title: Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs.
abstract: OBJECTIVE
  To delineate the genetic, neurodevelopmental and epileptic spectrum associated with GRIN2A alterations with emphasis on epilepsy treatment.
  
  
  METHODS
  Retrospective study of 19 patients (7 females; age: 1-38 years; mean 10.1 years) with epilepsy and GRIN2A alteration. Genetic variants were classified according to the guidelines and recommendations of the American College of Medical Genetics (ACMG). Clinical findings including epilepsy classification, treatment, EEG findings, early childhood development and neurodevelopmental outcome were collected with an electronic questionnaire.
  
  
  RESULTS
  7 out of 19 patients fulfilled the ACMG-criteria of carrying "pathogenic" or "likely pathogenic variants", in twelve patients the alterations were classified as variants of unknown significance. The spectrum of pathogenic/likely pathogenic mutations was as follows: nonsense n = 3, missense n = 2, duplications/deletions n = 1 and splice site n = 1. First seizures occurred at a mean age of 2.4 years with heterogeneous seizure types. Patients were treated with a mean of 5.6 AED. 4/5 patients with VPA had an improved seizure frequency (n = 3 with a truncation: n = 1 missense). 3/5 patients with STM reported an improvement of seizures (n = 2 truncation, n = 1 splicing). 3/5 CLB patients showed an improvement (n = 2: truncation; n = 1 splicing). Steroids were reported to have a positive effect on seizure frequency in 3/5 patients (n = 1 each truncation, splicing or deletion).
  
  
  CONCLUSIONS
  Our data indicate that children with epilepsy due to pathogenic GRIN2A mutations present with different clinical phenotypes and a spectrum of seizure types in the context of a pharmacoresistant epilepsy providing information for clinicians treating children with this form of genetically determined epileptic syndrome.
authors.affiliation: Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany; Paracelsus Medical University Salzburg, Salzburg, Austria. Electronic address: cvstuelpnagel@steinbeis.co.
authors.forename: C
authors.initials: C
authors.lastname: von Stülpnagel
authors.affiliation: Department of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Epilepsy Center, University of Munich, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ensslen
authors.affiliation: Danish Epilepsy Centre, Dianalund, Denmark; Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
authors.forename: R S
authors.initials: RS
authors.lastname: Møller
authors.affiliation: Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, England, United Kingdom.
authors.forename: D K
authors.initials: DK
authors.lastname: Pal
authors.affiliation: Child Neuropsychiatry Division, Neurological Institute Casimiro Mondino Foundation IRCCS, Pavia, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Masnada
authors.affiliation: Child Neuropsychiatry Division, Neurological Institute Casimiro Mondino Foundation IRCCS, Pavia, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Veggiotti
authors.affiliation: Child Neuropsychiatry Division, Neurological Institute Casimiro Mondino Foundation IRCCS, Pavia, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Piazza
authors.affiliation: Sozialpädiatrisches Zentrum Potsdam, Ernst von Bergmann Klinik, Potsdam, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Dreesmann
authors.affiliation: Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Hartlieb
authors.affiliation: Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Herberhold
authors.affiliation: King's College Hospital & Evelina Children's Hospital, London, England, United Kingdom.
authors.forename: E
authors.initials: E
authors.lastname: Hughes
authors.affiliation: Department of Pediatric Neurology, Developmental Neurology and Social Pediatrics, Vestische Kinder-und Jugendklinik Datteln, University Witten/Herdecke, Datteln, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Koch
authors.affiliation: Kinderzentrum St. Martin, Regensburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Kutzer
authors.affiliation: Cegat GmbH, Laboratory of Medical Genetics, Tuebingen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Hoertnagel
authors.affiliation: Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Nitanda
authors.affiliation: Children's Hospital Dritter Orden, Passau, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pohl
authors.affiliation: Department of Pediatric Neurology, Developmental Neurology and Social Pediatrics, Vestische Kinder-und Jugendklinik Datteln, University Witten/Herdecke, Datteln, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Rostásy
authors.affiliation: Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
authors.forename: T B
authors.initials: TB
authors.lastname: Haack
authors.affiliation: Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Stöhr
authors.affiliation: Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany; Paracelsus Medical University Salzburg, Salzburg, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Kluger
authors.affiliation: Department of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Epilepsy Center, University of Munich, Munich, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Borggraefe
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance / Q000235:genetics; D004827:Epilepsy / Q000188:drug therapy* / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D010641:Phenotype; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Epilepsy; Epileptic encephalopathy; GRIN2A; Specialized therapy