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 mexiletine).
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 anti-seizure medications with varying effectiveness include lamotrigine, topiramate, 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.
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