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Developmental and epileptic encephalopathy 45 (DEE45) is a neurogenetic disorder caused by heterozygous pathogenic variants of GABRB1, encoding the beta1 subunit of the GABA type A receptor. Only three infants with DEE45 have been reported so far, and a detailed description of the disease history of these patients is still lacking. We describe the clinical and genetic findings of a 21-year-old woman with DEE45 carrying a novel de novo GABRB1 mutation (c.841A>G, p.T281A). The patient presented at birth with hypotonia and focal apneic seizures evolving in a phenotype of epilepsy of infancy with migrating focal seizures that were refractory to antiseizure medications. Epileptic spasms partially responsive to steroid therapy appeared in the second year of life. Acquired microcephaly, profound mental retardation, and tetraparesis became evident with development. During childhood and adolescence, the epileptic phenotype evolved toward a Lennox-Gastaut Syndrome. Atypical absence status and clusters of tonic seizures occurred, often triggered by respiratory infections. The main strengths of this work are the identification of a novel pathogenic GABRB1 variant localized in the same transmembrane domain of a previously described mutation and the detailed description of the clinical trajectory of GABRB1-related encephalopathy along 21 years of disease history.

The International League Against Epilepsy (ILAE) Task Force on Nosology and Definitions proposes a classification and definition of epilepsy syndromes in the neonate and infant with seizure onset up to 2 years of age. The incidence of epilepsy is high in this age group and epilepsy is frequently associated with significant comorbidities and mortality. The licensing of syndrome specific antiseizure medications following randomized controlled trials and the development of precision, gene-related therapies are two of the drivers defining the electroclinical phenotypes of syndromes with onset in infancy. The principal aim of this proposal, consistent with the 2017 ILAE Classification of the Epilepsies, is to support epilepsy diagnosis and emphasize the importance of classifying epilepsy in an individual both by syndrome and etiology. For each syndrome, we report epidemiology, clinical course, seizure types, electroencephalography (EEG), neuroimaging, genetics, and differential diagnosis. Syndromes are separated into self-limited syndromes, where there is likely to be spontaneous remission and developmental and epileptic encephalopathies, diseases where there is developmental impairment related to both the underlying etiology independent of epileptiform activity and the epileptic encephalopathy. The emerging class of etiology-specific epilepsy syndromes, where there is a specific etiology for the epilepsy that is associated with a clearly defined, relatively uniform, and distinct clinical phenotype in most affected individuals as well as consistent EEG, neuroimaging, and/or genetic correlates, is presented. The number of etiology-defined syndromes will continue to increase, and these newly described syndromes will in time be incorporated into this classification. The tables summarize mandatory features, cautionary alerts, and exclusionary features for the common syndromes. Guidance is given on the criteria for syndrome diagnosis in resource-limited regions where laboratory confirmation, including EEG, MRI, and genetic testing, might not be available.

SCN2A encodes a voltage-gated sodium channel (NaV1.2) expressed throughout the central nervous system in predominantly excitatory neurons. Pathogenic variants in SCN2A are associated with epilepsy and neurodevelopmental disorders. Genotype-phenotype correlations have been described, with loss-of-function variants typically being associated with neurodevelopmental delay and later-onset seizures, whereas gain-of-function variants more often result in early infantile-onset epilepsy. However, the true electrophysiological effects of most disease-causing SCN2A variants have yet to be characterized. We report an infant who presented with migrating focal seizures in the neonatal period. She was found to have a mosaic c.2635G>A, p.Gly879Arg variant in SCN2A. Voltage-clamp studies of the variant expressed on adult and neonatal NaV1.2 isoforms demonstrated a mixed gain and loss of function, with predominantly a loss-of-function effect with reduced cell surface expression and current density. Additional small electrophysiological alterations included a decrease in the voltage dependence of activation and an increase in the voltage dependence of inactivation. This finding of a predominantly loss-of-function effect was unexpected, as the infant\'s early epilepsy onset would have suggested a predominantly gain-of-function effect. This case illustrates that our understanding of genotype-phenotype correlations is still limited and highlights the complexity of the underlying electrophysiological effects of SCN2A variants.NEW & NOTEWORTHY Voltage-gated sodium channels play an important role in the central nervous system, mutations in which have been reported to be responsible for epilepsy. We report here an infant presenting with epilepsy of infancy with migrating focal seizures (EIMFS) in the neonatal period with a mosaic c.2635G>A, resulting in a p.Gly879Arg missense mutation on the SCN2A gene encoding NaV1.2 sodium channels. Biophysical characterization of this variant revealed a mixture of gain- and loss-of-function effects.

The histone demethylase family plays a key role in chromatin structure and gene regulation during development. Mutations in the genes encoding the lysine demethylase 5 (KDM5) were reported in individuals with many diseases, including neurodevelopmental disorders such as intellectual disability. Recently, KDM5B has been identified as a gene regulator causative of recessive neurodevelopmental disorders. Although numerous variants in this gene have been identified, genotype / phenotype correlation remains variable. We report a patient with two de novo mutations, a frameshift KDM5B variant and a 2q deletion of 8.2 Mb, associated with a phenotype including facial and finger dysmorphisms, severe intellectual and motor disorders, and a rare epileptic syndrome identified as epilepsy of infancy with migrating focal seizures. Comparison with previous reports suggests that the KDM5B variant could play a potential role on dysmorphic features; conversely, the epileptic disorder is mainly caused by the haploinsufficiency of the Nav1 mediated gabaergic inhibition.

Variants in KCNT1, encoding a sodium-gated potassium channel (subfamily T member 1), have been associated with a spectrum of epilepsies and neurodevelopmental disorders. These range from familial autosomal dominant or sporadic sleep-related hypermotor epilepsy ((AD)SHE) to epilepsy of infancy with migrating focal seizures (EIMFS) and include developmental and epileptic encephalopathies (DEE). This study aims to provide a comprehensive overview of the phenotypic and genotypic spectrum of KCNT1 mutation-related epileptic disorders in 248 individuals, including 66 unpreviously published and 182 published cases, the largest cohort reported so far. Four phenotypic groups emerged from our analysis: i) EIMFS (152 individuals, 33 previously unpublished); ii) DEE other than EIMFS (non-EIMFS DEE) (37 individuals, 17 unpublished); iii) (AD)SHE (53 patients, 14 unpublished); iv) other phenotypes (6 individuals, 2 unpublished). In our cohort of 66 new cases, the most common phenotypic features were: a) in EIMFS, heterogeneity of seizure types, including epileptic spasms, epilepsy improvement over time, no epilepsy-related deaths; b) in non-EIMFS DEE, possible onset with West syndrome, occurrence of atypical absences, possible evolution to DEE with SHE features; one case of sudden unexplained death in epilepsy (SUDEP); c) in (AD)SHE, we observed a high prevalence of drug-resistance, although seizure frequency improved with age in some individuals, appearance of cognitive regression after seizure onset in all patients, no reported severe psychiatric disorders, although behavioural/psychiatric comorbidities were reported in about 50% of the patients, SUDEP in one individual; d) other phenotypes in individuals with mutation of KCNT1 included temporal lobe epilepsy, and epilepsy with tonic-clonic seizures and cognitive regression. Genotypic analysis of the whole cohort of 248 individuals showed only missense mutations and one inframe deletion in KCNT1. Although the KCNT1 mutations in affected individuals were seen to be distributed among the different domains of the KCNT1 protein, genotype-phenotype considerations showed many of the (AD)SHE-associated mutations to be clustered around the RCK2 domain in the C-terminus, distal to the NADP domain. Mutations associated with EIMFS/non-EIMFS DEE did not show a particular pattern of distribution in the KCNT1 protein. Recurrent KCNT1 mutations were seen to be associated with both severe and less severe phenotypes. Our study further defines and broadens the phenotypic and genotypic spectrums of KCNT1-related epileptic conditions and emphasizes the increasingly important role of this gene in the pathogenesis of early onset DEEs as well as in focal epilepsies, namely (AD)SHE.

OBJECTIVE: Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare and severe developmental epileptic encephalopathy. The aim of this study was to improve our understanding of EIMFS by using phenotype-genotype correlation.
METHODS: We recruited, performed clinical genetic testing, and summarized the clinical features and genetic characteristics in five patients with EIMFS in China.
RESULTS: The five recruited patients included 2 males and 3 females. The median age of seizure onset was 2 months (range, day 3 to 3 months). All patients exhibited the characteristics of clinically migrating focal motor (tonic or clonic) seizures. Typical migrating ictal electrical patterns were found in 1 patient; the remaining four patients presented with overlapping seizures with different areas of ictal onset in differing hemispheres. All the patients had the associated variants, including KCNT1, SCN1A, SCN2A, TBC1D24 and ALG1. All patients received two or more antiseizure medications, and 1 patient became seizure-free, 1 reported >75 % seizure reduction, 2 reported >50 % seizure reduction, and 1 patient showed no improvement. Varying degrees of psychomotor developmental delays were observed in all patients.
CONCLUSIONS: The course of EIMFS could be related to the type of gene variant present, and different genes may have specific clinical features. Larger cohorts are required to elucidate such potential phenotype-genotype correlations.

To study the epilepsy syndromes among the severe epilepsies of infancy and assess their incidence, etiologies, and outcomes.
A population-based cohort study was undertaken of severe epilepsies with onset before age 18 months in Victoria, Australia. Two epileptologists reviewed clinical features, seizure videos, and electroencephalograms to diagnose International League Against Epilepsy epilepsy syndromes. Incidence, etiologies, and outcomes at age 2 years were determined.
Seventy-three of 114 (64%) infants fulfilled diagnostic criteria for epilepsy syndromes at presentation, and 16 (14%) had \"variants\" of epilepsy syndromes in which there was one missing or different feature, or where all classical features had not yet emerged. West syndrome (WS) and \"WS-like\" epilepsy (infantile spasms without hypsarrhythmia or modified hypsarrhythmia) were the most common syndromes, with a combined incidence of 32.7/100 000 live births/year. The incidence of epilepsy of infancy with migrating focal seizures (EIMFS) was 4.5/100 000 and of early infantile epileptic encephalopathy (EIEE) was 3.6/100 000. Structural etiologies were common in \"WS-like\" epilepsy (100%), unifocal epilepsy (83%), and WS (39%), whereas single gene disorders predominated in EIMFS, EIEE, and Dravet syndrome. Eighteen (16%) infants died before age 2 years. Development was delayed or borderline in 85 of 96 (89%) survivors, being severe-profound in 40 of 96 (42%). All infants with EIEE or EIMFS had severe-profound delay or were deceased, but only 19 of 64 (30%) infants with WS, \"WS-like,\" or \"unifocal epilepsy\" had severe-profound delay, and only two of 64 (3%) were deceased.
Three quarters of severe epilepsies of infancy could be assigned an epilepsy syndrome or \"variant syndrome\" at presentation. In this era of genomic testing and advanced brain imaging, diagnosing epilepsy syndromes at presentation remains clinically useful for guiding etiologic investigation, initial treatment, and prognostication.

BACKGROUND: Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the early-onset epileptic encephalopathies resistant to antiepileptic drugs, therefore carrying an extremely poor neurodevelopmental outcome. KCNT1, encoding for a sodium-activated potassium channel (KCa4.1 channel), has recently been reported as the major gene responsible for EIMFS. Since gain of function is the only type of mutation identified in patients with EIMFS, quinidine, a partial antagonist of KCa4.1 channel, is considered as a potential candidate for targeted treatment of EIMFS. However, treatment results reported so far vary from seizure-free state to no response, and cardiac side effect remains a challenge for dose titration and long-term treatment.
METHODS: Our case was an infant diagnosed with EIMFS with confirmed mutation in KCNT1 gene. Quinidine therapy was started as early as 9 months old. Within the first month of treatment, the number of seizures reduced to about one third. However, seizure-free state was not obtained and his neuropsychological development remained severely delayed. After 16 months of treatment, quinidine had to be discontinued because of cardiac side effects. At 27 months of age, however, his seizures suddenly stopped and he remained seizure-free for five days. This coincided with the prescription of tipepidine, a commonly used antitussive, administered for his persistent cough. Reduction in seizure frequency was also observed with dextromethorphan, another conventional antitussive drug. Although the relation between these treatments and his symptom improvement is a matter of elucidation, there is a possibility that these nonnarcotic antitussive drugs might play a role in the treatment of EIFMS.

Through international collaboration, we evaluated the phenotypic aspects of a multiethnic cohort of KCNT1-related epilepsy and explored genotype-phenotype correlations associated with frequently encountered variants.
A cross-sectional analysis of children harboring pathogenic or likely pathogenic KCNT1 variants was completed. Children with one of the two more common recurrent KCNT1 variants were compared with the rest of the cohort for the presence of particular characteristics.
Twenty-seven children (15 males, mean age = 40.8 months) were included. Seizure onset ranged from 1 day to 6 months, and half (48.1%) exhibited developmental plateauing upon onset. Two-thirds had epilepsy of infancy with migrating focal seizures (EIMFS), and focal tonic seizures were common (48.1%). The most frequent recurrent KCNT1 variants were c.2800G>A; p.Ala934Thr (n = 5) and c.862G>A; p.Gly288Ser (n = 4). De novo variants were found in 96% of tested parents (23/24). Sixty percent had abnormal magnetic resonance imaging (MRI) findings. Delayed myelination, thin corpus callosum, and brain atrophy were the most common. One child had gray-white matter interface indistinctness, suggesting a malformation of cortical development. Several antiepileptic drugs (mean = 7.4/patient) were tried, with no consistent response to any one agent. Eleven tried quinidine; 45% had marked (>50% seizure reduction) or some improvement (25%-50% seizure reduction). Seven used cannabidiol; 71% experienced marked or some improvement. Fourteen tried diet therapies; 57% had marked or some improvement. When comparing the recurrent variants to the rest of the cohort with respect to developmental trajectory, presence of EIMFS, >500 seizures/mo, abnormal MRI, and treatment response, there were no statistically significant differences. Four patients died (15%), none of sudden unexpected death in epilepsy.
Our cohort reinforces common aspects of this highly pleiotropic entity. EIMFS manifesting with refractory tonic seizures was the most common. Cannabidiol, diet therapy, and quinidine seem to offer the best chances of seizure reduction, although evidence-based practice is still unavailable.