Developmental epileptic encephalopathies (DEEs) are a group of disorders characterized by early-onset seizures, abnormal electroencephalogram (EEG) patterns, and developmental delay or regression. They are characterized by complex etiology and are often refractory to treatment, severely impacting affected children, particularly infants and toddlers, and pose a challenge in pediatric neurology. In recent years, with the rise of precision medicine, an increasing number of pathogenic genes associated with DEEs have been discovered. However, the specific pathogenic mechanisms and signaling pathways of these genes in the body still require further investigation. This article primarily discusses the genetic patterns of DEEs and the selection of genetic testing, emphasizing the timing of genetic testing assisted by the epilepsy phenotype, especially in DEEs associated with single-gene mutations and new therapeutic drugs, to aid in clinical decision-making for DEEs. It also introduces the use of neurobiological models for DEE research to effectively advance epilepsy research, thereby enabling targeted gene therapy.
ObjectiveTo explore the clinical, genetic and prognostic features of early infantile epileptic encephalopathy caused by DNM1 gene pathogenic variations.MethodsClinical phenotype, genotype and prognosis of 3 individuals with de novo variants in DNM1 gene were analyzed retrospectively. Through using “Dynamin-1” or “DNM1” as key words to search literature at database of China National Knowledge Infrastructure, Wanfang, PubMed and OMIM. Genotype-phenotype correlations were analyzed by analysis of variance (ANOVA).ResultAmong the 3 patients, 1 female and 2 males. 2 cases with epileptic spasm and 1 case with focal clonic seizure or secondary generalized tonic-clonic seizure were manifested with onset age from 2 to 17 months. De novo variants at NM_004408.4: c.415 G>A(P. Gly 139Arg) in 2 inviduals and NM_004408.4: c.545 C>A(P. Ala 182Asp)in 1 invidual of DNM1 gene were identified by gene testing. After follow-up at age of 2~3 years, all patients were presented with hypotonia, severe intellectual disability, non-verbal, non-ambulatory, drug-resistant epilepsy and feeding difficulties. 36 cases with pathogenic DNM1 variants were reported by far, totally 39 cases were included. Of the 39 patients, hypotonia were found to be independent of the locus of genetic variants, while those inviduals with variants in the GTPase and middle domains almost presented severe or profound intellectual disability and epilepsy. 31 patients diagnosed with epilepsy and complete clinical data were further analyzed, epileptic spasm was the most common types of seizure. Absent seizure was significantly more common in those patients with variants in the GTPase domains (P=0.02), compared to those patients with variants in the middle domains. No statistical differences were found in gender, onset age, other types of seizure and drug treatment response between variants in the GTPase and middle domains.ConclusionHypotonia, early onset epilepsy, severe intellectual and movement disability were the common features in patients with DMN1 related encephalopathy. Epileptic spasm was the most common types of seizure, no significant differences were found in the phenotype between the GTPase and middle domains expect for absent seizure. Our patients also presented with feeding difficulties.
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.
Objective To explore the efficacy and safety of the ketogenic diet (KD) in the treatment of genetic developmental and epileptic encephalopathy (DEE). Methods Clinical data from 42 children with genetically confirmed refractory epileptic encephalopathy treated in the Department of Neurology, Jinan Children’s Hospital, between January 2021 and October 2023 were retrospectively analyzed. A classic KD protocol was implemented, and outcomes including seizure frequency, electroencephalogram (EEG) improvement, and adverse reactions were observed at 3, 6, and 12 months post-treatment. Results Among the 42 children, the seizure-free rates at 3, 6, and 12 months of KD treatment were 16.7%, 16.7%, and 14.3%, respectively, while the effective seizure control rates were 69.0%, 52.4%, and 35.7%. At 3 months, comparison of baseline characteristics between the effective and ineffective groups showed no statistically significant differences in gender (P=0.095), age at onset (P=0.648), age at KD initiation(P=0.768), disease duration before KD (P=0.519), presence of abnormal brain MRI findings (P=0.226), epilepsy syndrome classification(P=0.344), or ion channel gene involvement (P=0.066). EEG improvement rates at 6 and 12 months were 54.2% (24 cases) and 42.8% (14 cases), respectively. Retention rates for KD at 3, 6, and 12 months were 100.0%, 71.4%, and 42.8%. Adverse reactions occurred in 7 patients (16.7%), primarily gastrointestinal symptoms (vomiting, constipation, diarrhea; 6 cases) and elevated uric acid (1 case), with no severe adverse events reported. Conclusion KD is an effective treatment for genetic DEE with favorable short-term safety, though long-term adherence requires attention.