FPRF Symposium 2026: Genetics of Trigeminal Neuralgia – Highlights

Key Insights from Dr. Kim Burchiel’s Presentation

  • Dr. Kim Burchiel and his multi-center team (US, Canada, UK) presented new genetic findings about trigeminal neuralgia (TN).
  • Their research found that while TN symptoms (sharp, electric-shock-like facial pain) appear similar, the causes may be different:
    • Older patients (>45) often have neurovascular compression (artery pressing on the nerve).
    • Younger patients, mainly women, often lack this compression—suggesting a genetic cause.
  • They analyzed DNA from 781 TN patients and over 1,000 controls, performing a genome-wide scan.
  • Strongest evidence implicated myelin-related genes, especially:
    • BDNF: Regulates myelin, often found altered in young women with TN.
    • LRP1B: Involved in nerve repair.
    • KCNK10/TREK-2: May explain response to some medications like baclofen.
  • The core takeaway: TN is not a single disease, but a set of different conditions leading to similar symptoms. This means more personalized treatments could be possible.
  • A practical development: Using eight genetic markers, the team can now predict TN with about 86% accuracy from a simple saliva sample—a new “spit test” potentially on the horizon for easier diagnosis and improved treatment decisions.

Full Versions

Genetics of Trigeminal Neuralgia: What Do We Know and How Can It Be Used?
Kim Burchiel, MD, FACS

FPRF Symposium 2026 — Day 1, 9:45–10:15 AM CDT
Co-Chair SAB
Oregon Health and Science University
Dr. Burchiel is the John Raaf Professor and Chairman Emeritus of the Department of Neurological Surgery at OHSU, he served as department chair for 27 years from 1988-2015.
Dr. Burchiel is Head of the Division of Functional Neurosurgery at OHSU, and also directs the Functional and Stereotactic Neurosurgery fellowship program that encompasses the surgical treatment of pain, movement disorders, and epilepsy. His major clinical interests are in Deep Brain Stimulation (DBS) for movement disorders and other conditions, and the surgical treatment of pain, particularly trigeminal neuralgia.
His research interests are concerned with the physiology of nociception and neuropathic pains, including trigeminal neuralgia, the neurosurgical treatment of movement disorders, epilepsy surgery, image-guided neurosurgery, and the application of DBS to the problem of obesity.

1. Lay Summary (for patients and caregivers)
Dr. Kim Burchiel from Oregon Health & Science University presented findings from a long-running genetic study of trigeminal neuralgia, the nerve-pain condition this meeting was built around. The study was funded by the Facial Pain Research Foundation and brought together 9 medical centers across the United States, Canada, and the United Kingdom.

The starting observation was simple but striking. People with trigeminal neuralgia (TN) all look similar in the clinic — sudden, severe, electric-shock-like facial pain — but the underlying biology may not be the same in every person. Older patients (mostly above age 45) usually have a small artery pressing on the trigeminal nerve, what doctors call “neurovascular compression.” But younger patients, who are mostly women, often don’t have any artery pressing on the nerve. That suggested something else was driving their pain — possibly something genetic.

To test this, the team analyzed DNA from more than 780 TN patients and over 1,000 people without TN. They scanned the whole genome to find genetic differences linked to TN.

The results pointed clearly toward myelin — the protective coating around nerves. The strongest finding, in young women, was in a gene called BDNF, which helps regulate myelin. Other important genes, including one called LRP1B, are involved in repairing nerve coverings. A separate gene, called KCNK10 or TREK-2, helps explain why an old medicine called baclofen sometimes helps TN.

The bigger message: TN is not one disease. It’s the same painful appearance produced by several different underlying conditions — older patients with arterial compression, younger women without compression, multiple sclerosis–related TN, and rare cases linked to tumors or vascular malformations. Different patients may need different treatments.

There is also a practical promise. Combining the eight strongest genetic markers, Dr. Burchiel’s team can predict TN with about 86% accuracy from a saliva sample. He described the team as “on the verge of developing a spit test for trigeminal neuralgia.” If validated in further studies, that test could improve diagnosis, guide treatment choices, and help match patients to the right therapy or clinical trial.

2. Graduate-Level Summary (for scientists, clinicians, and industry CSOs)

Burchiel presented updated results from a long-running, FPRF-funded multicenter genetics study of trigeminal neuralgia (TN), originally organized at the request of Marshall Devoe (FPRF). The consortium integrates patient data from nine institutions: OHSU (Burchiel, coordinating), UCSF (Edward Chang), University of Pennsylvania (John Lee), NYU (Doug Kondziolka), University of Florida (Andrew Ahn), UCSD (John Alksne), University of Illinois Chicago (Konstantin Slavin), University of Toronto (Mojgan Hodaie), and University of London (Joanna Zakrzewska). One founding investigator has since died.

Phenotypic premise. The analysis was anchored in two clinical observations from the OHSU surgical cohort: (1) TN1 patients without neurovascular compression (NVC) present at significantly younger ages than those with NVC (means ~46 vs. ~57 years; ORs for age <40 = 4.14 and age <30 = 4.90, both p<0.001), and (2) the younger-without-NVC subgroup is overwhelmingly female. The crossover from no-NVC predominance to NVC predominance occurs at approximately age 45. Together these findings argued for at least two distinct populations within ICHD-defined classical TN1 and motivated sex- and age-stratified genetic analysis.

Study design. Genome-wide association study (GWAS) on 781 TN cases vs. 1,015 controls, restricted to Caucasian (including Latinx) ancestry to control for population stratification. Cases were validated by two independent diagnostic methods: the OHSU online TGN questionnaire (in use approximately 20 years) and on-site clinical PI diagnosis. Subset analyses were performed for females <45 years old (TN1 n=185; TN2 n=46). A whole-genome sequencing (WGS) substudy was performed on 100 patients with bioinformatic prioritization of rare variants by predicted protein-functional impact, low minor allele frequency, and overlap with single-gene-disorder symptom profiles.

GWAS — BDNF antisense in young females. The strongest GWAS signal (Manhattan-plot peak surviving genome-wide multiple-testing thresholds) localized to the BDNF antisense (BDNF-AS) regulatory region in females <45. The associated SNPs were strongly linked to expression and intron/exon splicing of BDNF-AS, which regulates BDNF mRNA translation. Recessive risk-genotype frequency in this peak region was negligible in controls and TN2 patients but markedly elevated in young-female TN1 cases. BDNF-AS has been independently implicated in inflammatory demyelinating polyradiculopathy, Alzheimer’s, Huntington’s, and Parkinson’s diseases — supporting biological plausibility.

Additional gene-level findings. LRP1B (LDL receptor–related protein 1B) was strongly associated in the TN-WONVC subgroup (alongside TENM3); LRP1B is implicated in oligodendrocyte maturation, Schwann cell activation/migration/repair, myelin sheath restoration after injury, CNS myelin development, and attenuation of neuropathic pain. KCNK10 (TREK-2) — a two-pore-domain potassium channel — was strongly associated in the TN-WNVC subgroup. KCNK10 attenuates axotomy-induced neuropathic pain in rat sensory neurons (Messina, Exp. Neurol. 2022); GABA-B receptor activation enhances KCNK10 channel activity and baclofen reduces action potential firing of IB4+ rat maxillary trigeminal neurons (Chang, Mol. Pain 2021), establishing a mechanistic chain between this genetic signal and an existing TN therapeutic.

Predictive performance. A Genomic Best Linear Unbiased Prediction (GBLUP) model built from eight GWAS-identified SNPs, fit using a sex-adjusted single-locus mixed model with additive transmission, achieved AUC 0.86 (sensitivity 0.65, specificity 0.85) in 626 TN cases vs. 827 controls. Mean predicted phenotype score was 0.57 ± 0.007 in cases vs. 0.28 ± 0.007 in controls (p = 6.8 × 10⁻¹⁴⁵). Burchiel framed this performance as “on the verge of a spit test for trigeminal neuralgia.”

WGS findings. Rare-variant gene-set enrichment analysis (AI-based bioinformatics pipelines processing millions of features) identified, in females <45: significant enrichment of mutations in genes related to myelin / Charcot-Marie-Tooth disease (p=0.0006) and epilepsy / seizure disorders (p=0.03). Ion channel gene categories did not show enrichment in this analysis. Burchiel explicitly characterized ion channels as “part of the process but not the problem,” while acknowledging this is a personal interpretation.

Synthesis. Different polymorphisms associate with the TN-WNVC and TN-WONVC subgroups, with sex and age-of-onset providing further stratification. TN is best understood as a phenotype with multiple etiologies — older-with-NVC, younger-female-without-NVC, multiple-sclerosis–associated (STN), and rare tumor / AVM cases — that share clinical presentation but likely require different therapeutic strategies. Burchiel’s working frame: TN1 occurs on a background of genetic predisposition (TN1 W NVC associated with 5 variants; TN1 WO NVC with 5+2 variants).