C von Stülpnagel1, M Ensslen2, R S Møller3, D K Pal4, S Masnada5, P Veggiotti5, E Piazza5, M Dreesmann6, T Hartlieb7, T Herberhold7, E Hughes8, M Koch9, C Kutzer10, K Hoertnagel11, J Nitanda7, M Pohl12, K Rostásy9, T B Haack13, K Stöhr7, G Kluger14, I Borggraefe2. 1. 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. 2. Department of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Epilepsy Center, University of Munich, Munich, Germany. 3. Danish Epilepsy Centre, Dianalund, Denmark; Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark. 4. Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience, King's College, London, England, United Kingdom. 5. Child Neuropsychiatry Division, Neurological Institute Casimiro Mondino Foundation IRCCS, Pavia, Italy. 6. Sozialpädiatrisches Zentrum Potsdam, Ernst von Bergmann Klinik, Potsdam, Germany. 7. Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany. 8. King's College Hospital & Evelina Children's Hospital, London, England, United Kingdom. 9. Department of Pediatric Neurology, Developmental Neurology and Social Pediatrics, Vestische Kinder-und Jugendklinik Datteln, University Witten/Herdecke, Datteln, Germany. 10. Kinderzentrum St. Martin, Regensburg, Germany. 11. Cegat GmbH, Laboratory of Medical Genetics, Tuebingen, Germany. 12. Children's Hospital Dritter Orden, Passau, Germany. 13. Institute of Human Genetics, Technische Universität München, Munich, Germany; Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. 14. Hospital for Neuropediatrics and Neurological Rehabilitation, Epilepsy Center for Children and Adolescents, Schön Klinik Vogtareuth, Vogtareuth, Germany; Paracelsus Medical University Salzburg, Salzburg, Austria.
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.
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: Jia Li; Jin Zhang; Weiting Tang; Ruth K Mizu; Hirofumi Kusumoto; Wenshu XiangWei; Yuchen Xu; Wenjuan Chen; Johansen B Amin; Chun Hu; Varun Kannan; Stephanie R Keller; William R Wilcox; Johannes R Lemke; Scott J Myers; Sharon A Swanger; Lonnie P Wollmuth; Slavé Petrovski; Stephen F Traynelis; Hongjie Yuan Journal: Hum Mutat Date: 2019-09-10 Impact factor: 4.878
Authors: Stephanie Oates; Shan Tang; Richard Rosch; Rosalie Lear; Elaine F Hughes; Ruth E Williams; Line H G Larsen; Qin Hao; Hans Atli Dahl; Rikke S Møller; Deb K Pal Journal: NPJ Genom Med Date: 2018-05-10 Impact factor: 8.617