Anxiety and dysautonomia symptoms in patients with a NaV1.7 mutation and the potential benefits of low-dose short-acting guanfacine

Purpose

Guanfacine is an α_2A-adrenergic receptor agonist, FDA-approved to treat attention-deficit hyperactivity disorder and high blood pressure, typically as an extended-release formulation up to 7 mg/day. In our dysautonomia clinic, we observed that off-label use of short-acting guanfacine at 1 mg/day facilitated symptom relief in two families with multiple members presenting with severe generalized anxiety. We also noted anecdotal improvements in associated dysautonomia symptoms such as hyperhidrosis, cognitive impairment, and palpitations. We postulated that a genetic deficit existed in these patients that might augment guanfacine susceptibility.

Methods

We used whole-exome sequencing to identify mutations in patients with shared generalized anxiety and dysautonomia symptoms. Guanfacine-induced changes in the function of voltage-gated Na⁺ channels were investigated using voltage-clamp electrophysiology.

Results

Whole-exome sequencing uncovered the p.I739V mutation in SCN9A in the proband of two nonrelated families. Moreover, guanfacine inhibited ionic currents evoked by wild-type and mutant Na_V1.7 encoded by SCN9A, as well as other Na_V channel subtypes to a varying degree.

Conclusion

Our study provides further evidence for a possible pathophysiological role of Na_V1.7 in anxiety and dysautonomia. Combined with off-target effects on Na_V channel function, daily administration of 1 mg short-acting guanfacine may be sufficient to normalize Na_V channel mutation-induced changes in sympathetic activity, perhaps aided by partial inhibition of Na_V1.7 or other channel subtypes. In a broader context, expanding genetic and functional data about ion channel aberrations may enable the prospect of stratifying patients in which mutation-induced increased sympathetic tone normalization by guanfacine can support treatment strategies for anxiety and dysautonomia symptoms.