons expressing D623N was depolarized compared to neurons expressing WT-NaV1.7. Exposure to TTX hyperpolarized resting potential by 7mV, increased current-threshold, decreased firing-frequency, and reduced NMDG-induced-hyperpolarization in DRG neurons expressing D623N. To assess the contribution of depolarized resting potential to DRG neuron excitability, we mimicked the mutant channel's depolarizing effect by current injection to produce equivalent depolarization; the depolarization decreased current threshold and increased firing-frequency. Voltage-clamp using ramp or repetitive action potentials as commands showed that D623N channels enhance the TTX-sensitive inward current, persistent at subthreshold membrane voltages, as predicted by a Hodgkin-Huxley model. Our results demonstrate that a variant of NaV1.7 associated with painful neuropathy depolarizes resting membrane potential and produces an enhanced inward current during interspike intervals, thereby contributing to DRG neuron hyperexcitability.

  13. The clinical approach to small fibre neuropathy and painful channelopathy

    PubMed Central

    Themistocleous, Andreas C; Ramirez, Juan D; Serra, Jordi; Bennett, David L H

    2014-01-01

    Small fibre neuropathy (SFN) is characterised by structural injury selectively affecting small diameter sensory and/or autonomic axons. The clinical presentation is dominated by pain. SFN complicates a number of common diseases such as diabetes mellitus and is likely to be increasingly encountered. The diagnosis of SFN is demanding as clinical features can be vague and nerve conduction studies normal. New diagnostic techniques, in particular measurement of intraepidermal nerve fibre density, have significantly improved the diagnostic efficiency of SFN. Management is focused on the treatment of the underlying cause and analgesia, as there is no neuroprotective therapy. A recent and significant advance is the finding that a proportion of cases labelled as idiopathic SFN are in fact associated with gain of function mutations of the voltage-gated sodium channels Nav1.7 and Nav1.8 (encoded by the genes SCN9A and SCN10A, respectively). There is a further group of heritable painful conditions in which gain of function mutations in ion channels alter excitability of sensory neurones but do not cause frank axon degeneration; these include mutations in Nav1.7 (causing erythromelalgia and paroxysmal extreme pain disorder) and TRPA1 (resulting in familial episodic pain disorder). These conditions are exceptionally rare but have provided great insight into the nociceptive system as well as yielding potential analgesic drug targets. In patients with no pre-existing risk factor, the investigation of an underlying cause of SFN should be systematic and appropriate for the patient population. In this review, we focus on how to incorporate recent developments in the diagnosis and pathophysiology of SFN into clinical practice. PMID:24778270

  14. Can robots patch-clamp as well as humans? Characterization of a novel sodium channel mutation

    PubMed Central

    Estacion, M; Choi, J S; Eastman, E M; Lin, Z; Li, Y; Tyrrell, L; Yang, Y; Dib-Hajj, S D; Waxman, S G

    2010-01-01

    Ion channel missense mutations cause disorders of excitability by changing channel biophysical properties. As an increasing number of new naturally occurring mutations have been identified, and the number of other mutations produced by molecular approaches such as in situ mutagenesis has increased, the need for functional analysis by patch-clamp has become rate limiting. Here we compare a patch-clamp robot using planar-chip technology with human patch-clamp in a functional assessment of a previously undescribed Nav1.7 sodium channel mutation, S211P, which causes erythromelalgia. This robotic patch-clamp device can increase throughput (the number of cells analysed per day) by 3- to 10-fold. Both modes of analysis show that the mutation hyperpolarizes activation voltage dependence (−8 mV by manual profiling, −11 mV by robotic profiling), alters steady-state fast inactivation so that it requires an additional Boltzmann function for a second fraction of total current (∼20% manual, ∼40% robotic), and enhances slow inactivation (hyperpolarizing shift −15 mV by human, −13 mV robotic). Manual patch-clamping demonstrated slower deactivation and enhanced (∼2-fold) ramp response for the mutant channel while robotic recording did not, possibly due to increased temperature and reduced signal-to-noise ratio on the robotic platform. If robotic profiling is used to screen ion channel mutations, we recommend that each measurement or protocol be validated by initial comparison to manual recording. With this caveat, we suggest that, if results are interpreted cautiously, robotic patch-clamp can be used with supervision and subsequent confirmation from human physiologists to facilitate the initial profiling of a variety of electrophysiological parameters of ion channel mutations. PMID:20123784

  15. Novel SCN9A Mutations Underlying Extreme Pain Phenotypes: Unexpected Electrophysiological and Clinical Phenotype Correlations

    PubMed Central

    Emery, Edward C.; Habib, Abdella M.; Cox, James J.; Nicholas, Adeline K.; Gribble, Fiona M.

    2015-01-01

    The importance of NaV1.7 (encoded by SCN9A) in the regulation of pain sensing is exemplified by the heterogeneity of clinical phenotypes associated with its mutation. Gain-of-function mutations are typically pain-causing and have been associated with inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is usually caused by enhanced NaV1.7 channel activation, whereas mutations that alter steady-state fast inactivation often lead to PEPD. In contrast, nonfunctional mutations in SCN9A are known to underlie congenital insensitivity to pain (CIP). Although well documented, the correlation between SCN9A genotypes and clinical phenotypes is still unclear. Here we report three families with novel SCN9A mutations. In a multiaffected dominant family with IEM, we found the heterozygous change L245 V. Electrophysiological characterization showed that this mutation did not affect channel activation but instead resulted in incomplete fast inactivation and a small hyperpolarizing shift in steady-state slow inactivation, characteristics more commonly associated with PEPD. In two compound heterozygous CIP patients, we found mutations that still retained functionality of the channels, with two C-terminal mutations (W1775R and L1831X) exhibiting a depolarizing shift in channel activation. Two mutations (A1236E and L1831X) resulted in a hyperpolarizing shift in steady-state fast inactivation. To our knowledge, these are the first descriptions of mutations with some retained channel function causing CIP. This study emphasizes the complex genotype–phenotype correlations that exist for SCN9A and highlights the C-terminal cytoplasmic region of NaV1.7 as a critical region for channel function, potentially facilitating analgesic drug development studies. PMID:25995458

  16. Essential thrombocythemia

    PubMed Central

    Brière, Jean B

    2007-01-01

    Essential thrombocythemia (ET) is an acquired myeloproliferative disorder (MPD) characterized by a sustained elevation of platelet number with a tendency for thrombosis and hemorrhage. The prevalence in the general population is approximately 30/100,000. The median age at diagnosis is 65 to 70 years, but the disease may occur at any age. The female to male ratio is about 2:1. The clinical picture is dominated by a predisposition to vascular occlusive events (involving the cerebrovascular, coronary and peripheral circulation) and hemorrhages. Some patients with ET are asymptomatic, others may experience vasomotor (headaches, visual disturbances, lightheadedness, atypical chest pain, distal paresthesias, erythromelalgia), thrombotic, or hemorrhagic disturbances. Arterial and venous thromboses, as well as platelet-mediated transient occlusions of the microcirculation and bleeding, represent the main risks for ET patients. Thromboses of large arteries represent a major cause of mortality associated with ET or can induce severe neurological, cardiac or peripheral artery manifestations. Acute leukemia or myelodysplasia represent only rare and frequently later-onset events. The molecular pathogenesis of ET, which leads to the overproduction of mature blood cells, is similar to that found in other clonal MPDs such as chronic myeloid leukemia, polycythemia vera and myelofibrosis with myeloid metaplasia of the spleen. Polycythemia vera, myelofibrosis with myeloid metaplasia of the spleen and ET are generally associated under the common denomination of Philadelphia (Ph)-negative MPDs. Despite the recent identification of the JAK2 V617F mutation in a subset of patients with Ph-negative MPDs, the detailed pathogenetic mechanism is still a matter of discussion. Therapeutic interventions in ET are limited to decisions concerning the introduction of anti-aggregation therapy and/or starting platelet cytoreduction. The therapeutic value of hydroxycarbamide and aspirin in high risk

  17. Mutations at opposite ends of the DIII/S4-S5 linker of sodium channel NaV1.7 produce distinct pain disorders

    PubMed Central

    2010-01-01

    Background Two groups of gain-of-function mutations in sodium channel NaV1.7, which are expressed in dorsal root ganglion (DRG) neurons, produce two clinically-distinct pain syndromes - inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD). IEM is characterized by intermittent burning pain and skin redness in the feet or hands, triggered by warmth or mild exercise, while PEPD is characterized by episodes of rectal, ocular and mandibular pain accompanied with skin flushing, triggered by bowel movement and perianal stimulation. Most of the IEM mutations are located within channel domains I and II, while most of the PEPD mutations are located within domains III and IV. The structural dichotomy parallels the biophysical effects of the two types of mutations, with IEM mutations shifting voltage-dependence of NaV1.7 activation in a hyperpolarized direction, and PEPD mutations shifting fast-inactivation of NaV1.7 in a depolarized direction. While four IEM and four PEPD mutations are located within cytoplasmic linkers joining segments 4 and 5 (S4-S5 linkers) in the different domains (IEM: domains I and II; PEPD: domains III and IV), no S4-S5 linker has been reported to house both IEM and PEPD mutations thus far. Results We have identified a new IEM mutation P1308L within the C-terminus of the DIII/S4-S5 linker of NaV1.7, ten amino acids from a known PEPD mutation V1298F which is located within the N-terminus of this linker. We used voltage-clamp to compare the biophysical properties of the two mutant channels and current-clamp to study their effects on DRG neuron excitability. We confirm that P1308L and V1298F behave as prototypical IEM and PEPD mutations, respectively. We also show that DRG neurons expressing either P1308L or V1298F become hyperexcitable, compared to DRG neurons expressing wild-type channels. Conclusions Our results provide evidence for differential roles of the DIII/S4-S5 linker N- and C-termini in channel inactivation and