Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs

C. Von Stülpnagel, M. Ensslen, Rikke S. Møller, Karin van der Pal, Silvia Masnada, P. Veggiotti, E. Piazza, M. Dreesmann, T. Hartlieb, T. Herberhold, Anne E. Hughes, M. Koch, C. Kutzer, K. Hoertnagel, J. Nitanda, M. Pohl, K. Rostásy, Tobias B. Haack, K. Stöhr, Gerhard KlugerIngo Borggraefe

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalEuropean Journal of Paediatric Neurology
DOIs
Publication statusAccepted/In press - Jun 30 2016

Keywords

  • Epilepsy
  • Epileptic encephalopathy
  • GRIN2A
  • Specialized therapy

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Clinical Neurology

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    Von Stülpnagel, C., Ensslen, M., Møller, R. S., van der Pal, K., Masnada, S., Veggiotti, P., Piazza, E., Dreesmann, M., Hartlieb, T., Herberhold, T., Hughes, A. E., Koch, M., Kutzer, C., Hoertnagel, K., Nitanda, J., Pohl, M., Rostásy, K., Haack, T. B., Stöhr, K., ... Borggraefe, I. (Accepted/In press). Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs. European Journal of Paediatric Neurology. https://doi.org/10.1016/j.ejpn.2017.01.001