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Objective To summarize the clinical phenotype and gene mutation characteristics of early epileptic encephalopathy caused by STXBP1 gene mutation and the application of second-generation gene sequencing in etiological diagnosis.Methods Retrospective analysis of clinical characteristics,gene test results,treatment and efficacy of 19 children with epileptic encephalopathy with genetic diagnosis of STXBP1 gene mutation who were seen in the Department of Pediatrics of the Second Hospital of Zhejiang University School of Medicine from January 2017 to January 2021.Results The disease started within 1 month after birth in 15 children(78.9%).All 19 children had significant electro-encephalo gram(EEG)changes:13 cases of burst suppression(68.4%)and high arrhythmia in 12 cases(63.2%).A total of 18 pathogenic variants were detected in 19 children,all of them new,of which 7 loci have not been reported so far.Five children were diagnosed with Otahara syndrome,five with infantile spasms,and nine with an epileptic syndrome that could not be classified.At a follow-up of 6 months to 4 years and 5 months,1 case was discontinued,5 cases had complete remission of seizures,6 cases had partial remission,and 7 cases were ineffective.8 of the 12 children with seizure remission or control were treated effectively with combination levetiracetam,4 of the 6 children with spasms responded with the addition of vigabatrin,and 7 presented with drug refractory epilepsy.All 19 children had varying degrees of developmental delay.Conclusion Mental-motor retardation and recurrent seizures are the main,independent phenotypic features of STXBP1-encephalopathy,STXBP1 gene variants are predominantly de novo variants,second-generation gene sequencing diagnosis helps in the early diagnosis of STXBP1-encephalopathy,levetiracetam and aminocaproic acid may be partially effective in controlling seizures in STXBP1-encephalopathy,and ketogenic diet provides new ideas for early-onset epileptic encephalopathy treatment provides a new idea.
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BACKGROUND@#Advanced technology has become a valuable tool in etiological studies of intellectual disability/global developmental delay (ID/GDD). The present study investigated the role of genetic analysis to confirm the etiology in ID/GDD patients where the cause of the disease was uncertain in central China.@*METHODS@#We evaluated 1051 ID/GDD children aged 6 months to 18 years from March 2009 to April 2017. Data concerning basic clinical manifestations were collected, and the method of etiology confirmation was recorded. Genome-wide copy number variations (CNVs) detection and high-throughput sequencing of exons in the targeted regions was performed to identify genetically-based etiologies. We compared the incidence of different methods used to confirm ID/GDD etiology among groups with differing degrees of ID/GDD using the Chi-square or Fisher exact probability test.@*RESULTS@#We recruited 1051 children with mild (367, 34.9%), moderate (301, 28.6%), severe (310, 29.5%), and profoundly severe (73, 6.9%) ID/GDD. The main causes of ID/GDD in the children assessed were perinatal factors, such as acquired brain injury, as well as single gene imbalance and chromosomal gene mutation. We identified karyotype and/or CNVs variation in 46/96 (47.9%) of cases in severe ID/GDD patients, which was significantly higher than those with mild and moderate ID/GDD of 34/96 (35.4%) and 15/96 (15.6%), respectively. A total of 331/536 (61.8%) patients with clear etiology have undergone genetic analysis while 262/515 (50.9%) patients with unclear etiology have undergone genetic analysis (χ = 12.645, P < 0.001). Gene structure variation via karyotype analysis and CNV detection increased the proportion of children with confirmed etiology from 51.0% to 56.3%, and second-generation high-throughput sequencing dramatically increased this to 78.9%. Ten novel mutations were detected, recessive mutations in X-linked genes (ATPase copper transporting alpha and bromodomain and WD repeat domain containing 3) and dominant de novo heterozygous mutations in X-linked genes (cyclin-dependent kinase like 5, protocadherin 19, IQ motif and Sec7 domain 2, and methyl-CpG binding protein 2) were reported in the study.@*CONCLUSIONS@#The present study indicates that genetic analysis is an effective method to increase the proportion of confirmed etiology in ID/GDD children and is highly recommended, especially in ID/GDD children with uncertain etiology.
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Background@#Advanced technology has become a valuable tool in etiological studies of intellectual disability/global developmental delay (ID/GDD). The present study investigated the role of genetic analysis to confirm the etiology in ID/GDD patients where the cause of the disease was uncertain in central China.@*Methods@#We evaluated 1051 ID/GDD children aged 6 months to 18 years from March 2009 to April 2017. Data concerning basic clinical manifestations were collected, and the method of etiology confirmation was recorded. Genome-wide copy number variations (CNVs) detection and high-throughput sequencing of exons in the targeted regions was performed to identify genetically-based etiologies. We compared the incidence of different methods used to confirm ID/GDD etiology among groups with differing degrees of ID/GDD using the Chi-square or Fisher exact probability test.@*Results@#We recruited 1051 children with mild (367, 34.9%), moderate (301, 28.6%), severe (310, 29.5%), and profoundly severe (73, 6.9%) ID/GDD. The main causes of ID/GDD in the children assessed were perinatal factors, such as acquired brain injury, as well as single gene imbalance and chromosomal gene mutation. We identified karyotype and/or CNVs variation in 46/96 (47.9%) of cases in severe ID/GDD patients, which was significantly higher than those with mild and moderate ID/GDD of 34/96 (35.4%) and 15/96 (15.6%), respectively. A total of 331/536 (61.8%) patients with clear etiology have undergone genetic analysis while 262/515 (50.9%) patients with unclear etiology have undergone genetic analysis (χ2 = 12.645, P < 0.001). Gene structure variation via karyotype analysis and CNV detection increased the proportion of children with confirmed etiology from 51.0% to 56.3%, and second-generation high-throughput sequencing dramatically increased this to 78.9%. Ten novel mutations were detected, recessive mutations in X-linked genes (ATPase copper transporting alpha and bromodomain and WD repeat domain containing 3) and dominant de novo heterozygous mutations in X-linked genes (cyclin-dependent kinase like 5, protocadherin 19, IQ motif and Sec7 domain 2, and methyl-CpG binding protein 2) were reported in the study.@*Conclusions@#The present study indicates that genetic analysis is an effective method to increase the proportion of confirmed etiology in ID/GDD children and is highly recommended, especially in ID/GDD children with uncertain etiology.
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Objective@#To explore the association between the phenotype and KCNB1 gene mutation.@*Method@#Clinical information including physical features, laboratory and genetic data of one patient of mental retardation with refractory epilepsy from Department of Pediatrics, Xiangya Hospital in January 2016 was analyzed. This patient was discovered to have KCNB1 gene mutations through whole exome sequencing. Relevant information about KCNB1 gene mutation was searched and collected from Pubmed, CNKI, Human Gene Mutation Database(HGMD) and Online Mendelian Inheritance in Man(OMIM). Searching was done using "KCNB1" as a keyword.@*Result@#A 3.5 years old boy who visited our hospital firstly at the age of 2 years because of development delay came for follow up as he developed seizures.The forms included tonic, clonic seizures and spasm. The condition became more severe 10 months later. Electroencephalogram(EEG) showed high frequency discharge (>85%). He had poor response to multiple anti-epileptic drugs, methylprednisolone and ketogenic diet. At the age of 3, he started to have mental regression. Whole exome-sequencing study (trios) identified a novel heterozygous mutation c. G1136T (p.G379V) in KCNB1, which is not available in the databases mentioned above. This is the first case report of KCNB1 gene mutation in China. Eight cases have been reported so far worldwide and all of them were diagnosed with refractory epilepsy. Those 8 reported cases of encephalopathy were all due to de novo mutation.@*Conclusion@#The main clinical features of patients with KCNB1 mutations include severe to profound intellectual disability, intractable seizures, hypotonia and regression of cognition and motor activity which lead to poor prognosis.
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Objective To explore the clinical features,genetic causes and prognosis of intellectual disability with epilepsy(ID-E)in children.Methods The data of unknown causes of ID-E children(n=40)who were identified in Department of Pediatrics,Xiangya Hospital of Central South University from March 2015 to March 2016 were respectively analyzed,and follow-up studies were performed to investigate the epilepsy control and intellectual deve-lopment.Results Forty unexplained ID-E included 25(62.5%)male,and 34(85.0%)cases were severe intellectual disability patients.The onset age of epilepsy was 0.16 to 8.00 years old,median age was 1.5 years old.Twenty cases(50.0%)had slow electroencephalogram background,and 22 cases(55.0%)had focal spikes.Ten cases(25.0%)had abnormal cranial images,with brain dysplasia or atrophy.Follow-up lasted from 0.58 to 1.58 years,and 19 cases(47.5%)had seizure control.Twenty-five cases(62.5%)had used at least 2 anti-epilepsy drugs during follow-up,and 19 cases(47.5%)had drug refractory epilepsy.Improvement of mental or motor development in epilepsy controlled group and the uncontrolled group were 12 cases(63.2%)and 2 cases(9.5%).There were separately 8 cases(8/40 cases,20.0%)and 3 cases(3/16 cases,18.8%)diagnosed respectively by whole genome-wide analysis of copy number variants(CNVs)and gene-panel whose CNVs test findings were negative.Conclusions ID-E patients of unknown causes have the following clinical features:they were mostly found in male patients with severe intellectual disability,and drug refractory epilepsy patients have rather high percentage;well controlling of epilepsy is useful for improvement of mental and motor development.Genetic analysis is significant for control and prognosis of ID-E patients,and genome-wide CNVs have high positive rates which can be used as first-tier test to detect genetic etiology of ID-E of unknown cause.
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Intellectual disability is a genetically heterogeneous disease,however,more than half of the genetic etiologies still remain unexplained.Since whole exome sequencing is applied for intellectual disability,a mature work flow has been established,which firstly discovered some important causative genes.This paper reviews the application,advantages and disadvantages of whole exome sequencing for sporadic,unexplained intellectual disability.
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OBJECTIVE@#To investigate the effects of pectic polysaccharides extracted from Rauwolfia verticillata (Lour.) Baill.var.hainanensis Tsiang on an experimental murine colitis model.@*METHODS@#Experimental colitis was induced by dextran sulfate sodium (DSS), and mice were divided into 4 groups: control, DSS alone, DSS plus SASP, DSS plus pectic polysaccharides. The disease activity index (DAI) and histological score were observed. The tumor necrosis factor (TNF)- α and interleukin (IL)-17 levels were measured by enzyme-linked immunosorbent assay. I κ B and NF- κ B p65 expression were assessed by western blot analysis. Myeloperoxidase (MPO) activity was determined by using MPO assay kit.@*RESULTS@#Administration of pectic polysaccharides significantly reduced the severity of DSS-induced colitis as assessed by DAI and histological score, and resulted in down regulation of MPO activity and NF- κ B p65 expression and subsequent degradation of I κ B protein, strikingly reduced the production of TNF- a and IL-17.@*CONCLUSIONS@#Pectic polysaccharides extracted from Rauvolfia verticillata (Lour.)Baill.var. hainanensis Tsiang exerts beneficial effects in experimental colitis and may therefore provide a useful therapeutic approach for the treatment of UC.
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Objective: To investigate the effects of pectic polysaccharides extracted from Rauwolfia verticillata (Lour.) Baill.var.hainanensis Tsiang on an experimental murine colitis model. Methods: Experimental colitis was induced by dextran sulfate sodium (DSS), and mice were divided into 4 groups: control, DSS alone, DSS plus SASP, DSS plus pectic polysaccharides. The disease activity index (DAI) and histological score were observed. The tumor necrosis factor (TNF)- α and interleukin (IL)-17 levels were measured by enzyme-linked immunosorbent assay. I κ B and NF- κ B p65 expression were assessed by western blot analysis. Myeloperoxidase (MPO) activity was determined by using MPO assay kit. Results: Administration of pectic polysaccharides significantly reduced the severity of DSS-induced colitis as assessed by DAI and histological score, and resulted in down regulation of MPO activity and NF- κ B p65 expression and subsequent degradation of I κ B protein, strikingly reduced the production of TNF- a and IL-17. Conclusions: Pectic polysaccharides extracted from Rauvolfia verticillata (Lour.)Baill.var. hainanensis Tsiang exerts beneficial effects in experimental colitis and may therefore provide a useful therapeutic approach for the treatment of UC.