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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

Rita de Cassia de Oliveira Collaco (UGent) , Maxime Lammens (UGent) , Carley Blevins, Kristen Rodgers, Andrei Gurau, Suguru Yamauchi, Christine Kim, Jeannine Forrester, Edward Liu, Jinny Ha, et al.
(2024) CLINICAL AUTONOMIC RESEARCH. 34(1). p.191-201
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Abstract
Purpose: Guanfacine is an alpha(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(V)1.7 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(V)1.7 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(V)1.7 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.
Keywords
Guanfacine, Na(V)1.7, Anxiety, Voltage-gated sodium channel, Dysautonomia

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MLA
de Oliveira Collaco, Rita de Cassia, et al. “Anxiety and Dysautonomia Symptoms in Patients with a NaV1.7 Mutation and the Potential Benefits of Low-Dose Short-Acting Guanfacine.” CLINICAL AUTONOMIC RESEARCH, vol. 34, no. 1, 2024, pp. 191–201, doi:10.1007/s10286-023-01004-1.
APA
de Oliveira Collaco, R. de C., Lammens, M., Blevins, C., Rodgers, K., Gurau, A., Yamauchi, S., … Bosmans, F. (2024). Anxiety and dysautonomia symptoms in patients with a NaV1.7 mutation and the potential benefits of low-dose short-acting guanfacine. CLINICAL AUTONOMIC RESEARCH, 34(1), 191–201. https://doi.org/10.1007/s10286-023-01004-1
Chicago author-date
Oliveira Collaco, Rita de Cassia de, Maxime Lammens, Carley Blevins, Kristen Rodgers, Andrei Gurau, Suguru Yamauchi, Christine Kim, et al. 2024. “Anxiety and Dysautonomia Symptoms in Patients with a NaV1.7 Mutation and the Potential Benefits of Low-Dose Short-Acting Guanfacine.” CLINICAL AUTONOMIC RESEARCH 34 (1): 191–201. https://doi.org/10.1007/s10286-023-01004-1.
Chicago author-date (all authors)
de Oliveira Collaco, Rita de Cassia, Maxime Lammens, Carley Blevins, Kristen Rodgers, Andrei Gurau, Suguru Yamauchi, Christine Kim, Jeannine Forrester, Edward Liu, Jinny Ha, Yuping Mei, Corrine Boehm, Elizabeth Wohler, Nara Sobreira, Peter Rowe, David Valle, Malcolm V Brock, and Frank Bosmans. 2024. “Anxiety and Dysautonomia Symptoms in Patients with a NaV1.7 Mutation and the Potential Benefits of Low-Dose Short-Acting Guanfacine.” CLINICAL AUTONOMIC RESEARCH 34 (1): 191–201. doi:10.1007/s10286-023-01004-1.
Vancouver
1.
de Oliveira Collaco R de C, Lammens M, Blevins C, Rodgers K, Gurau A, Yamauchi S, et al. Anxiety and dysautonomia symptoms in patients with a NaV1.7 mutation and the potential benefits of low-dose short-acting guanfacine. CLINICAL AUTONOMIC RESEARCH. 2024;34(1):191–201.
IEEE
[1]
R. de C. de Oliveira Collaco et al., “Anxiety and dysautonomia symptoms in patients with a NaV1.7 mutation and the potential benefits of low-dose short-acting guanfacine,” CLINICAL AUTONOMIC RESEARCH, vol. 34, no. 1, pp. 191–201, 2024.
@article{01HGZ7J96B8A243NEXY1TVPKJC,
  abstract     = {{Purpose: Guanfacine is an alpha(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(V)1.7 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(V)1.7 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(V)1.7 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.}},
  author       = {{de Oliveira Collaco, Rita de Cassia and Lammens, Maxime and Blevins, Carley and Rodgers, Kristen and Gurau, Andrei and Yamauchi, Suguru and Kim, Christine and Forrester, Jeannine and Liu, Edward and Ha, Jinny and Mei, Yuping and Boehm, Corrine and Wohler, Elizabeth and Sobreira, Nara and Rowe, Peter and Valle, David and Brock, Malcolm V and Bosmans, Frank}},
  issn         = {{0959-9851}},
  journal      = {{CLINICAL AUTONOMIC RESEARCH}},
  keywords     = {{Guanfacine,Na(V)1.7,Anxiety,Voltage-gated sodium channel,Dysautonomia}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{191--201}},
  title        = {{Anxiety and dysautonomia symptoms in patients with a NaV1.7 mutation and the potential benefits of low-dose short-acting guanfacine}},
  url          = {{http://doi.org/10.1007/s10286-023-01004-1}},
  volume       = {{34}},
  year         = {{2024}},
}
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