Original article

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

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.

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.

Keywords

GRIN2A
Epilepsy
Epileptic encephalopathy
Specialized therapy

Abbreviations

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