Association of small-fiber polyneuropathy with three previously unassociated rare missense SCN9A variants.
Kelley, Mary A, Oaklander, Anne Louise · Canadian journal of pain = Revue canadienne de la douleur · 2020 · DOI
Quick Summary
This study describes two patients who developed small fiber nerve damage (affecting the smallest nerves in the body) and severe fatigue after infections. Both had immune system abnormalities and improved dramatically with immune-suppressing treatments. Genetic testing found rare changes in a gene called SCN9A that affects how nerve cells communicate. The findings suggest that genetic variations in this gene might play a role in some cases of small fiber nerve damage that respond to immune therapy.
Why It Matters
Many ME/CFS patients report neuropathic pain and autonomic dysfunction; this study provides mechanistic evidence that small fiber nerve damage combined with immune dysregulation may underlie these symptoms in some cases. The finding that genetic variants in sodium channel genes are associated with immunotherapy-responsive neuropathy suggests potential therapeutic pathways and the importance of screening for autoimmunity in ME/CFS patients with neuropathic symptoms. Understanding the genetic and immunological basis of small fiber pathology could lead to better diagnostic and treatment approaches.
Observed Findings
A 47-year-old with 4 years of widespread neuropathic pain and exertional intolerance had skin-biopsy-confirmed SFN, high-titer ANAs, low complement C4, and improved dramatically over 6 years with IVIg therapy, with normalization of neurite density.
A 32-year-old post-zoster developed disabling exertional intolerance, postural syncope, tachycardia, paresthesias, reduced sweating, and hair loss; had detectable ANAs and potassium channel autoantibodies; and normalized on prednisone and IVIg over 4 years.
Three novel SCN9A missense variants were identified (one in case 1, two compound heterozygous in case 2), none previously reported in neuropathy literature.
Both patients had objective improvement in autonomic testing and skin biopsy findings correlating with clinical improvement during immunotherapy.
Inferred Conclusions
Novel SCN9A variants may contribute to an immunotherapy-responsive small fiber neuropathy phenotype characterized by exertional intolerance, autonomic dysfunction, and neuropathic pain.
The association of genetic sodium channel variants with autoimmune markers (ANAs, autoantibodies) suggests potential gene-environment or gene-immune interactions in some SFN cases.
Immunotherapy should be considered in patients with SFN and serological evidence of dysimmunity, particularly those with exertional intolerance and autonomic symptoms.
Remaining Questions
Are these three SCN9A variants actually pathogenic, and do they occur in the general population or only in patients with neuropathy?
What This Study Does Not Prove
This case report cannot establish whether the identified SCN9A variants are causative, contributory, or incidental findings—this requires larger population studies. The study does not prove that all ME/CFS patients have small fiber neuropathy or that genetic SCN9A variants are common in ME/CFS. Because there are no control subjects without these variants, causation cannot be inferred from the genetic data alone.
About the PEM badge: “PEM required” means post-exertional malaise was an explicit required diagnostic criterion for participant inclusion in this study — not that PEM was studied, observed, or discussed. Studies using criteria that do not require PEM (e.g. Fukuda, Oxford) are tagged “PEM not required”. How the atlas works →
How common are SCN9A variants in larger cohorts of ME/CFS or SFN patients, and what is their prevalence in matched controls?
Do sodium channel blockers improve outcomes in patients with these specific variants, or is immunotherapy the primary effective intervention?
What is the relationship between the genetic variants and the development of autoimmunity—are variants triggers for immune dysregulation, or is autoimmunity primary?