7.5 Familial Trigeminal Neuralgia
By Giulia Di Stefano, MD, PhD (USA)
Trigeminal neuralgia (TN) is a neuropathic facial pain condition that causes unilateral paroxysmal pain, in the region of one or more divisions of the trigeminal nerve, usually described as an electric-shock-like sensation or stabbing pain. This paroxysmal pain is typically triggered by innocuous stimuli on the face or intraoral trigeminal territory. The incidence of this condition increases with age and is higher in women than in men. Unlike migraine and other pain conditions that are influenced by hereditary factors, TN is considered to be a sporadic condition, despite the description of rare familial cases. Recent publications have opened new perspectives. Case series and cross-sectional studies have reported a familial occurrence, thus supporting the presence of genetic factors. In a recent cross-sectional study of a large cohort of people with TN, the authors identified 12 occurrences of TN with positive family history out of 88 enrollees. These study participants reported at least one first- or second-degree relative affected by what was described as TN. Individuals with familial occurrence had either classical TN, from a neurovascular conflict, or idiopathic TN, without a clear etiology. Some of them reported an onset of TN at an early age, an extremely rare condition in classical and idiopathic TN. Clinical characteristics in the patients examined, including affected divisions, trigger factors, the development of concomitant continuous pain, and refractory periods, did not differ between those with sporadic and familial TN, making the two forms of TN clinically indistinguishable. In people with a familial history of TN, the authors observed a higher frequency of refractoriness to pharmacological treatment in comparison with previous data collected on a large sample of people with TN. This finding suggests that the possible pathophysiological mechanisms underlying familial TN might reduce the effectiveness of first-line drugs (carbamazepine and oxcarbazepine). A better comprehension of genetic factors would be helpful for the development of the most appropriate treatment. Because paroxysmal pain in TN is related to an abnormal hyperexcitability of trigeminal ganglion neurons, the authors of one study performed a genetic analysis of the neuronal electrogenisome in these patients and identified rare variants of genes encoding voltage-gated channels and transient receptor potential (TRP) channels.
In one patient with familial history, the authors identified a known mutation in the sodium channel gene SCN10A (Nav1.8, p.Ala1304Thr), which was previously reported in a patient with neuropathic pain related to peripheral neuropathy.
Another study reported abnormal expression of voltage-gated sodium channels Nav1.7, Nav1.3, and Nav1.8 in patients with TN, thus supporting the hypothesis that a channelopathy might concur to the pathophysiology of this facial pain condition.
The identification of rare variants of gene-encoding TRP channels opened the way to in vitro functional studies to assess their possible pathogenetic role. Gualdani and colleagues assessed two of the previously identified TRPM7 and TRPM8 mutations through patch-clamp analysis. The authors found that the TRPM7 mutation (A931T) produces a destabilization of the transmembrane domains of the channel, leading to an abnormal sodium ion influx. The authors also found that the expression of TRPM7-mutant channels increases the hyperexcitability of trigeminal ganglion neurons, possibly contributing to the development of TN in patients carrying this mutation. The same authors found that the mutation in TRPM8 (R30Q) modifies the channel properties, enhancing the activation, increasing the basal current amplitude and intracellular calcium ion concentration in cells carrying the mutant channel, and enhancing the channel response to menthol.
A familial occurrence of TN supports the hypothesis of a multihit model in which genetic factors contribute to the pathophysiology. Genetic factors may increase the vulnerability of trigeminal axons and predispose an individual to the development of TN in response to vascular compression.
Genetic factors may affect a person’s response to pharmacological treatment, especially in those without severe neurovascular conflict. Further studies will be needed to clarify this hypothesis.
Editor’s Note: Whereas the signature patient in whom a genetic variant was found was evaluated for TN, the two relatives who also had the variant and were said to have TN were not evaluated clinically to confirm the diagnosis of TN. Their facial pain may have been from another cause. One should wait, as is stated in the conclusion of this discussion, for clarification of the issue of genetic factors in trigeminal neuropathic pain.
