Epileptic Encephalopathy
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR351268.fastq.gz | Fastqsanger.gz | |||
| ERR351268_1.fastq.gz | Fastqsanger.gz | |||
| ERR351268_2.fastq.gz | Fastqsanger.gz |
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Project description:We presented analyses of the GLUL-related developmental and epileptic encephalopathy with detailed clinical descriptions and identified novel pathogenic variants. Comparative analysis of genotypes and phenotypes revealed the diverse nature of the disease, expanding our knowledge about the genetic and clinical spectrum of GLUL-related disorder.
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Project description:Pathogenic heterozygous missense mutations in the DNM1 gene result in a novel form of epileptic encephalopathy. DNM1 encodes for the large GTPase dynamin-1, an enzyme with an obligatory role in the endocytosis of synaptic vesicles (SVs) at mammalian nerve terminals. Pathogenic DNM1 mutations cluster within regions required for its essential GTPase activity, implicating disruption of this enzyme activity as being central to epileptic encephalopathy. We reveal that the most prevalent pathogenic mutation in the GTPase domain of DNM1, R237W, disrupts dynamin-1 enzyme activity and SV endocytosis when overexpressed in central neurons. To determine how this dominant-negative heterozygous mutant impacted cell, circuit and behaviour when expressed from its endogenous locus, we generated a mouse carrying the R237W mutation. Neurons isolated from heterozygous mice displayed dysfunctional SV endocytosis, which translated into altered excitatory neurotransmission and seizure-like phenotypes. Importantly, these phenotypes were corrected at the cell, circuit and in vivo level by the drug, BMS-204352, which accelerates SV endocytosis in wild-type neurons. This study therefore provides the first direct link between dysfunctional SV endocytosis and epilepsy, and importantly reveals that SV endocytosis is a viable therapeutic route for monogenic intractable epilepsies.
2023-08-14 | PXD039667 | Pride
Project description:Aristaless-related homeobox (ARX) is an X-linked gene encoding a bi-functional morphogenetic transcription factor with a key role in neuronal migration and brain development. Mutations in ARX have been identified in patients with X-linked Lissencephaly with Abnormal Genitalia (XLAG) and Early-infantile epileptic encephalopathy (EIEE). The aim of this project was to perform a proteomic analysis in whole neonatal brains isolated from XLAG and EIEE mouse models, ArxKO/Y and Arx(GCG)7/Y, to compare the mutant proteome profiles versus the wild-type ones by LC-MS/MS. By comparing the two proteomics profiles, common and different protein regulations emerged. Collectively, these findings could provide novel molecular insights into the proteomic mechanisms underlying XLAG and EIEE pathogenesis and may accelerate the design of pathway-guided therapeutic interventions for ARX-endophenotypes.
2024-06-14 | PXD021358 | Pride
Project description:KCNQ2 potassium channel variants are linked to developmental and epileptic encephalopathy (DEE). However, the mechanisms by which pathogenic variants, especially those outside known hotspots, such as the S4–S5 linker, lead to disease remain unknown. Here, we examined the H228R variant, a pathogenic mutation in the S4-S5 linker associated with DEE. We tested whether H228R induces KCNQ2 channel mistargeting in addition to its biophysical effects, given recent evidence of impaired trafficking in KCNQ2 DEE variants. We confirmed the H228R variant as a loss-of-function (LOF) mutation when expressed as a homomer and as a dominant-negative when co-expressed with wild-type (WT) KCNQ3. Surprisingly, it exhibited some gain-of-function effects when co-expressed with WT KCNQ2. To determine its cellular localization in vivo, we used male and female heterozygous Kcnq2H228R knock-in mice, some of which die prematurely despite limited to no changes to hippocampal excitatory neuron excitability. We validated two different KCNQ2 antibodies via immunohistochemistry. These antibodies detected KCNQ2 in axons, with signal loss observed in Kcnq2 knockout mice. Using these antibodies, we found that the H228R variant caused KCNQ2 channels to concentrate in the soma, strongly reducing their presence in axons. In contrast, analysis of heterozygous mice expressing both a FLAG-tagged WT KCNQ2 and H228R revealed that the FLAG-WT KCNQ2 could still traffic to axons; indicating that some KCNQ2 channels are correctly targeted within neurons. In summary, our results demonstrate that the LOF H228R variant disrupts the localization of variant KCNQ2 channels, suggesting mistargeting as a general endophenotype of KCNQ2 encephalopathy.
2026-01-12 | PXD069563 | Pride
Project description:Therapeutic Potential of ASO-Mediated KCNT1 Knockdown in KCNT1 Epileptic Encephalopathy
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Project description:KCNT1-related epileptic encephalopathy, including Epilepsy of Infancy with Migrating Focal Seizures (EIMFS), 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 which 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 (ASO)-mediated KCNT1 knockdown as a therapeutic strategy for patients with EIMFS. Intrathecal delivery of an experimental, non-allele-specific, KCNT1-targeting ASO by lumbar puncture in two patients with KCNT1 p.R474H, a severe, recurrent pathogenic variant, led to a significant reduction in seizure frequency and intensity, supporting the potential efficacy of suppression of KCNT1 expression as a therapeutic strategy for EIMFS. However, investigational treatment was also associated with development of ventricular enlargement or hydrocephalus in both patients, prompting in one case redirection of goals of care. This finding was not clearly related to EIMFS itself, drawing attention to an important possible toxicity of some intrathecal antisense oligonucleotides.
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Project description:De novo mutations of the voltage-gated sodium channel SCN8A cause severe developmental and epileptic encephalopathy (DEE). Since pathogenic variants have gain-of-function effects on SCN8A activity, reduction of SCN8A expression is an effective therapeutic strategy. We previously described an antisense oligonucleotide (ASO) that delays seizure onset in a mouse model of SCN8A-DEE when administered at postnatal day 2. To investigate the potential effectiveness of post-onset ASO treatment, we first examined the extent of differential gene expression in hippocampus during the pre-onset period. Hippocampal single-nucleus RNA-sequencing detected only minor expression changes after the two month pre-seizure period. ASO treatments that were initiated after seizure onset were protective in the Scn8a mutant mice during the 12 month observation period. As an alternative treatment for down-regulation of Scn8a, we administered a single dose of an AAV10 virus expressing Scn8a shRNA. The viral shRNA was protective against seizures and lethality during the 12 month observation period. These data indicate that reduction of SCN8A expression, either by repeated administration of ASO or a single dose of shRNA virus, may be effective for longterm control of SCN8A-DEE.
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Project description:Expanding the clinical and genetic spectrum of GLUL-related developmental and epileptic encephalopathy
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Project description:Long-term downregulation of SCN8A in mouse models of developmental and epileptic encephalopathy
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Project description:De novo mutations of the voltage-gated sodium channel SCN8A cause severe developmental and epileptic encephalopathy (DEE). Since pathogenic variants have gain-of-function effects on SCN8A activity, reduction of SCN8A expression is an effective therapeutic strategy. We previously described an antisense oligonucleotide (ASO) that delays seizure onset in a mouse model of SCN8A-DEE when administered at postnatal day 2. To investigate the potential effectiveness of post-onset ASO treatment, we first examined the extent of differential gene expression in hippocampus during the pre-onset period. Hippocampal single-nucleus RNA-sequencing detected only minor expression changes after the two month pre-seizure period. ASO treatments that were initiated after seizure onset were protective in the Scn8a mutant mice during the 12 month observation period. As an alternative treatment for down-regulation of Scn8a, we administered a single dose of an AAV10 virus expressing Scn8a shRNA. The viral shRNA was protective against seizures and lethality during the 12 month observation period. These data indicate that reduction of SCN8A expression, either by repeated administration of ASO or a single dose of shRNA virus, may be effective for longterm control of SCN8A-DEE.
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