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GRIN2A mutations cause epilepsy-aphasia spectrum disorders.

ABSTRACT: Epilepsy-aphasia syndromes (EAS) are a group of rare, severe epileptic encephalopathies of unknown etiology with a characteristic electroencephalogram (EEG) pattern and developmental regression particularly affecting language. Rare pathogenic deletions that include GRIN2A have been implicated in neurodevelopmental disorders. We sought to delineate the pathogenic role of GRIN2A in 519 probands with epileptic encephalopathies with diverse epilepsy syndromes. We identified four probands with GRIN2A variants that segregated with the disorder in their families. Notably, all four families presented with EAS, accounting for 9% of epilepsy-aphasia cases. We did not detect pathogenic variants in GRIN2A in other epileptic encephalopathies (n = 475) nor in probands with benign childhood epilepsy with centrotemporal spikes (n = 81). We report the first monogenic cause, to our knowledge, for EAS. GRIN2A mutations are restricted to this group of cases, which has important ramifications for diagnostic testing and treatment and provides new insights into the pathogenesis of this debilitating group of conditions.

SUBMITTER: Carvill GL

PROVIDER: S-EPMC3868952 | biostudies-literature | 2013 Sep

REPOSITORIES: biostudies-literature

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GRIN2A mutations cause epilepsy-aphasia spectrum disorders.

Carvill Gemma L GL Regan Brigid M BM Yendle Simone C SC O'Roak Brian J BJ Lozovaya Natalia N Bruneau Nadine N Burnashev Nail N Khan Adiba A Cook Joseph J Geraghty Eileen E Sadleir Lynette G LG Turner Samantha J SJ Tsai Meng-Han MH Webster Richard R Ouvrier Robert R Damiano John A JA Berkovic Samuel F SF Shendure Jay J Hildebrand Michael S MS Szepetowski Pierre P Scheffer Ingrid E IE Mefford Heather C HC

Nature genetics 20130811 9

Epilepsy-aphasia syndromes (EAS) are a group of rare, severe epileptic encephalopathies of unknown etiology with a characteristic electroencephalogram (EEG) pattern and developmental regression particularly affecting language. Rare pathogenic deletions that include GRIN2A have been implicated in neurodevelopmental disorders. We sought to delineate the pathogenic role of GRIN2A in 519 probands with epileptic encephalopathies with diverse epilepsy syndromes. We identified four probands with GRIN2A ...[more]

PMID: 23933818

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Project 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.

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GRIN2A mutations cause epilepsy-aphasia spectrum disorders.

Publications

GRIN2A mutations cause epilepsy-aphasia spectrum disorders.

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