Skip to main content

Main menu

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • For authors
    • Instructions for authors
    • Submit a manuscript
    • Author FAQs
    • Open access
    • COVID-19 submission information
  • Alerts
  • Podcasts
  • Subscriptions
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

User menu

  • Log in
  • Subscribe
  • Contact Us
  • My Cart

Search

  • Advanced search
  • ERS Publications
    • European Respiratory Journal
    • ERJ Open Research
    • European Respiratory Review
    • Breathe
    • ERS Books
    • ERS publications home

Login

European Respiratory Society

Advanced Search

  • Home
  • Current issue
  • ERJ Early View
  • Past issues
  • For authors
    • Instructions for authors
    • Submit a manuscript
    • Author FAQs
    • Open access
    • COVID-19 submission information
  • Alerts
  • Podcasts
  • Subscriptions

Pulmonary arterial hypertension in familial hemiplegic migraine with ATP1A2 channelopathy

David Montani, Barbara Girerd, Sven Günther, Florence Riant, Elisabeth Tournier-Lasserve, Laurent Magy, Nizar Maazi, Christophe Guignabert, Laurent Savale, Olivier Sitbon, Gérald Simonneau, Florent Soubrier, Marc Humbert
European Respiratory Journal 2014 43: 641-643; DOI: 10.1183/09031936.00147013
David Montani
1Université Paris-Sud, Le Kremlin-Bicêtre
2Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, DHU Thorax Innovation (DHU TORINO), Hôpital Bicêtre, Le Kremlin-Bicêtre
3Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche en Santé (UMR_S) 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: david.montani@bct.aphp.fr
Barbara Girerd
1Université Paris-Sud, Le Kremlin-Bicêtre
2Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, DHU Thorax Innovation (DHU TORINO), Hôpital Bicêtre, Le Kremlin-Bicêtre
3Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche en Santé (UMR_S) 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sven Günther
1Université Paris-Sud, Le Kremlin-Bicêtre
2Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, DHU Thorax Innovation (DHU TORINO), Hôpital Bicêtre, Le Kremlin-Bicêtre
3Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche en Santé (UMR_S) 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Florence Riant
4Service de Génétique Neuro-Vasculaire, AP-HP, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de L’Œil, Groupe Hospitalier Lariboisière – Fernand Widal, Paris
5INSERM UMR_S 740, Université Paris Diderot, Sorbonne Paris Cité, Paris
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elisabeth Tournier-Lasserve
4Service de Génétique Neuro-Vasculaire, AP-HP, Centre de Référence des Maladies Vasculaires Rares du Cerveau et de L’Œil, Groupe Hospitalier Lariboisière – Fernand Widal, Paris
5INSERM UMR_S 740, Université Paris Diderot, Sorbonne Paris Cité, Paris
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laurent Magy
6Service de Neurologie, CHU de Limoges, Hôpital Dupuytren, Limoges
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nizar Maazi
7Service de Cardiologie, CHU de Limoges, Hôpital Dupuytren, Limoges
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Christophe Guignabert
1Université Paris-Sud, Le Kremlin-Bicêtre
2Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, DHU Thorax Innovation (DHU TORINO), Hôpital Bicêtre, Le Kremlin-Bicêtre
3Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche en Santé (UMR_S) 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Laurent Savale
1Université Paris-Sud, Le Kremlin-Bicêtre
2Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, DHU Thorax Innovation (DHU TORINO), Hôpital Bicêtre, Le Kremlin-Bicêtre
3Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche en Santé (UMR_S) 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Olivier Sitbon
1Université Paris-Sud, Le Kremlin-Bicêtre
2Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, DHU Thorax Innovation (DHU TORINO), Hôpital Bicêtre, Le Kremlin-Bicêtre
3Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche en Santé (UMR_S) 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Gérald Simonneau
1Université Paris-Sud, Le Kremlin-Bicêtre
2Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, DHU Thorax Innovation (DHU TORINO), Hôpital Bicêtre, Le Kremlin-Bicêtre
3Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche en Santé (UMR_S) 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Florent Soubrier
8UMR_S 956, Université Pierre & Marie Curie (UPMC), Université Paris 06, INSERM, Paris
9Genetics Dept, Hôpital Pitié-Salpêtrière, AP-HP, Paris
10Institute for Cardiometabolism and Nutrition (ICAN), Paris, France
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marc Humbert
1Université Paris-Sud, Le Kremlin-Bicêtre
2Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, DHU Thorax Innovation (DHU TORINO), Hôpital Bicêtre, Le Kremlin-Bicêtre
3Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche en Santé (UMR_S) 999, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

To the Editor:

Pulmonary arterial hypertension (PAH) has been the focus of major research in recent years [1]. Involvement of mutations in genes encoding for members of the transforming growth factor-β signalling pathway (BMPR2, ACVRL1, ENG and SMAD8) has been demonstrated in the development of heritable PAH, allowing novel experimental and clinical approaches [2–4]. However, ∼30% of familial forms of PAH remain without any identification of genetic mutations. Recently, mutations of the KCNK3 gene (encoding K+ channel subfamily K member 3) have been reported in patients with familial and sporadic PAH [5]. KCNK3 belongs to a family of mammalian K+ channels, and are involved in the regulation of resting membrane potential, pulmonary vascular tone and in vascular remodelling. This result paves the way to the involvement of novel signalling pathways in the development of heritable PAH. Herein, we describe a novel association of PAH and a channelopathy due to mutation in ATP1A2 (encoding the α2-subunit of the Na+/K+-ATPase), a mutation known to cause familial hemiplegic migraine (FHM), a rare autosomal dominant disease [6].

A 24-year-old male was referred with a 1-year history of progressive exertional dyspnoea. Since the age of 8 years, he has reported recurrent episodes of hemiplegic migraine associated with muscle weakness and pain. The proband’s mother (II4) (fig. 1) and two of his brothers (III6 and III7) had recurrent hemiplegic migraine with aura. There was no familial history of PAH. On admission, the patient was in New York Heart Association (NYHA) functional class III. His 6-min walk distance (6MWD) was 409 m. Pulmonary function tests were normal except for decreased diffusing capacity of the lungs for carbon monoxide. Doppler transthoracic echocardiography revealed signs of severe pulmonary hypertension with an estimated systolic pulmonary artery pressure of 75 mmHg, right ventricular dilatation and hypertrophy, and mild pericardial effusion. Right heart catheterisation confirmed pre-capillary pulmonary hypertension, with a mean pulmonary artery pressure (mPAP) of 51 mmHg, a pulmonary capillary wedge pressure of 12 mmHg, a right atrial pressure of 7 mmHg, a cardiac index of 1.90 L·min−1·m−2 and pulmonary vascular resistance (PVR) of 12.3 Wood units. No acute vasodilator response to nitric oxide was observed. Screening for other causes of pulmonary hypertension was negative. The patient was treated with a combination of intravenous epoprostenol, an endothelin receptor antagonist (ERA) and a phosphodiesterase type 5 inhibitor (PDE5i). The patient stopped taking the PDE5i after a few days because of side-effects, including increased symptoms of migraine. 4 months later, re-evaluation showed moderate clinical (NYHA functional class II and 6MWD 518 m) and haemodynamic improvement (mPAP 43 mmHg, cardiac index 2.29 L·min−1·m−2 and PVR 8.4 Wood units). The patient is still alive 1 year after diagnosis on intravenous epoprostenol and an ERA.

Figure 1–
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1–

Family tree. Ages indicated are those at pulmonary arterial hypertension (PAH) diagnosis or the beginning of familial hemiplegic migraine (FHM) symptoms. Arrow: proband.

According to our local procedures, the patient underwent genetic counselling and gave written informed consent for genetic screening. No point mutations or large rearrangements of the BMPR2 and ACVRL1 genes were identified. To date, three genes (CACNA1A, ATP1A2 and SCNA1) encoding ion transporters are known to be associated with FHM. Genetic analysis revealed a nucleotide substitution in the coding sequence of the ATP1A2 gene (c.2819C>T; p.S940L) located on chromosome 1 (1q23). This mutation, which was not found in 200 control chromosomes, and was absent from the dbSNP, 1000 Genomes and Exome Sequencing Project data, affects a highly conserved amino acid, but has never been reported before. The patient’s brothers, III4 and III6, were screened for the familial ATP1A2 mutation. Patient III4 did not carry the familial mutation and, as suggested by the clinical symptoms, the mutation was identified in patient III6 (fig. 1). Mutations of the ATP1A2 gene are known to cause FHM, a rare autosomal dominant disease characterised by migraine with motor weakness and aura [6]. Other neurological symptoms include various types of epileptic seizures and intellectual deficit; permanent cerebellar signs may be present in patients carrying a CACNA1A mutation [6]. FHM has an estimated prevalence of one in 20 000, 20–30% of cases carrying an ATP1A2 mutation [6]. In France, only 216 FHM patients (126 families) carry an ATP1A2 mutation (unpublished data).

The association of two rare diseases (PAH and FHM) supports the hypothesis of a potential common pathophysiological link. It is important to note that the presence and the activity of the α2-subunit of the Na+/K+-ATPase in lung and, more particularly, in pulmonary vascular smooth muscle cells have been previously reported [7]. In addition, several studies have reported substantial decreases in expression and/or activity of different types of K+ channels in pulmonary arterial smooth muscle cells of patients displaying idiopathic PAH, together with abnormalities in resting membrane potential and Ca2+ homeostasis [8]. Furthermore, pulmonary hypertension improvement has been demonstrated by restoring the expression of K+ channels in a chronic hypoxic pulmonary hypertension rodent model (by treatment with a voltage-gated K+ (KV) channel activator or by gene transfer using adenovirus carrying the human KV1.5 gene (KCNA5)) [9, 10]. The chemical gradient produced by the normal activity of the Na+/K+-ATPase is important for restoration of low intracellular Ca2+ concentration. Inhibition of K+ channels leads to an increase in intracellular Ca2+ concentration, which is a major stimulus for cell growth, migration and vasoconstriction [11]. Notably, inhibition of the Na+/K+-ATPase by ouabain rapidly activates the Ras/mitogen-activated protein kinase (MAPK) signalling pathway, leading to the proliferation of cultured vascular smooth cells [12, 13]. Interestingly, we have reported eight cases of neurofibromatosis type 1 and one case of Cowden syndrome associated with pre-capillary pulmonary hypertension [14]. Neurofibromatosis type 1 and Cowden syndrome are due to mutations in the NF1 and PTEN genes, respectively, leading to the activation of the Ras/MAPK signalling pathway and proliferation. Finally, it has been demonstrated that a decreased activity of K+ channels can inhibit apoptosis by attenuating the activity of intracellular caspases [11]. Altogether, these observations support a possible role of mutations in ATP1A2 gene in the development of PAH through the disturbance of intracellular Ca2+ and K+ concentrations.

We thus suggest that mutations in the ATP1A2 gene may contribute to pulmonary arterial remodelling and PAH. However, we must emphasise that our report of a single family remains hypothesis-generating and requires future additional information. Importantly, no other families with mutations in ATP1A2 with a history of PAH have been reported to date. In addition, within the present family, the phenotype of FHM segregates with the ATP1A2 mutation, but only one member has PAH. While this family is intriguing, it remains possible that PAH is unrelated to the ATP1A2 mutation or FHM. Although these are both rare diseases, there is a small number of patients who do have coincidental rare diseases. In the future, our task will be to demonstrate the presence of ATP1A2 mutations in other individuals with PAH and/or functionally demonstrate how the mutation may affect the pulmonary vasculature. Similarly, patients displaying hereditary haemorrhagic telangiectasia and PAH have been very rarely reported in the past. Currently, <50 heritable PAH cases have been reported in ACVRL1 mutation carriers, while most mutation carriers develop hereditary haemorrhagic telangiectasia by the age of 60 years, emphasising that a single gene may cause different vascular diseases, alone or in combination, with markedly different penetrance [15]. In conclusion, our present case report reinforces the potential interest of ion channels in the pathogenesis of PAH.

Acknowledgments

The authors thank M. Eyries (Laboratoire d’Oncogénétique et Angiogénétique Moléculaire, Groupe Hospitalier Pitié-Salpétrière, Paris, France) for the genetic analysis of BMPR2 and ACVRL1.

Footnotes

  • Conflict of interest: Disclosures can be found alongside the online version of this article at www.erj.ersjournals.com

  • Received August 22, 2013.
  • Accepted September 24, 2013.
  • ©ERS 2014

References

  1. ↵
    1. Voelkel NF,
    2. Gomez-Arroyo J,
    3. Abbate A,
    4. et al
    . Pathobiology of pulmonary arterial hypertension and right ventricular failure. Eur Respir J 2012; 40: 1555–1565.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. Liu D,
    2. Liu QQ,
    3. Eyries M,
    4. et al
    . Molecular genetics and clinical features of Chinese idiopathic and heritable pulmonary arterial hypertension patients. Eur Respir J 2012; 39: 597–603.
    OpenUrlAbstract/FREE Full Text
    1. Frydman N,
    2. Steffann J,
    3. Girerd B,
    4. et al
    . Pre-implantation genetic diagnosis in pulmonary arterial hypertension due to BMPR2 mutation. Eur Respir J 2012; 39: 1534–1535.
    OpenUrlFREE Full Text
  3. ↵
    1. Reynolds AM,
    2. Holmes MD,
    3. Danilov SM,
    4. et al
    . Targeted gene delivery of BMPR2 attenuates pulmonary hypertension. Eur Respir J 2012; 39: 329–343.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    1. Ma L,
    2. Roman-Campos D,
    3. Austin ED,
    4. et al
    . A novel channelopathy in pulmonary arterial hypertension. N Engl J Med 2013; 369: 351–361.
    OpenUrlCrossRefPubMedWeb of Science
  5. ↵
    1. Russell MB,
    2. Ducros A
    . Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis, and management. Lancet Neurol 2011; 10: 457–470.
    OpenUrlCrossRefPubMedWeb of Science
  6. ↵
    1. Ghosh B,
    2. Kar P,
    3. Mandal A,
    4. et al
    . Ca2+ influx mechanisms in caveolae vesicles of pulmonary smooth muscle plasma membrane under inhibition of α2β1 isozyme of Na+/K+-ATPase by ouabain. Life Sci 2009; 84: 139–148.
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Yuan JX,
    2. Aldinger AM,
    3. Juhaszova M,
    4. et al
    . Dysfunctional voltage-gated K+ channels in pulmonary artery smooth muscle cells of patients with primary pulmonary hypertension. Circulation 1998; 98: 1400–1406.
    OpenUrlAbstract/FREE Full Text
  8. ↵
    1. Morecroft I,
    2. Murray A,
    3. Nilsen M,
    4. et al
    . Treatment with the Kv7 potassium channel activator flupirtine is beneficial in two independent mouse models of pulmonary hypertension. Br J Pharmacol 2009; 157: 1241–1249.
    OpenUrlCrossRefPubMedWeb of Science
  9. ↵
    1. Pozeg ZI,
    2. Michelakis ED,
    3. McMurtry MS,
    4. et al
    . In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats. Circulation 2003; 107: 2037–2044.
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Kuhr FK,
    2. Smith KA,
    3. Song MY,
    4. et al
    . New mechanisms of pulmonary arterial hypertension: role of Ca2+ signaling. Am J Physiol Heart Circ Physiol 2012; 302: H1546–H1562.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Aydemir-Koksoy A,
    2. Abramowitz J,
    3. Allen JC
    . Ouabain-induced signaling and vascular smooth muscle cell proliferation. J Biol Chem 2001; 276: 46605–46611.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    1. Kometiani P,
    2. Li J,
    3. Gnudi L,
    4. et al
    . Multiple signal transduction pathways link Na+/K+-ATPase to growth-related genes in cardiac myocytes. The roles of Ras and mitogen-activated protein kinases. J Biol Chem 1998; 273: 15249–15256.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Montani D,
    2. Coulet F,
    3. Girerd B,
    4. et al
    . Pulmonary hypertension in patients with neurofibromatosis type I. Medicine (Baltimore) 2011; 90: 201–211.
    OpenUrlCrossRefPubMedWeb of Science
  14. ↵
    1. Girerd B,
    2. Montani D,
    3. Coulet F,
    4. et al
    . Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med 2010; 181: 851–861.
    OpenUrlCrossRefPubMedWeb of Science
View Abstract
PreviousNext
Back to top
View this article with LENS
Vol 43 Issue 2 Table of Contents
European Respiratory Journal: 43 (2)
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
Email

Thank you for your interest in spreading the word on European Respiratory Society .

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Pulmonary arterial hypertension in familial hemiplegic migraine with ATP1A2 channelopathy
(Your Name) has sent you a message from European Respiratory Society
(Your Name) thought you would like to see the European Respiratory Society web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Print
Alerts
Sign In to Email Alerts with your Email Address
Citation Tools
Pulmonary arterial hypertension in familial hemiplegic migraine with ATP1A2 channelopathy
David Montani, Barbara Girerd, Sven Günther, Florence Riant, Elisabeth Tournier-Lasserve, Laurent Magy, Nizar Maazi, Christophe Guignabert, Laurent Savale, Olivier Sitbon, Gérald Simonneau, Florent Soubrier, Marc Humbert
European Respiratory Journal Feb 2014, 43 (2) 641-643; DOI: 10.1183/09031936.00147013

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero

Share
Pulmonary arterial hypertension in familial hemiplegic migraine with ATP1A2 channelopathy
David Montani, Barbara Girerd, Sven Günther, Florence Riant, Elisabeth Tournier-Lasserve, Laurent Magy, Nizar Maazi, Christophe Guignabert, Laurent Savale, Olivier Sitbon, Gérald Simonneau, Florent Soubrier, Marc Humbert
European Respiratory Journal Feb 2014, 43 (2) 641-643; DOI: 10.1183/09031936.00147013
del.icio.us logo Digg logo Reddit logo Technorati logo Twitter logo CiteULike logo Connotea logo Facebook logo Google logo Mendeley logo
Full Text (PDF)

Jump To

  • Article
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF

Subjects

  • Pulmonary vascular disease
  • Tweet Widget
  • Facebook Like
  • Google Plus One

More in this TOC Section

Agora

  • Ivacaftor modifies cystic fibrosis neutrophil phenotype
  • Serum mitochondrial DNA predicts exacerbation and progression of IPF
  • CTEPH and totally implantable central venous access systems
Show more Agora

Research letters

  • CTEPH and totally implantable central venous access systems
  • Ivacaftor modifies cystic fibrosis neutrophil phenotype
  • Serum mitochondrial DNA predicts exacerbation and progression of IPF
Show more Research letters

Related Articles

Navigate

  • Home
  • Current issue
  • Archive

About the ERJ

  • Journal information
  • Editorial board
  • Reviewers
  • CME
  • Press
  • Permissions and reprints
  • Advertising

The European Respiratory Society

  • Society home
  • myERS
  • Privacy policy
  • Accessibility

ERS publications

  • European Respiratory Journal
  • ERJ Open Research
  • European Respiratory Review
  • Breathe
  • ERS books online
  • ERS Bookshop

Help

  • Feedback

For authors

  • Instructions for authors
  • Submit a manuscript
  • ERS author centre

For readers

  • Alerts
  • Subjects
  • Podcasts
  • RSS

Subscriptions

  • Accessing the ERS publications

Contact us

European Respiratory Society
442 Glossop Road
Sheffield S10 2PX
United Kingdom
Tel: +44 114 2672860
Email: journals@ersnet.org

ISSN

Print ISSN:  0903-1936
Online ISSN: 1399-3003

Copyright © 2021 by the European Respiratory Society