FROM GENES TO SYMPTOMS: SENSORY PROFILING IN CHRONIC PAIN PATIENTS WITH TRPA1 AND SCN9A MUTATIONS

M. Marchi¹, A. Telesca¹, E. Salvi¹, M. Andelic¹, A. Strippoli¹, I. D'Amato¹, R. Lombardi¹, D. Cartelli¹, D. Cazzato², M. De Tommaso³, G. Lauria^1,4, G. Devigili¹ | ¹Department of Clinical Neuroscience, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano; ²SC Neurophysiopathology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano; ³DiBrain Department, Aldo Moro University, Bari; ⁴Department of Medical Biotechnology and Translational Medicine, University of Milano

INTRODUCTION
Genetic mutations in ion channels expressed in DRG neurons, such as transient receptor potential TRPA1¹ and voltage-gated sodium channel Nav1.7 (SCN9A)^2,3, can alter the fine-tuning of membrane potential affecting pain signaling. This study aimed to characterize the phenotype of patients carrying TRPA1 or SCN9A mutations in comparison with idiopathic patients, and to correlate the clinical findings with the molecular mechanisms.
METHODS
We examined 47 patients with chronic pain, including small fiber neuropathy (n=36) and fibromyalgia (n=11): 16 carrying TRPA1 mutations, 13 SCN9A mutations, 3 combined mutations in both the genes, and 15 with no mutation in these genes. All patients underwent clinical, autonomic, and pharmacological history assessment, neuropsychological questionnaires, multimodal quantitative sensory testing (QST), and skin biopsies for intraepidermal nerve fiber density.
RESULTS
All patients exhibited a chronic painful syndrome, with distinctive features based on genetic mutations. TRPA1-mutated patients showed abnormal sensory profiles at QST, with altered cold and pressure pain thresholds. Cold allodynia was detected in 12 carriers, while 6 had higher cold detection thresholds with errata perception of cold perceived as burning pain or tingling. None showed central sensitization. Patients carrying SCN9A mutations prevalently reported burning pain and showed increased warm detection thresholds and heat hyperalgesia at QST. Overall, TRPA1 and SN9A carriers showed more stereotypical pattern compared to idiopathic patients. Typical denervation pattern at skin biopsies was consistent with diagnosis.
CONCLUSIONS
Using an integrative approach, we captured sensory-discriminative profiles, which revealed distinct genotype-phenotype correlations in chronic pain patients harboring mutations in TRPA1 and SCN9A. Our preliminary data highlight the role of TRPA1 and SCN9A in nociception and thermal sensitivity, and emphasize the potential of genetic-based stratification in neuropathic pain assessment.