Clinical Characteristics Of 267 Children With Developmental Epileptic Encephalopathy And Gene Analysis Of 90 Cases

BackgroundDevelopmental and epileptic encephalopathy(DEE)is a group of progressive psychomotor dysfunction,caused by brain development and epilepsy.DEE is characterized by complicated etiology,poor drug control and has severe influences on on the development of young children,which is a challenge in children’s nervous system diseases.With the development of research in precision medicine,genetic testing has played an important role in the diagnosis and treatment of genetic diseases.There are nearly one third of DEE children have genetic causes.At present some pathogenic genes of DEE have been identified,and treatments according to relevant pathogenic mechanisms have also achieved certain results.Genetic testing provides a new theoretical basis and diagnostic means for the determination of etiology,guidance of treatment and prediction of prognosis.There are few studies on DEE in China,and the relevant clinical and genetic information needs to be improved.ObjectiveThe diagnosis and treatment data of 267 children with DEE were retrospectively analyzed to summarize the clinical features,analyze the prognostic factors,and summarize the genes and phenotypes of DEE.MethodsWe collected the clinical data of 267 children with DEE diagnosed in the Department of Pediatric Neurology of Shandong Provincial Hospital from June 2015 to May 2020.Whole exome sequencing was performed on some of the children and their parents.We retrospectively analyzed the clinical characteristics and gene mutations,followed up the treatment and development of the children.Results1.Among the 267 DEE children,the male to female ratio of 1.59:1.The median onset age was 6.3 month old,and the peak onset age was under 1 year of age(73%).2.Among the 267 DEE children,82(30.7%)were diagnosed with West syndrome,50(18.7%)were diagnosed with Dravet syndrome,15(5.6%)were diagnosed with Lennox-Gastaut syndrome,14(5.2%)were diagnosed with Ohtahara syndrome,3(1.1%)were diagnosed with early myoclonic encephalopathy and 103(38.6%)were diagnosed with unknown type of epileptic syndrome.3.Among the 267 children,the clinical and EEG manifestations of the children with epileptic syndrome were typical,while the children with unknown classification had no characteristic manifestations of epileptic seizure and EEG.4.Among the 267 DEE children,49(18.4%)had abnormal birth history;38(14.2%)had a family history of epilepsy or mental retardation;17(6.4%)had positive signs of non-nervous system on physical examination;118(44.2%)had abnormal MRI.5.Compared with the group with significant treatment effect and the group with poor treatment effect,there was statistically significant difference in the distribution of diagnosis time between the two groups(P<0.001),while there was no statistically significant difference in the age of onset,time from onset to first time seeing a doctor,time from onset to diagnosis,birth history,family history,physical examination and MRI results(P>0.05).6.All the 267 DEE children were treated with at least two drugs for epilepsy,with a median of three drugs(2,7).122(45.7%)children received two drugs for epilepsy,which were the main type.There was statistically significant difference in the amount of drugs used between the group with significant treatment effect and the group with poor treatment effect(P=0.006).In children with West syndrome,there was a statistically significant difference in whether ACTH was used in different treatment response groups(P<0.001).7.Up to the follow-up time,among the 267 children,105(39.3%)had complete control of epilepsy,64(24.0%)showed significant effect,33(12.4%)were effective,and 65(24.3%)were ineffective.There were 148(55.4%)children with global developmental delay,39(14.6%)children with motor developmental delay,18(6.8%)children with language developmental delay,8(3.0%)children with intellectual developmental delay,and 54(20.2%)children returned to normal.The development of children with unknown classification and children with well epilepsy control improved better.8.90 children completed the whole exome sequencing analysis.Among them,26(26/90,28.9%)cases were detected pathogenic genetic variation,39(39/90,43.3%)cases were detected likely pathogenic genetic variation,and 25(25/90,27.8%)cases were detected uncertain pathogenic genetic variation.There were 45 pathogenic and likely pathogenic mutated genes,including SCN1A,KCNQ2,SCN2A,KCNT1,MECP2,STXBP1,PRRT2,SCN9A,RYR3,TSC1,et al.The mutated gene was mainly related to channel genes.Genes and phenotypes were heterogeneous.Conclusions1.Children with DEE were early onset.They had a variety of seizure forms and systemic spasms and generalized tonic-clonic seizures were the most common forms.2.Among the DEE children,West syndrome and Dravet syndrome were the main types of epileptic syndrome.There was no obvious regularity in the form of seizures,clinical characteristics and EEG of the children with unknown type of epileptic syndrome.3.The rate of well-controlled epilepsy of DEE children was low.The development of children with unknown classification and children with well epilepsy control improved better.4.The mutated gene was mainly related to channel genes.Different gene mutations can cause same epilepsy syndrome.The SCN1A gene had the highest number of mutations.Genes and phenotypes were heterogeneous.