title: Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Heather E
authors.initials: HE
authors.lastname: Olson
authors.affiliation: Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA.
authors.forename: McKenna
authors.initials: M
authors.lastname: Kelly
authors.affiliation: Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: LaCoursiere
authors.affiliation: Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Pinsky
authors.affiliation: Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA.
authors.forename: Dimira
authors.initials: D
authors.lastname: Tambunan
authors.affiliation: Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA.|Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Shain
authors.affiliation: Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA.|Department of Pediatrics, Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Sriram
authors.initials: S
authors.lastname: Ramgopal
authors.affiliation: Harvard Medical School, Boston, MA.|Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA.
authors.forename: Masanori
authors.initials: M
authors.lastname: Takeoka
authors.affiliation: Harvard Medical School, Boston, MA.|Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Libenson
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, MA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Julich
authors.affiliation: Harvard Medical School, Boston, MA.|Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA.
authors.forename: Tobias
authors.initials: T
authors.lastname: Loddenkemper
authors.affiliation: Neurogenetics Program, Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Marsh
authors.affiliation: Department of Neurology, Rutgers New Jersey Medical School, Newark, NJ.|Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York, NY.
authors.forename: Devorah
authors.initials: D
authors.lastname: Segal
authors.affiliation: Department of Pediatrics and Neurology, Children's Hospital of Colorado, Aurora, CO.
authors.forename: Susan
authors.initials: S
authors.lastname: Koh
authors.affiliation: 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.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Salman
authors.affiliation: Departments of Genetics and Neurology, University of Rochester, Rochester, NY.
authors.forename: Alex R
authors.initials: AR
authors.lastname: Paciorkowski
authors.affiliation: Harvard Medical School, Boston, MA.|Department of Radiology, Boston Children's Hospital, Boston, MA.
authors.forename: Edward
authors.initials: E
authors.lastname: Yang
authors.affiliation: Harvard Medical School, Boston, MA.|Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bergin
authors.affiliation: Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA.
authors.forename: Beth Rosen
authors.initials: BR
authors.lastname: Sheidley
authors.affiliation: Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA.|Harvard Medical School, Boston, MA.
authors.forename: Annapurna
authors.initials: A
authors.lastname: Poduri
mesh_terms: D000293:Adolescent; D000604:Amino Acyl-tRNA Synthetases / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004569:Electroencephalography; D059472:Exome; D005260:Female; D005500:Follow-Up Studies; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051658:KCNQ2 Potassium Channel / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D010641:Phenotype; D013036:Spasms, Infantile / Q000235:genetics* / Q000503:physiopathology*
chemical_list: D051658:KCNQ2 Potassium Channel; C496914:KCNQ2 protein, human; D000604:Amino Acyl-tRNA Synthetases; C542370:O-phosphoseryl-tRNA:selenocysteinyl-tRNA synthase, human