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SCN9A-Related Inherited Erythromelalgia

, MD, , PhD, and , MD, PhD.

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Initial Posting: ; Last Update: August 15, 2013.


Clinical characteristics.

SCN9A-related inherited erythromelalgia (SCN9A-related IEM) is characterized by recurrent attacks of bilateral and symmetric intense pain, redness, warmth, and swelling involving the feet and, less frequently, the hands. SCN9A-related IEM is not associated with an organic disease. Manifestations may vary within a family. Onset is usually in childhood or adolescence but has been recognized in infants and adults. At onset, episodes are triggered by warmth; other precipitating factors include: exercise, tight shoes, wearing socks, alcohol, spicy foods, and other vasodilating agents. In advanced disease, symptoms may occur many times a day or become constant. Some individuals have allodynia (pain evoked by a normally innocuous stimulus) and hyperalgesia (increased sensitivity to a painful stimulus). 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.


The diagnosis of SCN9A-related IEM is made on clinical grounds. Pathogenic variants in SCN9A encoding the sodium channel protein Nav1.7 subunit are known to cause IEM; pathogenic variants in additional genes may also be associated with IEM.


Treatment of manifestations: Pain is often refractory to treatment; no treatment is consistently effective. Treatment is individualized and depends on other medical conditions, known medication allergies, and potential for drug-drug interactions. Drugs shown to be effective in relieving pain in some individuals include: aspirin, misoprostol, serotonin-norepinephrine reuptake inhibitors and selective serotonin reuptake inhibitors, gabapentin, sodium channel blockers, carbamazepine, tricyclic antidepressants, calcium antagonists, magnesium, sodium nitroprusside infusion, and cyclosporine. Other treatments include: sympathetic block, surgical sympathectomy, and epidural infusion of opiates. Cooling of the extremities typically reduces pain in a symptomatic person.

Prevention of primary manifestations: Avoidance of triggers (warmth, prolonged standing) may reduce the number or severity of episodes.

Prevention of secondary complications: Secondary complications from prolonged immersion in ice baths include: skin maceration, infection, and gangrene; cooling with a fan is generally safer than immersion in water.

Surveillence: There are no published guidelines for surveillance; however, it is important to monitor for side effects of treatment.

Agents/circumstances to avoid: Heat, standing, alcohol, and spicy foods may trigger symptoms.

Genetic counseling.

SCN9A-related IEM is inherited in an autosomal dominant manner. If a parent of the proband is affected, the risk to the sibs is 50%. Each child of an individual with an SCN9A-related IEM pathogenic variant has a 50% chance of inheriting the variant.


Clinical Diagnosis

The 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).

Figure 1.

Figure 1.

Red and swollen feet of an 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 detection of an SCN9A pathogenic variant in a clinical laboratory.

Molecular Genetic Testing

Gene. Pathogenic variants in SCN9A encoding the sodium channel protein Nav1.7 subunit are known to cause 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].

Evidence for locus heterogeneity

  • Linkage 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 pathogenic variants in SCN9A, SCN10A, and SCN11A in familial cases also supports genetic heterogeneity [Drenth et al 2008].

Clinical testing

Table 1.

Summary of Molecular Genetic Testing Used in SCN9A-Related Inherited Erythromelalgia

Gene 1Test MethodAllelic Variants Detected 2Variant Detection Frequency 3, 4
Family History 5
SCN9ASequence analysis 6Sequence variants50%-100%~30%

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


Because so few individuals have been tested to date, detection rates need to be considered preliminary.


Variant detection frequency differs depending on whether the family history is positive (i.e., 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].


Examples of pathogenic variants detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband, sequence analysis of SCN9A is performed.

SCN9A may also be represented on multi-gene panels used to evaluate individuals with seizure disorders.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Characteristics

Clinical Description

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.

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. Although rare, onset of SCN9A-related IEM has been reported in individuals or families after age 20 years [Choi et al 2010].

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 14 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:

Although vasculopathy and neuropathy may coexist in individuals with primary or secondary EM, it is not possible to distinguish cause from secondary effects.

Genotype-Phenotype Correlations

Disease severity varies within families; whether the cause of the variation is genetic or environmental is unknown.

Age of onset of symptoms has been correlated with the degree of the shift in activation of the voltage-gated sodium channel produced by pathogenic variants in SCN9A, with older onset associated with smaller shifts in channel activation [Cheng et al 2008, Han et al 2009].

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 pathogenic variants and response to drugs that block the sodium channel [Drenth & Waxman 2007, Dib-Hajj et al 2013].


The penetrance in families with SCN9A-related IEM reported to date is 100%; however, molecular genetic data are available for fewer than 30 families.


Anticipation has not been reported.


The term "erythromelalgia" was coined by the American neurologist S Weir Mitchell, MD, and is derived from the Greek words: erythro (red), melos (extremity), and algos (pain) [Mitchell 1878].

Some authors have proposed the term "erythermalgia" for the idiopathic genetic form of EM, and "erythromelalgia" for disease associated with an underlying medical condition or drug [Drenth & Michiels 1994].

Other authors prefer "erythromelalgia" for both idiopathic (primary) EM and acquired forms of the disease (secondary EM).


No accurate data on the worldwide prevalence of SCN9A-related IEM are available.

One study estimated the prevalence of all forms of EM to be 2:100,000 in Norway [Kvernebo 1998].

Thus far, families with a clinical diagnosis of erythromelalgia (some with an SCN9A pathogenic variant) have been identified in Canada, China, Japan, Taiwan, France, Belgium, the Netherlands, the United Kingdom, and the United States [Sano et al 2003, Yang et al 2004, Dib-Hajj et al 2005, Drenth et al 2005, Michiels et al 2005, Han et al 2006, Lee et al 2007, Ahn et al 2010].

It is likely that erythromelalgia is underdiagnosed or often misdiagnosed.

Differential Diagnosis

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 pathogenic variant is identified.

Secondary EM

Secondary 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 purpura
  • Rheumatologic disorders such as gout and autoimmune disorders including systemic lupus erythematosus (SLE), rheumatoid arthritis, or vasculitis
  • Paraneoplastic syndrome, a rare cause of secondary erythromelalgia [Mork et al 1999]
  • Medications such as verapamil, nifedipine, bromocriptine, and ticlopidine [Yosipovitch et al 1999]
  • Environmental toxins
    • Inorganic mercury poisoning, which produces acrodynia (erythema and edema of the hands and feet)
    • Mushroom poisoning [Diaz 2005]


Painful neuropathies associated with diabetes mellitus, alcoholism, HIV infection, idiopathic small fiber neuropathy, and Lyme disease may cause burning pain similar to erythromelalgia but are much less likely to be associated with redness, warmth, heat intolerance, and relief with cooling [Mork et al 2000b].

Other Conditions

Reflex 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, typically evolves to include signs such as 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 including angiokeratomas, characteristic corneal and lenticular opacities, and increased occurrence of renal and cerebrovascular disease.


Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with SCN9A-related inherited erythromelalgia (SCN9A-related IEM), the following are recommended:

Treatment of Manifestations

The 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, Choi et al 2009]. 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 whether 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]. A family with a known SCN9A pathogenic variant (p.Val400Met) reported significant improvement of symptoms while using carbamazepine [Fischer et al 2009].

    The combination of carbamazepine and gabapentin has been reported to produce relief in one individual with SCN9A-related IEM [Natkunarajah et al 2009].
  • 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 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 infusion

  • Sympathetic 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.


  • Reports of a single or a few individuals have noted 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 by Davis et al [2000] (see Table 2) and Cohen [2000] (see Table 3).

Prevention of Primary Manifestations

Avoidance of triggers (warmth, prolonged standing) may reduce the number or severity of episodes.

Prevention of Secondary Complications

Secondary 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.


There are no published guidelines for surveillance. Most affected individuals are treated in dermatology clinics, neurology clinics, or pain clinics, or by anesthesiologists specializing in the management of chronic pain. It is important to monitor for side effects of treatment.

Agents/Circumstances to Avoid

Symptoms 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. Swimming is a preferred exercise because the extremities remain cool.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Potential teratogenic effects of medications given for treatment of erythromelalgia should be discussed with affected women of childbearing age. The ideal time to discuss this is prior to conception.

Therapies Under Investigation

Small molecule inhibitors of the SCN9A encoded sodium channel Nav1.7 have been developed. In one exploratory, randomized, double-blind crossover trial of four subjects with EM in whom the presence of SCN9A pathogenic variants had been confirmed, the compound was reported to be more effective than placebo in reducing the amount of pain for two hours following a pain induction stimulus [Goldberg et al 2012]. Given the small number of treated individuals and short duration of the study, strong conclusions cannot be drawn from these results.

Search for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

SCN9A-related inherited erythromelalgia (SCN9A-related IEM) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Many individuals diagnosed with SCN9A-related IEM have an affected parent.
  • A proband with SCN9A-related IEM may have the disorder as the result of a de novo pathogenic variant. The proportion of cases caused by de novo mutation is unknown because the evaluation of family members for milder symptoms has been incomplete and molecular genetic data are insufficient.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo pathogenic variant include: a detailed clinical and family history and molecular genetic testing of both parents if the pathogenic variant has been identified in the proband. In a simplex case (individual with no known family history of SCN9A-related IEM), the data on heritability are incomplete.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • When the parents are clinically unaffected, it is likely that the proband has a de novo pathogenic variant. The risk to the sibs of a proband appears to be low but greater than that of the general population because of the possibility of germline mosaicism. Two affected sibs with an unaffected mosaic father have been reported [Han et al 2006].

Offspring of a proband. Each child of an individual with an IEM-causing variant in SCN9A has a 50% chance of inheriting the variant.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected or has a pathogenic variant, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder or the pathogenic variant, it is likely that the proband has a de novo pathogenic variant. However, possible non-medical explanations, including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

If the pathogenic variant has been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Requests for prenatal testing for conditions which (like SCN9A-related IEM) do not affect intellect and have some treatment available are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant has been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

Molecular Genetics

Information 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 Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus, locus name, critical region, complementation group from OMIM; protein 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)


Molecular Genetic Pathogenesis

A number of 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 mutation of 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 pathogenic variants 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 variant p.Leu858His in superior cervical ganglion neurons (sympathetic neurons) causes these neurons to become less excitable [Rush et al 2006], which may contribute to the loss of tonic cutaneous vasoconstriction associated with skin flushing in individuals with IEM. See Table 2.

Gene structure. 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 and the functional effect of these variants 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.

The orthologs of SCN9A have been identified in rat and rabbit. The exon-intron boundaries are highly conserved among rodent, rabbit, and human SCN9A in the regions that have been investigated. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic allelic variants. See Table 2. Twenty missense variants in SCN9A have been identified and functionally validated in persons with SCN9A-related IEM and reported in public databases [reviewed in Dib-Hajj et al 2010, Estacion et al 2013]. The relative position of many pathogenic variants along the polypeptide is shown on the schematic of the channel in Figure 2. An additional seven variants of unknown functional effects on the channel properties or link to disease are reported in professional (limited-access) databases.

Figure 2.

Figure 2.

The exon/intron boundary in the genomic sequence of SCN9A

Some SCN9A mutant alleles:

Table 2.

Selected SCN9A Allelic Variants

Class of Variant AlleleDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.1828C>Ap.Pro610Thr 1

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​ See Quick Reference for an explanation of nomenclature.


The contribution of the variant p.Pro610Thr to the disease phenotype is not clear (see Pathogenic 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 pathogenic variants in 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 variant 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 pathogenic variants 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].


Literature Cited

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Chapter Notes


This work is supported in part by a gift from the Erythromelalgia Association.

Revision History

  • 15 August 2013 (me) Comprehensive update posted live
  • 25 September 2008 (cd) Revision: prenatal testing available
  • 26 August 2008 (cg) Comprehensive update posted live
  • 28 March 2007 (fmh) Revision: sequence analysis for SCN9A clinically available
  • 18 January 2007 (cd) Revision: mutations in SCN9A resulting in loss of function of sodium channel protein type 9 subunit alpha cause channelopathy-associated insensitivity to pain.
  • 5 May 2006 (me) Review posted to live Web site
  • 2 August 2005 (fmh) Original submission
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