Sudden unexpected death in epilepsy is prevented by blocking postictal hypoxia

George, Antis G.; Farrell, Jordan S.; Colangeli, Roberto; Wall, Alexandra K.; Gom, Renaud C.; Kesler, Mitchell; Hoz, Cristiane Rodriguez de la; Villa, Bianca R.; Perera, Tefani; Rho, Jong M.; Kurrasch, Deborah M.; Teskey, G. Campbell

doi:10.1016/j.neuropharm.2023.109513

Cited by 15 publications

(3 citation statements)

References 85 publications

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“…Dbx1 encodes Developing brain homeobox 1, a transcription factor critical for interneuron differentiation, including Cajal Retzius cells in the cortex and brainstem pre-Bötzinger complex interneurons (Akins et al 2017; Powers et al 2022; Vann et al 2018). Interestingly, the pre-Bötzinger complex is a critical nucleus for generating respiratory rhythms and has been implicated in SUDEP (Akins et al 2017; George et al 2023; Xia et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Fine Mapping and Candidate Gene Analysis of Dravet Syndrome Modifier Loci on Mouse Chromosomes 7 and 8

Hawkins,

Speakes,

Kearney

2024

Preprint

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Dravet syndrome is a developmental and epileptic encephalopathy (DEE) characterized by intractable seizures, comorbidities related to developmental, cognitive, and motor delays, and a high mortality burden due to sudden unexpected death in epilepsy (SUDEP). Most Dravet syndrome cases are attributed toSCN1Ahaploinsufficiency, with genetic modifiers and environmental factors influencing disease severity. Mouse models with heterozygous deletion ofScn1arecapitulate key features of Dravet syndrome, including seizures and premature mortality; however, severity varies depending on genetic background. Here, we refined two Dravet survival modifier (Dsm) loci,Dsm2on chromosome 7 andDsm3on chromosome 8, using interval-specific congenic (ISC) mapping.Dsm2was complex and encompassed at least two separate loci, whileDsm3was refined to a single locus. Candidate modifier genes within these refined loci were prioritized based on brain expression, strain-dependent differences, and biological relevance to seizures or epilepsy. High priority candidate genes forDsm2includeNav2, Ptpn5, Ldha, Dbx1, Prmt3 and Slc6a5, whileDsm3has a single high priority candidate,Psd3. This study underscores the complex genetic architecture underlying Dravet syndrome and provides insights into potential modifier genes that could influence disease severity and serve as novel therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Fine Mapping and Candidate Gene Analysis of Dravet Syndrome Modifier Loci on Mouse Chromosomes 7 and 8

Hawkins,

Speakes,

Kearney

2024

Preprint

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“…It is in this context that George and colleagues 2 took a closer look at hypoxia in the brainstem and asked whether blocking vasoconstriction and subsequent hypoxia could postpone SUDEP in 2 preclinical models. For the acute model, a series of seizures were induced in control mice (ie, with no history of spontaneous recurrent seizures) via intrahippocampal kainate infusion, with the last seizure being terminal.…”

Section: Commentarymentioning

confidence: 99%

“…Brainstem spreading depolarization contributes to sudden death; however, it has been reported to occur both before hypoxia in anesthetized mice, and following hypoxia in both anesthetized and nonanesthetized mice. 2 , 9 , 10 , 12 Whether the varied sequence is a result of the anesthesia or specific to certain types of epilepsy requires further study.…”

Section: Commentarymentioning

confidence: 99%

SUDEP: A Local Low Pressure [pO₂] System Makes It Hard to Breathe

Simeone

2023

Epilepsy Curr

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Fine mapping and candidate gene analysis of Dravet syndrome modifier loci on mouse chromosomes 7 and 8

Hawkins,

Speakes,

Kearney

2024

Mamm Genome

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Dravet syndrome is a developmental and epileptic encephalopathy (DEE) characterized by intractable seizures, comorbidities related to developmental, cognitive, and motor delays, and a high mortality burden due to sudden unexpected death in epilepsy (SUDEP). Most Dravet syndrome cases are attributed to SCN1A haploinsufficiency, with genetic modifiers and environmental factors influencing disease severity. Mouse models with heterozygous deletion of Scn1a recapitulate key features of Dravet syndrome, including seizures and premature mortality; however, severity varies depending on genetic background. Here, we refined two Dravet survival modifier (Dsm) loci, Dsm2 on chromosome 7 and Dsm3 on chromosome 8, using interval-specific congenic (ISC) mapping. Dsm2 was complex and encompassed at least two separate loci, while Dsm3 was refined to a single locus. Candidate modifier genes within these refined loci were prioritized based on brain expression, strain-dependent differences, and biological relevance to seizures or epilepsy. High priority candidate genes for Dsm2 include Nav2, Ptpn5, Ldha, Dbx1, Prmt3 and Slc6a5, while Dsm3 has a single high priority candidate, Psd3. This study underscores the complex genetic architecture underlying Dravet syndrome and provides insights into potential modifier genes that could influence disease severity and serve as novel therapeutic targets.

show abstract

Sudden unexpected death in epilepsy is prevented by blocking postictal hypoxia

Cited by 15 publications

References 85 publications

Fine Mapping and Candidate Gene Analysis of Dravet Syndrome Modifier Loci on Mouse Chromosomes 7 and 8

Fine Mapping and Candidate Gene Analysis of Dravet Syndrome Modifier Loci on Mouse Chromosomes 7 and 8

SUDEP: A Local Low Pressure [pO₂] System Makes It Hard to Breathe

Fine mapping and candidate gene analysis of Dravet syndrome modifier loci on mouse chromosomes 7 and 8

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Sudden unexpected death in epilepsy is prevented by blocking postictal hypoxia

Cited by 15 publications

References 85 publications

Fine Mapping and Candidate Gene Analysis of Dravet Syndrome Modifier Loci on Mouse Chromosomes 7 and 8

Fine Mapping and Candidate Gene Analysis of Dravet Syndrome Modifier Loci on Mouse Chromosomes 7 and 8

SUDEP: A Local Low Pressure [pO2] System Makes It Hard to Breathe

Fine mapping and candidate gene analysis of Dravet syndrome modifier loci on mouse chromosomes 7 and 8

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SUDEP: A Local Low Pressure [pO₂] System Makes It Hard to Breathe