Targeting KNa1.1 channels in KCNT1-associated epilepsy

Cole, Bethan A.; Clapcote, Steven J.; Muench, Stephen P.; Lippiat, Jonathan D.

doi:10.1016/j.tips.2021.05.003

Cited by 35 publications

(24 citation statements)

References 82 publications

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“…KCNT1 is widely expressed throughout the brain, kidney and heart and is responsible for slow hyperpolarisation after action potential bursts. KCNT1 also interacts directly with fragile X-related proteins, and is involved in a highly extensive protein network, suggesting a putative role in cognitive-developmental processes [13].…”

Section: Discussionmentioning

confidence: 99%

Long-term follow-up of vagus nerve stimulation in drug-resistant KCNT1-related epilepsy: a case presentation

Wang

Geng

Meng

et al. 2022

Acta Epileptologica

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Background The KCNT1 gene encodes a Na+-activated K+ channel. Gain-of-function mutations of KCNT1 lead to autosomal dominant sleep-related hypermotor epilepsy, early-onset epileptic encephalopathy, focal epilepsy and other epileptic encephalopathies. In this paper, we report a boy carrying a KCNT1 gene mutation, who presented with drug-resistant focal-onset seizures. He had decreased seizure frequency and improvement of background changes in electroencephalography (EEG) after vagus nerve stimulation (VNS). Case presentation The case was a nonverbal 9-year-old male who presented with drug-resistant focal-onset seizures since age 3 and had underwent VNS therapy for 2 years. He had hypermotor symptoms, automatism and bilateral asymmetric tonic seizures with cognitive decline and aphasis from age 3. The patient had a variety of seizure types that only occurred at night. The most common seizure type was automatisms, and ictal video EEG showed high-amplitude delta waves, followed by a fast rhythmic sharp activity in the mesial frontal and bitemporal regions. The patient was diagnosed with KCNT1-related epilepsy, epileptic encephalopathy and cognitive disorder. He was refractory to multiple anti-seizure medicines (ASM) and ketogenic diet. After VNS treatment at age 7, the frequency of seizures was reduced significantly and EEG was improved in background slowing. Conclusions Children with KCNT1-related epilepsy usually have early onset of disease, are nonverbal, and are refractory to ASM. This boy with drug-resistant KCNT1-related epilepsy showed significantly reduced seizure frequency after VNS. This report may provide reference for management of cases of KCNT1-related epilepsy.

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Section: Discussionmentioning

confidence: 99%

Long-term follow-up of vagus nerve stimulation in drug-resistant KCNT1-related epilepsy: a case presentation

Wang

Geng

Meng

et al. 2022

Acta Epileptologica

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“…Slo2.2, encoded by KCNT1 , is a potassium channel in the high-conductance potassium channel family. It plays an important role in afterhyperpolarization and maintaining the resting potential and controlling the basal excitability of neurons [ 30 ]. Gain of function mutations of KCNT1 induce epilepsy [ 31 ], while loss of function of KCNT1 results in autism [ 32 ].…”

Section: Discussionmentioning

confidence: 99%

Neuroblastoma SH-SY5Y Cell Differentiation to Mature Neuron by AM580 Treatment

et al. 2022

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Neuroblastoma is a type of developmental childhood cancer that arises from the neural crest. It is the most common pediatric solid tumor in the world. AM580 is a powerful cyto-differentiating molecule on acute promyelocytic leukemia cells and induced pluripotent stem cells, but its effect on neuroblastoma is still unknown. In this study, the neuronal differentiation impact of AM580 was investigated using the human neuroblastoma cell line SH-SY5Y as a model. AM580 successfully stimulated the SH-SY5Y cells to develop into neuron-like cells. Functional enrichment analysis of RNAseq data revealed that differentially expressed genes (DEGs) were substantially enriched for GO keywords and KEGG pathways linked to neuron development. Some potassium ion channel genes associated with neuronal excitation, such as KCNT1, were shown to be upregulated. Through the MEA tests, we found the AM580-induced neurons possessed electrical spikes as mature neurons. AM580 also induced the neuronal marker β-tubulin III and mature neurons marker Neurofilament H. Our study proved that AM580 can promote the differentiation of neurons and has the potential to treat neuroblastoma, neurodevelopmental and neurodegenerative diseases.

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“…The neurological status progressively deteriorates, with progressive hypotonia, and severe development arrest. De novo heterozygous mutations have been also identified in severe autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), sleep-related hypermotor epilepsy SHE (334) and other less common DEE phenotypes (335).…”

Section: Na + -Activated K + Channelsmentioning

confidence: 99%

“…Blocking KCNT GoF mutants with quinidine, a class I antiarrhythmic drug, has shown variable success in patients because of dose-limiting off-target effects, poor blood-brain barrier (BBB) penetration, and low potency (335).…”

Section: Na + -Activated K + Channelsmentioning

confidence: 99%

Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum

Guerrini

Conti

Mantegazza

et al. 2023

Physiological Reviews

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Developmental and epileptic encephalopathies are a heterogeneous group of disorders characterized by early-onset, often severe epileptic seizures, EEG abnormalities, on a background of developmental impairment that tends to worsen as a consequence of epilepsy. DEEs may result from both non-genetic and genetic etiologies. Genetic DEEs have been associated with mutations in many genes involved in different functions including cell migration, proliferation, and organization, neuronal excitability, and synapse transmission and plasticity. Functional studies performed in different animal models and clinical trials on patients have contributed to elucidate pathophysiological mechanisms underlying many DEEs and explored the efficacy of different treatments. Here, we provide an extensive review of the phenotypic spectrum included in the DEEs, of the genetic determinants and pathophysiological mechanisms underlying these conditions. We also provide a brief overview of the most effective treatment now available and of the emerging therapeutic approaches.

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Targeting KNa1.1 channels in KCNT1-associated epilepsy

Cited by 35 publications

References 82 publications

Long-term follow-up of vagus nerve stimulation in drug-resistant KCNT1-related epilepsy: a case presentation

Long-term follow-up of vagus nerve stimulation in drug-resistant KCNT1-related epilepsy: a case presentation

Neuroblastoma SH-SY5Y Cell Differentiation to Mature Neuron by AM580 Treatment

Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum

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