Genetic And Phenotypic Characteristics Of SCN8A Related Epilepsy

Objective: To explore the relationship between clinical phenotypic characteristics and gene mutation characteristics of epilepsy associated with SCN8A gene mutation,and provide the basis for early diagnosis,precise treatment and genetic counseling.Methods: Eight cases of SCN8A gene mutation detected by whole exon sequencing were screened.Their clinical manifestations,family history,electroencephalogram,MRI,and gene mutation sites,method,type and ACMG classification were summarized and analyzed by retrospective analysis.In addition,the correlation between phenotypes and different gene mutation patterns of SCN8A gene mutation as well as the correlation between different gene mutation types and phenotypes were analyzed by combining with the domestic and foreign literature.Furthermore,the relationship between the location of the domain of the gene mutein and the severity of the phenotype was analyzed.Results :There were 6 males and 2 females in the 8 cases.The first episode was febrile seizure-free.There were seven seizure types observed,mainly generalized seizures.Six children had two or more seizure types.EEG shows multifocal discharge changes.Among the 8 cases,5 cases had speech delay,2 cases had gait disturbance,4 cases had hypotonia,4 cases had ataxia and 7 cases had mental retardation.Case 5(p.G1475R)had the characteristics of convulsion after being frightened.Case 3(p.R530W)was considered as benign familial infantile epilepsy,which started at the age of 13 months,had a history of father convulsions,only showed tonic-clonic seizures twice,had normal EEG and normal cognitive motor development,and had been observed without treatment for more than one year.Case 2(p.T1773I)and Case 7(p.V216A)of the seven SCN8A-related epileptic encephalopathy cases were of intermediate phenotype,showing treatable epilepsy,mild mental retardation or autism-like symptoms;The other 5 cases showed severe epilepsy encephalopathy,which was accompanied by moderate to severe mental retardation,low muscle tension,ataxia and speech retardation,and all of them were treated with more than three antiepileptic drugs;Among them,Case 1(p.A1575V)started with spasm and mental retardation before the seizure and later developed Lennox-Gastaut syndrome.All eight cases were missense mutations,of which five cases were new mutations and the performance of three hereditary mutations was still different.Four reported pathogenic mutations and four unreported mutations were identified.Three of the eight cases had hot spot recurrence mutations,T767 I,G1475R,and N1877 S.The mutation sites located at NA1.6 channel included transmembrane region in three cases(DI(S3-S4),DII(S1)and DIV(S3).One case was located in the cytoplasmic ring 1 di(S6)-DII(S1);One case was located in the loss valve DIII(S6)-DIV(S1);The phenotypes of the 3 mutations located in the C-terminal were also different.Conclusion: 1.The clinical manifestations of patients with SCN8A gene mutation epilepsy were complex and variable,and they could present a series of clinical phenotypes of benign familial infantile epilepsy with good prognosis,intermediate type and severe epileptic encephalopathy.2.The mutation mode of SCN8A gene was mainly new mutation,and a few were genetic heterozygous variation,and non-genetic mutation could be seen.3.Mild to severe epileptic encephalopathy might appear due to new mutation.Hereditary heterozygous mutations might also present as manifestations of epileptic encephalopathy.There was no correlation between mutation pattern and phenotype.4.SCN8A gene mutation at the same site might occur with different severity manifestations.5.The mutation of SCN8A gene at the same locus had different amino acid substitution changes,and might also had different manifestations.6.Hot spot recurrence and mutation exist,but phenotypic differences also exist.7.Mutations at different sites within the same domain might had different clinical manifestations,and mutations at the same site within the same domain might also had different manifestations.There was no phenomenon that different domains had corresponding specific clinical manifestations.Moreover,there was no correlation between mutation type and source and domain position.8.The missense mutations were the main mutation types,together with the frameshift,truncated,and nonsense mutations,exon deletion,change of start codon.The phenotypes of different mutation types were still different and not specific.9.Oxcarbazepine was the most effective sodium channel blocker,and ketogenic therapy could be used for children with refractory epilepsy.