title: Neonatal nonepileptic myoclonus is a prominent clinical feature of KCNQ2 gain-of-function variants R201C and R201H.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
authors.forename: Sarah B
authors.identifier: 0000-0002-8084-526X
authors.initials: SB
authors.lastname: Mulkey
authors.affiliation: Department of Pediatrics, Sackler School of Medicine, Tel Hashomer, Israel.
authors.forename: Bruria
authors.initials: B
authors.lastname: Ben-Zeev
authors.affiliation: Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Nicolai
authors.affiliation: Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, Arkansas, U.S.A.
authors.forename: John L
authors.initials: JL
authors.lastname: Carroll
authors.affiliation: Center for Rare Diseases, Department of Clinical Genetics, University Hospital Copenhagen, Copenhagen, Denmark.
authors.forename: Sabine
authors.initials: S
authors.lastname: Grønborg
authors.affiliation: Departments of Pediatrics and Neurobiology, Duke University Medical Center, Durham, North Carolina, U.S.A.
authors.forename: Yong-Hui
authors.initials: YH
authors.lastname: Jiang
authors.affiliation: Departments of Neurology, Neuroscience, and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, U.S.A.
authors.forename: Nishtha
authors.initials: N
authors.lastname: Joshi
authors.affiliation: Departments of Pediatrics and Neurobiology, Duke University Medical Center, Durham, North Carolina, U.S.A.
authors.forename: Megan
authors.initials: M
authors.lastname: Kelly
authors.affiliation: Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: David A
authors.initials: DA
authors.lastname: Koolen
authors.affiliation: Departments of Pediatrics and Neurobiology, Duke University Medical Center, Durham, North Carolina, U.S.A.
authors.forename: Mohamad A
authors.initials: MA
authors.lastname: Mikati
authors.affiliation: Department of Pediatrics, University of Colorado, Aurora, Colorado, U.S.A.
authors.forename: Kristen
authors.initials: K
authors.lastname: Park
authors.affiliation: Departments of Pediatrics and Neurology, Boston Children's Hospital, Boston, Massachusetts, U.S.A.
authors.forename: Phillip L
authors.initials: PL
authors.lastname: Pearl
authors.affiliation: Royal Children's Hospital, Melbourne, Victoria, Australia.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: Departments of Pediatrics and Neurobiology, Duke University Medical Center, Durham, North Carolina, U.S.A.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Spillmann
authors.affiliation: Department of Neuroscience, University of Naples Federico II, Naples, Italy.|Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Taglialatela
authors.affiliation: Protestant Hospital Bielefeld, Bielefeld, Germany.
authors.forename: Silvia
authors.initials: S
authors.lastname: Vieker
authors.affiliation: Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium.|Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.|Department of Neurology, University Hospital Antwerp, Antwerp, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.affiliation: Departments of Neurology, Neuroscience, and Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, U.S.A.
authors.forename: Edward C
authors.initials: EC
authors.lastname: Cooper
authors.affiliation: Departments of Neurology and Pediatrics, University of California San Francisco, San Francisco, California, U.S.A.
authors.forename: Maria Roberta
authors.initials: MR
authors.lastname: Cilio
mesh_terms: D000927:Anticonvulsants / Q000627:therapeutic use; D001120:Arginine / Q000235:genetics; D002675:Child, Preschool; D003545:Cysteine / Q000235:genetics; D004569:Electroencephalography; D005260:Female; D006639:Histidine / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D051658:KCNQ2 Potassium Channel / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D008297:Male; D009207:Myoclonus / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012042:Registries; D012120:Respiration Disorders / Q000209:etiology / Q000235:genetics; D013036:Spasms, Infantile / Q000235:genetics*
chemical_list: D000927:Anticonvulsants; D051658:KCNQ2 Potassium Channel; D006639:Histidine; D001120:Arginine; D003545:Cysteine
keywords: Epileptic encephalopathy; Infantile spasms; KCNQ2; Myoclonus; Neonatal seizures