Erythermalgia: Molecular basis for an inherited pain syndrome

Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, CT 06510, USA.
Trends in Molecular Medicine (Impact Factor: 9.45). 01/2006; 11(12):555-62. DOI: 10.1016/j.molmed.2005.10.004
Source: PubMed


Inherited erythermalgia (also termed erythromelalgia) is characterized by severe pain in the limbs in response to mild thermal stimuli or exercise. Its molecular basis has, until recently, been enigmatic. Studies of families with autosomal dominant erythermalgia have now demonstrated mutations in sodium channel Na(v)1.7, which is selectively expressed within nociceptive dorsal root ganglion and sympathetic ganglion neurons. Shifts in activation and deactivation, and enhanced responses to small stimuli in mutant channels, decrease the threshold for single impulses and high-frequency trains of impulses in pain-sensing neurons. Erythermalgia, the first inherited painful neuropathy to be understood at a molecular level, is a model disease that could hold lessons for other painful conditions and for the development of rational, mechanism-based treatments for pain.

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    • "Thus far, 17 mutations (as shown in Fig. 1C, except for N395K, Q875E, and novel mutation, V1316A) relating to PE have been characterized and all mutant Nav1.7 channels exhibit significant hyperpolarizing shift in voltage dependent activation compared with wild type channel [19], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37]. The mutant channels also produce depolarizing shift in steady-state fast inactivation [23], [24], [32], [34], [35], [37], slow inactivation [19], [25], [26], [28], [30], [31], [32], [33], [36], [37], slow deactivation [19], [24], [25], [26], [28], [29], [30], [31], [32], [34], [35], [36], and increased ramp current [19], [24], [25], [26], [27], [28], [29], [30], [31], [32], [34], [35], [36]. "
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    ABSTRACT: 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 IC(50) values of selective sodium channel blockers, lidocaine and mexiletine. The IC(50) for mexiletine is lower for I848T mutant channel as compared to that of the wild type and other two mutants which is comparable to the clinical observations.
    Full-text · Article · Jan 2013 · PLoS ONE
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    • "In contrast, inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD) are distinct severe pain syndromes associated with gain-of-function mutations in SCN9A. IEM is characterized by episodes of burning pain, erythema, and mild swelling in the hands and feet (Waxman and Dib-Hajj, 2005). PEPD is characterized by severe rectal, ocular, and mandibular pain (Fertleman et al., 2007). "
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    ABSTRACT: Chronic and neuropathic pain constitute significant health problems affecting millions of individuals each year. Pain sensations typically originate in sensory neurons of the peripheral nervous system which relay information to the central nervous system (CNS). Pathological pain sensations can arise as result of changes in excitability of these peripheral sensory neurons. Voltage-gated sodium channels are key determinants regulating action potential generation and propagation; thus, changes in sodium channel function can have profound effects on neuronal excitability and pain signaling. At present, most of the clinically available sodium channel blockers used to treat pain are non-selective across sodium channel isoforms and can contribute to cardio-toxicity, motor impairments, and CNS side effects. Numerous strides have been made over the last decade in an effort to develop more selective and efficacious sodium channel blockers to treat pain. The purpose of this review is to highlight some of the more recent developments put forth by research universities and pharmaceutical companies alike in the pursuit of developing more targeted sodium channel therapies for the treatment of a variety of neuropathic pain conditions.
    Preview · Article · Oct 2011 · Frontiers in Pharmacology
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    • "Genomic studies have linked mutation of the Na(v)1.1 protein to familial hemiplegic migraine headaches. A point mutation in Na(v)1.7 (F1449V) leads to "primary erythermalgia", a congenital disorder of severe pain and flushing [38]. Na(v)1.7 is expressed in dorsal root ganglia with Na(v)1.8. "
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    ABSTRACT: : Idiopathic nonallergic rhinitis (iNAR) has been difficult to define because of the long differential diagnosis of rhinopathy in the absence of allergic rhinitis. iNAR has traditionally been a diagnosis of exclusion with no clear unifying pathophysiology. Increased sensitivity to triggers such has climate changes, cold air, tobacco smoke, strong odors, and perfumes have been thought to be characteristic, but recent studies do not support this hypersensitivity hypothesis. New investigations of the local nasal environment and systemic "functional" syndromes have offered new insights into this condition. iNAR may be a heterogenous disorder that includes (1) anatomic abnormalities requiring nasal endoscopy for diagnosis, (2) incipient, local atopy (entopy), (3) dysfunction of nociceptive nerve sensor and ion channel proteins, and (4) autonomic dysfunction as found in chronic fatigue syndrome and other functional disorders.
    Full-text · Article · Jun 2009 · World Allergy Organization Journal
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