Burning pain, episodic, typically in the distal extremities, particularly the hands and feet (bilateral, symmetric), triggered by warm stimuli, exercise, standing
'Primary erythermalgia' is an autosomal dominant disorder characterized by childhood onset of episodic symmetrical red congestion, vasodilatation, and burning pain of the feet and lower legs provoked by exercise, long standing, and exposure to warmth. Relief is obtained ... 'Primary erythermalgia' is an autosomal dominant disorder characterized by childhood onset of episodic symmetrical red congestion, vasodilatation, and burning pain of the feet and lower legs provoked by exercise, long standing, and exposure to warmth. Relief is obtained with cold (Michiels et al., 2005). The severity of the disorder may progress with age, and symptoms may extend over a larger body area, such as over the ankles and lower legs, and become constant (Mandell et al., 1977). Waxman and Dib-Hajj (2005) provided a review of primary erythermalgia. Although 'primary' or 'familial erythromelalgia' are sometimes used as alternative terms for primary erythermalgia (Waxman and Dib-Hajj, 2005), secondary erythromelalgia is a distinct acquired disorder associated with thrombocythemia or myeloproliferative disorders. It has relatively late onset and symptoms are caused by platelet aggregation in end-arteriolar circulation, leading to ischemia and symptoms (Michiels and van Joost, 1990). Treatment with aspirin, which irreversibly inhibits platelet cyclooxygenase activity, affords relief from acquired erythromelalgia (Michiels et al., 1984; Drenth et al., 1996). Similarly, acquired erythromelalgia vanishes with lowering the platelet count to normal with chemotherapy (Michiels et al., 1985). van Genderen et al. (1993) emphasized the distinction between hereditary erythermalgia and acquired erythromelalgia. In primary erythermalgia, the burning pain, redness, and warmth of feet and lower legs, with relative sparing of the toes, are easily provoked by warmth and exercise. In contrast, in acquired erythromelalgia the burning pain and red congestion preferentially involves one or more toes or fingers or sole of the forefoot (Michiels and van Joost, 1990). Van Genderen et al. (1993) noted that 3 of the 5 patients reported by Smith and Allen (1938) were not consistent with the diagnosis of primary erythromelalgia because the symptoms were relieved promptly by aspirin, consistent with acquired erythromelalgia. - Small Fiber Neuropathy Small nerve fiber neuropathy (SFNP) is a relatively common disorder of thinly myelinated and unmyelinated nerve fibers characterized clinically by adult onset of neuropathic pain, often of a burning quality, and autonomic symptoms. Affected individuals have reduced intraepidermal nerve fiber density affecting the small diameter nerve fibers; large diameter fibers are spared (summary by Faber et al., 2012).
Mandell et al. (1977) reported a child with primary erythermalgia with onset at age 3 years.
Finley et al. (1988) described a family in which autosomal dominant inheritance of primary erythermalgia was supported by the fact ... Mandell et al. (1977) reported a child with primary erythermalgia with onset at age 3 years. Finley et al. (1988) described a family in which autosomal dominant inheritance of primary erythermalgia was supported by the fact that some males had unaffected daughters and an affected man had an affected son. The proband, a 26-year-old white female, had onset of burning feet while walking at age 9 years. Gradually the frequency of episodes, correlated with heat, increased. Humidity seemed to aggravate the symptoms. Relief of pain was achieved by an electric fan blowing on the feet, by putting the feet into a bucket of ice, or by taking large doses of aspirin. The same family had been reported by Burbank et al. (1966). Finley et al. (1992) provided follow-up of the family reported by Finley et al. (1988). There were 29 affected individuals spanning 5 generations. Onset was in early childhood, as early as the first year of life. Affected individuals reported intermittent pain, redness, and burning sensation of the hands and feet that was triggered by exercise, warm weather, and humidity. The episodes seemed to increase in frequency and severity with age. Medical treatment was unsatisfactory. Herskovitz et al. (1993) described a 31-year-old man with hereditary sensory neuropathy first manifesting at the age of 18 years and with erythermalgia beginning at the age of 21. The burning pain in the feet occurred episodically especially during the spring and summer months, was precipitated by heat, and was associated with redness or purplish discoloration, warmth, and slight swelling of the feet. It was found that amitriptyline, 75 mg daily, provided marked relief of symptoms. The father was thought to be mildly affected on the basis of pes planus and clinical and nerve conduction studies. Although not described as erythromelalgia, the same situation was described by Dyck et al. (1983) in a family with 'burning feet' as the only manifestation of dominantly inherited sensory neuropathy. Their patient required sural nerve biopsy to demonstrate objective neuropathic abnormalities. Michiels et al. (2005) reported a Flemish family in which 10 members spanning 4 generations had autosomal dominant primary erythermalgia. Five patients were available for study. Age at onset ranged from 2.5 to 10 years. Episodes were typically elicited by warmth, exercise, or standing, and relief was provided by cold. Attacks were characterized by moderate to severe painful, red, swollen feet; some patients developed skin lesions resulting from repeated exposure to cold water. - Small Fiber Neuropathy Faber et al. (2012) reported 8 unrelated Dutch Caucasian patients with SFNP, 3 of whom reported similar complaints in family members. All 8 patients complained of pain, with onset ranging from 16 to 68 years of age. Most had onset of pain in the distal extremities, usually the feet, but 2 presented with pain throughout the body before affecting distal limbs. Pain was aggravated by warmth in 3, and relieved by cooling only in 1. One patient initially experienced excruciating pain in the teeth/jaw triggered by cold and heat, and pain behind the eyes, which was not relieved by multiple tooth extractions. Most patients reported persistence of the pain or burning over several years to involve the hands, mouth, or body. Seven of 8 patients had autonomic symptoms, including orthostatic dizziness, palpitations, dry eyes, and dry mouth. Two patients had significant gastrointestinal complaints. All had a decrease in skin small diameter nerve fibers below the fifth percentile for controls. All patients had some sort of distally altered temperature sensation.
In affected members of a Chinese family with primary erythermalgia linked to chromosome 2q and in a sporadic patient, Yang et al. (2004) identified mutations in the SCN9A gene (L858H, 603415.0001; I848T, 603415.0002).
In 5 affected ... In affected members of a Chinese family with primary erythermalgia linked to chromosome 2q and in a sporadic patient, Yang et al. (2004) identified mutations in the SCN9A gene (L858H, 603415.0001; I848T, 603415.0002). In 5 affected members of a Flemish family with primary erythermalgia, Michiels et al. (2005) identified a heterozygous mutation in the SCN9A gene (603415.0003). In 17 affected members of the family reported by Finley et al. (1992), Dib-Hajj et al. (2005) identified a heterozygous mutation in the SCN9A gene (603415.0004). - Small Fiber Neuropathy In 8 (28.6%) of 28 patients with biopsy-confirmed small fiber neuropathy, Faber et al. (2012) identified a heterozygous gain-of-function mutation in the SCN9A gene (see, e.g., 603415.0023-603415.00025). In vitro functional expression studies in HEK293 cells and dorsal root ganglion neurons showed that all the mutations caused hyperexcitability of dorsal root ganglion neurons, either by impairing slow inactivation, depolarizing slow and fast inactivation, or causing enhanced resurgent currents and increasing the number of action potentials evoked by depolarization. Faber et al. (2012) postulated that increased sodium channel activity may also trigger axonal degeneration via calcium-importing reverse sodium-calcium exchange. None of the mutations were the same as those found in primary erythermalgia or paroxysmal extreme pain disorder (PEPD; 167400). The findings expanded the phenotype associated with SCN9A mutations.
The diagnosis of SCN9A-related inherited erythromelalgia (SCN9A-related IEM), also known as primary erythromelalgia or erythermalgia, is made on clinical grounds....
DiagnosisClinical DiagnosisThe diagnosis of SCN9A-related inherited erythromelalgia (SCN9A-related IEM), also known as primary erythromelalgia or erythermalgia, is made on clinical grounds.SCN9A-related IEM is characterized by recurrent episodes of bilateral intense, burning pain; redness; warmth; and, occasionally, swelling affecting the distal extremities. The feet are more commonly affected than the hands, but, in severely affected individuals, symptoms may involve the legs, arms, face, or ears. Note: If symptoms are intermittent, photographs of the affected extremities during a flare can help with diagnosis (see Figure 1).FigureFigure 1. Red and swollen feet of individual with SCN9A-related IEM SCN9A-related IEM is not associated with an organic disease.Note: In the initial evaluation of painful, erythematous extremities, other treatable conditions resulting in secondary EM must be excluded (see Differential Diagnosis).The disorder is confirmed by detecting an SCN9A mutation in a clinical laboratory.Molecular Genetic TestingGene. Mutations in SCN9A encoding the sodium channel protein Nav1.7 subunit are known to be associated with IEM [Yang et al 2004, Dib-Hajj et al 2005, Drenth et al 2005, Michiels et al 2005, Han et al 2006, Harty et al 2006, Lee et al 2007, Takahashi et al 2007].Other lociLinkage to chromosome 2q was excluded in a three-generation family [Burns et al 2005], suggesting the possible existence of additional genes in which mutation is causative.Exclusion of mutations in SCN9A, SCN10A, and SCN11A in familial cases also supports genetic heterogeneity [Drenth et al 2008].Clinical testingSequence analysis. Mutation detection frequency varies depending on whether the family history is positive (other family members are affected) or negative (no other family members are affected) [Yang et al 2004, Dib-Hajj et al 2005, Drenth et al 2005, Michiels et al 2005, Han et al 2006, Harty et al 2006, Lee et al 2007, Takahashi et al 2007, Drenth et al 2008].Table 1. Summary of Molecular Genetic Testing Used in SCN9A-Related Inherited ErythromelalgiaView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency 1, 2Test AvailabilityFamily HistoryPositiveNegativeSCN9ASequence analysisSequence variants50%-100%~30%Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Because so few individuals have been tested to date, detection rates need to be considered preliminary.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyTo confirm the diagnosis in a proband, molecular genetic testing of SCN9A is used.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) DisordersMutations in SCN9A have been reported in paroxysmal extreme pain disorder, previously termed familial rectal pain (OMIM 167400) [Fertleman et al 2004, Fertleman & Ferrie 2006, Fertleman et al 2006, Fertleman et al 2007]. This autosomal dominant disorder is characterized by episodes of rectal, ocular, or submandibular pain accompanied by erythema.Mutations in SCN9A resulting in loss of function of sodium channel Nav1.7 subunit alpha cause channelopathy-associated insensitivity to pain (OMIM 243000) [Cox et al 2006]. Three nonsense homozygous mutations in SCN9A were identified in six affected individuals from three consanguineous families. All affected children (age range: 4-14 years) had insensitivity to pain and were otherwise normal and healthy. Loss-of-function mutations have been identified in patients from various ethnic backgrounds [Ahmad et al 2007, Goldberg et al 2007].
SCN9A-related inherited erythromelalgia (SCN9A-related IEM) is characterized by recurrent attacks of intense pain, redness, warmth, and swelling involving the feet and, less frequently, the hands [Dib-Hajj et al 2007, Drenth & Waxman 2007]. Warmth is an essential part of the syndrome. During the attacks, the extremities appear red or purple and may be swollen. Commonly, the attacks occur in the evening or at night and so may not be observed by a physician. The individual may seek medical advice for painful extremities but neglect to mention the characteristic warmth or redness (especially if limited to the soles of the feet). The symptoms are usually bilateral and symmetric. Within a family, the manifestations of the disorder may vary considerably....
Natural HistorySCN9A-related inherited erythromelalgia (SCN9A-related IEM) is characterized by recurrent attacks of intense pain, redness, warmth, and swelling involving the feet and, less frequently, the hands [Dib-Hajj et al 2007, Drenth & Waxman 2007]. Warmth is an essential part of the syndrome. During the attacks, the extremities appear red or purple and may be swollen. Commonly, the attacks occur in the evening or at night and so may not be observed by a physician. The individual may seek medical advice for painful extremities but neglect to mention the characteristic warmth or redness (especially if limited to the soles of the feet). The symptoms are usually bilateral and symmetric. Within a family, the manifestations of the disorder may vary considerably.Onset of SCN9A-related IEM is usually in childhood or adolescence; however, it has been recognized in infants in families who are familiar with the disorder. Onset of SCN9A-related IEM has not been reported in individuals or families after age 20 years.Initially, the symptoms involve the soles of the feet and the hands; with age, the lower legs and the arms may become involved. In individuals with advanced disease, symptoms may occur many times a day and last hours, especially at night, or become constant and unremitting.At the onset, the episodes are triggered by exposure to warmth. A pathognomonic feature is triggering of episodes by warm or hot ambient temperature and relief with cooling of the extremities.Less consistent precipitating factors include: exercise, tight shoes, wearing socks, alcohol, spicy foods, and other vasodilating agents.Some individuals have allodynia (pain evoked by a normally innocuous stimulus) and hyperalgesia (increased sensitivity to a painful stimulus).The episodes may be disabling, interfere with sleep, and severely limit normal activities such as walking, participation in sports, wearing socks and shoes, and attending school or going to work. Individuals tend to limit their activities in warm weather and to stay in air-conditioned environments. Some individuals move from hot, humid climates to cooler climates.Affected individuals prefer to wear open-toed shoes and to sleep with their feet uncovered. Swimming can be helpful because it keeps the limbs cool during exercise.Neurologic examination is typically normal, although reduced ankle reflexes and decreased distal sensation can be seen.Electrophysiologic studies. Nerve conduction velocity studies and electromyography were reported to be abnormal in approximately 50% of 24 individuals with "idiopathic" erythermalgia [Davis et al 2003]. It is unknown if the prevalence of electrophysiologic abnormalities is similar in individuals with SCN9A-related IEM.Histopathologic examination of skin biopsy shows nonspecific thickening of blood vessel basement membrane, perivascular edema and mononuclear infiltrate, and reduced density of the autonomic nerve plexuses.Pathophysiology. Underlying mechanisms that have been proposed:Alterations in microvascular blood flow or capillary density [Mork et al 2000a, Mork et al 2002, Davis et al 2003]Interplay between neural and vasoactive agents [Littleford et al 1999]Small-fiber neuropathy [Davis et al 2003, Orstavik et al 2003, Orstavik et al 2004]. Although vasculopathy and neuropathy may coexist in individuals with primary or secondary EM, it is not possible to distinguish cause from secondary effects.
Disease severity varies within families; whether the cause of the variation is genetic or environmental is unknown....
Genotype-Phenotype CorrelationsDisease severity varies within families; whether the cause of the variation is genetic or environmental is unknown.Paroxysmal extreme pain disorder may be more responsive to carbamazepine than SCN9A-related IEM, which has a less consistent response. A correlation may exist between individual mutations and response to drugs that block the sodium channel [Drenth & Waxman 2007].
The differential diagnosis of SCN9A-related inherited erythromelalgia (SCN9A-related IEM) includes secondary EM resulting from an underlying organic disease, medication, or toxin; neuropathies; other conditions with some overlapping features; and inherited erythromelalgia in which no SCN9A mutation is identified....
Differential DiagnosisThe differential diagnosis of SCN9A-related inherited erythromelalgia (SCN9A-related IEM) includes secondary EM resulting from an underlying organic disease, medication, or toxin; neuropathies; other conditions with some overlapping features; and inherited erythromelalgia in which no SCN9A mutation is identified.Secondary EMSecondary erythromelalgia occurs in a variety of disorders and begins at any age. Medications and toxins are potentially reversible causes of secondary erythromelalgia:Essential thrombocythemia, a myeloproliferative disorder, is the most significant cause of secondary erythromelalgia, occurring in up to 25% of individuals with this condition [Drenth & Michiels 1994, McCarthy et al 2002]. Erythromelalgia is frequently the presenting complaint and may precede a diagnosis of myeloproliferative disease by several years. A significant clinical characteristic of erythromelalgia secondary to thrombocythemia is marked pain relief lasting up to several days following ingestion of a single dose of aspirin. Neither SCN9A-related IEM nor other forms of secondary EM demonstrate the same dramatic response to aspirin treatment.Polycythemia vera or thrombotic thrombocytopenic purpuraRheumatologic disorders such as gout and autoimmune disorders including systemic lupus erythematosus (SLE), rheumatoid arthritis, or vasculitisParaneoplastic syndrome, a rare cause of secondary erythromelalgia [Mork et al 1999]Medications such as verapamil, nifedipine, bromocriptine, and ticlopidine [Yosipovitch et al 1999]Environmental toxinsInorganic mercury poisoning, which produces acrodynia (erythema and edema of the hands and feet)Mushroom poisoning [Diaz 2005]NeuropathiesPainful neuropathies associated with diabetes mellitus, alcoholism, HIV infection, and Lyme disease may cause burning pain similar to erythermalgia but are much less likely to be associated with redness, warmth, heat intolerance, and relief with cooling [Mork et al 2000b].Other ConditionsReflex sympathetic dystrophy (RSD), a complex regional pain syndrome, may be indistinguishable from SCN9A-related IEM in its early stages; however, RSD is much more likely to be unilateral. RSD usually follows an injury in the affected limb, such as a wrist fracture, and typically evolves to include signs and reduced circulation and may also be associated with changes in the nails, joints, or bone density [Schott 2001].Peripheral vascular disease may be associated with pain of the distal extremities triggered by exercise (claudication) and, with chronic disease, cause change in skin color. Peripheral vascular disease is associated with smoking and cardiovascular or cerebrovascular disease.Raynaud's phenomenon, in contrast to SCN9A-related IEM, is typically exacerbated by exposure to cold, with vasospasm, pain, and skin color changes.Fabry disease causes burning pain of the distal extremities in childhood but is differentiated by an X-linked pattern of inheritance and other clinical features such as angiokeratomas and increased occurrence of renal and cerebrovascular disease.IEM Not Related to Mutation of SCN9AA three-generation family with EM, in which mutations in SCN9A were excluded by mutation screening and linkage to the SCN9A locus was excluded by linkage analysis and haplotype analysis, has been reported [Burns et al 2005]. A distinctive clinical feature was an age of onset from 21 years to 76 years. The molecular basis of this condition is unknown.Additional families with IEM have been tested for mutations in SCN9A, SCN10A, and SCN11A with normal results, lending additional support for genetic heterogeneity in this condition [Drenth et al 2008].
To establish the extent of disease in an individual diagnosed with SCN9A-related inherited erythromelalgia (SCN9A-related IEM), assessment of the pain management strategies used is recommended. See Treatment of Manifestations....
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with SCN9A-related inherited erythromelalgia (SCN9A-related IEM), assessment of the pain management strategies used is recommended. See Treatment of Manifestations.Treatment of ManifestationsThe pain of SCN9A-related IEM or secondary erythromelalgia is often refractory to treatment.Reports on treatments in a series involve heterogeneous populations. In a report of 169 individuals with erythromelalgia of mixed etiologies, 84 medications or treatments were used [Davis et al 2000]. Response is highly variable, and no treatment is consistently effective. No controlled treatment trial has compared the effectiveness of various classes of medications.Cooling the extremities reduces pain in a symptomatic person.Medications. The effectiveness of medications and the order in which they should be tried is highly controversial, according to a consensus of expert opinion. Treatment should be determined by the individual’s treating physician, based on factors including other medical conditions, known medication allergies, and potential for drug-drug interactions.Aspirin should be tried because of the known, dramatic response of thrombocythemia-associated EM to low-dose aspirin. A positive response warrants evaluation for and monitoring for myeloproliferative disease because the symptoms of thrombocythemia-associated EM may precede a diagnosis by several years. If pain is not relieved, aspirin should be discontinued.Misoprostol, an oral prostaglandin E1 analog, was tested in a double-blind, placebo-controlled, one-way crossover clinical trial in 21 adults with erythromelalgia and 11 healthy controls. Improvements in pain and cooling scores were significant (p<0.01) [Mork et al 2004].Seratonin-norepinephrine reuptake inhibitors (SNRIs) /selective serotonin reuptake inhibitors (SSRIs). Venlafaxine, an SNRI, has induced remissions in approximately a dozen individuals even after other classes of medications have been unsuccessful [DiCaudo & Kelley 2004]. SSRIs (fluoxetine, sertraline) have been reported to be helpful in some additional affected individuals.Gabapentin has been one of the more effective medical treatments in both primary and secondary EM. Of 16 individuals taking gabapentin in a survey of Erythromelalgia Association members, all 16 reported benefit, although the degree was not quantified. Experts have reported typically mild to moderate pain relief. Remissions (i.e., remaining pain-free for 4-6 months) on gabapentin have been reported in an adult and a child [Cohen 2000].Sodium channel blockers including lidocaine infusion, lidocaine patch, or oral mexilitine have been used successfully in inherited erythromelalgia and secondary erythromelalgia [Kuhnert et al 1999, Davis & Sandroni 2005, Nathan et al 2005]. Because of the absence of systemic side effects, partial relief in 55% of the individuals studied, and greater than 80% pain relief in 12% of individuals, Davis & Sandroni [2005] have suggested a lidocaine patch as first-line treatment. It is not known if sodium channel blockers are more effective in individuals with SCN9A-related IEM than in individuals with other forms of EM.Carbamazepine. In a survey of 41 members of the Erythromelalgia Association, one of four persons using carbamazepine reported improvement [Cohen 2000].Oxcarbazepine use in treating EM has not been reported.Tricyclic antidepressants used alone or in combination with other classes of medications have reduced pain. Their use has diminished with the introduction of newer agents with a more favorable side-effect profile, but they should be considered in refractory individuals. Topical application of 1.0% amitriptyline hydrochloride and 0.5% ketamine hydrochloride in pluronic lecithin organogel has been reported effective in four of five patients with refractory EM [Sandroni & Davis 2006].Calcium antagonists. Diltiazem is very effective in some individuals, inducing at least one remission. Paradoxically, diltiazem and other calcium channel antagonists have been reported to trigger secondary EM.Magnesium. In 13 persons, high doses of oral magnesium induced remission in one person, improved symptoms in seven, did not change them in four, and exacerbated symptoms in one. Diarrhea was a limiting side effect [Cohen 2002]. Remission (freedom from pain) was also reported in a case report of an Italian child [Dell'era et al 2004].Sodium nitroprusside infusion has been successful in the acute hospital setting in individuals with severe attacks [Chan et al 2002].Cyclosporine was successful in one person with erythromelalgia. The postulated mechanism was inhibition of nitric oxide synthase in vascular smooth muscle and endothelial cells [Sano et al 2003]. Conversely, cyclosporine caused EM in another individual treated for psoriasis vulgaris [Thami & Bhalla 2003].Sympathetic block, surgical sympathectomy, and epidural infusionSympathetic block has had mixed results in individuals with severe symptoms. Some have improved, some have not improved, and others have worsened [Cohen 2000]. Sympathetic block should be tried – and the response to repeated blocks considered – prior to surgical sympathectomy.In at least two individuals, sympathectomy reduced redness but not pain.Epidural infusions of opiates have been used in combination with bupivicaine and other oral and topical medications with good results in a few individuals.OtherReports of a single or a few individuals have reported remission or significant improvement with cyproheptadine, propranolol, or thalamic stimulation [Delye et al 2005].Additional combinations of medical, surgical, and alternative treatments tried with varying success in individuals with either primary EM or secondary EM are summarized in Table II in the report by Davis et al [2000] and in Table III in the review by Cohen [2000].Prevention of Primary ManifestationsAvoidance of triggers (warmth, prolonged standing) may reduce the number or severity of episodes.Prevention of Secondary ComplicationsSecondary complications from prolonged immersion in ice baths include: skin maceration, infection, and gangrene. Amputation has occasionally been necessary to treat these complications.Cooling with a fan is generally safer than immersion in water.Agents/Circumstances to AvoidSymptoms are triggered by warmth and standing and, in some individuals, by alcohol and spicy foods including chili peppers or garlic.In some individuals, exercise can trigger symptoms. However, for many individuals, the benefits of mild exercise outweigh the disadvantages.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. SCN9A-Related Inherited Erythromelalgia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSCN9A2q24.3Sodium channel protein type 9 subunit alphaSCN9A homepage - Mendelian genesSCN9AData are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for SCN9A-Related Inherited Erythromelalgia (View All in OMIM) View in own window 133020ERYTHERMALGIA, PRIMARY 603415SODIUM CHANNEL, VOLTAGE-GATED, TYPE IX, ALPHA SUBUNIT; SCN9AMolecular Genetic PathogenesisRecent reviews [Waxman & Dib-Hajj 2005a, Waxman & Dib-Hajj 2005b, Dib-Hajj et al 2007, Drenth & Waxman 2007] describe the molecular genetic pathogenesis of SCN9A-related inherited erythromelalgia (SCN9A-related IEM), which is associated with mutations in the gene that encodes the sodium channel protein type 9 alpha subunit (also known as the voltage-gated sodium channel subunit alpha Nav1.7) [Drenth et al 2001, Yang et al 2004, Dib-Hajj et al 2005, Drenth et al 2005, Michiels et al 2005, Han et al 2006, Harty et al 2006, Lee et al 2007, Takahashi et al 2007]. The Nav1.7 sodium channel is preferentially expressed within dorsal root ganglia and sympathetic ganglion neurons [Djouhri et al 2003]. These mutations alter the biophysical properties of the channel by shifting activation in a hyperpolarizing direction (thus lowering the threshold for channel opening) by slowing deactivation (thus keeping the channel open longer) and by increasing the response of the channel to small, slow depolarizations close to the resting potential [Cummins et al 2004, Dib-Hajj et al 2005, Choi et al 2006, Han et al 2006, Harty et al 2006, Lampert et al 2006, Sheets et al 2007, Cheng et al 2008]. The effects of these changes in channel properties have been studied within dorsal root ganglia neurons, in which they increase excitability and increase the frequency of firing [Dib-Hajj et al 2005, Harty et al 2006, Rush et al 2006]. The Nav1.7 sodium channel is also expressed in neurons of the sympathetic ganglion. The expression of the IEM-causing mutation p.Leu858His in superior cervical ganglion neurons (sympathetic neurons) cause these neurons to become less excitable [Rush et al 2006], which may contribute to loss of tonic cutaneous vasoconstriction that is associated with skin flushing in individuals with IEM. See Table 2.Normal allelic variants. SCN9A is composed of 26 exons spanning 167.3 Mb. Exon 5 (E5), which is 92 bp long, is present in embryonic/neonatal (E5N) and adult (E5A) isoforms [Raymond et al 2004]. E5N is located upstream from E5A in SCN9A; the sequence encoded by these alternative exons differs by two amino acids only: Leu201 in E5N compared to Val201 in E5A (p.Leu201Val) and Asn206 in E5N compared to Asp206 in E5A (p.Asn206Asp). The control elements for this alternative splicing or the functional effect of these mutations have yet to be determined.The utilization of an alternative 5' splice site for intron 12 lengthens exon 11 by 33 bp, leading to an extension of loop 1 (L1), which joins domains 1 and 2 by 11 amino acids for an Nav1.7 isoform of 1988 amino acids [Raymond et al 2004]. The functional effect of the extension of L1 of Nav1.7 has yet to be determined.Another variant, p.Arg1150Trp, has been reported in a simplex case of SCN9A-related IEM [Drenth et al 2005], but this variant likely represents a polymorphism.The orthologs of SCN9A have been identified in rat and rabbit. The exon-intron boundaries are highly conserved among rodent, rabbit, and human SCN9A genes in the regions that have been investigated.Pathologic allelic variants. See Table 2. Ten missense mutations in SCN9A have been identified in persons with SCN9A-related IEM and reported in public databases [Yang et al 2004, Dib-Hajj et al 2005, Drenth et al 2005, Michiels et al 2005, Han et al 2006, Harty et al 2006, Lee et al 2007, Takahashi et al 2007]. The relative position of these mutations along the polypeptide is shown on the schematic of the channel in Figure 2. An additional 33 mutations are reported in professional (limited-access) databases.FigureFigure 2. The exon/intron boundary in the genomic sequence of SCN9A Some SCN9A mutant alleles:p.Ile136Val in the S1 of domain 1 [Lee et al 2007, Cheng et al 2008]p.Phe216Ser in the S4 of domain I [Drenth et al 2005, Choi et al 2006]p.Ser241Thr in the linker joining S4 and S5 of domain I [Michiels et al 2005]p.Asn395Lys in the S6 of domain I [Drenth et al 2005]p.Leu823Arg in the S4 of domain II [Takahashi et al 2007]p.Ile848Thr, p.Leu858His, and p.Leu858Phe in the linker joining S4 and S5 of domain II [Yang et al 2004, Drenth et al 2005, Han et al 2006, Drenth et al 2008] Note: The contribution of the variant p.Pro610Thr to the disease phenotype is not clear at this time. p.Pro610Thr has been reported in the same individual along with the p.Leu858Phe mutation in a multigenerational Canadian family [Drenth et al 2005], suggesting that it is a normal allelic variant (NP_002968.1). p.Leu858Phe was the only mutation reported in a Chinese individual; thus, this substitution alone is sufficient to alter the biophysical properties of mutant Nav1.7/p.Leu858Phe channels [Han et al 2006], similar to the effect of the Nav1.7/p.Leu858His mutant channel [Cummins et al 2004]. Recently, analysis of the Canadian family has shown that p.Pro610Thr segregates independently of the p.Leu858Phe mutation and is present in one unaffected sibling in this family and in 10/210 ethnically matched control chromosomes [Samuels et al 2008].p.Ala863Pro in the S5 of domain II [Harty et al 2006]p.Phe1449Val in the linker joining domains III and IV [Dib-Hajj et al 2005]Table 2. Selected SCN9A Allelic VariantsView in own windowClass of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference SequenceNormalc.601T>Gp.Leu201Val NM_002977.2 NP_002968.1c.616A>Gp.Asn206Aspc.3448C>Tp.Arg1150TrpPathologicc.406A>Gp.Ile136Valc.647T>Cp.Phe216Serc.721T>Ap.Ser241Thrc.1185C>Ap.Asn395Lysc.1828C>Ap.Pro610Thr 1c.2468T>Gp.Leu823Rc.2543T>Cp.Ile848Thrc.2573T>Ap.Leu858Hisc.2572C>Tp.Leu858Phec.2587G>Cp.Ala863Proc.4345T>Gp.Phe1449ValSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. The contribution of the variant p.Pro610Thr to the disease phenotype is not clear (see Molecular Genetic Pathogenesis, Pathologic allelic variants, Note).Normal gene product. The normal product of SCN9A is the sodium channel protein type 9 alpha subunit (voltage-gated sodium channel Nav1.7). Nav1.7 comprises 1977 amino acids organized into four domains, each with six transmembrane segments (S1-6), similar to members of the voltage-gated sodium and calcium ion channels [Catterall 2000]. The channel produces a fast inactivating sodium current that is sensitive to nanomolar concentrations of the neurotoxin tetrodotoxin (TTX-S). Nav1.7 is expressed predominantly in dorsal root ganglia neurons, particularly nociceptive neurons [Djouhri et al 2003] and sympathetic ganglion neurons [Rush et al 2006]. Because of its slow closed-state inactivation, Nav1.7 produces depolarizing current in response to small depolarizing stimuli close to resting potential, thus amplifying small depolarizations such as generator potentials [Cummins et al 1998].SCN9A is expressed within dorsal root ganglion neurons and sympathetic ganglion neurons [Yang et al 2004, Dib-Hajj et al 2005, Drenth et al 2005, Michiels et al 2005, Han et al 2006, Rush et al 2006].Abnormal gene product. Two mutations of SCN9A (p.Ile848Thr and p.Leu858His), identified in two Chinese families with SCN9A-related IEM, produce a hyperpolarizing shift in activation and slow deactivation, and enhance the channel's response to small depolarizing stimuli, changes that can confer hyperexcitability on cells in which the channel is expressed [Cummins et al 2004].A third mutation of SCN9A (p.Phe1449Val), from an American family with SCN9A-related IEM, produces a hyperpolarizing shift in activation and a depolarizing shift in steady-state inactivation and lowers thresholds of single action potentials and high-frequency firing in dorsal root ganglia neurons [Dib-Hajj et al 2005]. Several other mutations have been characterized by voltage-clamp recordings and show the common feature of hyperpolarizing shift in activation of the channel [Choi et al 2006, Han et al 2006, Harty et al 2006, Lampert et al 2006, Sheets et al 2007, Cheng et al 2008].