Novel copy number variations and phenotypes of infantile epileptic spasms syndrome.

We summarize the copy number variations (CNVs) and phenotype spectrum of infantile epileptic spasms syndrome (IESS) in a Chinese cohort. The CNVs were identified by genomic copy number variation sequencing. The CNVs and clinical data were analyzed. 74 IESS children with CNVs were enrolled. 35 kinds of CNVs were identified. There were 11 deletions and 5 duplications not reported previously in IESS, including 2 CNVs not reported in epilepsy. 87.8% were de novo, 9.5% were inherited from mother and 2.7% from father. Mosaicism occurred in one patient with Xq21.31q25 duplication. 16.2% (12/74) were 1p36 deletion, and 20.3% (15/74) were 15q11-q13 duplication. The age of seizure onset ranged from 17 days to 24 months. Seizure types included epileptic spasms, focal seizures, tonic seizures, and myoclonic seizures. All patients displayed developmental delay. Additional features included craniofacial anomaly, microcephaly, congenital heart defects, and hemangioma. 29.7% of patients were seizure-free for more than 12 months, and 70.3% still had seizures after trying 2 or more anti-seizure medications. In conclusion, CNVs is a prominent etiology of IESS. 1p36 deletion and 15q duplication occurred most frequently. CNV detection should be performed in patients with IESS of unknown causes, especially in children with craniofacial anomalies and microcephaly.

Phenotypic Spectrum and Prognosis of Epilepsy Patients With GABRG2 Variants.

Objective: This study aimed to obtain a comprehensive understanding of the genetic and phenotypic aspects of GABRG2-related epilepsy and its prognosis and to explore the potential prospects for personalized medicine. Methods: Through a multicenter collaboration in China, we analyzed the genotype-phenotype correlation and antiseizure medication (ASM) of patients with GABRG2-related epilepsy. The three-dimensional protein structure of the GABRG2 variant was modeled to predict the effect of GABRG2 missense variants using PyMOL 2.3 software. Results: In 35 patients with GABRG2 variants, 22 variants were de novo, and 18 variants were novel. The seizure onset age was ranged from 2 days after birth to 34 months (median age: 9 months). The seizure onset age was less than 1 year old in 22 patients (22/35, 62.9%). Seizure types included focal seizures (68.6%), generalized tonic-clonic seizures (60%), myoclonic seizures (14.3%), and absence seizures (11.4%). Other clinical features included fever-sensitive seizures (91.4%), cluster seizures (57.1%), and developmental delay (45.7%). Neuroimaging was abnormal in 2 patients, including dysplasia of the frontotemporal cortex and delayed myelination of white matter. Twelve patients were diagnosed with febrile seizures plus, eleven with epilepsy and developmental delay, two with Dravet syndrome, two with developmental and epileptic encephalopathy, two with focal epilepsy, two with febrile seizures, and four with unclassified epilepsy. The proportions of patients with missense variants in the extracellular region and the transmembrane region exhibiting developmental delay were 40% and 63.2%, respectively. The last follow-up age ranged from 11 months to 17 years. Seizures were controlled in 71.4% of patients, and 92% of their seizures were controlled by valproate and/or levetiracetam. Conclusion: The clinical features of GABRG2-related epilepsy included seizure onset, usually in infancy, and seizures were fever-sensitive. More than half of the patients had cluster seizures. Phenotypes of GABRG2-related epilepsy were ranged from mild febrile seizures to severe epileptic encephalopathies. Most patients with GABRG2 variants who experienced seizures had a good prognosis. Valproate and levetiracetam were effective treatments for most patients.

GABRB3-related epilepsy: novel variants, clinical features and therapeutic implications.

OBJECTIVE: This study aimed to comprehensively examine the genetic and phenotypic aspects of GABRB3-related epilepsy and to explore the potential prospects of personalized medicine. METHODS: Genetic testing was conducted in all epilepsy patients without acquired factors for epilepsy. Through the collaboration of multicenter in China, we analyzed the genotype-phenotype correlation and antiepileptic therapy of 26 patients with GABRB3-related epilepsy. RESULTS: Thirteen GABRB3 variants were novel, and 25 were de novo. The seizure onset age ranged from 1 to 21 months (median age 3.75 months). Seizure types predominated including focal seizures (92.3%), generalized tonic-clonic seizures (23.1%), and epileptic spasms (15.4%). Clinical features included cluster seizures (80.8%), fever sensitivity (53.8%), and developmental delay (96.2%). Neuroimaging was abnormal in 10 patients, including dysplasia of the cerebral cortex, dysplasia of the frontal and temporal cortex, delayed myelination, and corpus callosum dysplasia. Eleven patients were diagnosed with developmental and epileptic encephalopathy (DEE), four with West syndrome, three with epilepsy of infancy with migrating focal seizures (EIMFS), one with epilepsy with myoclonic-atonic seizures (EMAS), one with Dravet syndrome, and one with febrile seizures plus (FS+). Seizures were controlled in 57.7% of patients by valproate, levetiracetam, or perampanel in the majority. CONCLUSIONS: The clinical features of GABRB3-related epilepsy included seizure onset in early infancy, cluster seizures and fever sensitivity. Most patients manifest severe epilepsy phenotypes. Valproate, levetiracetam and perampanel seem to have positive effects on seizure control for patients with GABRB3 variants.