Sarah B Mulkey1, Bruria Ben-Zeev2, Joost Nicolai3, John L Carroll1, Sabine Grønborg4, Yong-Hui Jiang5, Nishtha Joshi6, Megan Kelly5, David A Koolen7, Mohamad A Mikati5, Kristen Park8, Phillip L Pearl9, Ingrid E Scheffer10, Rebecca C Spillmann5, Maurizio Taglialatela11,12, Silvia Vieker13, Sarah Weckhuysen14,15,16, Edward C Cooper6, Maria Roberta Cilio17. 1. Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A. 2. Department of Pediatrics, Sackler School of Medicine, Tel Hashomer, Israel. 3. Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands. 4. Center for Rare Diseases, Department of Clinical Genetics, University Hospital Copenhagen, Copenhagen, Denmark. 5. Departments of Pediatrics and Neurobiology, Duke University Medical Center, Durham, North Carolina, U.S.A. 6. Departments of Neurology, Neuroscience, and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, U.S.A. 7. Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands. 8. Department of Pediatrics, University of Colorado, Aurora, Colorado, U.S.A. 9. Departments of Pediatrics and Neurology, Boston Children's Hospital, Boston, Massachusetts, U.S.A. 10. Royal Children's Hospital, Melbourne, Victoria, Australia. 11. Department of Neuroscience, University of Naples Federico II, Naples, Italy. 12. Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy. 13. Protestant Hospital Bielefeld, Bielefeld, Germany. 14. Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium. 15. Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. 16. Department of Neurology, University Hospital Antwerp, Antwerp, Belgium. 17. Departments of Neurology and Pediatrics, University of California San Francisco, San Francisco, California, U.S.A.
Abstract
OBJECTIVE: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome. METHODS: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)-approved KCNQ2 patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course. RESULTS: Nine patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epileptic spasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism. SIGNIFICANCE: Heterozygous KCNQ2 R201C and R201H gain-of-function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss-of-function variants, supporting the value of in vitro functional screening. These findings suggest that gain-of-function and loss-of-function variants need different targeted therapeutic approaches. Wiley Periodicals, Inc.
OBJECTIVE: To analyze whether KCNQ2 R201C and R201H variants, which show atypical gain-of-function electrophysiologic properties in vitro, have a distinct clinical presentation and outcome. METHODS: Ten children with heterozygous, de novo KCNQ2 R201C or R201H variants were identified worldwide, using an institutional review board (IRB)-approved KCNQ2patient registry and database. We reviewed medical records and, where possible, interviewed parents and treating physicians using a structured, detailed phenotype inventory focusing on the neonatal presentation and subsequent course. RESULTS: Nine patients had encephalopathy from birth and presented with prominent startle-like myoclonus, which could be triggered by sound or touch. In seven patients, electroencephalography (EEG) was performed in the neonatal period and showed a burst-suppression pattern. However, myoclonus did not have an EEG correlate. In many patients the paroxysmal movements were misdiagnosed as seizures. Seven patients developed epilepticspasms in infancy. In all patients, EEG showed a slow background and multifocal epileptiform discharges later in life. Other prominent features included respiratory dysfunction (perinatal respiratory failure and/or chronic hypoventilation), hypomyelination, reduced brain volume, and profound developmental delay. One patient had a later onset, and sequencing indicated that a low abundance (~20%) R201C variant had arisen by postzygotic mosaicism. SIGNIFICANCE: Heterozygous KCNQ2 R201C and R201H gain-of-function variants present with profound neonatal encephalopathy in the absence of neonatal seizures. Neonates present with nonepileptic myoclonus that is often misdiagnosed and treated as seizures. Prognosis is poor. This clinical presentation is distinct from the phenotype associated with loss-of-function variants, supporting the value of in vitro functional screening. These findings suggest that gain-of-function and loss-of-function variants need different targeted therapeutic approaches. Wiley Periodicals, Inc.
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