Abstract
Objective: 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 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.
Highlights
Benign epilepsy of children with centrotemporal spikes (BECTs) is the most common idiopathic focal epileptic syndrome in childhood, accounting for 15–25% of childhood-onset epilepsy
The atypical evolution of BECTs may lead to atypical benign childhood partial epilepsy (ABPE), status epilepticus of BECTS (SEBECTS), Landau-Kleffner syndrome (LKS), and epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS)
We reviewed all the published literature reporting patients with pathogenic GRIN2A variants, and missense mutations which were proved to result in N-methyl-D-aspartate receptor (NMDAR)-LOF change were selected from those literatures along with GRIN2A truncation variants (Table 6)
Summary
Benign epilepsy of children with centrotemporal spikes (BECTs) is the most common idiopathic focal epileptic syndrome in childhood, accounting for 15–25% of childhood-onset epilepsy. The atypical evolution of BECTs may lead to atypical benign childhood partial epilepsy (ABPE), status epilepticus of BECTS (SEBECTS), Landau-Kleffner syndrome (LKS), and epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS). These diseases are considered to be different entities but part of a wide single spectrum of disorders named epileptic-aphasia spectrum (EAS), with BECTs situated at the mildest end having a relatively good prognosis while CSWS located at the most severe end has a mostly poor prognosis. EAS, a spectrum of epileptic, cognitive, and language disorders, is associated with (and presumably influenced by) the presence of electrical status epilepticus during slow-wave sleep (ESES) and imposes a catastrophic effect on the family and the growth of children [5,6,7,8,9,10]
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