Case report of early-onset epileptic encephalopathy caused by compound heterozygous mutation of the WWOX gene / 中华实用儿科临床杂志

Clinical data of a case with early-onset epileptic encephalopathy admitted in the Department of Neuroendocrinology, Jinan Children′s Hospital in April 2020 were retrospectively analyzed.A 1-month-old male patient was hospitalized for convulsion for 4 days.The child had repeated seizures in the form of tonic and tonic-spasm seizures, accompanied by feeding difficulties, slow weight gain, and overall developmental delay.Electroencephalogram showed multifocal discharge, atypical hypsarrhythmia, and brain magnetic resonance imaging showed delayed myelination.The whole exome sequencing showed compound heterozygous mutation of the WWOX gene.Topiramate, Levetiracetam and Valporate were ineffective to this case.Genetic testing should be performed timely in patients with early-onset epileptic encephalopathy and overall developmental delay to make a clear etiology and prognosis, thus guiding prenatal diagnostics and genetic counseling.

Early-onset epileptic encephalopathy caused by the UBA5 gene mutation: a case report and literature review / 中华实用儿科临床杂志

Objective:To explore the clinical and genetic characteristics of a case of early-onset epileptic encephalopathy caused by the UBA5 gene mutation and to review relevant literatures. Methods:The clinical characte-ristics and genetic data of a child with the UBA5 gene mutation in the Department of Pediatrics, the Third Affiliated Hospital of Zhengzhou University in June 2020 were retrospectively analyzed.Clinical characteristics and gene variation characteristics of the disease were reviewed in the domestic and foreign databases. Results:(1) The female patient presented infantile spasms at the age of 4 months.Electroencephalogram(EEG) suggested hypsarrhythmia and she was not responsive to a variety of anti-epileptic drugs.Besides, the patient showed severe cognitive and motor development delay, hypotonia, and microcephaly.The results of whole exome sequencing showed that the compound heterozygous mutation of UBA5 gene: exon 3 c. 214C>T (p.R72C) and exon 9 c. 844_c.845 insA (p.Y282Xfs*1), her father carries c. 214C>T mutation and her mother carries c. 844_c.845 INSA mutation.(2) To December 2020, a total of 15 cases of early-onset epileptic encephalopathy caused by the UBA5 gene mutation have been reported abroad.The main clinical manifestations were uncontrollable spasms, abnormal EEG findings, hypotonia, severe cognitive and movement disorders, microcephaly, and brain atrophy.A total of 11 mutation sites of the UBA5 gene were found, all belonging to the autosomal recessive inheritance, of which c. 1111G>A was the most common. Conclusions:The UBA5 gene mutation can lead to early-onset epileptic encephalopathy, which belongs to the autosomal recessive inheritance.It is featured by the early onset, uncontrollable seizures and poor long-term prognosis.

Clinical features and genetic analysis of the early-onset epileptic encephalopathy caused by sodium channel mutations / 中华实用儿科临床杂志

Objective:To explore the clinical phenotype characteristics of early-onset epileptic encephalopathy (EOEE) caused by sodium channel mutations.Methods:A retrospective study was used.A total of 52 EOEE patients treated in the Department of Neurology, Children′s Hospital of Fudan University and Department of Neurology, Wuhan Children′s Hospital, Tongji Medical College, Huazhong University of Science & Technology from June 2016 to June 2019 were recruited.Peripheral blood samples of 52 patients and their parents were collected for analyzing pathogenic mutations by the next generation sequencing and copy number variations of whole exons in family. Chi- square test was used to compare seizure control data among different voltage-gated sodium channel α1 subunit ( SCN1A) mutation types. Results:A total of 35/52 cases (67.3%) were diagnosed as Dravet syndrome, 3/52 cases (5.8%) were West syndrome, and 14/52 cases (26.9%) were non-symptomatic EOEE.The electroencephalogram (EEG) findings showed a large number of multifocal spikes, spike-slow waves, sharp waves, and sharp-slow waves.A total of 45/52 cases (86.5%) showed normal brain magnetic resonance imaging(MRI), 1 case had slightly widened bilateral frontal sulcus, 1 case had widened bilateral temporal pole and frontal top subarachnoid space, and the remaining 5 cases had widened extracerebral space and slightly larger ventricles.Thirteen cases were re-examined with brain MRI, and 3 cases had mild brain atrophy.A total of 43/52 cases (82.7%) were examined with SCN1A gene mutations, of which 28/52 cases (53.8%) were missense mutations, 5/52 cases (9.6%) were nonsense mutations, 7/52 cases (13.5%) were frameshift mutations and 3/52 cases (5.8%) were splice site mutations.A total of 3/52 cases (5.8%) had SCN2A mutations, of which 2/52 cases (3.8%) were missense mutations, and 1/52 case (1.9%) was a frameshift mutation, 1/52 cases (1.9%) carrying the missense mutation of the SCN3A gene.A total of 5/52 cases (9.6%) had missense mutations of the SCN8A gene.After an average of 1-year follow-up, a total of 13/52 cases (25.0%) had more than 1-year control of seizure, of which 6/52 cases (11.5%) with seizure control for more than 2 years, and 4/52 cases (7.7%) with more than 3-year control.Children carrying SCN1A missense mutations were relatively easier to be controlled for seizures than those carrying SCN1A truncation mutations (nonsense mutations+ frameshift mutations) ( P<0.05). In 5 children carrying SCN8A mutations, 2 cases of them had seizures control for more than 1 year after adding Oxcarbazepine, but the improvement of mental motor function was not obvious. Conclusions:In children with EOEE associated with sodium channel gene mutations, SCN1A, SCN2A, SCN3A, and SCN8A mutations were pathogenic factors.Among them, SCN1A was the most common pathogenic gene for EOEE, with the mutation rate of 82.7%.Dravet syndrome was the most common clinical phenotype of EOEE associated with sodium channel gene mutations.Epileptic seizures in children carrying SCN1A missense mutations were easier to be controlled than those with truncated mutation (nonsense mutations + frameshift mutations), suggesting that the gene mutation type was related to the degree of seizures control.Oxcarbazepine was effective in the treatment of EOEE with SCN8A gene mutations, indicating that the combination therapy using anti-epilepsy drugs can be applied to EOEE patients according to the type of gene function.

Clinical features and ion channel gene mutations analysis in 17 cases of early﹣onset epileptic encephalopathy / 中华实用儿科临床杂志

Objective To analyze the clinical characteristics and gene mutations of early －onset epileptic encephalopathy(EOEE)caused by ion channel gene mutation,to identify the etiology,to guide the treatment and to pro﹣vide the basis for genetic counseling. Methods The clinical data from 17 children with EOEE caused by ion channel gene mutation and the peripheral blood of the children and their parents were collected from June 2014 to May 2018 at the Department of Neurology,Tianjin Children′s Hospital. Epilepsy gene sequencing was performed by using disease gene targeting second generation sequencing technology. The mutation of pathogenic ion channel gene was found. The confirmed mutations were verified by Sanger sequencing and the source of the mutation was identified. Results Among 17 case with EOEE,3 cases had genetic mutation,and 14 cases had denovo mutations. Dravet syndrome was found in 8 cases(47. 1﹪),there were SCN1A gene missense mutation in 5 cases,SCN1A gene nonsense mutation in 3 cases, KCNQ2 gene missense mutation in 1 case(5. 9﹪)and non－specific epileptic encephalopathy in 8 cases(47. 1﹪). SCN2A gene missense mutation,SCN4A gene missense mutation,SCN8A gene missense mutation,KCNQ2 gene missense mutation and KCNH gene missense mutation were found in suspected pathogenic mutations. There were 1 missense mu﹣tation out of 5 genes,1 missense mutation of CACNA1A gene,1 missense mutation of GRIN2A gene and 1 missense mu﹣tation of GRIN3A gene. Seventeen patients were treated with 2 or more antiepileptic drugs,4 with ketogenic diet and 1 with vitamin B6 supplementation. During 11 to 96 months of follow－up,seizures were completely controlled in 3 cases (17. 6﹪),decreased in 7 cases(41. 2﹪)by more than 50﹪,and decreased in 7 cases(41. 2﹪)by less than 50﹪. Conclusions The clinical phenotypes for children with unexplained EOEE are varied,and gene mutations of ion cha﹣nnel are most common. Some gene sites are denovo mutations which have not been reported such as missense mutation for 3 case SCN1A gene,1 case SCN2A gene,1 case CACNA1A gene,1 case KCNH5 gene,and nonsense mutation for 2 case SCN1A gene,which have enriched the mutation spectrum of EOEE.

Clinical features and ion channel gene mutations analysis in 17 cases of early-onset epileptic encephalopathy / 中华实用儿科临床杂志

Objective@#To analyze the clinical characteristics and gene mutations of early-onset epileptic encephalopathy(EOEE) caused by ion channel gene mutation, to identify the etiology, to guide the treatment and to provide the basis for genetic counseling.@*Methods@#The clinical data from 17 children with EOEE caused by ion channel gene mutation and the peripheral blood of the children and their parents were collected from June 2014 to May 2018 at the Department of Neurology, Tianjin Children′s Hospital.Epilepsy gene sequencing was performed by using disease gene targeting second generation sequencing technology.The mutation of pathogenic ion channel gene was found.The confirmed mutations were verified by Sanger sequencing and the source of the mutation was identified.@*Results@#Among 17 case with EOEE, 3 cases had genetic mutation, and 14 cases had denovo mutations.Dravet syndrome was found in 8 cases (47.1%), there were SCN1A gene missense mutation in 5 cases, SCN1A gene nonsense mutation in 3 cases, KCNQ2 gene missense mutation in 1 case (5.9%) and non-specific epileptic encephalopathy in 8 cases (47.1%). SCN2A gene missense mutation, SCN4A gene missense mutation, SCN8A gene missense mutation, KCNQ2 gene missense mutation and KCNH gene missense mutation were found in suspected pathogenic mutations.There were 1 missense mutation out of 5 genes, 1 missense mutation of CACNA1A gene, 1 missense mutation of GRIN2A gene and 1 missense mutation of GRIN3A gene.Seventeen patients were treated with 2 or more antiepileptic drugs, 4 with ketogenic diet and 1 with vitamin B6 supplementation.During 11 to 96 months of follow-up, seizures were completely controlled in 3 cases (17.6%), decreased in 7 cases (41.2%) by more than 50%, and decreased in 7 cases (41.2%) by less than 50%.@*Conclusions@#The clinical phenotypes for children with unexplained EOEE are varied, and gene mutations of ion cha-nnel are most common.Some gene sites are denovo mutations which have not been reported such as missense mutation for 3 case SCN1A gene, 1 case SCN2A gene, 1 case CACNA1A gene, 1 case KCNH5 gene, and nonsense mutation for 2 case SCN1A gene, which have enriched the mutation spectrum of EOEE.

Clinical features analysis in 5 children of early onset epileptic encephalopathy with dyskinesia / 中国实用儿科杂志

OBJECTIVE: To investigate the clinical phenotype of children with early-onset epileptic encephalopathy and dyskinesia. METHODS: The patients with early onset epileptic encephalopathy and dyskinesia were enrolled from September 2013 to September 2017. The clinical data was retrospectively analyzed. RESULTS: A total of 5 children with early onset epileptic encephalopathy with dyskinesia were collected. Including 1 male and 4 females. 1 case of dyskinesia showed dancing-like movements,2 cases of dyslexia,ataxia mixed,1 case of limb tremor accompanied by wrist alternating twisting action,1 case of muscle tension associated with tremor,speech is unclear. 4 cases were positive for 1 genotype,1 case was mutation of SCN1A gene,2 cases were PRRT2 gene mutation,1 case was SLC2A1 gene mutation. After treatment,2 cases of seizure control effect is good,3 cases of poor results. CONCLUSION: Early onset epileptic encephalopathy with dyskinesia is easy misdiagnosed as epileptic seizures. Genetic associated with the pathogenic genes are mostly reported in the previous gene,PRRT2 gene,SLC2A1 gene mutation. Early onset of epilepsy with dyskinesia caused by SCN1A gene mutation has rarely been reported in the literature. Some children enjoy good results.

Clinical features and genetic analysis of early-onset epileptic encephalopathy with pachygyria-lissencephaly / 中华实用儿科临床杂志

Objective To study the clinical phenotype and prognosis of children diagnosed with early-onset epileptic encephalopathy (EOEE) and pachygyria-lissencephaly,and to explore the potential genetic factors.Methods The clinical data of 65 children between December 2005 and December 2016 was obtained and analyzed.And the whole exome sequencing was analyzed by using second generation sequencing technology.Results Among 65 children,17 cases (26.1％) were diagnosed as lissencephaly,34 cases (52.3 ％) were pachygyria,and 14 cases (62.6％)were pachygyria with lissencephaly.Thirteen cases (20.0％) were infantile spasms,9 cases (13.8％) were ohtahara syndrome,3 cases (4.6％) were early myoclonic epileptic encephalopathy,and 40 cases (61.6％) were non-symptomatic EOEE.Six cases (6/65 cases,9.2％) were associated with dyskinesia,of whom 3 cases showed dystonia,2 cases of limb tremor,1 case of dancing-like movements.Electroencephalophalogram (EEG) showed serious multifocal discharge,40 cases had massive multifocal discharge.Brain images showed that simple pachygyria was more common (34/65 cases,52.3 ％).Among them,focal pachygyria was more common (25/34 cases,73.5 ％),mostly involving in the frontoparietal lobe (11/25 cases,44.0％).Copy number variations and whole exon sequencing were performed on 61 patients.Copy number variation was detected in 1 patient.There were 2 cases of lissencephaly-1/platelet-activating factor acetylhydrolase isoform 1B (LIS1/PAFAH1B1) mutation,1 case of syntaxin-blinding protein 1 (STXBP1)mutation,1 case of Aristaless-related homeobox (ARX) mutation,and 1 case of dynein cytoplasmic 1 heavy chain 1(DYNC1H1) mutation.The follow-up time varied from 1 year to 8 years [(3.5 ± 1.4) years],in which 20 cases had clinical seizures under control but 45 cases out of control.Conclusion Infantile spasms and non-syndromic EOEEare more common in children diagnosed with EOEE and pachygyria-lissencephaly.A small number of cases have dyskinesia.EEG shows serious abnormalities,mostly multifocal discharge.Brain images show simple pachygyria is more common,mostly involving in the frontoparietal lobe.Common gene mutations are LIS1/PAFAH1B1,STXBP1,ARX.Gene mutations can lead to both clinical manifestations of cortical deformity and EOEE,and genetic factors play an important role in children with brain developmental deformity and epilepsy.

Research advances in early-onset epileptic encephalopathy / 国际儿科学杂志

Early-onset epileptic encephalopathy (EEE) represents a group of devastating epileptic disorders that appear in neonatal or infantile period of life,characterized as pharmacoresistant generalized or focal seizures,severe electroencephalography (EEG) abnormalities,mental retardation and behavioral impairments.The interictal epileptic discharges are age-dependent and closely related to cognitive deterioration.EEE includes five epileptic syndromes,which are early myoclonic encephalopathy,ohtahara syndrome,and malignant migrating partial seizures in infancy,West syndrome and Dravet syndrome.The etiologies of EEE are highly heterogeneous,and most of them remain unknown.In many cases with EEE,seizures are resistant to treatment including anti-epileptic drugs and other methods.The prognosis for EEE is poor,and most of the children have severe mental retardation,some even are under the risk of sudden death.