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

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Abstract

Purpose

Guanfacine is an α2A-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 NaV1.7 encoded by SCN9A, as well as other NaV channel subtypes to a varying degree.

Conclusion

Our study provides further evidence for a possible pathophysiological role of NaV1.7 in anxiety and dysautonomia. Combined with off-target effects on NaV channel function, daily administration of 1 mg short-acting guanfacine may be sufficient to normalize NaV channel mutation-induced changes in sympathetic activity, perhaps aided by partial inhibition of NaV1.7 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.

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Data availability

All data supporting the findings of this study are available within the paper.

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Acknowledgements

This work was partly funded by a research grant from Dysautonomia International (90097658) to M. Brock and F. Bosmans. The Research Foundation – Flanders and ERA-NET Neuron (co-)financed part of this work under G000220N and G0H8120N. R.C. Collaço is funded by a FWO junior postdoctoral fellowship under application 12Z3922N and M. Lammens is funded by a FWO fundamental research fellowship under application 1125923N. The work was also (partly) funded by the NIH under R01NS126398 (M. Brock and F. Bosmans), 3UM1HG006542 (D. Valle), the Banks Family Foundation, Bermuda (M. Brock) and the Skalka-Kronsberg family (M. Brock). A. Gurau is funded by the NIH T32CA126607 Award. S. Yamauchi is funded in part by the Subsidies for Current Expenditures to Private Institutions of Higher Education from the Promotion and Mutual Aid Corporation for Private Schools of Japan. We thank all members of the Valle, Brock, and Bosmans laboratories for helpful discussions.

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  1. Rita de Cássia Collaço, Maxime Lammens, and Carley Blevins are co-first authors.

Authors and Affiliations

  1. Molecular Physiology and Neurophysics Group, Department of Basic and Applied Medical Sciences, University of Ghent, Ghent, Belgium

    Rita de Cássia Collaço, Maxime Lammens & Frank Bosmans

  2. Department of Surgery, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Carley Blevins, Kristen Rodgers, Andrei Gurau, Suguru Yamauchi, Christine Kim, Jeannine Forrester, Edward Liu, Jinny Ha, Yuping Mei & Malcolm V. Brock

  3. McKusick-Nathans Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Corrine Boehm, Elizabeth Wohler, Nara Sobreira & David Valle

  4. Department of Pediatrics, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Peter C. Rowe

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de Cássia Collaço, R., Lammens, M., Blevins, C. et al. Anxiety and dysautonomia symptoms in patients with a NaV1.7 mutation and the potential benefits of low-dose short-acting guanfacine. Clin Auton Res 34, 191–201 (2024). https://doi.org/10.1007/s10286-023-01004-1

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