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

• Published in: European journal of paediatric neurology Vol. 21; no. 3; pp. 530 - 541
• Main Authors: Stülpnagel, C.v., M.D, 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
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-05-2017
• Subjects: Adolescent; Adult; Anticonvulsants - therapeutic use; Child; Child, Preschool; Drug Resistance - genetics; Epilepsy; Epilepsy - drug therapy; Epilepsy - genetics; Epileptic encephalopathy; Female; GRIN2A; Humans; Infant; Male; Mutation; Neurology; Pediatrics; Phenotype; Receptors, N-Methyl-D-Aspartate - genetics; Retrospective Studies; Specialized therapy; Treatment Outcome; Young Adult; epilepsy; electrical status epilepticus during slow wave sleep; VPA; Atypical Benign Partial Epilepsy of childhood; ABPE; IFE; STM; epileptic encephalopathy; specialized therapy; American College of Medical Genetics; TPM; GRIN2A; clobazam; CSWS; ExAC; electroencephalogramm; BECTS; topiramate; AED; EE; antiepileptic drugs; ACMG; Continuous Spike Waves during Slow Wave Sleep; sultiame; EEG; Exom Aggregation Consortium; valproic acid; idiopathic focal epilepsy; LKS; CLB; benign focal epilepsy with centrotemporal spikes; ESES; LEV; Landau Kleffner Syndrome; levetiracetam; Epileptic encephalopathy; Specialized therapy; Epilepsy
• ISSN: 1090-3798; 1532-2130
• DOI: 10.1016/j.ejpn.2017.01.001

Summary 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.