Abstract:
Transient receptor potential vanilloid 1 (TRPV1) is a ligand and heat-gated ion channel expressed on nociceptors that plays a central role in thermal and chemical pain signaling. Loss-of-function variants in TRPV1 have been associated with reduced nociception. We report a 65-year-old woman with disabling polyneurofunctional/neuropathic symptomatology including migraine, functional gastrointestinal disorders, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).
Diagnostic evaluation revealed sensory polyneuropathy and autonomic instability. Whole genome sequencing reanalysis identified a heterozygous TRPV1 c.2174A > T (p.Lys725Met) Likely Pathogenic variant that is very rare and highly conserved.
Our patient reports consistent, longstanding, marked hypersensitivity to heat, capsaicin, and alcohol, all of which are known TRPV1 agonists, supporting a gain-of-function mechanism for this variant. Furthermore, prior studies have implicated TRPV1 hyperactivity in migraine, nociceptive sensitization, and ME/CFS. Despite the excellent clinical correlation, causality of the variant cannot be definitively established without functional studies.
This case expands the potential phenotypic spectrum associated with TRPV1, and highlights a possible role for TRPV1-mediated channelopathies in complex neurofunctional disorders including ME/CFS.
Source: Zimmermann PM, Boles RG. A Woman With Multiple Neuropathic Symptoms, Hypersensitivity to Heat, Peppers, and Alcohol, With a Variant in the TRPV1 Capsaicin Receptor Gene: Possible Implications to ME/CFS. Case Rep Genet. 2026 Nov 3;2026:1920171. doi: 10.1155/crig/1920171. PMID: 42979319; PMCID: PMC13729082. https://pmc.ncbi.nlm.nih.gov/articles/PMC13729082/ (Full text)