Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder
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 m...
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| Format: | Article |
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Frontiers Media S.A.
2020-11-01
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| Series: | Frontiers in Pediatrics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fped.2020.574803/full |
| _version_ | 1819212648269479936 |
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| author | Xiao Li Xiao Li Xiao Li Xiao Li Xiao Li Ling-Ling Xie Ling-Ling Xie Ling-Ling Xie Ling-Ling Xie Ling-Ling Xie Wei Han Wei Han Wei Han Wei Han Wei Han Si-Qi Hong Si-Qi Hong Si-Qi Hong Si-Qi Hong Si-Qi Hong Jian-Nan Ma Jian-Nan Ma Jian-Nan Ma Jian-Nan Ma Jian-Nan Ma Juan Wang Juan Wang Juan Wang Juan Wang Juan Wang Li Jiang Li Jiang Li Jiang Li Jiang Li Jiang |
| author_facet | Xiao Li Xiao Li Xiao Li Xiao Li Xiao Li Ling-Ling Xie Ling-Ling Xie Ling-Ling Xie Ling-Ling Xie Ling-Ling Xie Wei Han Wei Han Wei Han Wei Han Wei Han Si-Qi Hong Si-Qi Hong Si-Qi Hong Si-Qi Hong Si-Qi Hong Jian-Nan Ma Jian-Nan Ma Jian-Nan Ma Jian-Nan Ma Jian-Nan Ma Juan Wang Juan Wang Juan Wang Juan Wang Juan Wang Li Jiang Li Jiang Li Jiang Li Jiang Li Jiang |
| author_sort | Xiao Li |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-23T06:46:18Z |
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| issn | 2296-2360 |
| language | English |
| last_indexed | 2024-12-23T06:46:18Z |
| publishDate | 2020-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pediatrics |
| spelling | doaj.art-8f35cb43ccce46debf4a84c4be60bd7f2022-12-21T17:56:34ZengFrontiers Media S.A.Frontiers in Pediatrics2296-23602020-11-01810.3389/fped.2020.574803574803Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum DisorderXiao Li0Xiao Li1Xiao Li2Xiao Li3Xiao Li4Ling-Ling Xie5Ling-Ling Xie6Ling-Ling Xie7Ling-Ling Xie8Ling-Ling Xie9Wei Han10Wei Han11Wei Han12Wei Han13Wei Han14Si-Qi Hong15Si-Qi Hong16Si-Qi Hong17Si-Qi Hong18Si-Qi Hong19Jian-Nan Ma20Jian-Nan Ma21Jian-Nan Ma22Jian-Nan Ma23Jian-Nan Ma24Juan Wang25Juan Wang26Juan Wang27Juan Wang28Juan Wang29Li Jiang30Li Jiang31Li Jiang32Li Jiang33Li Jiang34Department of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, ChinaMinistry of Education Key Laboratory of Child Development and Disorders, Chongqing, ChinaNational Clinical Research Center for Child Health and Disorders, Chongqing, ChinaChina International Science and Technology Cooperation base of Child Development and Critical Disorders, Chongqing, ChinaChongqing Key Laboratory of Pediatrics, Chongqing, ChinaDepartment of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, ChinaMinistry of Education Key Laboratory of Child Development and Disorders, Chongqing, ChinaNational Clinical Research Center for Child Health and Disorders, Chongqing, ChinaChina International Science and Technology Cooperation base of Child Development and Critical Disorders, Chongqing, ChinaChongqing Key Laboratory of Pediatrics, Chongqing, ChinaDepartment of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, ChinaMinistry of Education Key Laboratory of Child Development and Disorders, Chongqing, ChinaNational Clinical Research Center for Child Health and Disorders, Chongqing, ChinaChina International Science and Technology Cooperation base of Child Development and Critical Disorders, Chongqing, ChinaChongqing Key Laboratory of Pediatrics, Chongqing, ChinaDepartment of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, ChinaMinistry of Education Key Laboratory of Child Development and Disorders, Chongqing, ChinaNational Clinical Research Center for Child Health and Disorders, Chongqing, ChinaChina International Science and Technology Cooperation base of Child Development and Critical Disorders, Chongqing, ChinaChongqing Key Laboratory of Pediatrics, Chongqing, ChinaDepartment of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, ChinaMinistry of Education Key Laboratory of Child Development and Disorders, Chongqing, ChinaNational Clinical Research Center for Child Health and Disorders, Chongqing, ChinaChina International Science and Technology Cooperation base of Child Development and Critical Disorders, Chongqing, ChinaChongqing Key Laboratory of Pediatrics, Chongqing, ChinaDepartment of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, ChinaMinistry of Education Key Laboratory of Child Development and Disorders, Chongqing, ChinaNational Clinical Research Center for Child Health and Disorders, Chongqing, ChinaChina International Science and Technology Cooperation base of Child Development and Critical Disorders, Chongqing, ChinaChongqing Key Laboratory of Pediatrics, Chongqing, ChinaDepartment of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, ChinaMinistry of Education Key Laboratory of Child Development and Disorders, Chongqing, ChinaNational Clinical Research Center for Child Health and Disorders, Chongqing, ChinaChina International Science and Technology Cooperation base of Child Development and Critical Disorders, Chongqing, ChinaChongqing Key Laboratory of Pediatrics, Chongqing, ChinaObjective: 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.https://www.frontiersin.org/articles/10.3389/fped.2020.574803/fullLandau-Kleffner syndrome (LKS)epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS)atypical benign partial epilepsy (ABPE)genotype-phenotype relationshipepileptic-aphasia spectrum disorder |
| spellingShingle | Xiao Li Xiao Li Xiao Li Xiao Li Xiao Li Ling-Ling Xie Ling-Ling Xie Ling-Ling Xie Ling-Ling Xie Ling-Ling Xie Wei Han Wei Han Wei Han Wei Han Wei Han Si-Qi Hong Si-Qi Hong Si-Qi Hong Si-Qi Hong Si-Qi Hong Jian-Nan Ma Jian-Nan Ma Jian-Nan Ma Jian-Nan Ma Jian-Nan Ma Juan Wang Juan Wang Juan Wang Juan Wang Juan Wang Li Jiang Li Jiang Li Jiang Li Jiang Li Jiang Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder Frontiers in Pediatrics Landau-Kleffner syndrome (LKS) epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) atypical benign partial epilepsy (ABPE) genotype-phenotype relationship epileptic-aphasia spectrum disorder |
| title | Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder |
| title_full | Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder |
| title_fullStr | Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder |
| title_full_unstemmed | Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder |
| title_short | Clinical Forms and GRIN2A Genotype of Severe End of Epileptic-Aphasia Spectrum Disorder |
| title_sort | clinical forms and grin2a genotype of severe end of epileptic aphasia spectrum disorder |
| topic | Landau-Kleffner syndrome (LKS) epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) atypical benign partial epilepsy (ABPE) genotype-phenotype relationship epileptic-aphasia spectrum disorder |
| url | https://www.frontiersin.org/articles/10.3389/fped.2020.574803/full |
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