Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder

Abstract

This study aims to analyze the electroclinical characteristics and gene test results of children on the severe end of the epilepsy aphasia spectrum (EAS) and also the correlation of EAS-related GRIN2A genes to explore the genotype-phenotype relationships, as well as potential pathogenic mechanism of EAS. Methods: A retrospective study was conducted on the participants diagnosed with Landau-Kleffner syndrome (LKS), epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS), and atypical benign partial epilepsy (ABPE) at the Children's Hospital of Chongqing Medical University from January 2013 to June 2019. Whole-exome sequencing was performed in six patients, and epileptic panel was carried out in two. In addition, we reviewed all the published literatures reporting EAS patients with pathogenic variants until June 2019 and conducted Gene Ontology (GO) analysis, as well as protein-protein interaction (PPI) network. Results: The mean age at seizure onset was 55.4 ± 27.0 months. The baseline severity of the spike-wave index (SWI) was not significantly correlated with intellectual disability (ID) level. Two pathogenic de novo GRIN2A null variants were identified in patients with ABPE who had less severe ID, despite the electrical status epilepticus during slow-wave sleep (ESES). By literature reviewing, 18 GRIN2A missense mutations and 11 GRIN2A truncating mutations which lead to N-methyl-d-aspartate receptors' loss of function has been reported. Of these mutations, 9 (31.0%) are situated in amino (N)-terminal domain, 6 (20.7%) in linger-binding domain S1, and 10 (34.5%) in linger-binding domain S2. EAS-related genes were enriched in the biological process of chemical synaptic transmission and vocalization (FDR, <0.01). The hub protein in PPI network is GluN2A, which might affect language function via foxp2-srpx2/uPAR signal network. Conclusion: Our data suggested that when children suspected with benign epilepsy of children with centrotemporal spikes (BECTs) have early-onset age, changed seizure semiology, and deterioration of behavior/cognition/motor function, neurologists should be alert of the appearance of ESES. The neuropsychological deterioration in children Li et al. Epileptic-Aphasia Spectrum Disorder with EAS might not only be completely affected by electric discharge severity but also genetic etiology. Our finding also enforced the current genotype-phenotype relationship theory about EAS. For EAS children, GRIN2A-FOXP2-SRPX2/uPAR signal network might contribute to the mechanism of their language deficit.

Effects of gestational haloperidol exposure on mRNA expressions related to glutamate and GABA receptors in offspring

“…This result may suggest that decreased Gria2 mRNA expression was a result of negative feedback via temporary stimulation by HAL during pregnancy. Grin2a , which encodes one of the glutamate NMDA receptor subunits, the epsilon-1 subunit of the NMDA receptor, is known as the epilepsy factor ( Li et al, 2020 , Yang et al, 2018 ). The reduction of Grin2a mRNA expression in the hippocampi and frontal lobes of F1 mice, but not in acute mice, was confirmed.…”

Imprecision in Precision Medicine: Differential Response of a Disease-Linked GluN2A Mutant to NMDA Channel Blockers

“…It is estimated that the diagnosis yield for these disorders is 15-20% (EpiPM Consortium, 2015). Intriguingly, GRIN mutations make up a high proportion of these disease-linked mutations, and GRIN2A mutations, specifically, have been identified as key drivers of epilepsy aphasia spectrum disorders (Carvill et al, 2013;Li et al, 2020;Lemke et al, 2013;Lesca et al, 2013). The identification and in vitro characterization of human disease-linked GRIN mutations has led to the successful implementation of personalized medicine for several pediatric patients.…”

GRIN2A and GRIN2B and Their Related Phenotypes

“…100 CECTS is classically associated with a horizontal dipole; tangential dipole across the Sylvian fissure has been reported in LKS. 101,102 Recently, Li et al 103 Brain MRI is normal in the vast majority of cases. However, it has been reported that severely affected individuals may have enlargement of extra-axial spaces and a thin corpus callosum.…”