Epilepsy in patients with GRIN2A alterations: Genetics, neurodevelopment, epileptic phenotype and response to anticonvulsive drugs. (May 2017)

• Record Type: Journal Article
• Authors: von Stülpnagel, C.; Ensslen, M.; Møller, R.S.; Pal, D.K.; Masnada, S.; Veggiotti, P.; Piazza, E.; Dreesmann, M.; Hartlieb, T.; Herberhold, T.; Hughes, E.; Koch, M.; Kutzer, C.; Hoertnagel, K.; Nitanda, J.; Pohl, M.; Rostásy, K.; Haack, T.B.; Stöhr, K.; Kluger, G.; Borggraefe, I.
• Is Part Of: European journal of paediatric neurology. Volume 21:Number 3(2017:May)
• Page Start: 530
• Page End: 541
• Publication Date: 2017-05
• Subjects: GRIN2A -- Epilepsy -- Epileptic encephalopathy -- Specialized therapy; ABPE Atypical Benign Partial Epilepsy of childhood -- ACMG American College of Medical Genetics -- AED antiepileptic drugs -- BECTS benign focal epilepsy with centrotemporal spikes -- CLB clobazam -- CSWS Continuous Spike Waves during Slow Wave Sleep -- EE epileptic encephalopathy -- EEG electroencephalogramm -- ESES electrical status epilepticus during slow wave sleep -- ExAC Exom Aggregation Consortium -- IFE idiopathic focal epilepsy -- LEV levetiracetam -- LKS Landau Kleffner Syndrome -- TPM topiramate -- STM sultiame -- VPA valproic acid; Pediatric neurology -- Periodicals; Nervous System Diseases -- Periodicals; Child -- Periodicals; Infant -- Periodicals; Neurologie pédiatrique -- Périodiques; Pediatric neurology; Electronic journals; Periodicals; Electronic journals; 618.928
• DOI: 10.1016/j.ejpn.2017.01.001
• Languages: English
• ISSNs: 1090-3798

Abstract

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. Highlights: Retrospective study of 7/19 patients with epilepsy and GRIN2A alteration. First report on the effect of commonly used AED in patients with GRIN2A mutations. Patients present with different clinical phenotypes and a spectrum of seizure types. GRIN2A patients responded well to commonly used drugs in idiopathic focal epilepsy. Above all to VPA, STM, CLB and Steroids.