Scn9a Neuropathic Pain Syndromes
Summary
Clinical characteristics.
SCN9A neuropathic pain syndromes (SCN9A-NPS) comprise SCN9A erythromelalgia (EM), SCN9A paroxysmal extreme pain disorder (PEPD), and SCN9A small fiber neuropathy (SFN).
- SCN9A-EM is characterized by recurrent episodes of bilateral intense, burning pain, and redness, warmth, and occasionally swelling. While the feet are more commonly affected than the hands, in severely affected individuals the legs, arms, face, and/or ears may be involved.
- SCN9A-PEPD is characterized by neonatal or infantile onset of autonomic manifestations that can include skin flushing, harlequin (patchy or asymmetric) color change, tonic non-epileptic attacks (stiffening), and syncope with bradycardia. Later manifestations are episodes of excruciating deep burning rectal, ocular, or submandibular pain accompanied by flushing (erythematous skin changes).
- SCN9A-SFN is characterized by adult-onset neuropathic pain in a stocking and glove distribution, often with a burning quality; autonomic manifestations such as dry eyes, mouth, orthostatic dizziness, palpitations, bowel or bladder disturbances; and preservation of large nerve fiber functions (normal strength, tendon reflexes, and vibration sense).
Diagnosis/testing.
The diagnosis of SCN9A-NPS is established in a proband with a heterozygous pathogenic variant in SCN9A identified by molecular genetic testing.
Management.
Treatment of manifestations: Most affected individuals are treated in dermatology clinics, neurology clinics, or pain clinics, or by anesthesiologists specializing in the management of chronic pain.
- SCN9A-EM. Cooling the extremities reduces pain; note that use of a fan is preferable to prolonged immersion in cold water, which can result in skin maceration, infection, and gangrene. Medications to consider are nonselective sodium channel blockers (e.g., carbamazepine, lidocaine infusion, or oral mexilitine).
- SCN9A-PEPD. Use of stool softeners and passing stool slowly to reduce the likelihood of triggering an attack. Carbamazepine is the most effective (albeit not completely effective) treatment in reducing the number and severity of attacks. Other antiepileptic medications with varying effectiveness include lamotrigine, topirimate, tiagabine, and sodium valproate.
- SCN9A-SFN. Lacosamide is associated with reduced pain ratings, improved general well-being and sleep quality, but not with changed overall quality of life or autonomic manifestations.
Surveillance: Follow up with a neurologist or neuromuscular specialist to assess for disease progression. Routine monitoring for side effects of medications used in treatment (such as Stevens-Johnson syndrome, liver toxicity, neutropenia seen with carbamazepine).
Agents/circumstances to avoid: Triggers including warmth, standing, alcohol, and spicy foods (SCN9A-EM); defecation, cold wind, eating, and emotion (SCN9A-PEPD); diabetes mellitus, alcohol, and chemotherapy (SCN9A SFN).
Evaluation of relatives at risk: It is appropriate to clarify the genetic status of apparently asymptomatic older and younger relatives of an affected individual at risk for SCN9A-NPS in order to identify as early as possible those who would benefit from avoidance of activities that are known to trigger onset of pain.
Pregnancy management: Potential teratogenic effects of medications used for treatment of SCN9A-NPS should be discussed with affected women of childbearing age, ideally prior to conception.
Genetic counseling.
SCN9A neuropathic pain syndromes are inherited in an autosomal dominant manner. Each child of an individual with an NPS-causing variant in SCN9A has a 50% chance of inheriting the variant. Once the SCN9A pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
Diagnosis
Suggestive Findings
An SCN9A neuropathic pain syndrome (SCN9A-NPS) should be suspected in individuals with one of the following three neuropathic pain disorders.
Erythromelalgia (EM), characterized by:
- Recurrent episodes of bilateral intense, burning pain;
- Redness, warmth, and occasionally swelling of the distal extremities;
- Feet more commonly affected than the hands; although in severely affected individuals, the legs, arms, face, and/or ears may be involved.
Note: If manifestations are intermittent, photographs of the affected extremities during a flare can help with diagnosis (see Figure 1).
Figure 1.
Red and swollen feet of an individual with SCN9A erythromelalgia
Paroxysmal extreme pain disorder (PEPD), characterized by:
- Neonatal or infantile onset of autonomic manifestations that can include skin flushing, harlequin (patchy or asymmetric) color change, tonic non-epileptic attacks (stiffening), and syncope with bradycardia;
- Later, episodes of excruciating deep burning rectal, ocular, or submandibular pain accompanied by flushing (erythematous skin changes).
- Attacks are precipitated by defecation or perineal wiping (rectal attacks), eating (jaw attacks), or cold wind, temperature change, or crying (ocular attacks).
- The pain typically is localized at the beginning of an episode, but spreads (e.g., from the rectum to the abdomen).
- Attacks usually begin abruptly and range in duration from seconds to as long as two hours.
Between episodes, constipation is common (from a reluctance to pass stool, thereby precipitating a painful attack).
Inherited small fiber neuropathy (I-SFN), characterized by [Faber et al 2012]:
- Adult-onset neuropathic pain in a stocking and glove distribution, often with a burning quality;
- Autonomic manifestations such as dry eyes, mouth, orthostatic dizziness, palpitations, and bowel or bladder disturbances;
- Preservation of large nerve fiber functions (normal strength, tendon reflexes, and vibration sense);
- Normal nerve conduction studies;
- Reduced intraepidermal nerve fiber density and/or abnormal quantitative sensory testing.
Note: Exogenous and systemic causes of small fiber neuropathy such as diabetes mellitus, HIV, and neurotoxic drugs (chemotherapy) must be excluded.
Establishing the Diagnosis
The diagnosis of SCN9A-NPS is established in a proband with a heterozygous pathogenic variant in SCN9A by molecular genetic testing (see Table 1).
Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing and multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of SCN9A-NPS is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of SCN9A-NPS has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
Single-gene testing. Sequence analysis of SCN9A is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Depending on the sequencing method used, (multi)exon or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is typically to perform gene-targeted deletion/duplication analysis to detect an exon or whole-gene deletion or duplication; however, because SCN9A-NPS is caused by gain-of-function variants, intragenic deletions or duplications are not expected to be causative, and none have been reported.
A peripheral neuropathy multigene panel that includes SCN9A and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. Of note, given the rarity of SCN9A-NPS, some panels for erythromelalgia and/or paroxysmal extreme pain disorder may not include this gene. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
Comprehensive genomic testing does not require the clinician to determine which gene(s) are likely involved. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in SCN9A Neuropathic Pain Syndromes
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| SCN9A | Sequence analysis 3 | ~100% 4 |
| Gene-targeted deletion/duplication analysis 5 | None reported 4 |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants 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.
- 4.
Data derived from Human Gene Mutation Database [Stenson et al 2017]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
Clinical Characteristics
Clinical Description
Pain is the predominant symptom of SCN9A neuropathic pain syndromes. Triggers for episodes of pain vary with the specific syndrome. Pain may be accompanied by signs of redness, warmth, or autonomic dysfunction. Erythromelalgia (EM) and paroxysmal extreme pain disorder (PEPD) typically begin in infancy or childhood, whereas small fiber neuropathy (SFN) typically begins in adulthood, and the prevalence increases with age. All three disorders have been reported with intrafamilial variability in age of onset and severity.
Erythromelalgia (EM) is characterized by recurrent attacks of intense pain, redness, warmth, and swelling involving the feet and, less frequently, the hands [Dib-Hajj et al 2013, McDonnell et al 2016]. 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-EM is usually in childhood or adolescence; however, it has been recognized in infants in families who are familiar with the disorder. While rare, later onset (age >20 years) has been reported in some individuals and families [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.
Histopathologic examination of skin biopsy in individuals with erythromelalgia shows nonspecific thickening of blood vessel basement membrane, perivascular edema and mononuclear infiltrate, and reduced density of the autonomic nerve plexuses.
Paroxysmal extreme pain disorder (PEPD) is characterized by episodes of rectal, ocular, or submandibular pain accompanied by erythema. The onset is in early infancy, and may occur prenatally [Fertleman et al 2007]. Infants may appear stiff and red at the time of delivery, but recover within minutes. Attacks are triggered by defecation, wiping the perineum, taking rectal temperature, or feeding. Pain is inferred from the infant's grimacing and crying.
Older children and adults describe the pain as excruciating, and burning or sharp. The attacks are always accompanied by erythematous flushing of the skin, which usually corresponds to the affected region. In severe attacks, the pain spreads and become generalized.
The number of rectal attacks can decrease with age, whereas the ocular and jaw attacks can increase with age [Fertleman et al 2007].
In PEPD, biopsies of rectum or colon have been reported as normal or only nonspecific findings [Fertleman et al 2007]
Inherited small fiber neuropathy (SFN) is characterized by symmetric, distal burning pain, numbness, and paresthesias. Autonomic manifestations such as dry eyes or mouth, orthostatic dizziness, change in sweating, and bowel or bladder dysfunction may be present. The prevalence of SFN increases with age.
Pathogenic missense variants in SCN9A were reported in eight of 28 adults (age ≥18 years) with inherited small fiber neuropathy (I-SFN) in whom other known causes for small fiber neuropathy (e.g., diabetes mellitus, impaired glucose tolerance, hyperlipidemia) were excluded, and who met strict diagnostic criteria for I-SFN with reduced intraepidermal nerve fiber density on skin biopsy or abnormal quantitative sensory testing [Faber et al 2012].
Of note, in SFN, the intraepidermal nerve fiber density (IENFD) in a skin biopsy is quantitatively reduced compared with age- and gender-adjusted normative values [Faber et al 2012], although I-SFN can occur in persons with normal IENFD [Eijkenboom et al 2019].
Genotype-Phenotype Correlations
Disease severity varies within families. In one family, an infant with SCN9A-PEPD had a father with only ocular attacks [Fertleman et al 2007].
Although SCN9A variants resulting in greater hyperpolarizing shifts in Nav1.7 sodium channels correlated with onset of manifestations at younger ages (P = .016), unknown inter-individual differences also influence age of onset: in two families in which individuals with erythromelalgia had the same variant (p.Ser241Thr), the age of onset was in the first decade in one family and the second decade in the other [Geha et al 2016].
Penetrance
The penetrance in families with SCN9A erythromelalgia and paroxysmal extreme pain disorder reported to date is 100%; individuals with SCN9A small fiber neuropathy show incomplete penetrance.
Of note, in 2008 the Erythromelalgia Association conducted a survey of its members regarding diagnosis, symptoms, and response to medications (see www.erythromelalgia.org). In this heterogeneous group of 427 participants (of which an unknown subset has SCN9A-EM), only 5% reported a relative with a diagnosis of erythromelalgia – fewer than would be expected for an autosomal dominant disorder with high penetrance; however, a pattern of autosomal dominant inheritance with 100% penetrance was always observed in multi-generation families with SCN9A-EM.
Nomenclature
Erythromelalgia. 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).
Some authors prefer "erythromelalgia" for both primary EM (OMIM 133020) and acquired forms of the disease (secondary EM); others use inherited EM as a synonym for primary EM.
Primary EM may also be referred to as "erythermalgia."
Paroxysmal extreme pain disorder was previously referred to as familial rectal pain [Fertleman et al 2007].
Prevalence
No accurate data on the worldwide prevalence of SCN9A-NPS are available. Molecular genetic data in the medical literature are available for between 100 and 200 individuals with SCN9A erythromelalgia and SCN9A paroxysmal extreme pain disorder.
It is likely that SCN9A neurogenic pain syndromes are underdiagnosed or often misdiagnosed.
Differential Diagnosis
Erythromelalgia
The differential diagnosis of SCN9A erythromelalgia (SCN9A-EM) 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 See Table 3.
Table 3.
Differential Diagnosis of SCN9A Erythromelalgia
| Category | Disorder/Exposure | Comment/Characteristics |
|---|---|---|
| Secondary EM | Essential thrombocythemia | Myeloproliferative disorder (MPD):
|
| Polycythemia vera or thrombotic thrombocytopenic purpura | ||
| Rheumatologic disorders | Gout & autoimmune disorders incl systemic lupus erythematosus, rheumatoid arthritis, & vasculitis | |
| Paraneoplastic syndrome | Rare cause of secondary EM | |
| Medication |
| |
| Environmental toxins |
| |
| Neuropathies |
| These conditions may cause burning pain similar to EM but are much less likely to be assoc w/redness, warmth, heat intolerance, or relief w/cooling. |
| Other conditions | Reflex sympathetic dystrophy |
|
| Peripheral vascular disease |
| |
| Raynaud's phenomenon |
| |
| Fabry disease |
| |
| Other genetic causes of neuropathic pain | TRPA1 familial episodic pain syndrome | AD inheritance (OMIM 615040). Episodes of upper-body pain beginning in infancy triggered by fasting, cold, fatigue, & exercise, accompanied by altered breathing, sweating, tachycardia & followed by exhaustion |
| SCN10A familial episodic pain syndrome | AD inheritance (OMIM 615551). Burning, intense itch, hyperalgesia or pain in distal extremities reported in middle-aged adults | |
| SCN11A familial episodic pain syndrome | AD inheritance (OMIM 615552). Numbness, tingling, & pain of the hands & feet accompanied by autonomic features (e.g., hyperhidrosis, diarrhea, & palpitations) |
AD= autosomal dominant; EM = erythromelalgia; XL=X-linked
Paroxysmal Extreme Pain Disorder
Table 4.
Differential Diagnosis of SCN9A Paroxysmal Extreme Pain Disorder
| Disorder | Comment/Characteristics |
|---|---|
| Epilepsy | Atonic attacks infants are frequently thought to be epileptic seizures. EEG during attacks shows slowing but no epileptiform activity. |
| Hyperekplexia | See Hereditary Hyperekplexia. |
| Cardiac arrhythmia | Bradycardia & even asystole during atonic attacks may prompt evaluation for a primary cardiac cause. |
| Gastrointestinal reflux | Pain, facial erythema, & crying after eating may resemble gastroesophageal reflux. |
SCN9A Small Fiber Neuropathy (SFN)
Table 5.
Conditions in the Differential Diagnosis of SCN9A Small Fiber Neuropathy
| Cause | Comment/Characteristics |
|---|---|
| Diabetic peripheral neuropathy | History of diabetes; ↑ hemoglobin A1C |
| Rheumatologic disease | Rheumatoid arthritis, systemic lupus erythematosus, Sjogren syndrome; positive autoimmune antibodies |
| Monoclonal gammopathy | Occurs at older ages; IgM monoclonal gamma globulins |
| Amyloidosis | A group of disorders characterized by amyloid protein deposition → neuropathy & cardiac or renal dysfunction
|
| Paraneoplastic sensory neuropathy | More common w/lung cancer; may precede cancer diagnosis; anti-Hu antibodies |
In a cohort of 921 patients with SFN, diagnostic evaluations identified immunologic conditions (19%), sodium channel gene variants (16.7%), diabetes mellitus (7.7%), vitamin B12 deficiency (4.7%), alcohol abuse (3%), chemotherapy side effects (2.2%), monoclonal gammopathy of undetermined significance (1.4%), and hemochromatosis (0.3%). No cause was found in 53% of patients [de Greef et al 2018].
In one study, 58 of 1139 (5%) of individuals with SFN of unknown cause were found to have a heterozygous SCN9A variant [Eijkenboom et al 2019].
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with an SCN9A neuropathic pain syndrome (SCN9A-NPS), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
- Neurologic examination, including a quantitative sensory test and pain assessment
- Clinical assessment of SCN9A-NPS that may include questionnaires such as the Small Fibre Neuropathy and Symptoms Inventory Questionnaire [Terkelsen et al 2017] or the Neuropathic Pain Scale [Galer & Jensen 1997]
- Assessment of the pain management strategies used (see Treatment of Manifestations)
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Most affected individuals are treated in dermatology, neurology, or pain clinics; or by anesthesiologists specializing in the management of chronic pain.
SCN9A Erythromelalgia (SCN9A-EM)
The pain is often refractory to treatment.
Cooling the extremities reduces pain in a symptomatic person. Cooling with a fan is generally safer than immersion in water; complications from prolonged immersion in ice baths include skin maceration, infection, and gangrene. Amputation has occasionally been necessary to treat these complications.
Medications. The individual's treating physician should determine treatment based on factors including other medical conditions, known medication allergies, and potential for drug-drug interactions.
- Nonselective sodium channel blockers including carbamazepine, lidocaine infusion, or oral mexilitine have been used successfully in SCN9A-EM [Choi et al 2009, Fischer et al 2009, Cregg et al 2014].
- Carbamazepine. While it is generally less effective in treating EM than PEPD, a family with the SCN9A pathogenic variant p.Val400Met reported significant improvement of EM symptoms while using carbamazepine [Fischer et al 2009]. Since then, patients with the p.Ser241Thr and p.Ile234Thr variants have reported pain relief from carbamazepine [Geha et al 2016, Yang et al 2018].
- A combination of gabapentin and carbamazepine has been reported effective in at least one individual with the SCN9A variant p.Ile848Thr [Natkunarajah et al 2009].
Other
- See Tham & Giles [2018] for a review of additional combinations of medical, surgical, and alternative treatments used with varying success in individuals with erythromelalgia (not limited to SCN9A-EM).
- Use of oxcarbazepine in treating EM has not been reported.
SCN9A Paroxysmal Extreme Pain Disorder (SCN9A-PEPD)
Use of stool softeners and passing stool slowly can reduce the likelihood of triggering an attack.
Medications. The most effective (albeit not completely effective) treatment in reducing the number and severity of attacks in PEPD is carbamazepine [Fertleman et al 2007]. While 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], no current comprehensive review addresses this issue.
Additional antiepileptic medications including lamotrigine, topirimate, tiagabine, and sodium valproate have been reported to have varying effectiveness. See Supplemental Table E3 in Fertleman et al [2007].
Analgesics and opiates are ineffective in the treatment of PEPD.
SCN9A Small Fiber Neuropathy (SCN9A-SFN)
A small randomized placebo-controlled double-blind crossover-design clinical trial of the antiepileptic drug lacosamide in 24 individuals with SCN9A-SFN reported reduction in pain ratings, improvement in general well-being and sleep quality, but no change in overall quality of life or autonomic manifestations compared with 23 individuals who received placebo [de Greef et al 2019].
Surveillance
There are no published guidelines for surveillance for SCN9A-NPS.
Follow up with a neurologist or neuromuscular specialist to assess for progression of the disease.
It is important to monitor for known side effects of treatment of medications (e.g., Stevens-Johnson syndrome, liver toxicity, and neutropenia – associated with carbamazepine treatment).
Agents/Circumstances to Avoid
SCN9A erythromelalgia. 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.
SCN9A paroxysmal extreme pain disorder is often triggered by defecation, cold wind, eating, and emotion.
SCN9A small fiber neuropathy. Avoid additional risk factors for small fiber neuropathy such as diabetes mellitus, alcohol, and chemotherapy.
Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger relatives of an affected individual at risk for SCN9A-NPS in order to identify as early as possible those who would benefit from avoidance of activities that are known to trigger onset of pain.
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 SCN9A-NPS should be discussed with affected women of childbearing age, ideally prior to conception.
See MotherToBaby for further information on medication use during pregnancy.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.