| Objective: To analyze the clinical manifestations,neuropsychological characteristics,EEG and gene test results of children with severe epilepsy aphasia spectrum(EAS),and to explore the relationship between genotype and phenotype.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 August 2019.During the follow-up period,all of the enrolled patients underwent multiple 24-hour EEG,neuropsychological evaluation and physical neurological examination.WholeExome Sequencing was performed on eight patients.Results:(1)In our study,88.9% children had seizure attack,and their mean age at seizure onset was 27-107(54.5±26.5)months.The average time from seizure onset to ESES signal onset was 1-53(24.1±15.7)months.The new seizure types appeared in 9 patients within 3 months before and after the appearance of ESES,and the average time from the first seizure to appearance of new attack forms was 26.4±15.7 months.All the children had cognitive impairment.The overall intelligence quotient was between 41 and 96,with an average intelligence score of 66.7 ± 17.0.Neuropsychiatric comorbidity was found in two cases with ADHD(10%).In this group,the appearance of clinical deterioration(including the emergence of new seizure types or behavioral / cognitive / motor dysfunction)of all the patients with ESES was earlier than or simultaneous with the appearance of ESES in EEG.(2)Follow-up duration of patients in our group ranged from 31 to104(62.8 ± 25.7)months by August 2019.The time from the onset of seizure to the seizure free was 1-60(27.5 ± 23.3,n = 12)months,to EEG normalization was 4-70(37 ± 25.4,n = 7)months.Among the patients with EEG-SWI ≥ 50%,who ultimately reached seizure free,7.7%,46.1% and 7.7% of them were treated with AEDs,steroids and ketogenic diet respectively.Among the 12 patients who were treated multiple AEDs combined with steroids,75% of them had good response,including 1 case carrying pathogenic GRIN2A(p.y698 *)variants.(3)Two pathogenic de novol GRIN2 A null variants were identified in two patients diagnosed with ABPE-II,they had less severe DD/ID in spite of the ESES-EEG.Two GRIN2 A truncational mutations resulted in the earlier termination of protein transcription.(4)EAS related genes are enriched in the biological process of chemical synaptic transmission and vocalization(FDR < 0.01).The key protein in EAS related PPI network is GluN2 A coded by GRIN2 A gene,which might affect language function by foxp2-srpx2/uPAR signal network.Conclusion: In this study,we retrospectively reviewed the electroclinical characteristics,gene tests results,treatment and prognosis features of 20 children diagnosed with EAS,and further explored the GO of EAS related genes and the PPI of those genes expressed.(1)Our data might suggest that when children suspected with BECTs have early onset age,changed seizure semiology,and deterioration of behavior/ cognition/ motor function,neurologists should be alert the appearance of ESES.(2)The neuropsychological deterioration in children with EAS might not be completely affected by electric discharge,but also interruption of complete sleep circle,autoimmune response and genetic etiology.(3)Our finding supported the genotype-phenotype relationship theory in EAS.In addition,for EAS children carrying GRIN2 A mutation,functional experiments are called for to start individualized treatment as early as possible. |
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