Deficiencia del transportador de glucosa tipo 1: aspectos clínicos, diagnóstico y terapéutica / Glucose transporter type 1 deficiency syndrome: clinical aspects, diagnosis, and treatment

El síndrome de deficiencia del transportador de glucosa tipo 1 es una enfermedad de causa genética, que involucra el gen SLC2A1. En general, se presenta durante los primeros años de vida con retraso en la adquisición de pautas madurativas, epilepsia farmacorresistente y desórdenes del movimiento. La clínica y la disminución de glucosa en líquido cefalorraquídeo permiten sospechar el diagnóstico, el cual debe ser confirmado mediante el estudio molecular del gen SLC2A1. Debido a que se trata de una enfermedad poco frecuente y de expresión clínica variable, el diagnóstico precoz suele representar un desafío para los equipos de salud. Este es importante, ya que la implementación de la terapia cetogénica logra controlar las manifestaciones clínicas y mejora el pronóstico a largo plazo. Presentamos una revisión sobre el déficit del transportador de glucosa tipo 1, que abarca sus características clínicas, bioquímicas, moleculares y terapéuticas.

Glucose transporter type 1 deficiency with a typical onset is a genetic disorder associated with the SLC2A1 gene. Usually appears during the first years of life with severe developmental delay, drugresistant epilepsy, and movement disorders. Diagnosis is suspected based on clinical manifestations and a low glucose level in cerebrospinal fluid, and should be confirmed by the molecular genetic study of the SLC2A1 gene. As it is a rare disease with variable clinical expression, early diagnosis is often challenging for the healthcare team. Nevertheless, this is important because early implementation of ketogenic therapy will lead to control of the clinical manifestations and a better long-term prognosis. Here we review the glucose transporter type 1 deficiency syndrome focusing on its clinical, biochemical, molecular, and therapeutic characteristics.

Clinical features of 6 children with uridine-responsive developmental epileptic encephalopathy 50 caused by CAD gene variants / 中华儿科杂志

Objective: To analyze the clinical features of children with uridine responsive developmental epileptic encephalopathy 50 (DEE50) caused by CAD gene variants. Methods: A retrospective study was conducted on 6 patients diagnosed with uridine-responsive DEE50 caused by CAD gene variants at Beijing Children's Hospital and Peking University First Hospital from 2018 to 2022. The epileptic seizures, anemia, peripheral blood smear, cranial magnetic resonance imaging (MRI), visual evoked potential (VEP), genotype features and the therapeutic effect of uridine were descriptively analyzed. Results: A total of 6 patients, including 3 boys and 3 girls, aged 3.5(3.2,5.8) years, were enrolled in this study. All patients presented with refractory epilepsy, anemia with anisopoikilocytosis and global developmental delay with regression. The age of epilepsy onset was 8.5 (7.5, 11.0) months, and focal seizures were the most common seizure type (6 cases). Anemia ranged from mild to severe. Four patients had peripheral blood smears prior to uridine administration, showing erythrocytes of variable size and abnormal morphology, and normalized at 6 (2, 8) months after uridine supplementation. Two patients suffered from strabismus, 3 patients had VEP examinations, indicating of suspicious optic nerve involvement, and normal fundus examinations. VEP was re-examined at 1 and 3 months after uridine supplementation, suggesting significant improvement or normalization. Cranial MRI were performed at 5 patients, demonstrating cerebral and cerebellar atrophy. They had cranial MRI re-examined after uridine treatment with a duration of 1.1 (1.0, 1.8) years, indicating significant improvement in brain atrophy. All patients received uridine orally at a dose of 100 mg/(kg·d), the age at initiation of uridine treatment was 1.0 (0.8, 2.5) years, and the duration of treatment was 2.4 (2.2, 3.0) years. Immediate cession of seizures was observed within days to a week after uridine supplementation. Four patients received uridine monotherapy and were seizure free for 7 months, 2.4 years, 2.4 years and 3.0 years respectively. One patient achieved seizure free for 3.0 years after uridine supplementation and had discontinued uridine for 1.5 years. Two patients were supplemented with uridine combined with 1 to 2 anti-seizure medications and had a reduced seizure frequency of 1 to 3 times per year, and they had achieved seizure free for 8 months and 1.4 years respectively. Conclusions: The clinical manifestations of DEE50 caused by CAD gene variants present a triad of refractory epilepsy, anemia with anisopoikilocytosis, and psychomotor retardation with regression, accompanied by suspected optic nerve involvement, all of which respond to uridine treatment. Prompt diagnosis and immediate uridine supplementation could lead to significant clinical improvement.

Genetic analysis of a case of mild epilepsy due to variant of SCN9A gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology of a patient with epilepsy and provide genetic counseling.@*METHODS@#A patient who had visited the Center for Reproductive Medicine of Shandong University on November 11, 2020 was selected as the study subject, and her clinic information was collected. Candidate variant was identified through whole exome sequencing (WES), and Sanger sequencing was used for validation. Possible transcriptional changes caused by the variant was detected by reverse transcription-PCR and Sanger sequencing.@*RESULTS@#The patient was a 35-year-old female with no fever at the onset, loss of consciousness and abnormal firing in the temporal lobe, manifesting predominantly as convulsions and fainting. WES revealed that she had harbored a heterozygous c.2841+5G>A variant of the SCN9A gene, which was verified by Sanger sequencing. cDNA sequencing confirmed that 154 bases were inserted between exons 16 and 17 of the SCN9A gene, which probably produced a truncated protein and affected the normal function of the SCN9A protein. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.2841+5G>A variant was classified as likely pathogenic (PVS1_Strong+PM2_Supporting).@*CONCLUSION@#The c.2841+5G>A variant of the SCN9A gene probably underlay the epilepsy in this patient. Above finding has enriched the variant spectrum of the SCN9A gene and provided a basis for the prenatal diagnosis and preimplantation genetic testing for this patient.

Research progress in diseases associated with genetic variants of GATOR1 complex / 中华医学遗传学杂志

The GATOR1 complex is located at the upstream of the mTOR signal pathway and can regulate the function of mTORC1. Genetic variants of the GATOR1 complex are closely associated with epilepsy, developmental delay, cerebral cortical malformation and tumor. This article has reviewed the research progress in diseases associated with genetic variants of the GATOR1 complex, with the aim to provide a reference for the diagnosis and treatment of such patients.

Clinical features and genetic analysis of two children with Williams-Beuren syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the clinical and genetic characteristics of two children with Williams-Beuren syndrome (WBS).@*METHODS@#Two children who had presented at the Department of Pediatrics, General Hospital of Ningxia Medical University respectively on January 26 and March 18, 2021 were selected as the study subjects. Clinical data and results of genetic testing of the two patients were analyzed.@*RESULTS@#Both children had featured developmental delay, characteristic facies and cardiovascular malformation. Child 1 also had subclinical hypothyroidism, whilst child 2 had occurrence of epilepsy. Genetic testing revealed that child 1 has harbored a 1.54 Mb deletion in the 7q11.23 region, whilst child 2 has a 1.53 Mb deletion in the same region, in addition with a c.158G>A variant of the ATP1A1 gene and a c.12181A>G variant of the KMT2C gene. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.158G>A and c.12181A>G variants were rated as variants of unknown significance (PM1+PM2_Supporting+PP2+PP3；PM2_Supporting).@*CONCLUSION@#Both children had characteristic features of WBS, for which deletions of the 7q11.23 region may be accountable. For children manifesting developmental delay, facial dysmorphism and cardiovascular malformations, the diagnosis of WBS should be suspected, and genetic testing should be recommended to confirm the diagnosis.

Advance of research on endoplasmic reticulum stress and genetic epilepsy / 中华医学遗传学杂志

Epilepsies are a group of chronic neurological disorders characterized by spontaneous recurrent seizures caused by abnormal synchronous firing of neurons and transient brain dysfunction. The underlying mechanisms are complex and not yet fully understood. Endoplasmic reticulum (ER) stress, as a condition of excessive accumulation of unfolded and/or misfolded proteins in the ER lumen, has been considered as a pathophysiological mechanism of epilepsy in recent years. ER stress can enhance the protein processing capacity of the ER to restore protein homeostasis through unfolded protein response, which may inhibit protein translation and promote misfolded protein degradation through the ubiquitin-proteasome system. However, persistent ER stress can also cause neuronal apoptosis and loss, which may aggravate the brain damage and epilepsy. This review has summarized the role of ER stress in the pathogenesis of genetic epilepsy.

Analysis of clinical features and PAK1 gene variant in a child with epilepsy and global developmental delay / 中华医学遗传学杂志

OBJECTIVE@#To investigate the clinical phenotype and genetic basis of a child with epilepsy and global developmental delay.@*METHODS@#A child with epilepsy and global developmental delay who had visited West China Second University Hospital, Sichuan University on April 1, 2021 was selected as the study subject. Clinical data of the child were reviewed. Genomic DNA was extracted from peripheral blood samples of the child and his parents. Whole exome sequencing (WES) was carried out for the child, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. A literature review was also carried out by searching databases such as Wanfang data knowledge service platform, China National Knowledge Infrastructure, PubMed, ClinVar and Embase to summarize the clinical phenotypes and genotypes of the affected children.@*RESULTS@#The child was a 2-year-and-2-month-old male with epilepsy, global developmental delay and macrocephaly. Results of WES showed that the child has harbored a c.1427T>C variant of the PAK1 gene. Sanger sequencing confirmed that neither of his parents has carried the same variant. Only one similar case had been recorded by the dbSNP, OMIM, HGMD, and ClinVar databases. No frequency for this variant among Asian population was available in the ExAC, 1000 Genomes, and gnomAD databases. Prediction with IFT, PolyPhen-2, LRT, Mutation Taster, and FATHMM online software suggested that this variant is deleterious to the function of encoded protein. Based on the Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics (ACMG), the PAK1 gene c.1427T>C variant was determined to be likely pathogenic.@*CONCLUSION@#The PAK1 gene c.1427T>C variant probably underlay the epilepsy and global developmental delay in this child, which has provided a reference for the clinical diagnosis and genetic counseling in children with similar disorders.

NEXMIF mutations in intellectual disability and epilepsy: A report of 2 cases and literature review / 中南大学学报(医学版)

More than 100 genes located on the X chromosome have been found to be associated with X-linked intellectual disability (XLID) to date, and NEXMIF is a pathogenic gene for XLID. In addition to intellectual disability, patients with NEXMIF gene mutation can also have other neurological symptoms, such as epilepsy, abnormal behavior, and hypotonia, as well as abnormalities of other systems. Two children with intellectual disability and epilepsy caused by NEXMIF gene mutation were treated in the Department of Pediatrics, Xiangya Hospital, Central South University from March 8, 2017 to June 20, 2020. Patient 1, a 7 years and 8 months old girl, visited our department because of the delayed psychomotor development. Physical examination revealed strabismus (right eye), hyperactivity, and loss of concentration. Intelligence test showed a developmental quotient of 43.6. Electroencephalogram showed abnormal discharge, and cranial imaging appeared normal. Whole exome sequencing revealed a de novo heterozygous mutation, c.2189delC (p.S730Lfs*17) in the NEXMIF gene (NM_001008537). During the follow-up period, the patient developed epileptic seizures, mainly manifested as generalized and absent seizures. She took the medicine of levetiracetam and lamotrigine, and the seizures were under control. Patient 2, a 6-months old boy, visited our department due to developmental regression and seizures. He showed poor reactions to light and sound, and was not able to raise head without aid. Hypotonia was also noticed. The electroencephalogram showed intermittent hyperarrhythmia, and spasms were monitored. He was given topiramate and adrenocorticotrophic hormone (ACTH). Whole exome sequencing detected a de novo c.592C>T (Q198X) mutation in NEXMIF gene. During the follow-up period, the seizures were reduced with vigabatrin. He had no obvious progress in the psychomotor development, and presented strabismus. There were 91 cases reported abroad, 1 case reported in China, and 2 patients were included in this study. A total of 85 variants in NEXMIF gene were found, involving 83 variants reported in PubMed and HGMD, and the 2 new variants presented in our patients. The patients with variants in NEXMIF gene all had mild to severe intellectual disability. Behavioral abnormalities, epilepsy, hypotonia, and other neurological symptoms are frequently presented. The phenotype of male partially overlaps with that of female. Male patients often have more severe intellectual disability, impaired language, and autistic features, while female patients often have refractory epilepsy. Most of the variants reported so far were loss-of-function resulted in the reduced protein expression of NEXMIF. The degree of NEXMIF loss appears to correlate with the severity of the phenotype.

Clinical phenotype and genetic features of 16p11.2 microdeletion-related epilepsy in children / 中国当代儿科杂志

OBJECTIVES@#To study the clinical phenotype and genetic features of 16p11.2 microdeletion-related epilepsy in children.@*METHODS@#The medical data of 200 children with epilepsy who underwent a genetic analysis of epilepsy by the whole exon sequencing technology were collected retrospectively, of whom 9 children with epilepsy had 16p11.2 microdeletion. The clinical phenotype and genetic features of the 9 children with 16p11.2 microdeletion were analyzed.@*RESULTS@#The detection rate of 16p11.2 microdeletion was 4.5% (9/200). The 9 children with 16p11.2 microdeletion were 3-10 months old. They experienced focal motor seizures with consciousness disturbance, and some of the seizures developed into generalized tonic-clonic seizures. The interictal electroencephalogram showed focal or multifocal epileptiform discharge, and all 9 children responded well to antiepileptic drugs. The 9 children had a 16p11.2 deletion fragment size of 398-906 kb, and the number of deleted genes was 23-33 which were all pathogenic mutations. The mutation was of maternal origin in 2 children, of paternal origin in 1 child, and de novo in the other children.@*CONCLUSIONS@#16p11.2 microdeletion can be detected in some children with epilepsy. Most of the 16p11.2 microdeletion is de novo mutation and large gene fragment deletion. The onset of 16p11.2 microdeletion-related epilepsy in children is mostly within 1 year of life, and the epilepsy is drug-responsive.

De novo variant of CSNK2B causes Poirier-Bienvenu neurodevelopmental syndrome: two case report / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical characteristics and CSNK2B gene variant of 2 children with Poirier-Bienvenu neurodevelopmental syndrome, and to identify the possible pathogenic causes and provide evidence for clinical diagnosis.@*METHODS@#Two children with Poirier-Bienvenu neurodevelopmental syndrome were selected from West China Second University Hospital, Sichuan University. The clinical manifestations, laboratory examination and CSNK2B gene variant were analyzed.@*RESULTS@#The main manifestations of 2 children were epilepsy, motor or intellectual retardation. Whole exon sequencing showed that CSNK2B gene c. 291+4A>T heterozygous splicing variant was found in case one, and CSNK2B copy number variation(CNV) was lost in case two. Case one received no special treatment, followed up for 8+ months, seizures and motor development were improved; case two had recurrent seizures for 9+ years, and received levetiracetam and clonazepam antiepileptic treatment. No seizures have occurred for 2 years now, and a large number of epileptic discharges can still be seen in video electroencephalogram (VEEG) with slightly backward intelligence and language development.@*CONCLUSION@#Our study further proves that the pathogenic variant of CSNK2B is related to epilepsy with developmental disorder, and enrich is the CSNK2B gene variant spectrum. The pathogenesis of CSNK2B has great clinical heterogeneity, with great difference in severity of nervous system injury and different prognosis, and agenesis of corpus callosum may be one of its clinical phenotypes.

Analysis of three patients with KBG syndrome and epileptic seizures due to variants of ANKRD11 gene / 中华医学遗传学杂志

OBJECTIVE@#To summarize the clinical phenotype and genotypic characteristics of 3 patients with KBG syndrome and epileptic seizure.@*METHODS@#Clinical data of the patients were collected. Family-trio whole exon sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing.@*RESULTS@#Patients 1 and 2 were boys, and patient 3 was an adult woman. All patients had epileptic seizures and mental deficiency. Their facial features included triangular face, low hair line, hypertelorism, large forward leaning auricles, broad nasal bridge, upturned nostrils, long philtrum, arched upper lip, and macrodontia. The two boys also had bilateral Simian creases. WES revealed that the three patients all harbored heterozygous de novo frameshift variants in exon 9 of the ANKRD11 gene including c.2948delG (p.Ser983Metfs*335), c.5397_c.5398insC (p.Glu1800Argfs*150) and c.1180_c.1184delAATAA (p.Asn394Hisfs*42). So far 291 patients with ANKRD11 gene variants or 16q24.3 microdeletions were reported, with over 75% being de novo mutations.@*CONCLUSION@#Above findings have enriched the spectrum of ANKRD11 gene mutations underlying KBG syndrome. WES is helpful for the early diagnosis of KBG, and provided reference for genetic counseling of this disease.

Analysis of CASR gene variant in a child with idiopathic epilepsy and autism / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child featuring idiopathic epilepsy and autism.@*METHODS@#Peripheral blood samples of the child and his parents were collected with informed consent for the extraction of genome DNA. Whole exome sequencing was carried out for the family trio. Candidate variants were verified by Sanger sequencing and bioinformatic analysis.@*RESULTS@#The proband was found to harbor a heterozygous nonsense c.3025C>T (p.Arg1009Ter) variant in exon 7 of the CASR gene exon 7, which may produce a truncated protein. Based on the guidelines of the American College of Medical Genetics and Genomics, the variant was predicted to be deleterious and classified as possibly pathogenic (PVS1+PM2).@*CONCLUSION@#The c.3025C>T (p.Arg1009Ter) variant of the CASR gene probably underlay the disease in this child.

Analysis of clinical features and ZBTB18 gene variant in a child with autosomal dominant mental disorder type 22 / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical characteristics and ZBTB18 gene variant in a child with epilepsy and global developmental delay.@*METHODS@#Clinical data and laboratory examination of the patient were reviewed. Whole exome sequencing (WES) was also carried out for the family trio.@*RESULTS@#The main manifestations of the child included global developmental delay, short stature, epileptic seizures. EEG revealed frequent occurrence of sharp (slow) waves in the right central region during sleeping, with sharp waves occasionally seen in the frontal and right posterior temporal regions. Cranial MRI has shown no obvious abnormality. WES has identified a de novo pathogenic variant in the ZBTB18 gene [NM_205768.3: exon 2: c.1282_1283del (p.Phe428Leufs*72)]. Based on the guidelines from American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PS2+PVS1_Moderate+PM2_Supporting). Following treatment with levetiracetam and rehabilitation, the seizures have been controlled for nearly half a year, with improvement of the psychomotor and language development. So far 28 children have been discovered with ZBTB18 gene mutations, and there was a significant difference in the clinical phenotypes of motor retardation, language retardation and epilepsy between those harboring frameshift/nonsense mutations and missense mutations.@*CONCLUSION@#The c.1282_1283del (p.Phe428leufs *72) variant of the ZBTB18 probably underlay the autosomal dominant mental disorder type 22 in this child. Compared with missense mutations, frameshift/nonsense mutations may predispose more to motor retardation, delayed language development and epilepsy.

Clinical phenotypes and genetic features of epilepsy children with MBD5 gene variants / 中华儿科杂志

Objective: To summarize the phenotypes of epilepsy in patients with MBD5 gene variants. Methods: A total of 9 epileptic patients, who were treated in the Department of Pediatrics, Peking University First Hospital from July 2016 to September 2021 and detected with MBD5 gene pathogenic variants, were enrolled. The features of clinical manifestations, electroencephalogram (EEG), and neuroimaging were analyzed retrospectively. Results: Among 9 patients, 6 were male and 3 were female. Age at seizure onset ranged from 5 to 89 months. Multiple seizure types were observed, including generalized tonic clonic seizures (GTCS) in 7 patients, myoclonic seizures in 5 patients, focal seizures in 5 patients, atypical absence seizures in 3 patients, atonic seizures in 2 patients, myoclonus absence seizures in 1 patient, epileptic spasms in 1 patient, and tonic seizures in 1 patient. There were 8 patients with multiple seizure types, 2 patients with sensitivity to fever and 5 patients with clustering of seizures. Two patients had a history of status epilepticus. All patients had developmental delay before seizure onset. Nine patients had obvious language delay, and 6 patients had autism-like manifestations. Five patients had slow background activity in EEG. Interictal EEG showed abnormal discharges in 9 patients. Brain magnetic resonance imaging (MRI) was normal in all patients. A total of 9 epileptic patients carried MBD5 gene variants, all of them were de novo variants. There were MBD5 gene overall heterozygous deletion in 1 patient, large fragment deletions including MBD5 gene in 3 patients and single nucleotide variations (c.300C>A/p.C100X, c.1775delA/p.N592Tfs*29, c.1759C>T/p.Q587X, c.150_151del/p.Lys51Asnfs*6, c.113+1G>C) in 5 patients. The age at last follow-up ranged from 2 years and 9 months to 11 years and 11 months. At the last follow-up, 2 patients were seizure-free for more than 11 months to 4 years 6 months, 7 patients still had seizures. Conclusions: The initial seizure onset in patients with MBD5 gene variants usually occurs in infancy. Most patients have multiple seizure types. The seizures may be fever sensitive and clustered. Developmental delays, language impairments, and autistic behaviors are common. MBD5 gene variants include single nucleotide variations and fragment deletions. Epilepsy associated with MBD5 gene variants is usually refractory.

Analysis of clinical and genetic characteristics of epilepsy associated with chromosome 16p11.2 microdeletion / 中华儿科杂志

Objective: To investigate the clinical and genetic characteristics of epilepsy associated with chromosome 16p11.2 microdeletion. Methods: The patients (n=10) with 16p11.2 microdeletion found in children with epilepsy treated in Beijing Children's Hospital Affiliated to Capital Medical University from January 2018 to January 2021 were collected. The clinical manifestations, gene variations and prognosis were analyzed retrospectively. Results: A total of 10 children's data were collected, including 5 male and 5 female. The onset age of epilepsy was 4.5 (4.1,5.0) months. Regarding the seizure types, 7 cases had focal seizures with secondary generalization, 2 cases had generalized seizures, and 1 case had tonic seizures and spasms. Nine cases had cluster seizure attacks and 3 cases had status epilepticus. Seven cases had focal or multifocal epileptiform discharges in interictal electroencephalogram (EEG), 3 cases had borderline or normal EEG. Brain magnetic resonance imaging showed polymicrogyria in 1 case, paraventricular leukomalacia in 1 case, delayed myelination of white matter in 3 cases, and no obvious abnormalities in the other 5 cases. The patients were followed up for 0.5-3.5 years, with 1-3 kinds of antiepileptic drugs taken orally. The case with polymicrogyria still had seizures, however the other 9 cases had seizures controlled. The age of the last seizure attack was 8 (6, 12) months. There were 6 cases with mental and motor developmental delay before epilepsy onset. During the follow-up, 7 cases were retarded to varying degrees, while 3 cases had normal development. Regarding the genetic detection methods, 7 cases underwent whole exome sequencing, 2 cases underwent whole genome copy number variation detection, and 1 case underwent whole genome sequencing. The length of the 16p11.2 deletion in 10 cases ranged from 525 to 951 kb, and all contained the PRRT2 gene intact. Six cases were de novo variants, 1 case was inherited from the mother who had a history of convulsions in early childhood, and the source of variant was not verified in 3 cases, none of whose parents had relevant phenotype. Conclusions: The epilepsy associated with 16p11.2 microdeletion is mainly induced by the heterozygous deletion of PRRT2 gene in this region, however the phenotype is usually severe, and often combined with developmental and epileptic encephalopathy. Detection of copy number variation should be emphasized in children whose etiology is considered genetic but second-generation sequencing result is negative.

Clinical characteristics and gene analysis of GRIN2B gene related neurological developmental disorders in children / 中华儿科杂志

Objective: To analyse the clinical and gene characteristics of GRIN2B gene related neurological developmental disorders in children. Methods: The data of 11 children with GRIN2B gene related neurological developmental disorders from November 2016 to February 2021 were collected from Department of Neurology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health and analyzed retrospectively. The clinical features, electroencephalogram (EEG), brain imaging and gene testing results were summarized. Results: Among 11 children 6 were boys and 5 were girls. Two of them were diagnosed with developmental and epileptic encephalopathy. The ages of seizures onset were 3 months and 9 months, respectively. Seizure types included epileptic spasm, tonic seizures, tonic spasm and focal seizures, and 1 patient also had startle attacks. EEG showed interictal multifocal epileptiform discharges. Both of them were added with more than 2 anti-seizure drugs, which were partially effective but could not control. They had moderate to severe mental and motor retardation. The phenotype of 9 cases was developmental delay or intellectual disability without epilepsy, age of visit 1 year to 6 year and 4 months of whom 5 cases had severe developmental delay, 2 cases had moderate and 2 cases had mild delay. Multi-focal epileptiform discharges were observed in 3 cases, no abnormality was found in 3 cases, and the remaining 3 cases did not undergo EEG examination. Ten cases underwent brain magnetic resonance imaging (MRI), 6 cases had nonspecific abnormalities and 4 cases were normal. Nine GRIN2B gene heterozygous variants were detected by next-generation sequencing in these 11 patients, 8 cases had missense variants and 1 case had nonsense variant, all of which were de novo and 3 of which were novel. Missense variants were found in 10 patients, among them 6 cases had severe developmental delay, 3 cases had moderate and 1 case had mild developmental delay, but the patient with nonsense variant showed mild developmental delay without epilepsy. Conclusions: The phenotypes of GRIN2B gene related neurological developmental disorders in children are diverse, ranging from mild intellectual impairment without epilepsy to severe epileptic encephalopathy. Patients with epileptic phenotype usually have an onset age of infancy, and spasm and focal seizures are the most common seizure types. And the epiletice episodes are refractory. Most of the patients with missense variants had severe developmental delay.

Clinical and genetic spectrum of SCN2A gene associated epilepsy and episodic ataxia / 中华儿科杂志

Objective: To explore the clinical manifestations and genetic characteristics of patients with epilepsy and episodic ataxia caused by SCN2A gene variation. Methods: The clinical data of seizure manifestation, imaging examination and genetic results of 5 patients with epilepsy and (or) episodic ataxia because of SCN2A gene variation admitted to the Department of Pediatrics, the Third Affiliated Hospital of Zhengzhou University from July 2017 to January 2021 were analyzed retrospectively. Results: Among 5 patients, 4 were female and 1 was male. The onset age of epilepsy ranged from 4 days to 8 months. There were 2 cases of benign neonatal or infantile epilepsy and 3 cases of epileptic encephalopathy, in whom 1 case had development retardation,1 case transformed from West syndrome to infantile spasm and another one transformed from infantile spasm to Lennox-Gastaut syndrome. One case of benign neonatal-infantile epilepsy was characterized by neonatal onset seizures and episodic ataxia developed at the age of 78 months. Electroencephalograms at first visit of 5 cases showed that 2 cases were normal, 1 case had focal epileptic discharge, and 2 cases had multi-focal abnormal discharge with peak arrhythmia. The brain magnetic resonance imaging (MRI) of 3 cases were nomal, 1 case was abnormal (brain atrophy with decreased white matter) and the results of 1 case was unknown. The follow-up time ranged from 17 months to 89 months. Four cases of epilepsy were controlled and 1 case died at 2 years of age. Two cases had normal intelligence and motor development, 2 had moderate to severe intelligence retardation and motor critical state, and 1 had moderate to severe intelligence and motor development retardation. SCN2A gene variations were identified in all cases. There were 4 missense variations and 1 frameshift variation. Three variations had not been reported so far, including c.4906A>G,c.3643G>T,c.638delT. Conclusions: Variations in SCN2A gene can cause benign neonatal or infantile epilepsy and epileptic encephalopathy. Some children develop episodic ataxia with growing age. The variation of SCN2A gene is mainly missense variation.

Caracterização fenotípica das epilepsias geneticamente determinadas diagnosticadas pelo sequenciamento de nova geração / Phenotypic characterization of genetically determined epilepsies diagnosed by next-generation sequencing

Nos últimos anos, o emprego na prática clínica de painéis genéticos e do sequenciamento do exoma e do genoma permitiu o diagnóstico em pacientes sem uma etiologia definida, principalmente nas Encefalopatias Epilépticas e do Desenvolvimento (EEDs). A identificação das formas de epilepsia geneticamente determinadas permite caracterizar melhor sua história natural e orientar o tratamento, ao mesmo tempo em que propicia o aconselhamento genético. O objetivo do estudo foi descrever o fenótipo de indivíduos com epilepsia geneticamente determinada com variantes patogênicas ou provavelmente patogênicas, previamente identificadas pelo NGS. Foram incluídos pacientes até a idade de 18 anos, acompanhados por serviços de Neurologia Infantil e/ou de Genética Médica no estado do Rio de Janeiro, provenientes de hospitais públicos ou de clínicas privadas. O estudo, de natureza descritiva e transversal, foi realizado através da análise de uma amostra de conveniência. No período de abril de 2020 até dezembro de 2021, foram incluídos 75 pacientes, cujo diagnóstico etiológico foi relacionado a 53 genes diferentes. O tipo de sequenciamento de nova geração realizado foi exoma em 56 (74,6%) pacientes, painel genético em 18 (24%) e genoma em um (1,7%). Em relação ao padrão de herança dos 53 genes, 50 (67%) pacientes apresentavam variantes deletérias em genes de herança autossômica dominante (AD), dez (13%) em genes com herança autossômica recessiva (AR), 12 (16%) em genes com o padrão dominante ligado ao X (XD) e 3 (4%) em genes com herança recessiva ligada ao X (XR). O teste em trio foi realizado em 37 pacientes (49,3%) e 33 pacientes apresentaram variantes de novo. O tipo de variante mais frequente foi a missense, seguida pelas variantes frameshift, variantes em regiões de sítio de splicing, deleções in-frame e variantes nonsense. A média de idade do diagnóstico da epilepsia foi de 18 meses, variando entre o primeiro dia de vida até 12 anos. Diagnóstico de EED foi estabelecido em 97,3% pacientes (N=73), na média de idade de 3 anos e 1 mês, e 36 pacientes apresentam uma síndrome epiléptica específica, sendo as mais comuns as Síndromes de West e de Lennox-Gastaut. O padrão de herança de maior frequência no grupo estudado foi AD. Os genes mais frequentes encontrados na nossa amostra foram: genes com herança AD: SCN8A (8%), STXBP1 (8%), KCNQ2 (6,6%), KCNT1 (4%); ligada ao XD: CDKL5 (4%); PCDH19 (4%); e AR: RARS2 (2,6%). O maior número de pacientes está associado a genes que sintetizam canais iônicos voltagem-dependentes (N=19/25,3%) e os genes mais frequentes foram, sucessivamente: SCN8A, KCNQ2, KCNT1, KCNA2. Na nossa amostra, somente dois pacientes conseguiram realizar o exame pelo SUS. O tempo médio de espera para realização do NGS foi de 8 meses. O conhecimento e a interpretação dos resultados dos testes genéticos moleculares têm evoluído de maneira substancial. Disponibilizar o NGS de forma universal para pacientes com suspeita de epilepsia de origem genética, permitirá o diagnóstico de um maior número de pacientes, a identificação de casos atípicos e a adequação terapêutica.

In recent years, the use in clinical practice of genetic panels, exome and genome sequencing has allowed the diagnosis in patients without a defined etiology, mainly in epileptic and developmental encephalopathies (EED). The identification of genetically determined forms of epilepsy makes it possible to better characterize its natural history, guide treatment and provide genetic counseling. The aim of the study was to describe the phenotype of individuals with genetically determined epilepsy with pathogenic or probably pathogenic variants, previously identified by NGS. Patients up to the age of 18 years, followed by Child Neurology and/or Medical Genetics services in the State of Rio de Janeiro, from Public Hospitals or private clinics were included. The study was descriptive and transversal, through the analysis of a convenience sample. From April 2020 to December 2021, 75 patients were included, whose etiological diagnosis was related to 53 different genes. The type of next-generation sequencing performed was exome in 56 (74.6%) patients, genetic panel in 18 (24%) and 1 (1.7%) performed the genome. Regarding the inheritance pattern of the 53 genes, 50 (67%) patients had deleterious variants in genes of autosomal dominant inheritance (AD), 10 (13%) in genes with autosomal recessive inheritance (AR), 12 (16%) with dominant pattern X-linked (XD) and 3 (4%) with X-linked recessive inheritance (XR). Trio testing was performed in 37 patients (49.3%) and 33 patients have de novo variants. The most frequent type of variant was missense, followed by frameshift variants, variants in splicing site regions, in- frame and nonsense variants. The mean age of epilepsy diagnosis was 18 months, ranging from the first day of life to 12 years. Diagnosis of DEE was established in 97.3% patients (N=73), with a mean age of 3 years and 1 month and 36 patients presented a specific epileptic syndrome, the most common being West syndrome and Lennox- Gastaut. The most frequent inheritance pattern in the studied group was AD. The most frequent genes found in our sample were: genes with AD inheritance: SCN8A (8%), STXBP1 (8%), KCNQ2 (6.6%), KCNT1 (4%); XD-linked: CDKL5 (4%); PCDH19 (4%); and AR: RARS2 (2.6%). The largest number of patients is associated with genes that synthesize voltage-gated ion channels (N=19/25.3%) and the most frequent genes were successively: SCN8A, KCNQ2, KCNT1, KCNA2. In our sample, only 2 patients were able to perform the exam through the SUS. The mean waiting time for performing the NGS was 8 months. Knowledge and interpretation of molecular genetic test results have evolved substantially. Making NGS universally available in patients suspected of having epilepsy of genetic origin, will allow the diagnosis of a greater number of patients, identification of atypical cases and therapeutic adequacy.

Progress on mitochondrial silence information regulator family in epilepsy / 浙江大学学报·医学版

SIRT3, SIRT4 and SIRT5 are located in mitochondria and also known as mitochondrial sirtuins. They play important roles in regulating many cellular functions including cell survival, cell cycle or apoptosis, DNA repair and metabolism. Mitochondrial sirtuins are involved in the protection of mitochondrial integrity and energy metabolism under stress regulating the expression of neurotransmitter receptors, neurotrophins, extracellular matrix proteins and various transcription factors, thus involved in epileptogenesis triggered by both genetic or acquired factors. Here we review research progress on the actions of mitochondrial sirtuin in epilepsy; and discuss the challenges and perspectives of mitochondrial sirtuin as a potential therapeutic target for epilepsy.