Figure 1. Red and swollen feet of individual with SCN9A-related IEM
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GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. The diagnosis of SCN9A-related IEM is made on clinical grounds. Mutations in SCN9A encoding the sodium channel protein Nav1.7 subunit are known to be associated with IEM; additional genes may also be associated with IEM. Molecular genetic testing for mutations in SCN9A is available on a clinical basis.
Management. 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. 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. 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 mutation has a 50% chance of inheriting the mutation. Prenatal molecular genetic testing is available but is rarely requested.
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.
Figure 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.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. 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 loci
Linkage to chromosome 2q was excluded in a three-generation family [Burns et al 2005], suggesting the possible existence of additional causative genes.
Exclusion of mutations in SCN9A, SCN10A, and SCN11A in familial cases also supports genetic heterogeneity [Drenth et al 2008].
Clinical testing
Sequence analysis is available on a clinical basis. 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].
| Gene Symbol | Test Method | Mutations Detected | Mutation Detection Frequency 1 | Test Availability | |
|---|---|---|---|---|---|
| Family History | |||||
| Positive | Negative | ||||
| SCN9A | Sequence analysis | Sequence variants | 50%-100% | ~30% | Clinical
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1. Because so few individuals have been tested to date, the detection rates need to be considered preliminary.
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
To 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.
Mutations 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.
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.
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 penetrance in families with SCN9A-related IEM reported to date is 100%; however, molecular genetic data are available for fewer than 20 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 mutation) have been identified in Canada, China, Japan, Taiwan, France, Belgium, the Netherlands, 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].
It is likely that erythromelalgia is underdiagnosed or misdiagnosed.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
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.
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, 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].
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, 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.
A 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.
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]. 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 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.
Other
Reports 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].
Avoidance of triggers (warmth, prolonged standing) may reduce the number or severity of episodes.
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.
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.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Search 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.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
SCN9A-related inherited erythromelalgia (SCN9A-related IEM) is inherited in an autosomal dominant manner.
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 new gene mutation. The proportion of cases caused by de novo mutations is unknown; because the evaluation of family members for milder symptoms has been incomplete, and the molecular genetic data are insufficient.
Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include: a detailed clinical and family history and molecular genetic testing of both parents if the mutation 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 mutation. 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 SCN9A-related IEM mutation has a 50% chance of inheriting the mutation.
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 disease-causing mutation, his or her family members are at risk.
Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder or the disease-causing mutation, it is likely that the proband has a de novo mutation. 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 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 of being affected.
DNA banking. 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, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant when the sensitivity of currently available testing is less than 100%. See
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Requests for prenatal testing for conditions such as SCN9A-related IEM that 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 available for families in which the disease-causing mutations have been identified. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | HGMD |
|---|---|---|---|
| SCN9A | 2q24 | Sodium channel protein type 9 subunit alpha | SCN9A |
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.
. An additional 33 mutations are reported in professional (limited-access) databases.
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]
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]
| Class of Variant Allele | DNA Nucleotide Change | Protein Amino Acid Change | Reference Sequence |
|---|---|---|---|
| Normal | c.601T>G | p.Leu201Val | NM_002977.2NP_002968.1 |
| c.616A>G | p.Asn206Asp | ||
| c.3448C>T | p.Arg1150Trp | ||
| Pathologic | c.406A>G | p.Ile136Val | |
| c.647T>C | p.Phe216Ser | ||
| c.721T>A | p.Ser241Thr | ||
| c.1185C>A | p.Asn395Lys | ||
| c.1828C>A | p.Pro610Thr 1 | ||
| c.2468T>G | p.Leu823R | ||
| c.2543T>C | p.Ile848Thr | ||
| c.2573T>A | p.Leu858His | ||
| c.2572C>T | p.Leu858Phe | ||
| c.2587G>C | p.Ala863Pro | ||
| c.4345T>G | p.Phe1449Val |
See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (http://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].
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
This work is supported in part by a gift from the Erythromelalgia Association.
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
