Anne Koy1, Sebahattin Cirak2, Victoria Gonzalez3, Kerstin Becker4, Thomas Roujeau5, Christophe Milesi6, Julien Baleine6, Gilles Cambonie6, Alain Boularan7, Frederic Greco7, Pierre-Francois Perrigault7, Claude Cances8, Nathalie Dorison9, Diane Doummar10, Agathe Roubertie11, Christophe Beroud12, Friederike Körber13, Burkhard Stüve14, Stephan Waltz14, Cyril Mignot15, Caroline Nava15, Mohammad Maarouf16, Philippe Coubes3, Laura Cif17. 1. Department of Pediatrics, University Hospital Cologne, Germany. Electronic address: anne.koy@uk-koeln.de. 2. Department of Pediatrics, University Hospital Cologne, Germany; Center for Molecular Medicine, University of Cologne, Germany. Electronic address: sebahattin.cirak@uk-koeln.de. 3. Département de Neurochirurgie, Centre Hospitalier Régional Montpellier, France; Unité de Recherche sur les Comportements et Mouvements Anormaux (URCMA), France; UMR 5203 CNRS-U1191 INSERM-UM-Institut de Génomique Fonctionnelle - IGF, Montpellier, France. 4. Department of Pediatrics, University Hospital Cologne, Germany; Center for Molecular Medicine, University of Cologne, Germany. 5. Département de Neurochirurgie, Centre Hospitalier Régional Montpellier, France. 6. Département Pédiatrie néonatale et réanimations, Centre Hospitalier Universitaire Montpellier, France. 7. Anesthésie-Réanimation Gui de Chauliac, Centre Hospitalier Universitaire Montpellier, France. 8. Service de Pédiatrie-Neurologie et infectiologie, CHU de Toulouse-Hôpital des Enfants, Toulouse, France. 9. Service de Neurochirurgie, Fondation Ophtalmologique Rothschild, Paris, France. 10. Service de Neuropédiatrie-Unité de neuropédiatrie et pathologie du développement, Service de Neuropédiatrie et Génétique-CR Cervelet, CHU Paris Est-Hôpital Armand-Trousseau, Paris, France. 11. Département de Neuropédiarie, Centre Hospitalier Universitaire Montpellier, France; INSERM U1051, Institut des Neurosciences de Montpellier, Montpellier, France. 12. Inserm, UMR_S 910, Marseille, France; Aix Marseille Université, Marseille, France; AP-HM, Hôpital d'Enfants de la Timone, Département de génétique Médicale, Marseille, France. 13. Department of Pediatric Radiology, University Hospital of Cologne, Germany. 14. Children's Hospital Amsterdamer Straße, Kliniken der Stadt Köln, Cologne, Germany. 15. APHP, Département de Génétique, Hôpital de la Pitié Salpêtriere, Centre de Référence « Déficience Intellectuelle de Causes Rares », Paris, France. 16. Department for Stereotaxy and Functional Neurosurgery, Cologne-Merheim Medical Center, University of Witten/Herdecke, Germany. 17. Département de Neurochirurgie, Centre Hospitalier Régional Montpellier, France; Unité de Recherche sur les Comportements et Mouvements Anormaux (URCMA), France; UMR 5203 CNRS-U1191 INSERM-UM-Institut de Génomique Fonctionnelle - IGF, Montpellier, France. Electronic address: A-CIF@chu-montpellier.fr.
Abstract
BACKGROUND: Exacerbation of hyperkinesia is a life-threatening complication of dyskinetic movement disorders, which can lead to multi-organ failure and even to death. GNAO1 has been recently identified to be involved in the pathogenesis of early infantile epileptic encephalopathy and movement disorders. Patients with GNAO1 mutations can present with a severe, progressive hyperkinetic movement disorder with prolonged life-threatening exacerbations, which are refractory to most anti-dystonic medication. OBJECTIVE: The objective was to investigate the evolution of symptoms and the response to deep brain stimulation of the globus pallidus internus (GPi-DBS) in patients with different GNAO1 mutations. METHODS: We report six patients presenting with global motor retardation, reduced muscle tone and recurrent episodes of severe, life-threatening hyperkinesia with dystonia, choreoathetosis, and ballism since early childhood. Five of them underwent GPi-DBS. RESULTS: The genetic workup revealed mutations in GNAO1 for all six patients. These encompass a new splice site mutation (c.723+1G>T) in patient 1, a new missense mutation (c.610G>C; p.Gly204Arg) in patient 2, a heterozygous mutation (c.625>T; p.Arg209Cys) in patients 3 and 4, and a heterozygous mutation (c.709G>A; p.Glu237Lys) in patients 5 and 6. By intervention with GPi-DBS the severe paroxysmal hyperkinetic exacerbations could be stopped in five patients. One patient is still under evaluation for neuromodulation. CONCLUSION: In complex movement disorders of unsolved etiology clinical WES can rapidly streamline pathogenic genes. We identified two novel GNAO1 mutations. GPi-DBS can be an effective and life-saving treatment option for patients with GNAO1 mutations and has to be considered early.
BACKGROUND: Exacerbation of hyperkinesia is a life-threatening complication of dyskinetic movement disorders, which can lead to multi-organ failure and even to death. GNAO1 has been recently identified to be involved in the pathogenesis of early infantile epilepticencephalopathy and movement disorders. Patients with GNAO1 mutations can present with a severe, progressive hyperkinetic movement disorder with prolonged life-threatening exacerbations, which are refractory to most anti-dystonic medication. OBJECTIVE: The objective was to investigate the evolution of symptoms and the response to deep brain stimulation of the globus pallidus internus (GPi-DBS) in patients with different GNAO1 mutations. METHODS: We report six patients presenting with global motor retardation, reduced muscle tone and recurrent episodes of severe, life-threatening hyperkinesia with dystonia, choreoathetosis, and ballism since early childhood. Five of them underwent GPi-DBS. RESULTS: The genetic workup revealed mutations in GNAO1 for all six patients. These encompass a new splice site mutation (c.723+1G>T) in patient 1, a new missense mutation (c.610G>C; p.Gly204Arg) in patient 2, a heterozygous mutation (c.625>T; p.Arg209Cys) in patients 3 and 4, and a heterozygous mutation (c.709G>A; p.Glu237Lys) in patients 5 and 6. By intervention with GPi-DBS the severe paroxysmal hyperkinetic exacerbations could be stopped in five patients. One patient is still under evaluation for neuromodulation. CONCLUSION: In complex movement disorders of unsolved etiology clinical WES can rapidly streamline pathogenic genes. We identified two novel GNAO1 mutations. GPi-DBS can be an effective and life-saving treatment option for patients with GNAO1 mutations and has to be considered early.
Authors: Erin A Yamamoto; Megan Berry; William Harris; Maryam N Shahin; Jenny L Wilson; Delaram Safarpour; Ahmed M Raslan Journal: Mov Disord Clin Pract Date: 2021-12-21
Authors: Sara A Lewis; Sheetal Shetty; Bryce A Wilson; Aris J Huang; Sheng Chih Jin; Hayley Smithers-Sheedy; Michael C Fahey; Michael C Kruer Journal: Front Neurol Date: 2021-01-21 Impact factor: 4.003
Authors: Laura Cif; Diane Demailly; Jean-Pierre Lin; Katy E Barwick; Mario Sa; Lucia Abela; Sony Malhotra; Wui K Chong; Dora Steel; Alba Sanchis-Juan; Adeline Ngoh; Natalie Trump; Esther Meyer; Xavier Vasques; Julia Rankin; Meredith W Allain; Carolyn D Applegate; Sanaz Attaripour Isfahani; Julien Baleine; Bettina Balint; Jennifer A Bassetti; Emma L Baple; Kailash P Bhatia; Catherine Blanchet; Lydie Burglen; Gilles Cambonie; Emilie Chan Seng; Sandra Chantot Bastaraud; Fabienne Cyprien; Christine Coubes; Vincent d'Hardemare; Asif Doja; Nathalie Dorison; Diane Doummar; Marisela E Dy-Hollins; Ellyn Farrelly; David R Fitzpatrick; Conor Fearon; Elizabeth L Fieg; Brent L Fogel; Eva B Forman; Rachel G Fox; William A Gahl; Serena Galosi; Victoria Gonzalez; Tracey D Graves; Allison Gregory; Mark Hallett; Harutomo Hasegawa; Susan J Hayflick; Ada Hamosh; Marie Hully; Sandra Jansen; Suh Young Jeong; Joel B Krier; Sidney Krystal; Kishore R Kumar; Chloé Laurencin; Hane Lee; Gaetan Lesca; Laurence Lion François; Timothy Lynch; Neil Mahant; Julian A Martinez-Agosto; Christophe Milesi; Kelly A Mills; Michel Mondain; Hugo Morales-Briceno; John R Ostergaard; Swasti Pal; Juan C Pallais; Frédérique Pavillard; Pierre-Francois Perrigault; Andrea K Petersen; Gustavo Polo; Gaetan Poulen; Tuula Rinne; Thomas Roujeau; Caleb Rogers; Agathe Roubertie; Michelle Sahagian; Elise Schaefer; Laila Selim; Richard Selway; Nutan Sharma; Rebecca Signer; Ariane G Soldatos; David A Stevenson; Fiona Stewart; Michel Tchan; Ishwar C Verma; Bert B A de Vries; Jenny L Wilson; Derek A Wong; Raghda Zaitoun; Dolly Zhen; Anna Znaczko; Russell C Dale; Claudio M de Gusmão; Jennifer Friedman; Victor S C Fung; Mary D King; Shekeeb S Mohammad; Luis Rohena; Jeff L Waugh; Camilo Toro; F Lucy Raymond; Maya Topf; Philippe Coubes; Kathleen M Gorman; Manju A Kurian Journal: Brain Date: 2020-12-05 Impact factor: 13.501