A5052082356- Epilepsy research and treatment
- Neuroscience and Neuropharmacology Research
- Genetics and Neurodevelopmental Disorders
- Ion channel regulation and function
- Genomics and Rare Diseases
- CRISPR and Genetic Engineering
- RNA regulation and disease
- RNA Research and Splicing
- Metabolism and Genetic Disorders
- Neurological disorders and treatments
- Viral Infections and Immunology Research
- Genomic variations and chromosomal abnormalities
- Cardiac electrophysiology and arrhythmias
- RNA and protein synthesis mechanisms
- Genetic Neurodegenerative Diseases
- Cellular transport and secretion
- Neuroscience of respiration and sleep
- Diet and metabolism studies
- Biotin and Related Studies
- Glycogen Storage Diseases and Myoclonus
- S100 Proteins and Annexins
- Drug Transport and Resistance Mechanisms
- Mitochondrial Function and Pathology
- Fungal and yeast genetics research
- Asthma and respiratory diseases
The Ohio State University
2019-2024
The Ohio State University Wexner Medical Center
2020-2024
University of Michigan
2015-2021
John Wiley & Sons (United States)
2020
Hudson Institute
2020
University Medical Center Utrecht
2017
University of Virginia
2017
Duke University
2017
Durham VA Medical Center
2017
University of Arkansas for Medical Sciences
2013
De novo mutations of the voltage-gated sodium channel gene SCN8A have recently been recognized as a cause epileptic encephalopathy, which is characterized by refractory seizures with developmental delay and cognitive disability. We previously described heterozygous missense mutation p.Asn1768Asp in child encephalopathy that included seizures, ataxia, sudden unexpected death epilepsy (SUDEP). The results increased persistent current hyperactivity transfected neurons. knock-in mouse model...
RNA–binding proteins have emerged as causal agents of complex neurological diseases. Mice deficient for neuronal protein CELF4 a disorder with epilepsy prominent feature. Human has recently been associated clinical features similar to those seen in mutant mice. is expressed primarily excitatory neurons, including large pyramidal cells the cerebral cortex and hippocampus, it regulates but not inhibitory neurotransmission. We examined mechanisms underlying hyperexcitability Celf4 mutants by...
Summary On April 21, 2015, the first SCN 8A Encephalopathy Research Group convened in Washington, DC , to assess current research into clinical and pathogenic features of disorder prepare an agenda for future collaborations. The group comprised basic scientists representatives patient advocacy groups. encephalopathy is a rare caused by de novo missense mutations sodium channel gene which encodes neuronal Na v 1.6. Since initial description 2012, approximately 140 affected individuals have...
Objective SCN8A encephalopathy is a developmental and epileptic (DEE) caused by de novo gain‐of‐function mutations of sodium channel Na v 1.6 that result in neuronal hyperactivity. Affected individuals exhibit early onset drug‐resistant seizures, delay, cognitive impairment. This study was carried out to determine whether reducing the abundance Scn8a transcript with an antisense oligonucleotide (ASO) would delay seizure prolong survival mouse model encephalopathy. Methods ASO treatment...
The early infantile epileptic encephalopathy type 13 (EIEE13, OMIM #614558) results from de novo missense mutations of SCN8A encoding the voltage-gated sodium channel Nav1.6. More than 20% patients have recurrent in residues Arg1617 or Arg1872. Our goal was to determine functional effects these on properties.Clinical exome sequencing carried out with early-onset seizures, developmental delay, and cognitive impairment. Two identified here, p.Arg1872Leu p.Arg1872Gln, two previously mutations,...
De novo mutations of the sodium channel gene SCN8A result in an epileptic encephalopathy with refractory seizures, developmental delay, and elevated risk sudden death. p.Arg1872Trp is a recurrent de mutation reported 14 unrelated individuals that included seizure onset prenatal or infantile period severe verbal ambulatory comorbidities. The major biophysical effect was previously shown to be impaired inactivation accompanied by increased current density. We have generated conditional mouse...
Sudden unexpected death in epilepsy (SUDEP) has been linked to respiratory dysfunction, but the mechanisms underlying this association remain unclear. Here we found that both focal and generalized convulsive seizures (GCSs) patients caused a prolonged decrease hypercapnic ventilatory response (HCVR; measure of CO 2 chemoreception). We then studied Scn1a R1407X /+ (Dravet syndrome; DS) Scn8a N1768D (D/+) mice sexes, two models SUDEP, postictal ventilation severely depressed HCVR subset...
Significance Patients with early infantile epileptic encephalopathy experience severe seizures and cognitive impairment are at increased risk for sudden unexpected death in epilepsy (SUDEP). Here, we investigated the neuronal phenotype of a mouse model (EIEE) 13 caused by mutation sodium channel gene SCN8A . We found that excitatory inhibitory neurons from mutant mice had persistent current density. Measurement action potential firing brain slices revealed hyperexcitability spontaneous...
To determine the functional effect of SCN8A missense mutations in 2 children with intellectual disability and developmental delay but no seizures.Genomic DNA was analyzed by next-generation sequencing. variants were introduced into Nav1.6 complementary site-directed mutagenesis. Channel activity measured electrophysiologically transfected ND7/23 cells. The stability mutant channels assessed Western blot.Both heterozygous for novel that altered conserved residues transmembrane segments...
Patients with early infantile epileptic encephalopathy (EIEE) are at increased risk for sudden unexpected death in epilepsy (SUDEP). De novo mutations of the sodium channel gene SCN8A, encoding Nav1.6, result EIEE13 (OMIM 614558), which has a 10% SUDEP. Here, we investigated cardiac phenotype mouse model expressing gain function patient mutation p.Asn1768Asp Scn8a (Nav1.6-N1768D). We tested Scn8aN1768D/+ mice alterations excitability. observed prolongation stages action potential (AP)...
Summary Objective De novo mutations of SCN 8A , encoding the voltage‐gated sodium channel Na V 1.6, have been associated with a severe infant onset epileptic encephalopathy. Individuals encephalopathy mean age seizure 4‐5 months, multiple types that are often refractory to treatment available drugs. Anecdotal reports suggest high‐dose phenytoin is effective for some patients, but there adverse effects and potential toxicity. Functional characterization several variants has shown elevated...
Objective Sudden unexpected death in epilepsy (SUDEP) is an unpredictable and devastating comorbidity of that believed to be due cardiorespiratory failure immediately after generalized convulsive seizures. Methods We performed monitoring seizure‐induced mice carrying either a p.Arg1872Trp or p.Asn1768Asp mutation single Scn8a allele—mutations identified from patients who died SUDEP—and pentylenetetrazole‐treated wild‐type mice. Results The primary cause for all was apnea, as (1) apnea began...
Sudden unexpected death in epilepsy (SUDEP) is a fatal complication experienced by otherwise healthy patients. Dravet syndrome (DS) an inherited epileptic disorder resulting from loss of function the voltage-gated sodium channel, NaV 1.1, and associated with particularly high SUDEP risk. Evidence mounting that NaVs abundant brain also occur heart, suggesting very molecular mechanisms underlying could precipitate cardiac arrhythmias sudden death. Despite marked reduction 1.1 functional...
SCN8A encephalopathy (early infantile epileptic encephalopathy; EIEE13) is caused by gain-of-function mutations resulting in hyperactivity of the voltage-gated sodium channel Nav 1.6. The concentrated at axon initial segment (AIS) and involved establishing neuronal excitability. Clinical features include seizure onset between 0 18 months age, intellectual disability, developmental delay. Seizures are often refractory to treatment with standard antiepileptic drugs, sudden unexpected death...
Variants in the neuronal sodium channel gene SCN8A have been implicated several neurological disorders. Early infantile epileptic encephalopathy type 13 results from de novo gain-of-function mutations that alter biophysical properties of channel. Complete loss-of-function variants identified cases isolated intellectual disability. We now report a novel heterozygous variant, p.Pro1719Arg, small pedigree with five family members affected autosomal dominant upper limb myoclonus without seizures...
The field of epilepsy genetics is advancing rapidly and emerging as a frequent indication for diagnostic genetic testing. Within the larger ClinGen framework, Epilepsy Gene Curation Expert Panel tasked with connecting two increasingly separate fields: domain traditional clinical epileptology, its own established language classification criteria, evolving area testing that adheres to formal criteria gene variant curation. We identify critical components unique curation effort, including: (a)...
Mice deficient for the gene encoding RNA-binding protein CELF4 (CUGBP, ELAV-like family member 4) have a complex seizure phenotype that includes both convulsive and non-convulsive seizures, depending upon dosage strain background, modeling genetically epilepsy. Invertebrate CELF is associated with translational control in fruit fly ovary epithelium neurogenesis neuronal function nematode. Mammalian expressed widely during early development, but restricted to central nervous system adults. To...
Mice deficient for CELF4, a neuronal RNA-binding protein, have complex seizure disorder that includes both convulsive and non-convulsive seizures, is dependent upon Celf4 gene dosage mouse strain background. It was previously shown expressed predominantly in excitatory neurons, deficiency results abnormal synaptic neurotransmission. To examine the physiological molecular basis of this, we studied Celf4-deficient neurons brain slices. Assessment intrinsic properties layer V cortical pyramidal...
Na v 1.6 ( SCN8A ) is a major voltage-gated sodium channel in the mammalian CNS, and highly concentrated at axon initial segment (AIS). As previously demonstrated, microtubule associated protein MAP1B binds cytoplasmic N terminus of 1.6, this interaction disrupted by mutation p.VAVP(77–80)AAAA. We now demonstrate that results WT expression levels on somatic surface but reduced AIS cultured rat embryonic hippocampal neurons from both sexes. The binding domain did not impair vesicular...
Abstract Objective Monoallelic de novo gain‐of‐function variants in the voltage‐gated sodium channel SCN8A are one of recurrent causes severe developmental and epileptic encephalopathy (DEE). In addition, a small number or inherited monoallelic loss‐of‐function have been found patients with intellectual disability, autism spectrum disorder, movement disorders. Inherited causing either gain also associated less conditions such as benign familial infantile seizures isolated all three...
Abstract Objective SCN8A encephalopathy is a developmental epileptic typically caused by de novo gain‐of‐function mutations in Na v 1.6. Severely affected individuals exhibit refractory seizures, delay, cognitive disabilities, movement disorders, and elevated risk of sudden death. Patients with the identical variant can differ clinical course, suggesting role for modifier genes determining disease severity. The identification genetic modifiers contributes to understanding pathogenesis...