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Objective:To study the clinical and genetics features of two families with dentatorubral-pallido-luysian atrophy (DRPLA), and to summarize the correlation between genotypes and phenotypes.Methods:The peripheral blood, clinical data and auxiliary examination results of probands and related members in 2 families with hereditary epilepsy and ataxia were collected from July 2018 to March 2019 in Peking University First Hospital.By whole exome sequencing and detecting the cytosine-adenine-guanine (CAG) repeats with capillary electrophoresis and fragment analysis, the genetic testing was conducted on the probands and their family members.The clinical and genetic characteristics of all affected members in the 2 families were also analyzed.Results:Two families were diagnosed with DRPLA.All 11 patients presented with psychomotor retardation, and 7 of them had seizures (including myoclonus, focal seizures and generalized tonic-clonic seizures, etc.). There were significant differences in clinical manifestations among different patients in the same family, and the filial generation had seizures at an earlier age with a more severe phenotype than the parental generation.The youngest onset age was 2 years old, and the largest was 45 years old.Five cases had seizures in childhood.Of the 11 patients, 5 cases were deceased, and the cause of death included seizure attacks, sudden unexpected death in epilepsy (SUDEP) and disease progression.The number of CAG repeat times in the fifth exon of the ATN1 gene were found abnormal in 6 surviving patients.The grandfather of the proband in pedigree 2 had normal clinical manifestations, but he also showed abnormal CAG repeats in the fifth exon of the ATN1 gene, which might be an intermediate allele. Conclusions:DRPLA is mainly featured by epilepsy, ataxia, psychomotor retardation and anticipation in clinical.This disease is rare in children with seizures as the first symptom, and has poor prognosis.An early diagnosis can facilitate genetic counseling.
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Objective@#To summarize the clinical phenotypes of epilepsy in patients with GABRA1 gene variants.@*Methods@#A total of 11 epileptic patients (4 boys and 7 girls) who were treated in the Department of Pediatrics, Peking University First Hospital from March 2016 to July 2019 and detected with GABRA1 gene heterozygous pathogenic variants by targeted next-generation sequencing were enrolled. The features of clinical manifestations, electroencephalogram (EEG), and neuroimaging were analyzed retrospectively.@*Results@#A total of 11 epileptic patients carried GABRA1 gene pathogenic variants, of whom 10 were de novo variants and the other one was inherited from the patient′s mother. Two patients had the same variants. Six variants were novel. Ages at seizure onset ranged from 3 to 14 months, and the median age was 8 months. The seizure was first observed within 1 year in 10 patients and beyond 1 year of age in 1 patient. Multiple seizure types were observed, including focal seizures in 10 patients, generalized tonic clonic seizures (GTCS) in 3 patients, myoclonic seizures in 3 patients, and epileptic spasm in 2 patients. There were 5 patients with multiple seizure types. Sensitivity to fever was observed in 9 patients, among whom 6 patients had a history of status epilepticus. Two patients had photoparoxysmal response. Five patients had abnormal EEG background, and 6 patients had abnormal discharges in EEG during interictal phase. Brain magnetic resonance imaging (MRI) was normal in all patients. Developmental delay in various degrees was present in 9 patients. Among the 11 patients, Dravet syndrome was diagnosed in 5 patients, West syndrome in 2 patients, undiagnosed early-onset epileptic encephalopathy in 1 patient, and focal epilepsy in the other 3 patients. The ages at the last follow-up ranged from 8 months to 12 years. During follow-up, 8 patients were seizure-free for 6 months to 8 years, and 1 patient had discontinuation of medication.@*Conclusions@#In epilepsy associated with GABRA1 gene variants, de novo pathogenic variants are more common than inherited. Most epilepsy caused by GABRA1 gene variants occurs in infancy. Most patients have multiple seizures and focal seizures are common. Most patients have a comparatively favorable prognosis, but they may still have varied degrees of developmental delay.
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Objective@#To analyze the clinical phenotypes of epilepsies in children with GABRB2 variants.@*Methods@#Data of 8 epileptic patients with heterozygous GABRB2 variants were retrospectively collected at the Department of Pediatrics, Peking University First Hospital from April 2016 to December 2018. The clinical, electroencephalographic, neuroimaging characteristics, therapeutic and follow-up were analyzed.@*Results@#Eight patients (4 boys, 4 girls) with heterozygous GABRB2 gene pathogenic variants were enrolled. Eight patients had different GABRB2 variants, among whom 2 patients inherited the variants from either parent, and the other 6 patients had de novo variants. Seven variants were novel. Ages at seizure onset ranged from 1 day to 22 months after birth, and the median age was 6 months. The seizure was first observed within one month of age in 2 patients, 1-6 months in 2 patients, 7-12 months in 2 patients, and beyond 1 year of age in 2 patients. Multiple seizure types were observed, including focal seizures in 6 patients, generalized tonic clonic seizures (GTCS) in 4 patients, myoclonic seizures in 3 patients, and epileptic spasm in 2 patients. Developmental delay was present in 6 patients. In 8 patients, Dravet syndrome was diagnosed in 3 patients, febrile seizures plus and West syndrome in 2 patients, respectively, Ohtahara syndrome in 1 patient. Six patients had epilepsy with fever sensitivity, and status epilepticus developed in all these patients. The ages at the last follow-up ranged from 8 months to 11 years, and the follow-up data showed that 5 patients were seizure-free, and 2 patients still had seizures, and 1 patient died of recurrent status epilepticus complicated with fungal infection.@*Conclusions@#Epilepsies associated with GABRB2 variants were characterized by an onset in infancy, and the clinical features were heterogenous in seizure types and severities. Most patients had multiple seizures with fever sensitivity, and status epilepticus was common. Their seizures were easily induced by fever or infection. Additionally, the majority of the patients had varying degrees of developmental delay.
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Objective@#To summarize the clinical phenotype and genotype features of 3 children with progre-ssive myoclonic epilepsy (PME) caused by KCNC1 gene mutations, and to review the related literatures.@*Methods@#The phenotype and genotype of 3 children with KCNC1 mutations in the Department of Pediatrics, Peking University First Hospital from October 2016 to January 2019 were analyzed.The 25 patients with KCNC1 mutations which had been reported internationally were also collected and analyzed.@*Results@#Three children in this study were identified with KCNC1 de novo mutations, in which 2 children were identified with c. 959G>A (p.Arg320His) mutation, and 1 child with c. 1262C>T (p.Ala421Val) mutation.The clinical features of 3 children were consistent with PME, and the seizure onset ages were 3 months, 10 years and 11 years, respectively.Three children all had myoclonic seizures, among whom 1 child had generalized tonic-clonic seizure and 2 children had focal seizures.Three children all had intellectual and/or motor development delay.The electroencephalograph showed generalized spike and waves or polyspike and waves in 3 children, and focal discharge in 2 children.The brain imaging of 3 children was normal.The last follow-up ages were 3 years old, 13 years old and 12 years old, respectively.Until March 2019, there were 25 cases with KCNC1 gene mutations reported internationally.Including 3 patients in this study, there were 28 patients in total, of which 25 patients were diagnosed with PME.In these 25 patients, 24 patients were identified with p. Arg320His variant in the transmembrane area, 1 patient was identified with p. Ala421Val variant in the transmembrane area.The remaining 3 patients were only found with psychomotor developmental delay without seizures, and they were identified with p. Arg339X variant in the intracellular area.In the 28 patients, 16 cases received cranial imaging data, in which 12 patients had ce-rebellar atrophy and 4 cases were normal.Of the 28 patients, 18 cases were mentally retarded, 27 cases were development retardation or retrogression among whom 9 cases could not walk independently.Ten patients were over 30 years old when reported, and only 1 patient died of pneumonia and respiratory failure at 63 years old.@*Conclusions@#KCNC1 gene mutation mainly leads to PME phenotype, and a few patients can only show mental retardation.p.Arg320His is the most common variant of KCNC1 gene.The variants in different structural regions result in different clinical phenotypes, and variants in the transmembrane region can lead to severer clinical phenotypes.The 3 patients with KCNC1 gene mutations in this study are firstly reported cases in China.
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Objective@#To analyze the clinical characteristics of patients with PCDH19-female limited epilepsy (PCDH19-FE).@*Methods@#The clinical data of 60 female epilepsy patients with PCDH19 gene heterozygous variations at the Department of Pediatrics, Peking University First Hospital from October 2007 to December 2018 were collected and analyzed retrospectively, their clinical manifestations, accessory examination and follow-up treatment were summarized.@*Results@#Data of a total of 60 cases of PCDH19-FE were collected. The seizure onset occurred between 4 and 42 months of age (median: 11 months of age). Focal seizures occurred in 47 patients (78%), generalized tonic-clonic seizures (GTCS) occurred in 30 patients (50%), and other rare types of seizures included atypical absence, myoclonic, clonic, tonic, and atonic seizures. Two or more seizures types existed in 24 patients (40%), and seven patients (12%) had attacks of status epilepticus. Sensitivity to fever was observed in 47 out of them (78%) and clustering of seizures as found in all patients. During the interictal phase, focal discharges were monitored in 22 cases (22/45, 49%), multifocal discharges in 12 cases (12/45, 27%), widely discharging in 2 cases (4%), and both focal and widely discharging in 9 cases (20%). Clinical seizures were detected in 30 patients during the electroencephalogram (EEG) recording, including focal seizures in 22 cases, GTCS seizures in 8 cases, tonic seizure in three cases, myoclonic seizure followed by GTCS in one case, and two types of seizures in four cases. Before seizure onset, 57 patients had normal development and three patients had delayed language development. After seizure onset, varied degrees of intelligence disability were present in 38 cases (63%), language delay in 36 cases (60%), and gait instability in 10 cases (17%). Autistic features occurred in 17 cases (28%); and other behavioral problems like learning difficulties, personality, or emotional disorders existed in 33 cases (55%). Age at last follow-up ranged from one year and 3 months to 22 years and 3 months of age, 17 patients (28%) were seizure-free for more than 2 years (5 to 22 years at the last follow-up). The efficiency of antiepileptic drugs were 65% (33/51) in sodium valproate, 63% (27/43) in levetiracetam and 59% (20/34) in topiramate.@*Conclusions@#The clinical features of PCDH19-FE are characterized by clustering of seizures, focal seizures in most cases, sensitivity to fever mostly, focal discharges principally in EEG, varied degrees of intellectual disability or movement disorder, combined with autism spectrum disorders in partial and high efficiency in sodium valproate or levetiracetam treatment.
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Objective@#To reveal the clinical and genetic features of neonatal/infantile epileptic disorders caused by KCNQ2 mutations and to provide a clue for the treatment and prognosis evaluation.@*Methods@#Twenty-two patients were collected in the Department of Pediatrics, Peking University First Hospital from April 2007 to July 2016.The phenotype-genotype analysis was conducted of the neonatal/infantile epileptic patients in whom a KCNQ2 mutation was identified by the targeted next generation sequencing.@*Results@#Twenty-two de novo KCNQ2 missense mutations from 22 patients with neonatal/infantile epileptic disorders were found.These patients had an onset of epilepsy in early infancy (median age: 2 days). The seizure type of the first onset was mainly focal seizure.Atypical absence epilepsy, a novel phenotype of KCNQ2 mutation-induced epilepsies was found.The mortality of these patients was high, as 5 patients of the 22 patients died in the follow-up period, 4 of which might result from sudden unexpected death in epilepsy.In the 22 patients, 8 patients with anti-epileptic monotherapy became seizure-free.Of the 8 patients with a monotherapy, 3 patients were treated with valproic acid and no clinical onset was observed.@*Conclusions@#This study expands the phenotype of KCNQ2-related epileptic disorders.These patients have high mortality.Valproate acid is the potentially effective monotherapy for these patients.
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Objective To reveal the clinical and genetic features of neonatal/infantile epileptic disorders caused by KCNQ2 mutations and to provide a clue for the treatment and prognosis evaluation. Methods Twenty－two patients were collected in the Department of Pediatrics,Peking University First Hospital from April 2007 to July 2016. The phenotype－genotype analysis was conducted of the neonatal/infantile epileptic patients in whom a KCNQ2 muta﹣tion was identified by the targeted next generation sequencing. Results Twenty－two de noνo KCNQ2 missense muta﹣tions from 22 patients with neonatal/infantile epileptic disorders were found. These patients had an onset of epilepsy in early infancy(median age:2 days). The seizure type of the first onset was mainly focal seizure. Atypical absence epi﹣lepsy,a novel phenotype of KCNQ2 mutation－induced epilepsies was found. The mortality of these patients was high,as 5 patients of the 22 patients died in the follow－up period,4 of which might result from sudden unexpected death in epi﹣lepsy. In the 22 patients,8 patients with anti－epileptic monotherapy became seizure－free. Of the 8 patients with a monotherapy,3 patients were treated with valproic acid and no clinical onset was observed. Conclusions This study expands the phenotype of KCNQ2－related epileptic disorders. These patients have high mortality. Valproate acid is the potentially effective monotherapy for these patients.
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Objective@#To explore the correlation between ATP1A3 genotype and phenotype in children with alternating hemiplegia of childhood (AHC).@*Methods@#This was a retrospective study. The clinical data and peripheral blood DNA of AHC patients were collected in Peking University First Hospital from August 2005 to December 2017. ATP1A3 gene mutations were screened by Sanger sequencing or next generation sequencing (NGS). AHC patients were divided into difference groups according to different hotspot mutations. SPSS 23.0 was used to analyze the correlation between genotype and phenotype. Variance analysis was used to compare the measurement data between groups. Chi square test was used to compare the categorical data between groups. Kruskal-Wallis test was used to compare the unidirectional ordered data between groups. Least-significant difference(LSD) was used to compare the data between two groups.@*Results@#A total of 119 AHC patients were recruited, including 68 males and 51 females. The onset age of 113 (95.0%) patients was within 18 months. There were 119 cases (100.0%) with hemiplegic seizures, 109 cases (91.6%) with abnormal eyeball movements, 104 cases (87.4%) with dystonia, 31 cases (26.1%) with autonomic neurological symptoms, 31 cases (26.1%) with epileptic seizures and 117 cases (98.3%) with long-term developmental delay. In 113 patients (95.0%) with ATP1A3 gene mutations, 111 were de novo mutation and 2 were genetic mutations. A total of 39 mutation types were found, including 37 missense mutations and 2 deletion mutations. Seventeen of them were novel mutations. The three hotspot mutations were D801N (n=34, 30.1%), E815K (n=20, 17.7%) and G947R (n=13, 11.5%). The age of onset of D801N and E815K were earlier than G947R ((3.1±2.1)and (2.3±2.3)vs.(6.4±7.7) months, P=0.004 and 0.003). The age of first hemiplegic events of D801N and E815K were earlier than G947R((6.4±3.1) and (6.8±3.3) vs. (11.4±10.1) months, P=0.004 and 0.016). More patients with E815K mutations presented epilepsy than those with D801N (P=0.003) and G947R (P=0.001). More patients with E815K mutations presented greater motor and intellectual disability than the patients with D801N (P=0.001) and G947R mutations (P=0.001).@*Conclusions@#ATP1A3 gene is the main causative gene of AHC. Three hotspot mutations, D801N, E815K and G947R, were found. Hotspot mutation E815K is associated with the most severe phenotype, which presented an earlier age at the time of the first paroxysmal manifestation and first hemiplegic event, severer developmental delay and a greater proportion of epilepsy.
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Objective@#To summarize the clinical features of TBC1D24 gene mutations associated with epilepsy.@*Methods@#All the patients with TBC1D24 gene compound heterozygous mutations were retrospectively collected at the Pediatric Department of Peking University First Hospital from March 2015 to July 2017, and the features of clinical manifestations, electroencephalogram, and neuroimaging were analyzed.@*Results@#Eighteen cases with TBC1D24 gene compound heterozygous mutations were included. The age of seizure onset was 1 day to 8 months, and the median age was 90 days. Seizure types included generalized tonic-clonic seizures (GTCS) in 3 cases, focal seizures in 18 cases, myoclonus in 18 cases, and 17 cases had focal myoclonus and myoclonus status. The focal myoclonus involving one or multiple muscle groups, sometimes migrating and alternating, lasting up to minutes to several days, and could be terminated by sleep or sedation drugs. In 11 cases, myoclonus was exacerbated by fever or infections, and 2 cases developed into myoclonic status during infection, in a severe case with the loss of consciousness. The magnetic resonance imaging (MRI) of seven patients was abnormal, including cerebral atrophy or cerebellar atrophy with abnormal signals. Segment myoclonus was captured in 10 patients, but without correlated epileptiform discharges. There were ten cases had varying degrees of developmental delay, 7 were normal, and one patient died of status epilepticus at the age of 4 months. Three cases had hearing disorders. In the 18 patients, the clinical phenotype of 4 cases consisted of epilepsy of infancy with migrating focal seizures, 2 with progressive myoclonus epilepsies, 1 with Dravet syndrome, 1 with DOORS syndrome, and 3 with unclassified epileptic encephalopathy.@*Conclusions@#The clinical feature of TBC1D24 gene mutation related epilepsy was focal myoclonus, and tended to develop into myoclonic status epilepticus, and could be aggravated by infections, and terminated by sleep or sedation drugs. Mental retardation involved or not, neuroimaging could present with cerebral atrophy or cerebellar atrophy with abnormal signals.
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Objective@#To summarize the phenotype of epileptic children with SCN2A mutations.@*Methods@#Epileptic patients who were treated in the Pediatric Department of Peking University First Hospital from September 2006 to October 2017 and detected with SCN2A mutations by targeted next-generation sequencing were enrolled. Clinical manifestations of all patients were analyzed retrospectively.@*Results@#A total of 21 patients (16 boys and 5 girls) with SCN2A mutations were collected. Twenty-one SCN2A mutations were identified. Ten patients had mutations inherited from one of their parents and 11 patients had de novo mutations. The age of epilepsy onset was from 2 days to 2 years and 6 months: six patients with seizure onset in neonates (29%) , six patients with seizure onset between 1 month and 3 months of age (29%), three patients with seizure onset between 4 months and 6 months of age, two patients with seizure onset between 7 months and one year of age, and four patients with seizure onset beyond one year of age. Multiple seizure types were observed. The focal seizure was the most common seizure type which was observed in 18 patients (86%) . Spasm seizure was observed in 6 patients (29%) . Other seizure types were rare. In 19 patients, seizures manifested in clusters (90%) . In 3 patients, seizures manifested fever-sensitive. Nine of ten patients with inherited SCN2A mutations had normal development. However, all patients with de novo SCN2A mutations had mild or severer development delay. In 21 patients with SCN2A mutations, five were diagnosed with benign familial infantile epilepsy, 3 with benign familial neonatal-infantile epilepsy, 3 with Ohtahara syndrome, 3 with West syndrome, 2 with encephalopathy with early infantile onset epilepsy, one with febrile seizures plus, one with Dravet syndrome, one with encephalopathy with childhood-onset epilepsy, one with autism with epilepsy and one with intellectual disability with epilepsy.@*Conclusions@#The clinical features of patients with SCN2A mutations include that main seizure onset is the neonate and early infancy, and the main seizure type is the focal seizure, manifested in clusters. The large spectrum of SCN2A-related epilepsy, which not only includes epilepsy with a comparatively favorable prognosis, but also epileptic encephalopathy. De novo mutations often lead to severe phenotype with development delay.
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Objective@#To investigate the spectrum of mutations in families with benign familial neonatal-infantile epilepsy (BFNIE) .@*Methods@#Clinical data and peripheral blood DNA samples of all BFNIE probands and their family members were collected from Peking University First Hospital between December 2012 and April 2016. Clinical phenotypes of affected members were analyzed. Genomic DNA was extracted from peripheral blood samples with standard protoco1. Mutations in PRRT2 were screened using Sanger sequencing. For families that PRRT2 mutations were not detected by Sanger sequencing, candidate gene mutations were further screened by next-generation sequencing for epilepsy.@*Results@#A total of 7 families were collected. Of the 30 affected members, 15 were male and 15 were female. The age of epilepsy onset was from 2 days to 6 months. Genetic testing led to the identification of gene mutations in all families. One family had the PRRT2 hotspot mutation (c.649dupC). Three families had missense SCN2A mutations (c.2674G>A/p.V892I, c.2872A>G/p.M958V, and c.2627A>G/p.N876S) . Both c.2872A>G/p.M958V and c.2627A>G/p.N876S were novel SCN2A mutations. Three families had KCNQ2 mutations. Two of them had missense mutations (c.958G>A/p.V320I and c.998G>A/p.R333Q) . The KCNQ2 mutation c.958G>A/p.V320I was novel. One family had a gene deletion of KCNQ2, which also extended to the adjacent gene, CHRNA4; and the deletion involved all the exons of KCNQ2 and CHRNA4.@*Conclusions@#Mutations in KCNQ2, SCN2A, and PRRT2 are genetic causes of BFNIE in Chinese families. The detection rate for gene mutations is high in BFNIE families. KCNQ2 and SCN2A mutations are common in BFNIE families. SCN2A mutations (c.2872A>G/p.M958V and c.2627A>G/p.N876S) and KCNQ2 mutation (c.958G>A/p.V320I) are novel mutations.
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Objective To summarize the clinical and electroencephalogram features of neuronal ceroid lipofus-cinosis (NCL). Methods A retrospective analysis of the clinical phenotypes and electroencephalogram features of pa-tients diagnosed with NCL in Department of Pediatrics,Peking University First Hospital from February 2000 to August 2015 were conducted. Results Among the 30 patients,18 were male and 12 were female. The age of onset was between 9 months to 7 years old. The first symptoms included seizure in 22 patients,psychomotor developmental delay or regre-ssion in 7 cases,and visual loss in 1 case. Clinical manifestations included psychomotor regression in 29 cases,epilepsy in 28 cases,visual impairment in 19 cases,ataxia in 20 patients,and positive pyramidal tract sign in 13 cases. Twenty-one patients accepted fundus oculi examination. Seven patients were found with macular degeneration,8 cases with optic nerve atrophy,2 cases with retinal pigment degeneration,and 8 patients were normal. Brain atrophy were found in all 30 cases,including diffuse brain atrophy in 14 cases,only cerebellar atrophy in 6 cases,and cerebral atrophy with periven-tricular T2W high signal in 10 cases. Video electroencephalogram(EEG)examination was performed in 27 patients and their backgrounds were diffuse slow waves. Seven patients didn't have physiological vertex sharp waves or sleep spin-dles. Generalized epileptiform discharges were captured in 6 cases,focal epileptiform discharges in 15 cases. Both of generalized and focal epileptiform discharges were captured in 6 cases. Generalized slow wave burst in 4 cases,and in-termittent photic stimulation evoked epileptiform discharges in 3 cases. Ten patients were observed with clinical sei-zures,including 4 cases of myoclonic episodes,3 cases of atypical absences,3 cases of focal seizures,1 case of atonic and one of tonic spasms. Peripheral blood enzyme examination was taken in 13 patients,among whom 8 patients were identified with tripeptidyl peptidase 1 (TPP1)deficiency and 1 patient with palmitoyl protein thioesterase 1 (PPT1) deficiency. Twenty-eight patients accepted skin and/or muscle electron microscope examination. Osmiophilic granular was found in 2 cases,curvilinear bodies in 15 cases,fingerprint profiles in 2 cases,curvilinear and linear bodies in 1 case,fingerprint profiles and osmiophilic granular in 1 case. NCL-related gene detection was conducted in 3 patients, with 1 patient identified with CLN6 compound heterozygous mutations and 2 patients with TPP1 homozygous mutations. Thirty patients were classified into 3 groups based on the onset age,enzymatic examination results and pathological examination of skin and muscle,including 5 cases of infantile NCL,20 cases of late-infantile NCL,and 5 cases of juvenile NCL. Conclusions The clinical features of NCL included multiple types of epileptic seizures (among which myoclonus was the most common type),psychomotor developmental delay or regression,vision loss,ataxia,and positive pyramidal tract sign. Its MRI was characterized with brain atrophy. EEG showed diffuse slow wave activity,with focal and/or generalized epileptiform discharges. Specific enzyme examination,and skin or muscle pathology or gene test could help to make diagnosis.
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Objective To investigate the effective rate of Flunarizine in treating alternating hemiplegia during childhood (AHC) kids,and to analyze the related factors influencing efficacy.Methods The clinical data and peripheral blood DNA of AHC patients at the Outpatient and Inpatient Ward of Department of Pediatrics,Peking University First Hospital from August 2005 to May 2016 were collected,and the A TP1A3 gene mutations were screened.Clinical efficacy of oral administration of Flunarizine for improving paroxysmal symptoms such as alternating hemiplegia in AHC patients was followed up.Results A total of 96 AHC patients were collected,and among them,75 cases received oral administration of flunarizine were followed up for 1-11 years.The age of last follow-up was 1-21 years old (the median age was 5 years old).Fifty of these 75 patients (66.7％) were improved,while 25 patients were not alleviated (33.3％).In 50 improved patients,43 patients (86.0％) reduced the frequency of hemiplegia attacks,28 patients (56.0％) reduced the duration,and 3 patients (6.0％) alleviated the severity.Univariate analysis between the effective group and ineffective group showed that differences in age of onset,age of initial treatment,dose and carrying D801N,E815K or G947R mutation of ATP1A3 gene were not statistically significant(all P ＞0.05).The findings by multivariate analysis indicated that age of onset,age of initial treatment,dose and carrying D801N,E815K or G947R mutation of ATP1A3 gene were not related to the efficacy of Flunarizine.Conclusion Flunarizine is effective for most AHC children,which can reduce the frequency of hemiplegia attacks,shorten the duration,and alleviate the severity of attacks.Age of onset,age of initial treatment,dose and carrying D801N,E815K or G947R mutation of gene A TP1A3 are not factors influencing efficacy.
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Objective To investigate the gene mutations in benign familial neonatal epilepsy(BFNE) in China.Methods Data of all BFNE probands and their family members were collected from Peking University First Hospital from January 2012 to December 2013.Clinical phenotypes of affected members were analyzed.Genomic DNA was extracted from peripheral blood samples with standard protocol.Mutations in candidate genes mutations were further screened by next-generation sequencing.Results A total of 4 families were collected,from which there were 10 affected members,6 males and 4 females.The age of epilepsy onset was from 1 day to 4 days after birth.The age of last seizure was from 3 days to 3 years and 10 months old.The age of last follow-up was from 4 years and 3 months old to 37 years old.All affected members had normal development.Genetic testing identified KCNQ2 mutations in 3 families (75％,3/4 cases).Two families had missense KCNQ2 mutations (c.1048A ＞ C/p.N350H and c.242T ＞ C/ p.L81P).One family had nonsense KCNQ2 mutation(c.2506G ＞ T/p.E836X).The other 3 KCNQ2 mutations were novel.The remaining BFNE family was not detected with any pathogenic mutation.The age of inital seizure onset of the proband was 1 day after birth.The seizures got controlled at 3 months old.However,this proband had another 2 afebrile seizures during sleep at 3 years and 10 months old.Electroenlephalography monitoring showed focal central temporal spikes.It is speculated that the seizures had evolved into benign epilepsy of childhood with central temporal spikes.Conclusions Mutations in KCNQ2 are major genetic causes in Chinese families with BFNE.KCNQ2 mutation c.1048A ＞ C/p.N350H,c.242T ＞ C/p.L81P,and c.2506G ＞ T/p.E836X are novel mutations.Identification of underlying gene mutation can be helpful for clinical diagnosis and judgment of the prognosis.
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<p><b>OBJECTIVE</b>To determine the type and frequency of SCN1A deletions and duplications among patients with Dravet syndrome (DS).</p><p><b>METHODS</b>For DS patients in which no mutations of the SCN1A gene were detected by PCR-DNA sequencing, SCN1A deletions and duplications were detected by multiplex ligation-dependent probe amplification (MLPA).</p><p><b>RESULTS</b>In 680 DS patients, 489 had SCN1A mutations identified by PCR-DNA sequencing. In 191 patients who were negative for the SCN1A PCR-DNA sequencing, 15 (15/191, 7.9%) were detected with heterozygous SCN1A deletions or duplications, which included 14 (14/15, 93.3%) SCN1A deletions and 1 SCN1A duplication. There were 13 types of mutations, including whole SCN1A deletions in 3 patients, partial SCN1A deletions in 11 patients and partial SCN1A duplications in one patient. By testing the parents, 14 mutations were found to be de novo. For the remaining case, no SCN1A deletion or duplication was found in the mother, while the father was not available.</p><p><b>CONCLUSION</b>Approximately 8% of Chinese patients who were negative for SCN1A mutation by PCR-sequencing have SCN1A deletions or duplications. The MLPA analysis should be considered as an important strategy for such patients. SCN1A deletions are more common than SCN1A duplications among DS patients, and the most common types are whole SCN1A deletions. The majority of SCN1A deletions or duplications are de novo.</p>
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Female , Humans , Infant , Male , Epilepsies, Myoclonic , Genetics , Gene Deletion , Gene Duplication , Multiplex Polymerase Chain Reaction , GeneticsABSTRACT
Objective@#To investigate the clinical phenotypes and the mutant allele proportion of parents with SCN1A gene mutation mosaicism of Dravet syndrome (DS) children, thus to provide guidance for family reproduction and prenatal diagnosis.@*Method@#The clinical data and peripheral blood DNA samples of DS patients with a SCN1A gene mutation proved by Sanger sequencing were collected prospectively from February 2005 to November 2016 in Department of Pediatrics, Peking University First Hospital. The same mutation was searched in parents and other available relatives. Parental somatic mosaicism was confirmed and quantified by Ion Torrent Personal Genome Machine (PGM) and Raindrop droplet digital PCR (ddPCR). The families were followed up and prenatal diagnosis was provided.@*Result@#Mosaicisms of SCN1A gene mutation in parents were identified in 5.2% (30 out of 575) DS families. Seventeen were fathers and thirteen were mothers. The mutant allele proportion ranged from 1.7% to 32.9% by PGM and from 0.82% to 34.51% by ddPCR, respectively. In 30 parents with somatic mosaicism, thirteen were asymptomatic, ten had a history of febrile seizures (FS), five with epilepsy, one with febrile seizure plus and one had a history of afebrile seizure. Four families had two children with DS. Three siblings of the probands were confirmed genetically with the same pathogenic mutation. One deceased sister of the proband was assumed to have the same pathogenic mutation because she matched DS diagnosis after medical history review despite no blood sample. Two families received prenatal diagnosis. One second pregnancy was terminated because the fetus inherited the mutation as the mother's wish.@*Conclusion@#Sanger sequencing detects parents of some children with DS are SCN1A mutation mosaics. PGM and ddPCR can be used for accurate quantification of mutant mosaics, which can provide accurate guidance for family genetic counseling.
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Objective@#To investigate the clinical and neuroimaging characteristics of acute encephalopathy (AE) after status epilepticus (SE) of patients with Dravet syndrome (DS).@*Method@#The clinical data of DS patients who had AE (coma ≥24 h) after SE were retrospectively collected from February 2005 to August 2016 in Peking University First Hospital and SCN1A gene tests were performed.The clinical and neuroimaging features were summarized.@*Result@#Twenty-two patients (9 males and 13 females) with AE were collected among 412 DS patients during follow-up.Of which 18 patients had SCN1A gene mutations while the remaining 4 patients had no SCN1A gene mutations.The onset age of AE was between 6 months and 10 years.The duration of SE varied between 40 minutes and 9 hours.Prior to the onset of SE, twenty-one patients had high fever, and one patient had normal temperature.Coma lasted from 2 days to 20 days.Nine patients died after the AE, and 13 patients survived with massive neurological regression.From AE to the last visit, the median time of follow-up was 2 years and 3 months (from 7 months to 4 years and 4 months). Nine of 13 survivors had varied improvement in motor, language and cognition, while the remaining 4 patients had no significant improvement.After AE, there were 6 patients with seizure-free, 4 patients with reduced seizures, and 3 patients with no change in seizure frequency, moreover, spasm occurred in 2 patients.Six patients had brain magnetic resonance imaging (MRI) in acute phase and showed bilateral (2 patients) or unilateral (4 patients) hemisphere edema, accompanied by subcortical white matter hyperintense signal in T1 and T2 weighted images in two patients.The neuroimaging of 13 survivors demonstrated diverse cortical atrophy during recovery phase, among which 4 patients showed cerebellar atrophy, one patient had right pontine atrophy, 4 patients accompanied by signal abnormalities in subcortical and periventricular white matter, 2 patients showed right hippocampal sclerosis, and one patient showed signal abnormalities in bilateral basal ganglia.@*Conclusion@#SE is more prone to occur in Dravet patients who have high fever.It may result in AE or even death in severe cases.Survivors will leave severe neurological sequelae.The neuroimaging shows brain edema in acute phase.In recovery phase the neuroimaging shows diverse brain atrophy, moreover, a few patients may be associated with cerebellar or pontine atrophy, hippocampal sclerosis or abnormal signals in white matter or basal ganglia.
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Objectives To provide genetic counseling and prenatal molecular diagnosis for two families with megalencephalic leukoencephalopathy with subcortical cysts (MLC).Methods Two MLC patients (probands 1 and 2) were admitted to the Department of Pediatrics of Peking University First Hospital in June 2011 and June 2009,respectively.Peripheral blood was collected and DNA sequencing was performed for genetic analysis for the two MLC patients and their parents.Amniotic fluid and villus of two fetuses (fetus 1 and 2) were collected at 21+4 and 12+3 weeks of gestational age from their mothers when they were pregnant again.The genomic DNA of the two fetuses was extracted and corresponding sites of MLC1 gene were sequenced.Haplotype analysis using a combination of 3 microsatellite markers (AR,DXS6807 and DXS6797) on chromosome X and sex determining region of Y chromosome was performed to detect maternal cell contamination.Verification of the prenatal molecular diagnosis and follow up study after birth were conducted for both fetuses.Results Macrocephaly,motor development delay and typical findings on brain MRI were identified in the two probands,and were clinically diagnosed with MLC.Compound heterozygous mutations were detected in proband 1 [c.353C＞T (p.T118M) and c.803C＞G (p.T268R)] and proband 2 [c.353C＞T (p.T118M) and c.836T＞C(p.L279P)],respectively.MLC was genetically diagnosed.Heterozygous variation in c.353[c.353C＞T (p.T118M)] and wild c.803C were identified in fetus 1,and both wild c.353C and c.836T were found in fetus 2.No maternal cell contamination was detected in both fetuses.Sequencing the corresponding sites after birth confirmed the prenatal diagnosis,and the head circumference and motor development were normal in fetus 1 at 5 months old.No macrocephaly was found and no DNA sequencing was done in fetus 2 at one month old.Conclusions Genetic counseling and prenatal molecular diagnosis for MLC families combined with clinical and genetic diagnosis are important in preventing MLC.Haplotype analysis with a combination of three microsatellite markers on chromosome X and sex determining region of Y chromosome is useful in detecting maternal cell contamination and avoiding its influence on prenatal diagnosis,and confirming the reliability of prenatal diagnosis.
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Objective To identify the rare causative genes of Dravet syndrome (DS) in patients who do not have SCN1A mutation and to analyze genotypes and phenotypes of DS patients with different rare causative genes.Methods DS patients were collected from the Pediatric Department of Peking University First Hospital from February 2005 to August 2016.SCN1A and PCDH19 gene mutations were screened by Sanger sequencing and multiple ligation-dependant probe amplification (MLPA).Next generation sequencing (NGS) for epilepsy-related gene-panel was applied to SCN1A and PCDH19 mutation-negative patients.The phenotypes of DS patients with different rare causative genes were analyzed.Results Six hundred and seventy patients with DS were collected and 556 patients (83.0％)carried SCN1A mutations and 6 patients with PCDH19 mutations.Epilepsy-related gene-panel was applied to remain 108 patients without SCN1A or PCDH19 mutation,and among them 12 patients were detected with 6 rare causative genes,with heterozygous mutations in GABRA1 mutations in 3,GABRG2 in 2 cases,GABRB2 mutations in 2 cases and SCN2A mutation in 1 case,complex heterozygous mutations in TBC1D24 in 2 cases and ALDH7A1 in 2 cases.The clinical phenotypes of 6 patients with PCDH19 mutations were featured by clustering of repeated seizures with short periods of times,only 1 case had an episode of status epilepticus.Patients with GABRB2 mutations had a relatively better outcome of seizure control.Many episodes of myoclonic status were emerging as hallmark features in patients with TBC1D24 mutations.Vitamin B had a dramatic therapeutic effect in patients with ALDH7A1 mutations.The clinical phenotypes of DS patients with GABRG2,SCN2A and GABRA1 had no obvious specificity.Conclusions The rare causative genes in DS patients include PCDH19,GABRG2,SCN2A,GABRA1,GABRB2,TBC1D24 and ALDH7A1.The finding of causative genes GABRB2 and TBC1D24 may enrich the gene spectrum of DS.Patients with PCDH19 mutations are featured by clustering of repeated seizures with short periods of time and rare status epilepticus.Patients with GABRB2 mutations have a relatively better outcome of seizure control.Many episodes of myoclonic status are emerging as hallmark features in patients with TBC1D24 mutations.
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<p><b>OBJECTIVE</b>To analyze the ATP1A3 mutations in patients with alternating hemiplegia of childhood (AHC) and recognize its value in diagnosing atypical cases.</p><p><b>METHOD</b>Data of all AHC patients seen at Peking University First Hospital from August 2005 to November 2014 were prospectively collected. Clinical information of the AHC patients and their family members were collected and analyzed. Genomic DNAs were extracted from their peripheral blood. Mutations in ATP1A3 were screened by Sanger sequencing after PCR.</p><p><b>RESULT</b>A total of 78 AHC patients were recruited, including 50 males and 28 females. Only three patients had family history of AHC. The first family case had affected mother with AHC; the second family case was the older one of a monozygotic male twins with AHC but their parents were normal; the third family case had a sister with AHC but their parents were normal. The age of onset ranged from six hours to eight years and six months (median: 4 months). According to the Aicardi's clinical diagnostic criteria, 72 patients were considered as typical AHC cases and the other six patients were considered as atypical AHC cases for their age of onset was older than 18 months. Twenty-seven different missense ATP1A3 mutations were detected in 71 (91.0%, 71/78) patients with AHC, including 66 typical and 5 atypical cases. 11 novel ATP1A3 mutations were first reported. ATP1A3 mutations were identified in the three AHC cases with family history. Parental analysis verified that the ATP1A3 mutation of 63 patients (95.5%, 63/66) were de novo origin except lack of five unavailable maternal or paternal genomic DNA. Mutation D801N was found in 20 cases (28.2%), and E815K in 12 cases (16.9%). In the six atypical AHC patients, ATP1A3 mutations were detected in five of them.</p><p><b>CONCLUSION</b>ATP1A3 was the major causative gene of AHC, and mutations were identified as de novo mostly. ATP1A3 mutations in AHC had mutational hotspot, and the most common mutations were D801N and E815K. ATP1A3 mutation screening is helpful for the genetic and definite diagnosis of the atypical AHC cases.</p>