ObjectiveTo investigate the clinical electrophysiological characteristics of Cyclin-dependent kinase-like 5 gene induced developmental epileptic encephalopathy (CDKL5-DEE). MethodsThe clinical data and series of video EEGs of children with CDKL5-associated developmental epileptic encephalopathy (CDKL5-DEE) who were admitted to the Children’s Medical Center of Peking University First Hospital from June 2016 to May 2024 were retrospectively analyzed. Results A total of 16 patients with CDKL5-DEE were enrolled, including 13 females and 3 males. All patients had de novo variants of CDKL5 gene, including 6 cases of missense variants, 5 cases of frameshift variants, 4 cases of nonsense variants, and 1 case of large fragment deletion. The age of onset was 8 days (d) after birth ~1 year (y) and 10 months (m), and the median age was (85.94±95.76) days. Types of seizures at onset: 4 cases of tonic seizures [age of onset 10~52 days, median age (25.5±15.84) days]; There were 5 cases of focal seizures [age of onset 8 d~8 m, median age (77.76±85.97) d]. There were 4 cases of epileptic spasmodic seizures [age of onset 3 m~1 y 10 m, median age (6.25±3.49) m]; There were 2 cases of bilateral tonic-clonic seizures [age of onset 30~40 days, median age (35.00±5.00) days]; focal concurrent epileptic spasm seizures 1 case (age of onset 2 m). A total of 59 VEEG sessions were performed in the pediatric EEG room of Peking University First Hospital for 4 hours. All the results were abnormal, including 26 normal background, 25 slow rhythm difference with background, and 8 no background. The interictal was 16 posterior or focal discharges, 19 multifocal discharges, 17 generalized or accompanied by focal/multifocal discharges, and 7 hypsarrhythmia; The ictal was 33 epileptic seizures, 6 myoclonic seizures, 5 focal seizures, 2 tonic-clonic seizures, 2 atypical absence seizures, 2 tonic seizures, 1 myoclonic sequential focal seizure, 1 focal sequential epileptic spasm, and 1 hypermotor-tonic-spasms. The background of patients within 6 months of age was normal, and the background abnormality increased significantly with age. generalized discharges are evident after 2 years of age between seizures. Conclusion CDKL5-DEE seizures have an early onset and are refractory to medications. Epileptic spasms are the most common type of seizure in every patient and long-lasting, with generalized seizures increasing markedly with age. EEG is characterized by a normal background within 6 months. With the increase of age, the background and interictal discharges have a tendency to deteriorate.
ObjectiveTo study SCN1A gene mutations and their inheritance in patients with Dravet syndrome (DS), and to analyze the phenotypes of their family members. MethodsGenomic DNA was extracted from peripheral blood samples from DS patients and their parents. SCN1A gene mutations were screened using PCR-DNA sequencing and multiplex ligation-dependent probe amplification (MLPA). Results547 DS patients were collected, SCN1A gene mutations were identified in 379 patients (69.3%), which included 179 missense mutations (47.2%), 78 nonsense mutations (20.6%), 77 frameshift mutations (20.3%), 37 splice site mutations (9.8%), and 8 cases with SCN1A gene fragment deletions or duplications (2.1%). Of 379 DS patients, the parents of 354 DS patients were further analyzed, the de novo mutations accounted for 92.9%, inherited mutations accounted for 7.1%, and in 5 of the latter families, the SCN1A-positive parent carried a somatic mutations mosaicism. For the 25 parents carrying SCN1A mutations, 1 had DS, 11 had febrile seizures plus, 9 had febrile seizures, whilst 4 were normal. ConclusionsThe mutation rate of SCN1A in DS patients is high. Most mutations are of missense and truncation mutations (including nonsense mutation and frameshift mutation). Only a few patients have carried fragment deletions or duplications. Most SCN1A mutations are de novo, only a few are inherited from the parents. SCN1A mutations carried by the parents can be in the form of mosaicism. The phenotypes of parents with SCN1A mutations can be severe, mild or normal, and a mosaic transmitting parent always shows mild or normal.
ObjectiveTo study the phenotype of children with KCNQ2 gene related epilepsy.MethodsForty epilepsy children who were detected with KCNQ2 gene variants were enrolled. Their genotype and phenotype were analyzed.ResultsThirty-six KCNQ2 variants were identified. Twenty variants were novel. Twelve patients had inherited variants, and 28 patients had de novo variants. The age of seizure onset was from one day to 9 months. 80.0% patients had their seizure onset in neonates (32/40). Multiple seizure types were observed. Focal seizure was observed in 38 patients (95.0%). Epileptic spasm was observed in 10 patients (25.0%). Myoclonic seizure was observed in 4 patients. Tonic spasm seizure was observed in 3 patients. In all patients, seizures manifested in clusters. In 28 patients with de novo KCNQ2 variants, 24 had development delay (85.7%), the other 4 patients had normal development. In 12 patients with inherited KCNQ2 variants, one had development delay, the other 11 patients had normal development (91.7%). The most common interictal EEG changes were local epilepsy discharges (31/40). The MRI of brain was abnormal in 14 patients with de novo KCNQ2 variants and developmental delay. The agenesis of corpus callosum was identified in 10 patient (25.0%). Enlargement of subarachnoid spaces in the frontal and temporal region was identified in 11 patients (27.5%). Cortial dysplasia in the bilateral frontal and temporal region was identified in 2 patients. Sulus deepening was identified in 4 patients. Enlargement of bilateral lateral ventricle was identified in 3 patients. In 40 patients with KCNQ2 variants, 3 were diagnosed as benign familial neonatal epilepsy (BFNE), 2 were diagnosed as benign familial neonatal-infantile epilepsy (BFNIE), 3 were benign familial infantile epilepsy (BFIE), 3 were benign infantile epilepsy (BIE), 5 were benign neonatal epilepsy (BNE), 3 wer Ohtahara syndrome (OS), 9 were West syndrome (WS), 12 were unclassified early infantile epileptic encephalopathy (EIEE), one was epilepsy with autism. Sodium channel blockers oxcarbazepine was the most effective among antiepileptic drugs, with a effective rate of 90.9%.ConclusionsMost KCNQ2 variants are missense variants. De novo variants are more common in patients with KCNQ2 variants. The clinical features of patients with KCNQ2 variants including that mainly with seizure onset in neonate, the main seizure type is focal seizures, seizures occur in clusters. Patients with de novo KCNQ2 variants often had developmental delay, and about half of them had frontal and temporal lobe dysplasia and agenesis of corpus callosum. Sodium channel blockers are effective agents for epilepsy patients with KCNQ2 variants.
ObjectiveTo analyze the genotype and clinical features of children with epilepsy associated with CACNA1A variants. MethodsThe genotype, phenotype and neuroimaging features of 27 patients with CACNA1A variants in the pediatrics department of Peking University First Hospital from September 2013 to February 2022 were analyzed. ResultsThere were 9 males and 18 females, whose age ranged from 6 months to 19 years old (medium: 4 years old and 3 months). There were 22 missense variants, three nonsense variants and two frameshift variants. 25 variants were de novo. Age at seizure onset ranged from 1 day to 8 years old and 6 months (medium: 14 months). Multiple seizure types were observed, including focal seizures in 20 patients, generalized tonic–clonic seizures (GTCS) in 7 patients, absence seizures in 5 patients, myoclonic seizures in 3 patients, epileptic spasms and tonic seizures in 1 patient respectively. 16 patients had status epilepticus, including focal motor status epilepticus in 14 patients and generalized motor status epilepticus occurred in two patients. Two patients had acute encephalopathy. All 27 patients showed developmental delay. Interictal electroencephalogram showed generalized discharges in 8 patients, multi-focal discharges in 4 patients and focal discharges in 11 patients. Unilateral cortical atrophy occurred in 5 patients after focal motor status epilepticus. Two patients had bilateral cerebral atrophy after acute encephalopathy. Cerebellar atrophy in 2 patients. The age of last follow-up ranged from one year old to 17 years old and 3 months. Six patients were seizure-free , whereas 21 still had seizures. ConclusionThe seizure onset age of patients with CACNA1A variants usually began in infancy. The common seizure types include focal seizures, GTCS and absence seizures. Seizures are prone to status epilepticus, mainly focal motor status epilepticus. Patients usually had developmental delay. Unilateral cortical atrophy may occur after focal motor status epilepticus. Epilepsy associated with CACNA1A variants is usually refractory.
ObjectiveTo explore the genotype and phenotype of PCDH19 gene related epilepsy.Methods41 probands, including 39 girls and 2 boys collected from pediatric department of the Peking University and Neurology Department of Wuhan Children's Hospital from February 2005 to April 2017, were diagnosed as PCDH19 gene related epilepsy. The clinical features of the probands and affected relatives were retrospectively analyzed. PCDH19 mutations were detected by Sanger sequencing or targeted next generation sequencing (NGS) and multiple ligation-dependent probe amplification (MLPA).Results40 in 41 probands with PCDH19 mutations were detected by sequencing and one was detected by MLPA.Two male epilepsy patients with mosaic PCDH19 mutations were detected by NGS with the mutant allele fraction of 85% and 33%. Among 39 female probands, 19 were with inherited mutations and 20 were de novo mutations. The penetrance of females with PCDH19 mutation was estimated as 90% (53/59). Twelve hemizygous fathers and one mosaic father were asymptomatic.The clinical phenotypes of female mutation carriers included epilepsy with mental retardation, Dravet syndrome, febrile seizures, or even asymptomatic. The phenotypic heterogeneity was noticed in females with identical mutations even in members from the same family. The median seizure onset age of 46 patients (including 41 probands and 5 affected relatives) were 11 months (range 4~42months).During the course, 87% (40/46) patients experienced generalized tonic clonic seizures (GTCSs) and 69.6% (32/46) experienced focal seizures. Other rare seizures types included myoclonic seizures (6/46), absence seizures (3/46) and atonic seizures (1/46). Seizures in clusters were observed in all patients, fever sensitivity in 80.4% (37/46), and status epilepticusin only three, cognitive impairment in 76% (35/46) and 7 with autistic features.ConclusionMutations in PCDH19 can be inherited or de novo. Most patients are females, rare mosaic males can be affected or asymptomatic. PCDH19 gene related epilepsy shows incomplete penetrance and variable expressivity.Seizures occurring in clusters and sensitive to fever are the major features.
ObjectiveTo summarize the clinical phenotype, electrophysiological characteristics, imaging characteristics, surgical treatment and prognosis of Rasmussen encephalitis (RE), so as to deepen the understanding of the disease. MethodsThe clinical data of patients with RE who underwent surgical therapy from October 2014 to October 2019 at Children's Epilepsy Center in Peking University First Hospital were retrospectively reviewed. Demographic characteristics, seizure forms, electroencephalogram (EEG), cranial nuclear magnetic resonance (MRI), operative methods as well as surgical outcomes evaluated by Engel classification during follow-up of the subjects were collected and analyzed. ResultsTotally 21 pediatric patients were enrolled, including 8 males and 13 females. The age at onset was (5.0±2.0) years old, the age at the time of surgery was (6.9±2.7) years old, and the disease duration at the time of surgery was (1.7±1.3) years. Twenty (20/21, 95.2%) patients had focal motor seizures, and 10 (10/21, 47.6%) patients had 2 or 3 forms of focal motor seizures. Fifteen patients (15/21, 71.4%) had epilepsia partialis continua (EPC), which occurred (0.7±0.6) years after the onset. All patients had hemiplegia, which appeared at (0.9±0.6) years after the onset. All patients showed a slow rhythm at their affected hemispheres during the EEG monitoring and 4 of them also showed slow rhythm at the contralateral hemispheres as the disease progressed. All patients had epileptiform discharges at the involved hemisphere, and 6 patients also had independent epileptiform discharges on the contralateral side. All 21 patients underwent hemispheric disconnection. The duration of follow-up was 2 to 7 years, and all patients achieved Engel class I after the surgery. The neurological dysfunction recovered to varying degrees during the postoperative period. ConclusionRE mostly occurs around the school age. Focal motor seizures are the main manifestations and the most common onset symptoms. With the progress of the disease, the condition of patients worsened gradually. The EEG of patients was mainly characterized by broad slow wave and spike wave in the affected hemisphere. Some patients can also have bilateral involvement, which was obviously asymmetrical. Through surgical treatment, the patients all achieved good results in terms of seizures and development.