Animal Models in Epileptic Spasms and the Development of Novel Treatment Options

Barrett, Karlene T.; Charkhand, Behshad; Scantlebury, Morris H.

doi:10.1097/wnp.0000000000000496

Cited by 6 publications

(7 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RAPGEF5 appears to be a good candidate gene for involvement in IE due to its role in neurological function [ 21 , 25 ]. The Wnt-β-catenin signaling pathway is critical for normal brain development and function [ 26 ] and a recent review on the pathogenesis of epilepsy suggests that the Wnt-β-catenin pathway could be considered a new target for treatment in epilepsy [ 27 ]. RAPGEF5 regulates a defining step in the Wnt signaling pathway: the nuclear translocation of β-catenin [ 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Validation of a Chromosome 14 Risk Haplotype for Idiopathic Epilepsy in the Belgian Shepherd Dog Found to Be Associated with an Insertion in the RAPGEF5 Gene

Belanger

Heinonen

Famula

et al. 2022

Genes

View full text Add to dashboard Cite

An idiopathic epilepsy (IE) risk haplotype on canine chromosome (CFA) 14 has been reported to interact with the CFA37 common risk haplotype in the Belgian shepherd (BS). Additional IE cases and control dogs were genotyped for the risk haplotypes to validate these previous findings. In the new cohort, the interaction between the two regions significantly elevated IE risk. When the haplotypes were analyzed individually, particular haplotypes on both CFA14 (ACTG) and 37 (GG) were associated with elevated IE risk, though only the CFA37 AA was significantly associated (p < 0.003) with reduced risk in the new cohort. However, the CFA14 ACTG risk was statistically significant when the new and previous cohort data were combined. The frequency of the ACTG haplotype was four-fold higher in BS dogs than in other breeds. Whole genome sequence analysis revealed that a 3-base pair predicted disruptive insertion in the RAPGEF5 gene, which is adjacent to the CFA14 risk haplotype. RAPGEF5 is involved in the Wnt-β-catenin signaling pathway that is crucial for normal brain function. Although this risk variant does not fully predict the likelihood of a BS developing IE, the association with a variant in a candidate gene may provide insight into the genetic control of canine IE.

show abstract

Section: Discussionmentioning

confidence: 99%

Validation of a Chromosome 14 Risk Haplotype for Idiopathic Epilepsy in the Belgian Shepherd Dog Found to Be Associated with an Insertion in the RAPGEF5 Gene

Belanger

Heinonen

Famula

et al. 2022

Genes

View full text Add to dashboard Cite

show abstract

“…We speculate that the CRH-excess theory possibly explained the response to treatment from prednisolone in our patient. Furthermore, vigabatrin and methylprednisolone treatment effectively suppressed spasms in the betamethasone-N-Methyl-D-Aspartic Acid (NMDA)-induced spasms model in rats [12].…”

Section: Discussionmentioning

confidence: 99%

Epileptic spasms related to neuronal differentiation factor 2 (NEUROD2) mutation respond to combined vigabatrin and high dose prednisolone therapy

et al. 2022

View full text Add to dashboard Cite

Background Epileptic spasms are a devastating form of early infantile epileptic encephalopathy (EIEE) with various etiologies. Early diagnosis and a shorter lead time to treatment are crucial to stop the seizures and optimize the neurodevelopmental outcome. Genetic testing has become an integral part of epilepsy care that directly guides management and family planning and discovers new targeted treatments. Neuronal differentiation Factor 2 (NEUROD2) variants have recently been a cause of neurodevelopmental disorders (NDDs) and EIEEs with distinctive features. However, there is limited information about the clinical and electroencephalographic response of epileptic spasm treatment in NEUROD2-related NDD syndrome. Case presentation We report a female patient of Southeast Asian ethnicity with global developmental delay and epileptic spasms commencing in the first few months of life. A novel de novo heterozygous pathogenic NEUROD2 variant, p. E130Q, was subsequently identified by whole-exome sequencing. Electroencephalogram before treatment showed multifocal independent spikes predominantly in both posterior head regions and demonstrated marked improvement following combined vigabatrin and high-dose prednisolone treatment. However, multiple courses of relapse occurred after weaning off the antiseizure medication. Conclusions We propose that epileptic spasms related to de novo NEUROD2 pathogenic variant respond well to combined vigabatrin and high-dose prednisolone therapy. These findings may imply the benefit of using combination therapy to treat epileptic spasms in NEUROD2-related NDD syndrome.

show abstract

“…There had been intensive effort to create rodent models of IESS, which has provided unprecedented opportunity to understand its pathophysiology and to design novel treatments. 7,8 It has been proposed that an "ideal" animal model of IESS would recapitulate the age specificity, clinical seizure types, relationship of spasms to sleep-wake cycle, electroencephalographic features, antiseizure treatment responses, etiologies, and developmental regression. 9 However, no animal model perfectly recapitulates all aspects of human IESS.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of infantile epileptic spasms syndrome: What have we learned from animal models?

Ng,

Choudhary,

Barrett

et al. 2023

Epilepsia

Self Cite

View full text Add to dashboard Cite

The devastating developmental and epileptic encephalopathy of infantile epileptic spasms syndrome (IESS) has numerous causes, including, but not limited to, brain injury, metabolic, and genetic conditions. Given the stereotyped electrophysiologic, age‐dependent, and clinical findings, there likely exists one or more final common pathways in the development of IESS. The identity of this final common pathway is unknown, but it may represent a novel therapeutic target for infantile spasms. Previous research on IESS has focused largely on identifying the neuroanatomic substrate using specialized neuroimaging techniques and cerebrospinal fluid analysis in human patients. Over the past three decades, several animal models of IESS were created with an aim to interrogate the underlying pathogenesis of IESS, to identify novel therapeutic targets, and to test various treatments. Each of these models have been successful at recapitulating multiple aspects of the human IESS condition. These animal models have implicated several different molecular pathways in the development of infantile spasms. In this review we outline the progress that has been made thus far using these animal models and discuss future directions to help researchers identify novel treatments for drug‐resistant IESS.

show abstract

Animal Models in Epileptic Spasms and the Development of Novel Treatment Options

Cited by 6 publications

References 74 publications

Validation of a Chromosome 14 Risk Haplotype for Idiopathic Epilepsy in the Belgian Shepherd Dog Found to Be Associated with an Insertion in the RAPGEF5 Gene

Validation of a Chromosome 14 Risk Haplotype for Idiopathic Epilepsy in the Belgian Shepherd Dog Found to Be Associated with an Insertion in the RAPGEF5 Gene

Epileptic spasms related to neuronal differentiation factor 2 (NEUROD2) mutation respond to combined vigabatrin and high dose prednisolone therapy

Mechanisms of infantile epileptic spasms syndrome: What have we learned from animal models?

Contact Info

Product

Resources

About