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Objective:To analyze the clinical manifestations, gene mutation characteristics and treatment effects of patients with GATOR1 complex-related epilepsy, and to explore the diagnosis and treatment of this disease.Methods:The medical history, electroencephalogram, brain imaging, genetic test results, treatment and follow-up data of patients with GATOR1 complex-related epilepsy who attended the Children′s Hospital Affiliated to Capital Institute of Pediatrics, Beijing Tsinghua Changgung Hospital, and Shanghai Deji Hospital from May 2017 to July 2022 were retrospectively analyzed.Results:A total of 16 patients with GATOR1 complex-related epilepsy were collected, including 7 males and 9 females. The age of onset of epilepsy was from 2 months to 14 years. Ten cases had focal seizures only, 2 cases had generalized seizures only, and 4 cases had coexistence of focal seizures and generalized seizures, of which generalized seizures included generalized tonic-clonic seizure, spastic seizure, and myoclonic seizure. Among the 16 patients, 2 had infantile spasms, 3 had familial focal epilepsy with variable focus, and 1 had sleep related hyperkinetic epilepsy. Electroencephalogram intervals suggested multiple brain areas discharge or diffuse discharge. A total of 13 DEPDC5 gene mutation sites, 1 NPRL2 gene mutation site, and 2 NPRL3 gene mutation sites were found; 4 sites of DEPDC5 gene were reported sites, the rest were unreported; all mutations had pathogenic significance; 8 cases had nonsense mutation, 1 case had large fragment deletion, 4 cases had frameshift mutation, 1 case had integer mutation, 2 cases had splicing mutation; 13 cases′ mutation was inherited from parents, 2 cases had new mutation, and 1 case had unverified mutation. Magnetic resonance imaging (MRI) showed 5 of the 16 patients were normal, and 11 had abnormal cerebral cortex structure, manifested as bottom-of-sulcus focal cortical dysplasia (FCD), abnormal formation of sulci and (or) gyri with or without ill-defined gray-white matter and malformation of cortical dysplasia of the bilateral brain. Seven patients underwent stereotactic electroencephalogram (SEEG) monitoring, and the SEEG showed low-amplitude fast rhythm at the beginning in 6 patients, of whom 5 cases started from the frontal lobe, and 1 case started from the parietal lobe. Eight patients were only treated with drugs, 1 with single-drug therapy and the rest with multi-drug combination therapy. Eight patients underwent surgery. Among them, 5 patients with DEPDC5 gene mutation underwent epileptogenic cortex excising after SEEG monitoring, and postoperative pathological examinations showed FCDⅡ, FCDⅢ or non-specific changes; 1 patient was waiting for surgery. One patient with NPRL3 gene mutation underwent epileptogenic foci resection and postoperative pathological examinations showed FCDⅡa; the other patient with NPRL3 gene mutation underwent radiofrequency thermocoagulation after SEEG monitoring. Follow-up showed that 3 patients were seizure-free with drug treatment, and 4 patients had fewer seizures after drug treatment. Six cases underwent epileptic foci resection. Five of them were assisted by SEEG to locate the epileptic foci before surgery and were seizure-free after the operation, but the range of surgical resection was wider than the abnormal range shown by MRI; whereas 1 case who was not assisted by SEEG showed no improvement. There was still 1 case who underwent SEEG-guided radiofrequency thermocoagulation and had no improvement after operation. Conclusions:GATOR1 complex-related epilepsy mostly manifests as focal seizures. SEEG shows that seizures originate from the frontal lobe more often, and cortical developmental abnormalities are often found. DEPDC5 gene mutations are the most common ones, mostly inherited from parents, with high incomplete penetrance rate. Therefore, genetic testing is recommended for non-acquired brain structural abnormalities. For those who are refractory to drugs, a radical cure can be obtained by resection of the epileptogenic foci after preoperative evaluation.
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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 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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<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>