Association of small-fiber polyneuropathy with three previously unassociated rare missense SCN9A variants.

Background: Small fiber polyneuropathy (SFN) involves ectopic firing and degeneration of small-diameter, somatic/autonomic peripheral axons. Causes include diabetes, inflammation and rare pathogenic mutations, including in genes that encode small fiber sodium channels.

Aims: The aim of this study is to associate a new phenotype-immunotherapy-responsive SFN-with rare amino acid-substituting variants and present potential explanations.

Methods: A retrospective chart review of two Caucasians with skin biopsy confirmed SFN and rare single nucleotide polymorphisms not previously reported in neuropathy.

Results: A 47-year-old with 4 years of disabling widespread neuropathic pain and exertional intolerance had nerve- and skin biopsy-confirmed SFN, with blood tests revealing only high-titer antinuclear antibodies and low complement C4 consistent with B cell dysimmunity. Six years of intravenous immunoglobulin (IVIg) therapy markedly improved sensory and autonomic symptoms and normalized his neurite density. After whole exome sequencing revealed a potentially pathogenic -A3734G variant, sodium channel blockers were tried. Herpes zoster left a 32-year-old with disabling exertional intolerance ("chronic fatigue syndrome"), postural syncope and tachycardia, arm and leg paresthesias, reduced sweating, and distal hairloss. Screening revealed antinuclear and potassium channel autoantibodies, so prednisone and then IVIg were prescribed with great benefit. During 4 years of immunotherapy, his symptoms and function improved, and all abnormal biomarkers (autonomic testing and skin biopsies) normalized. Whole exome sequencing then revealed two nearby compound heterozygous variants that were computer-predicted to be deleterious.

Conclusions: These cases newly associate three novel amino acid-substituting variants with immunotherapy-responsive neuropathy. Only larger studies can determine whether these are contributory or coincidental, but they associate new variants with moderate or high likelihood of pathogenicity with a new highly related phenotype.