Genetics and genotype–phenotype correlations in early onset epileptic encephalopathy with burst suppression
Heather E. Olson MD, MS
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Harvard Medical School, Boston, MA
Search for more papers by this authorMcKenna Kelly BS
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorChristopher M. LaCoursiere MS
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorRebecca Pinsky BS
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorDimira Tambunan BS
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorCatherine Shain MPH
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
Search for more papers by this authorSriram Ramgopal MD
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
Search for more papers by this authorMasanori Takeoka MD
Harvard Medical School, Boston, MA
Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorMark H. Libenson MD
Harvard Medical School, Boston, MA
Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorKristina Julich MD
Department of Neurology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorTobias Loddenkemper MD
Harvard Medical School, Boston, MA
Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorEric D. Marsh MD, PhD
Neurogenetics Program, Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA
Search for more papers by this authorDevorah Segal MD
Department of Neurology, Rutgers New Jersey Medical School, Newark, NJ
Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York, NY
Search for more papers by this authorSusan Koh MD
Department of Pediatrics and Neurology, Children's Hospital of Colorado, Aurora, CO
Search for more papers by this authorMichael S. Salman MBBS, PhD
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
Search for more papers by this authorAlex R. Paciorkowski MD, PhD
Departments of Genetics and Neurology, University of Rochester, Rochester, NY
Search for more papers by this authorEdward Yang MD, PhD
Harvard Medical School, Boston, MA
Department of Radiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorAnn M. Bergin MB, ScM
Harvard Medical School, Boston, MA
Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorBeth Rosen Sheidley MS, CGC
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorCorresponding Author
Annapurna Poduri MD, MPH
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Harvard Medical School, Boston, MA
Address correspondence to Dr Poduri, Fegan 9, Neurology, Mail Stop 3063, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: [email protected]Search for more papers by this authorHeather E. Olson MD, MS
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Harvard Medical School, Boston, MA
Search for more papers by this authorMcKenna Kelly BS
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorChristopher M. LaCoursiere MS
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorRebecca Pinsky BS
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorDimira Tambunan BS
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorCatherine Shain MPH
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
Search for more papers by this authorSriram Ramgopal MD
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
Search for more papers by this authorMasanori Takeoka MD
Harvard Medical School, Boston, MA
Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorMark H. Libenson MD
Harvard Medical School, Boston, MA
Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorKristina Julich MD
Department of Neurology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorTobias Loddenkemper MD
Harvard Medical School, Boston, MA
Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorEric D. Marsh MD, PhD
Neurogenetics Program, Department of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA
Search for more papers by this authorDevorah Segal MD
Department of Neurology, Rutgers New Jersey Medical School, Newark, NJ
Department of Pediatrics, Division of Pediatric Neurology, Weill Cornell Medicine, New York, NY
Search for more papers by this authorSusan Koh MD
Department of Pediatrics and Neurology, Children's Hospital of Colorado, Aurora, CO
Search for more papers by this authorMichael S. Salman MBBS, PhD
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
Search for more papers by this authorAlex R. Paciorkowski MD, PhD
Departments of Genetics and Neurology, University of Rochester, Rochester, NY
Search for more papers by this authorEdward Yang MD, PhD
Harvard Medical School, Boston, MA
Department of Radiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorAnn M. Bergin MB, ScM
Harvard Medical School, Boston, MA
Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorBeth Rosen Sheidley MS, CGC
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Search for more papers by this authorCorresponding Author
Annapurna Poduri MD, MPH
Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, MA
Harvard Medical School, Boston, MA
Address correspondence to Dr Poduri, Fegan 9, Neurology, Mail Stop 3063, Boston Children's Hospital, 300 Longwood Ave, Boston, MA 02115. E-mail: [email protected]Search for more papers by this authorAbstract
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
Supporting Information
Additional supporting information can be found in the online version of this article
| Filename | Description |
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| ana24883-sup-0001-suppinfot1.docx41.4 KB | Supporting Information Table 1 |
| ana24883-sup-0002-suppinfot2.docx52.4 KB | Supporting Information Table 2 |
| ana24883-sup-0003-suppinfot3.docx21.1 KB | Supporting Information Table 3 |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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