遊走性焦点発作を伴う乳児てんかん

The KCNT1 gene encodes for a sodium-activated potassium channel involved in neuronal excitability. Since its initial description in 2012 in patients with Epilepsy of Infancy with Migrating Focal Seizures (EIMFS) and in Sleep-related Hypermotor Epilepsy (SHE), the associated phenotypic spectrum has broadened-encompassing other focal epilepsies and Developmental and Epileptic Encephalopathies (DEEs)-and has included extra-neurological features. We aimed to characterize the neurological outcomes, extra-neurological features, mortality and genotype-phenotype correlations expanding the follow-up of the reported cases with KCNT1 variants. A comprehensive literature review was performed to identify all reported cases of KCNT1 pathogenic or likely pathogenic variants. Corresponding authors were contacted to obtain updated clinical data, including current vital status, epilepsy progression, extra-neurological features, cognitive and psychiatric status. The entire dataset, including updated data from the literature, was combined for subsequent analyses. A total of 316 patients from 88 publications were included. Follow-up data were obtained for 60 patients (from 28 papers and 11 countries), increasing the median age at last assessment from 4.4 to 6.0 years. 181 patients had an EIMFS phenotype, 62 had SHE, and 59 had various DEEs. Five individuals were asymptomatic parents, six had other focal epilepsies, and three had other phenotypes. Extra-neurological features were predominantly observed in patients with EIMFS and DEE, notably systemic-to-pulmonary collateral arteries, other vascular or cardiac malformations and various respiratory, orthopaedic or gastrointestinal disorders. The main cause of death was pulmonary complications (haemorrhage or infection). Genotype-phenotype correlations revealed a trend for variants in the first regulator of conductance of potassium (RCK1) domain to associate with EIMFS/non-EIMFS DEE, while SHE-associated variants were predominantly located in the second regulator of conductance of potassium (RCK2) domain. Additionally, variants p.Arg474Cys may confer increased risk for vascular malformations, but the issue appears to be broader, and systematic screening of patients carrying pathogenic KCNT1 variants would allow us to better define this risk. This study offers a comprehensive understanding of the clinical spectrum and genotype-phenotype correlation in KCNT1-related disorders. This study has inherent biases related to the retrospective collection of already published data and underscores the need to develop multisource data methodologies and registries to reduce follow-up loss in real-world data collections based on health records.

The potassium-chloride cotransporter 2 (KCC2) is a neuron-specific transporter essential for maintaining low intracellular chloride levels. By extruding chloride ions, KCC2 ensures that activation of GABAA receptors produces hyperpolarizing inhibitory responses rather than depolarizing responses. Disruption of KCC2 function can therefore impair GABAergic signaling and neuronal maturation, contributing to a range of neurodevelopmental and neurological disorders. Pathogenic biallelic variants in SLC12A5, the gene encoding KCC2, are a rare cause of severe early-onset developmental and epileptic encephalopathies, including epilepsy of infancy with migrating focal seizures (EIMFS). Here, we describe a novel homozygous SLC12A5 variant identified in a patient with severe, drug-resistant epilepsy, neonatal encephalopathy, and rapid neurological deterioration. Combined Western blot, thallium (Tl+) flux, and gramicidin-perforated patch-clamp assays revealed significantly reduced ion-transport function of the KCC2 construct encoding the variant, with no change in protein expression abundance or profile. Live-cell surface immunolabeling demonstrated markedly reduced plasma membrane expression and decreased internalization of the variant, suggesting that the functional deficit primarily results from defective trafficking or reduced membrane stability. These findings expand the spectrum of KCC2-related disorders and highlight the critical role of KCC2 in early brain development. By linking a specific SLC12A5 variant to impaired chloride homeostasis and neuronal hyperexcitability, this study provides mechanistic insight into disease pathogenesis and lays the groundwork for therapeutic strategies aimed at restoring or stabilizing KCC2 function.

BACKGROUND Potassium sodium-activated channel subfamily T member 1 (KCNT1)-related developmental and epileptic encephalopathy (DEE) is a rare and serious neurological condition attributed to damaging alterations in the KCNT1 gene, which encodes a sodium-activated potassium channel involved in neuronal excitability. It typically manifests in infancy with drug-resistant seizures, developmental delay, and hypotonia. Diagnosis is determined using whole-exome sequencing. Although KCNT1-related epilepsy is considered as a rare disorder, reporting such individual cases may help broaden the clinical and genetic spectrum of this condition. This report describes a Bahraini girl who first presented with symptoms at 2 weeks of age and at the time of this report was 4 years old, with developmental delay and epilepsy of infancy with migrating focal seizures (EIMFS), and early-onset DEE, associated with KCNT1 gene mutation. CASE REPORT A previously healthy term female baby presented at 2 weeks of age with focal seizures that progressed to intractable migrating focal epilepsy. At 4 months, she developed developmental regression, losing the ability to roll over, social-smile, and make eye contact. Neurological examination revealed central hypotonia with poor visual interaction. Electroencephalogram (EEG) showed multifocal epileptiform discharges with migrating seizure activity. Brain magnetic resonance imaging (MRI) and metabolic investigations were normal. Whole-exome sequencing identified a heterozygous KCNT1 variant, confirming developmental and epileptic encephalopathy type 14 (DEE14). CONCLUSIONS This case highlights the importance of timely genetic testing in infants showing severe epilepsy and developmental issues. To better understand the phenotypic variability and clinical course of KCNT1-related epileptic encephalopathy, more case reports are required. Identifying a KCNT1 mutation provides diagnostic clarity, supports precise prognosis and genetic counseling, and may help evaluate future targeted treatments.

KCNT1-related epileptic encephalopathy, including epilepsy of infancy with migrating focal seizures, is a severe neurodevelopmental disorder associated with refractory seizures, profound neurologic impairment and premature death. It is caused by de novo genetic variants in KCNT1 that alter the function of Slack, an evolutionarily conserved sodium-gated potassium channel that modulates neuronal firing patterns and excitability. Pathogenic KCNT1 variants lead to overactive Slack channels, boosting total neuronal potassium currents by up to 40%, driving cortical hyperexcitability and causing seizures. Here we investigate antisense oligonucleotide-mediated KCNT1 knockdown as a therapeutic strategy for patients with epilepsy of infancy with migrating focal seizures. Intrathecal delivery of an experimental, non-allele-specific, KCNT1-targeting antisense oligonucleotide by lumbar puncture in two 2-year-old females with KCNT1 p.R474H, a severe, recurrent pathogenic variant, led to a significant reduction in seizure frequency and intensity. However, investigational treatment was also associated with the development of ventricular enlargement or hydrocephalus in both patients, prompting in one case the redirection of goals of care, pointing to a potential monitorable toxicity of some intrathecal antisense oligonucleotides.

OBJECTIVE: Hyperactive KCNT1 potassium channels, caused by gain-of-function mutations, are associated with a range of epilepsy disorders. Patients typically experience drug-resistant seizures and, in cases with infantile onset, developmental regression can follow. KCNT1-related disorders include epilepsy of infancy with migrating focal seizures and sleep-related hypermotor epilepsy. There are currently no effective treatments for KCNT1 epilepsies, but suppressing overactive channels poses a potential strategy. METHODS: Using the KCNT1 channel structure we in silico screened a library of known drugs for those predicted to block the channel pore to inhibit channel activity. Cellular KCNT1 channel inhibition was analyzed using electrophysiology and Drosophila bang-sensitive assays were used to analyze seizure suppression. Brain penetration of one drug was analyzed using liquid chromatography-mass spectrometry in a mouse. RESULTS: Eight known drugs were investigated in vitro for their effects on patient-specific mutant KCNT1 channels, with 4 drugs showing significant reduction of K+ current amplitudes. The action of the 4 drugs was then analyzed in vivo and 2 were found to reduce the seizure phenotype in humanized Drosophila KCNT1 epilepsy models. One drug, antrafenine, was shown to cross the blood-brain barrier in mice. INTERPRETATION: This study identified a known drug, antrafenine, that reduces KCNT1 channel activity, reduces seizure activity in Drosophila, and crosses the blood-brain barrier in the mouse, suggesting its potential applicability as a new treatment for KCNT1 epilepsy. The sequential in silico, in vitro, and in vivo mechanism-based drug selection strategy used here may have broader application for other human disorders where a disease mechanism has been identified. ANN NEUROL 2025;98:1261-1274.