Julien Thevenon1, Gabriel Laurent2,3, Flavie Ader4, Pascal Laforêt5, Didier Klug6, Anju Duva Pentiah6, Laurent Gouya7, Claude Alain Maurage8,9,10, Salem Kacet6, Jean-Christophe Eicher2, Juliette Albuisson11,12,13, Michel Desnos11,12,13, Eric Bieth14, Denis Duboc15, Laurent Martin16, Patricia Réant17, François Picard17, Claire Bonithon-Kopp18, Elodie Gautier18, Christine Binquet18, Christel Thauvin-Robinet1, Laurence Faivre1, Patrice Bouvagnet19, Philippe Charron20,21, Pascale Richard4,21. 1. Centre de Génétique et Centre de Référence "Anomalies du Développement et Syndromes Malformatifs", Hôpital d'Enfants, CHU Dijon, Dijon, France. 2. Service de Rythmologie et Insuffisance Cardiaque, Hôpital du Bocage, Centre Hospitalo-Universitaire de Dijon, Dijon, France. 3. Laboratoire LE2I UMR CNRS 5158, Université de Bourgogne, 9 avenue Alain Savary, Dijon, France. 4. AP-HP, UF Cardiogénétique et Myogénétique, Service de Biochimie Métabolique, Groupe Hospitalier Pitié-Salpêtrière 47-83 boulevard de l'Hôpital, Paris cedex 13 75651, France. 5. AP-HP, Centre de Référence de pathologie neuromusculaire Paris-Est, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France. 6. Hôpital Cardiologique, Bd du Pr Leclercq 59037, Lille, France. 7. INSERM U773, Centre de Recherche Biomédicale Bichat Beaujon CRB3, Université Paris 7 Denis Diderot, site Bichat, Paris, France. 8. Université Lille Nord de France, USDL, EA 1056, Lille F-59000, France. 9. Département de Pathologie, Hôpital Universitaire de Lille, Lille F-59000, France. 10. INSERM U837, Lille F-59000, France. 11. INSERM, UMRS_970, Paris Cardiovascular Research Center, Paris, France. 12. AP-HP, Département de génétique, Hôpital européen Georges-Pompidou, 20, rue Leblanc, Paris 75015, France. 13. Inserm U 633, faculté de médecine, université Paris-5, Paris 75015, France. 14. Department of Medical Genetics, Hôpital Purpan, Toulouse, France. 15. AP-HP, Service de Cardiologie, Hôpital Cochin, Paris, France. 16. Laboratoire d'anatomopathologie, Plateau technique de Biologie, CHU de Dijon, Dijon, France. 17. Service de Cardiologie, Hôpital Haut-Lévèque, Pessac, France. 18. Centre d'investigation clinique-épidémiologie clinique/essais cliniques, CHU, Dijon, France. 19. Service médico-chirurgical Cardiologie Pédiatrique et Congénitale Adulte, Laboratoire Cardiogénétique, CHU de Lyon HCL-GH Est-Hôpital Louis Pradel, 69677 BRON CEDEX, et EA4173 Université Lyon 1 et Hôpital du Nord-Ouest, Lyon, France. 20. AP-HP, Centre de référence des maladies cardiaques héréditaires, Hôpital Ambroise Paré, Boulogne-Billancourt, Université de Versailles Saint Quentin en Yvelines, Paris, France. 21. AP-HP, Centre de référence des maladies cardiaques héréditaires, Inserm UMRS1166, Hôpital de la Pitié-Salpêtrière, Paris, France.
Abstract
AIMS: Mutations in PRKAG2, the gene encoding for the γ2 subunit of 5'-AMP-activated protein kinase (AMPK), are responsible for an autosomal dominant glycogenosis with a cardiac presentation, associating hypertrophic cardiomyopathy (HCM), ventricular pre-excitation (VPE), and progressive heart block. The aim of this study was to perform a retrospective time-to-event study of the clinical manifestations associated with PRKAG2 mutations. METHODS AND RESULTS: A cohort of 34 patients from 9 families was recruited between 2001 and 2010. DNA were sequenced on all exons and flanking sequences of the PRKAG2 gene using Sanger sequencing. Overall, four families carried the recurrent p.Arg302Gln mutation, and the five others carried private mutations among which three had never been reported. In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%. The global survival at 60 years of age was 66%. Thirty-two per cent of patients (N = 10) required a device implantation (5 pacemakers and 5 defibrillators) at a median age of 66 years, and two patients required heart transplant. Only one patient presented with significant skeletal muscle symptoms. No significant differences regarding the occurrence of VPE, ablation complications, or death incidence were observed between different mutations. CONCLUSION: This study of patients with PRKAG2 mutations provides a more comprehensive view of the natural history of this disease and demonstrates a high risk of cardiac complications. Early recognition of this disease appears important to allow an appropriate management. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Mutations in PRKAG2, the gene encoding for the γ2 subunit of 5'-AMP-activated protein kinase (AMPK), are responsible for an autosomal dominant glycogenosis with a cardiac presentation, associating hypertrophic cardiomyopathy (HCM), ventricular pre-excitation (VPE), and progressive heart block. The aim of this study was to perform a retrospective time-to-event study of the clinical manifestations associated with PRKAG2 mutations. METHODS AND RESULTS: A cohort of 34 patients from 9 families was recruited between 2001 and 2010. DNA were sequenced on all exons and flanking sequences of the PRKAG2 gene using Sanger sequencing. Overall, four families carried the recurrent p.Arg302Gln mutation, and the five others carried private mutations among which three had never been reported. In the total cohort, at 40 years of age, the risk of developing HCM was 61%, VPE 70%, conduction block 22%, and sudden cardiac death (SCD) 20%. The global survival at 60 years of age was 66%. Thirty-two per cent of patients (N = 10) required a device implantation (5 pacemakers and 5 defibrillators) at a median age of 66 years, and two patients required heart transplant. Only one patient presented with significant skeletal muscle symptoms. No significant differences regarding the occurrence of VPE, ablation complications, or death incidence were observed between different mutations. CONCLUSION: This study of patients with PRKAG2 mutations provides a more comprehensive view of the natural history of this disease and demonstrates a high risk of cardiac complications. Early recognition of this disease appears important to allow an appropriate management. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Jing Hu; Ben Tang; Jing Wang; Kun Huang; Yan Wang; Shuai Lu; Hnkeshsing Baboo Gowreesunkur; Ya Wang; Di Wu; Henry Anselmo Mayala; Zhao-Hui Wang Journal: Curr Med Sci Date: 2020-07-17
Authors: Dan Hu; Dong Hu; Liwen Liu; Daniel Barr; Yang Liu; Norma Balderrabano-Saucedo; Bo Wang; Feng Zhu; Yumei Xue; Shulin Wu; BaoLiang Song; Heather McManus; Katherine Murphy; Katherine Loes; Arnon Adler; Lorenzo Monserrat; Charles Antzelevitch; Michael H Gollob; Perry M Elliott; Hector Barajas-Martinez Journal: EBioMedicine Date: 2020-04-04 Impact factor: 8.143