Child ; Humans ; Infant ; Spasms, Infantile ; genetics ; Syndrome

OBJECTIVE: To analyze the clinical phenotype and genetic characterization of a child with early infantile epileptic encephalopathy. METHODS: The proband was subjected to history taking and was diagnosed based on his clinical manifestation, magnetic resonance imaging (MRI) and whole exome sequencing (WES). Sanger sequencing was carried out to determine the origin of pathogenic variant. RESULTS: The proband unconsciously tilts his head to one side with squint, which revealed an abnormal discharge. MRI indicated suspicious abnormal signal shadow in the left posterior frontal cortex in addition with inflammation signs in the right maxillary sinus and ethmoid sinus. WES revealed that the proband has carried a heterozygous c.5789G>A variant in the CACNAIA gene. The result of Sanger sequencing was in keeping with that of WES. Neither of his parents has carried the same variant. CONCLUSION The heterozygous c.5789G>A variant of the CACNAIA gene probably underlay the early infantile epileptic encephalopathy 42 in the proband, which has a de novo origin.
Calcium Channels/genetics* ; Genetic Testing ; Heterozygote ; Humans ; Infant ; Mutation ; Spasms, Infantile/genetics* ; Whole Exome Sequencing

OBJECTIVE: To explore the clinical characteristics of a child with early-onset infantile epileptic encephalopathy type 8 associated with synonymous variant of ARHGEF9 gene. METHODS: Clinical data of the patient was summarized. The child and his parents were subjected to trio-whole exome sequencing. RESULTS: The child has presented with global developmental delay, epilepsy, impulsive behavior, hypersensitivity to sound, and mental retardation. He was found to harbor a de novo synonymous variant c.741C>T (p.Cys247Cys) of the ARHGEF9 gene. RNA splicing analysis confirmed that the variant has led to abnormal splicing of exon 5, resulting in a 55-bp deletion. CONCLUSION The clinical features of ARHGEF9 gene-related early-onset infantile epileptic encephalopathy type 8 includes mental and motor developmental delay, epilepsy, auditory allergy, and hyperactivity impulsivity. For synonymous variant, in vitro study and transcriptional experiment may be carried out to evaluate its functional and splicing effect. Above finding has enriched the phenotypic and genotypic spectrum of the ARHGEF9 gene.
Child ; Epilepsy/genetics* ; Exons ; Humans ; Infant ; Intellectual Disability/genetics* ; Male ; Rho Guanine Nucleotide Exchange Factors/genetics* ; Spasms, Infantile/genetics*

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.
Child ; Developmental Disabilities/genetics* ; Electroencephalography ; Epilepsy/genetics* ; Female ; Humans ; Infant ; Male ; Retrospective Studies ; Seizures/genetics* ; Spasms, Infantile/genetics*

OBJECTIVE: To analyze the clinical features and genetic variants in two patients with Dravet syndrome (DS). METHODS: Peripheral blood samples of the children and their parents were collected for the extraction of genomic DNA and high-throughput sequencing. Suspected variants were confirmed by Sanger sequencing. RESULTS: By high-throughput sequencing, the two children were found to respectively harbor a c.2135delC frameshifting variant in exon 12 and a c.1522G>T nonsense variant in exon 10 of the SCN1A gene. Both variants were predicted to be pathogenic by bioinformatic analysis. Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.2135delC and c.1522G>A variants of the SCN1A gene were predicted to be pathogenic (PVS1+ PS2+ PM2+ PP3). CONCLUSION The variants of the SCN1A gene probably underlay the DS in the patients. Above finding has enriched the variant spectrum and enabled genetic counseling for their families.
Epilepsies, Myoclonic/genetics* ; Genomics ; Humans ; Infant ; Mutation ; NAV1.1 Voltage-Gated Sodium Channel/genetics* ; Pedigree ; Spasms, Infantile/genetics*

Child ; Epilepsy, Generalized ; Family ; GTP-Binding Proteins/genetics* ; Humans ; Infant ; Spasms, Infantile/genetics* ; Tumor Suppressor Proteins/genetics*

Objective: To analyze the genotypes and clinical phenotypes of patients with epilepsy associated with IQSEC2 gene variants. Methods: The genotypes, seizure types, electroencephalogram, neuroimage of 6 patients with IQSEC2 gene variants in the Department of Pediatrics, Peking University First Hospital from July 2019 to October 2021 were analyzed. Results: There were 5 males and 1 female. Six variants were de novo, including 2 frameshift variants (c.3801_3808dup/p.Q1270Rfs*130, c.1459_1460delAT/p.M487Vfs*2), 2 nonsense variants (c.3163C>T/p.R1055*, c.1417G>T/p.E473*), 1 in-frame deletion (c.2295_2297del/p.N765del) and 1 missense variant (c.2293A>G/p.N765D). Age at seizure onset ranged from 3 months to 2 years and 5 months. Multiple seizure types were observed, including epileptic spasms in 5 patients, focal seizures in 5 patients, tonic seizures in 3 patients, myoclonic seizures in 3 patients, atypical absence seizures in 2 patients and atonic seizures in 2 patients. All 6 patients showed global developmental delay before seizure onset. There were other clinical manifestations, including autistic features in 3 patients, microcephaly in 3 patients, dystonia in 2 patients and binocular esotropia in 1 patient. The electroencephalogram showed slow background activity and hypsarrhythmia in all 6 patients. Brain magnetic resonance imaging showed abnormal in 5 patients and normal in 1 patient. Five patients were diagnosed with infantile spasms. Among them, 4 patients had late-onset infantile spasms. One patient was unclassified developmental epileptic encephalopathy. The age of last follow-up ranged from 3 years and 2 months to 7 years and 2 months. All 6 patients still had seizures after multiple anti-seizure medications. Conclusions: The seizure onset of patients with IQSEC2 gene variants usually begins after 1 year of age. The common seizure types include epileptic spasms and focal seizures. Patients usually have a global developmental delay before seizure onset. IQSEC2 variants could be related to developmental and epileptic encephalopathy, and most patients are diagnosed with late onset infantile spasms. Epilepsy associated with IQSEC2 gene variants is usually refractory.
Female ; Male ; Child ; Humans ; Spasms, Infantile/genetics* ; Genotype ; Phenotype ; Epilepsy/genetics* ; Seizures ; Spasm ; Guanine Nucleotide Exchange Factors

OBJECTIVETo study the clinical features of early-onset epileptic encephalopathies (EEEs) of unknown cause, and to identify pathogenic microdeletion/microduplication of EEEs by genome-wide analysis of copy number variations (CNVs).

METHODSThe clinical data of 60 children diagnosed with unexplained EEEs between July 2012 and April 2013 were obtained and analyzed. Specimens were collected from the selected children and their parents. Single nucleotide polymorphism array was used to detect genome-wide CNVs, and fluorescence in situ hybridization was performed to verify the results and analyze the source of the parents, further to identify suspected pathogenic CNVs of EEEs.

RESULTSAmong the 60 children with unexplained EEEs, 34 were diagnosed with West syndrome, 3 with Ohtahara syndrome, 3 with Dravet syndrome, and 20 with unclassified EEEs. In total, 77% of the patients were associated with moderate to severe mental retardation. Head imaging test implied that 35% of the patients had brain dysplasia or astrophy. Among 54 patients, 17% showed microcephalus. After treatment, 28 patients had clinical seizures under control, 16 out of control, 5 dead, and 1 lost to follow-up. Genome-wide analysis of CNVs showed that 7 pathogenic or suspected pathogenic CNVs were present in 5 patients.

CONCLUSIONSEEEs of unknown cause are associated with high phenotypic heterogeneity and poor prognosis. Genome-wide CNVs analysis can demonstrate pathogenic or suspected pathogenic CNVs. This research expands the gene bank of EEEs and improves the understanding about possible etiology of unexplained EEEs. The results provide a reference for genetic counseling regarding reproduction in the patient's family.

Child ; DNA Copy Number Variations ; Female ; Genome-Wide Association Study ; Humans ; Infant ; Infant, Newborn ; Spasms, Infantile ; etiology ; genetics

Alexander disease (AD) is a rare leukodystrophy of the central nervous system of unknown etiology. AD is characterized by progressive failure of central myelination and the accumulation of Rosenthal fibers in astrocytes, and is inevitably lethal in nature. Symptomatically, AD is associated with leukoencephalopathy with macrocephaly, seizures, and psychomotor retardation in infants, and usually leads to death within the first decade. Its characteristic magnetic resonance imaging (MRI) findings have been described as demyelination predominantly in the frontal lobe. Moreover, dominant mutations in the GFAP gene, coding for glial fibrillary acidic protein (GFAP), a principal astrocytic intermediate filament protein, have been shown to lead to AD. The disease can now be detected by genetic diagnosis. We report the Korean case of an 8-month-old male patient with AD. He was clinically characterized due to the presence of psychomotor retardation, megalencephaly, spasticity, and recurrent seizures including infantile spasms which is a remarkable presentation. Demyelination in the frontal lobe and in a portion of the temporal lobe was demonstrated by brain MRI. Moreover, DNA analysis of peripheral blood showed the presence of a R239L mutation in the GFAP gene, involving the replacement of guanine with thymine.
Spasms, Infantile/*etiology ; *Mutation ; Male ; Magnetic Resonance Imaging ; Infant ; Humans ; Glial Fibrillary Acidic Protein/*genetics ; Electroencephalography ; Alexander Disease/complications/*diagnosis

Carrier Proteins ; genetics ; Evoked Potentials, Auditory, Brain Stem ; Humans ; Infant ; Iron Metabolism Disorders ; genetics ; physiopathology ; Male ; Mutation ; Neuroaxonal Dystrophies ; genetics ; physiopathology ; Spasms, Infantile ; genetics ; physiopathology