Heather E Olson1,2, McKenna Kelly1, Christopher M LaCoursiere1, Rebecca Pinsky1, Dimira Tambunan1, Catherine Shain1,3, Sriram Ramgopal1,4, Masanori Takeoka2,5, Mark H Libenson2,5, Kristina Julich6, Tobias Loddenkemper2,5, Eric D Marsh7, Devorah Segal8,9, Susan Koh10, Michael S Salman11, Alex R Paciorkowski12, Edward Yang2,13, Ann M Bergin2,5, Beth Rosen Sheidley1, Annapurna Poduri1,2. 1. Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA. 2. Harvard Medical School, Boston, MA. 3. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA. 4. Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA. 5. Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA. 6. Department of Neurology, Boston Children's Hospital, Boston, MA. 7. Neurogenetics Program, Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA. 8. Department of Neurology, Rutgers New Jersey Medical School, Newark, NJ. 9. Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York, NY. 10. Department of Pediatrics and Neurology, Children's Hospital of Colorado, Aurora, CO. 11. Section of Pediatric Neurology, Winnipeg Children's Hospital and Department of Pediatrics and Child Health, College of Medicine, Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada. 12. Departments of Genetics and Neurology, University of Rochester, Rochester, NY. 13. Department of Radiology, Boston Children's Hospital, Boston, MA.
Abstract
OBJECTIVE: We sought to identify genetic causes of early onset epileptic encephalopathies with burst suppression (Ohtahara syndrome and early myoclonic encephalopathy) and evaluate genotype-phenotype correlations. METHODS: We enrolled 33 patients with a referral diagnosis of Ohtahara syndrome or early myoclonic encephalopathy without malformations of cortical development. We performed detailed phenotypic assessment including seizure presentation, electroencephalography, and magnetic resonance imaging. We confirmed burst suppression in 28 of 33 patients. Research-based exome sequencing was performed for patients without a previously identified molecular diagnosis from clinical evaluation or a research-based epilepsy gene panel. RESULTS: In 17 of 28 (61%) patients with confirmed early burst suppression, we identified variants predicted to be pathogenic in KCNQ2 (n = 10), STXBP1 (n = 2), SCN2A (n = 2), PNPO (n = 1), PIGA (n = 1), and SEPSECS (n = 1). In 3 of 5 (60%) patients without confirmed early burst suppression, we identified variants predicted to be pathogenic in STXBP1 (n = 2) and SCN2A (n = 1). The patient with the homozygous PNPO variant had a low cerebrospinal fluid pyridoxal-5-phosphate level. Otherwise, no early laboratory or clinical features distinguished the cases associated with pathogenic variants in specific genes from each other or from those with no prior genetic cause identified. INTERPRETATION: We characterize the genetic landscape of epileptic encephalopathy with burst suppression, without brain malformations, and demonstrate feasibility of genetic diagnosis with clinically available testing in >60% of our cohort, with KCNQ2 implicated in one-third. This electroclinical syndrome is associated with pathogenic variation in SEPSECS. Ann Neurol 2017;81:419-429.
OBJECTIVE: We sought to identify genetic causes of early onset epilepticencephalopathies with burst suppression (Ohtahara syndrome and early myoclonic encephalopathy) and evaluate genotype-phenotype correlations. METHODS: We enrolled 33 patients with a referral diagnosis of Ohtahara syndrome or early myoclonic encephalopathy without malformations of cortical development. We performed detailed phenotypic assessment including seizure presentation, electroencephalography, and magnetic resonance imaging. We confirmed burst suppression in 28 of 33 patients. Research-based exome sequencing was performed for patients without a previously identified molecular diagnosis from clinical evaluation or a research-based epilepsy gene panel. RESULTS: In 17 of 28 (61%) patients with confirmed early burst suppression, we identified variants predicted to be pathogenic in KCNQ2 (n = 10), STXBP1 (n = 2), SCN2A (n = 2), PNPO (n = 1), PIGA (n = 1), and SEPSECS (n = 1). In 3 of 5 (60%) patients without confirmed early burst suppression, we identified variants predicted to be pathogenic in STXBP1 (n = 2) and SCN2A (n = 1). The patient with the homozygous PNPO variant had a low cerebrospinal fluid pyridoxal-5-phosphate level. Otherwise, no early laboratory or clinical features distinguished the cases associated with pathogenic variants in specific genes from each other or from those with no prior genetic cause identified. INTERPRETATION: We characterize the genetic landscape of epilepticencephalopathy with burst suppression, without brain malformations, and demonstrate feasibility of genetic diagnosis with clinically available testing in >60% of our cohort, with KCNQ2 implicated in one-third. This electroclinical syndrome is associated with pathogenic variation in SEPSECS. Ann Neurol 2017;81:419-429.
Authors: Sarah Weckhuysen; Simone Mandelstam; Arvid Suls; Dominique Audenaert; Tine Deconinck; Lieve R F Claes; Liesbet Deprez; Katrien Smets; Dimitrina Hristova; Iglika Yordanova; Albena Jordanova; Berten Ceulemans; An Jansen; Danièle Hasaerts; Filip Roelens; Lieven Lagae; Simone Yendle; Thorsten Stanley; Sarah E Heron; John C Mulley; Samuel F Berkovic; Ingrid E Scheffer; Peter de Jonghe Journal: Ann Neurol Date: 2012-01 Impact factor: 10.422
Authors: Eric Herlenius; Sarah E Heron; Bronwyn E Grinton; Deborah Keay; Ingrid E Scheffer; John C Mulley; Samuel F Berkovic Journal: Epilepsia Date: 2007-03-26 Impact factor: 5.864
Authors: Heather C Mefford; Hiltrud Muhle; Philipp Ostertag; Sarah von Spiczak; Karen Buysse; Carl Baker; Andre Franke; Alain Malafosse; Pierre Genton; Pierre Thomas; Christina A Gurnett; Stefan Schreiber; Alexander G Bassuk; Michel Guipponi; Ulrich Stephani; Ingo Helbig; Evan E Eichler Journal: PLoS Genet Date: 2010-05-20 Impact factor: 5.917
Authors: Andrew S Allen; Samuel F Berkovic; Patrick Cossette; Norman Delanty; Dennis Dlugos; Evan E Eichler; Michael P Epstein; Tracy Glauser; David B Goldstein; Yujun Han; Erin L Heinzen; Yuki Hitomi; Katherine B Howell; Michael R Johnson; Ruben Kuzniecky; Daniel H Lowenstein; Yi-Fan Lu; Maura R Z Madou; Anthony G Marson; Heather C Mefford; Sahar Esmaeeli Nieh; Terence J O'Brien; Ruth Ottman; Slavé Petrovski; Annapurna Poduri; Elizabeth K Ruzzo; Ingrid E Scheffer; Elliott H Sherr; Christopher J Yuskaitis; Bassel Abou-Khalil; Brian K Alldredge; Jocelyn F Bautista; Samuel F Berkovic; Alex Boro; Gregory D Cascino; Damian Consalvo; Patricia Crumrine; Orrin Devinsky; Dennis Dlugos; Michael P Epstein; Miguel Fiol; Nathan B Fountain; Jacqueline French; Daniel Friedman; Eric B Geller; Tracy Glauser; Simon Glynn; Sheryl R Haut; Jean Hayward; Sandra L Helmers; Sucheta Joshi; Andres Kanner; Heidi E Kirsch; Robert C Knowlton; Eric H Kossoff; Rachel Kuperman; Ruben Kuzniecky; Daniel H Lowenstein; Shannon M McGuire; Paul V Motika; Edward J Novotny; Ruth Ottman; Juliann M Paolicchi; Jack M Parent; Kristen Park; Annapurna Poduri; Ingrid E Scheffer; Renée A Shellhaas; Elliott H Sherr; Jerry J Shih; Rani Singh; Joseph Sirven; Michael C Smith; Joseph Sullivan; Liu Lin Thio; Anu Venkat; Eileen P G Vining; Gretchen K Von Allmen; Judith L Weisenberg; Peter Widdess-Walsh; Melodie R Winawer Journal: Nature Date: 2013-08-11 Impact factor: 49.962
Authors: Heather E Olson; Nolwenn Jean-Marçais; Edward Yang; Delphine Heron; Katrina Tatton-Brown; Paul A van der Zwaag; Emilia K Bijlsma; Bryan L Krock; E Backer; Erik-Jan Kamsteeg; Margje Sinnema; Margot R F Reijnders; David Bearden; Amber Begtrup; Aida Telegrafi; Roelineke J Lunsing; Lydie Burglen; Gaetan Lesca; Megan T Cho; Lacey A Smith; Beth R Sheidley; Christelle Moufawad El Achkar; Phillip L Pearl; Annapurna Poduri; Cara M Skraban; Jennifer Tarpinian; Addie I Nesbitt; Dietje E Fransen van de Putte; Claudia A L Ruivenkamp; Patrick Rump; Nicolas Chatron; Isabelle Sabatier; Julitta De Bellescize; Laurent Guibaud; David A Sweetser; Jessica L Waxler; Klaas J Wierenga; Jean Donadieu; Vinodh Narayanan; Keri M Ramsey; Caroline Nava; Jean-Baptiste Rivière; Antonio Vitobello; Frédéric Tran Mau-Them; Christophe Philippe; Ange-Line Bruel; Yannis Duffourd; Laurel Thomas; Stefan H Lelieveld; Janneke Schuurs-Hoeijmakers; Han G Brunner; Boris Keren; Julien Thevenon; Laurence Faivre; Gary Thomas; Christel Thauvin-Robinet Journal: Am J Hum Genet Date: 2018-04-12 Impact factor: 11.025
Authors: Paolo Ambrosino; Elena Freri; Barbara Castellotti; Maria Virginia Soldovieri; Ilaria Mosca; Laura Manocchio; Cinzia Gellera; Laura Canafoglia; Silvana Franceschetti; Barbara Salis; Nunzio Iraci; Francesco Miceli; Francesca Ragona; Tiziana Granata; Jacopo C DiFrancesco; Maurizio Taglialatela Journal: Mol Neurobiol Date: 2018-01-30 Impact factor: 5.590
Authors: Francisco Almeida Lobo; Susana Vacas; Andrea O Rossetti; Chiara Robba; Fabio Silvio Taccone Journal: Best Pract Res Clin Anaesthesiol Date: 2020-10-31