Study On The Relationship Between The Mutation Characteristics Of SCN1A Gene In Dravet Syndrome And Its Clinical Phenotype

BackgroundDravet syndrome(DS)is a refractory epilepsy syndrome with first seizure in infancy.which was first reported by French physician Dravet in 1978.It was previously also called early severe myoclonic epilepsy of infancy(SMEI).because myoclonic seizure did not occur in all patients during the course of the disease,the International League Of Against Epilepsy(ILAE)recommended the disease as Dravet syndrome,and It is classified as an epilepsy encephalopathy.DS has various forms of clinical seizures and is sensitive to heat.It is prone to convulsions as well.Most children are poorly treated with antiepileptic drugs,and seizures often persist into adulthood with varying degrees of intellectual impairment,which seriously affect the physical and mental health of children,and bring serious burden to the families.With the development of medical science and the deepening of scholars' research on DS,more and more children with DS can be diagnosed in time,but the mechanism of the complex diversity of clinical manifestations remains to be further explored.The pathogenesis of epilepsy is complex and the etiology is diverse.With the development of molecular biology technology,the role of genetic factors in the pathogenesis of epilepsy has been recognized.According to reports in the literature,hereditary epilepsy accounts for 40% to 50% of the etiology of epilepsy.DS is currently considered to be a hereditary epilepsy,which can be caused by a variety of genetic mutations,but is primarily caused by mutations in the SCN1 A gene encoding the ? subunit of the voltage-gated sodium channel.The SCN1 A gene mutation forms and mutation sites are diverse.More than 1,200 SCN1 A mutants have been identified,and more than 900 SCN1 A mutation have been reported to be associated with DS.Previous studies have shown that the SCN1 A gene mutation pattern and site are associated with different clinical phenotypes,can be expressed as a mild febrile convulsion phenotype,can also be expressed as a serious DS phenotype.But for DS,is there a correlation between the characteristics of SCN1 A mutation and its clinical phenotype? At present,there are a few scholars abroad who have reported a certain relationship between the two,but there are few overall studies,and further understanding is needed.ObjectiveTo analyze the clinical characteristics of children with DS and the mutation of SCN1 A gene,and to explore the relationship between different mutation characteristics(methods and loci)and clinical phenotype;MethodsThe clinical data of children diagnosed as DS from the Department of Pediatric Neurology,Third Affiliated Hospital of Zhengzhou University from January 2014 to May 2018 were collected.The Gesell scale or C-WISC intelligence scale was used to evaluate the intelligence of children.The peripheral blood DNA of the children was detected by next generation sequencing for Epilepsy-related gene-panel,The positive mutation was verified by sanger sequencing,and the parents' were screend by Sanger sequencing to family verification.Multiple ligation-dependent probe amplification(MLPA)technology was used to detect large fragment variation of SCN1 A gene if the mutations of the children were negative.The mutation characteristics of the gene were classified according to the mutation mode and the location of the mutation,and the clinical characteristics of the children with different mutation characteristics were compared.Statistical analysis was performed using SPSS21.0 statistical software.The measurement data are expressed by the mean ± standard deviation.The data is t-test under the condition of satisfying the normality and the homogeneity of the variance.The comparison of the count data is performed by Fisher exact probability method,and the ordered qualitative data is tested by rank sum test,P < 0.05.The difference was statistically significant.ResultsA total of 50 cases of DS were collected,38 cases of which were positive for SCN1 A mutation,and the mutation rate was 76.00%(38/50cases).Of which,the missense mutation[50.00%(19/38cases)] and frameshift mutation[28.9%(11/38 cases)] were dominant.The average onset age of 50 patients was 6 months old,oneset of seizures were triggered by ferve(temperature>37.5 ?)in 68.00%(34/50 cases)of children,the history of seizures in hot baths was found in 60.00%(30/50 cases)of children,status epilepticus was found in 74.00%(37/50 cases),cluster-like episodes was found in 80.00%(40/50 cases),?2 seizure types was found in 92.00%(46/50 cases).Mental retardation was found in Most of the children,of which 30.00%(15/50 cases)were mild mental retardation,38.00%(19/50 cases)were moderate mental retardation,14.00%(7/50 cases)were severe intelligence behind.Interictal abnormalities of electroencephalogram(EEG)before 1 year old was found in 24.0%(12/50 cases)and the average age of EEG abnormalities was 30.12 months old;the top three drug efficacy rates were 70.00%(28/40 cases)topiramate,48.00%(24/50 cases)sodium valproate,45.71%(16/35 cases)clonazepam or chlorobarba,.The time of onset of myoclonus and atypical absence of the truncation mutation group was earlier than that of the missense mutation group(14.8 months vs.21.2 months;16.8 months vs 26.0months),and the difference was statistically significant(all P<0.05).The proportion of clustered episodes in the truncation mutation group was higher than that in the missense mutation group [94.74%(18/19 cases)vs.63.15%(12/19 cases)],and the difference was statistically significant(P<0.05).There was no significant correlation between the SCN1 A gene mutation(type and position)and age of onset,type of seizure,proportion of convulsion persistence,the mental development or abnormal proportion of EEG and seizure frequency before 1 year of age(all P>0.05).ConclusionsThe SCN1 A gene mutation rate is high in children with DS,and the SCN1 A gene mutation characteristics has a certain correlation with DS clinical phenotype.