Sudden unexpected death in a mouse model of Dravet syndrome

It is well known that sudden unexpected death in epilepsy (SUDEP) is one of the most significant factors of mortality in epileptic patients. There is an increased risk of SUDEP in genetic epileptic encephalopathies (EE), partly because those syndromes are associated with mutations in the “neurocardiac” genes, which have been implicated in both epilepsy and cardiac arrhythmias. In these clinical conditions, functions of ion selective channels (sodium, potassium and etc.) are affected; for example, in children with Dravet syndrome, the risk of SUDEP is 40 times higher than that in children with common epilepsy syndromes. In a murine model of SCN1A epilepsy, a prolongation of QT interval coincided with a seizure; in addition, an excessive excitability of cultured cardiomyocytes was demonstrated. A high risk of SUDEP is characteristic for EE caused by mutation in the SCN8A gene. Other prognostic biomarkers of SUDEP may include mutations in sodium channel genes, such as SCN4A, SCN10A, and SCN11A. Our knowledge about SUDEP associated with potassium channel dysfunctions is still very limited. There are likely some mutations in other genes, that can modify (increase or decrease) the risk of SUDEP in EE. If patients with genetic EE are indeed at a high risk for SUDEP, they must be followed up by cardiologists alongside with neurologists. Provided this hypothesis is proved, any newly diagnosed arrhythmia should be carefully monitored and treated (with medications and/or interventions), in order to improve the survival rate in genetic EE.

Download Full-text

Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome

Nature Communications ◽

10.1038/s41467-021-27837-w ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Nicholas Valassina ◽

Simone Brusco ◽

Alessia Salamone ◽

Linda Serra ◽

Mirko Luoni ◽

...

Keyword(s):

Gene Expression ◽

Mouse Model ◽

Symptom Onset ◽

Epileptic Encephalopathy ◽

Dravet Syndrome ◽

Neurological Deficits ◽

Behavioral Alterations ◽

Unexpected Death ◽

Physiological Level ◽

Behavioral Abnormalities

AbstractDravet syndrome is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. Repetitive seizures can lead to endurable and untreatable neurological deficits. Whether this severe pathology is reversible after symptom onset remains unknown. To address this question, we generated a Scn1a conditional knock-in mouse model (Scn1a Stop/+) in which Scn1a expression can be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with sudden unexpected death in epilepsy (SUDEP) and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene re-activation when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures, marked amelioration of behavioral abnormalities and normalization of hippocampal fast-spiking interneuron firing. We also identified dramatic gene expression alterations, including those associated with astrogliosis in Dravet syndrome mice, that, accordingly, were rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Nav1.1 physiological level rescued seizures also in adult Dravet syndrome mice (P90) after months of repetitive attacks. Overall, these findings represent a solid proof-of-concept highlighting that disease phenotype reversibility can be achieved when Scn1a gene activity is efficiently reconstituted in brain cells.

Download Full-text

Effects of age, sex, and sertraline administration on seizure-induced respiratory arrest in the DBA/1 mouse model of sudden unexpected death in epilepsy (SUDEP)

Epilepsy & Behavior ◽

10.1016/j.yebeh.2013.04.003 ◽

2013 ◽

Vol 28 (1) ◽

pp. 78-82 ◽

Cited By ~ 27

Author(s):

Carl L. Faingold ◽

Marcus Randall

Keyword(s):

Mouse Model ◽

Respiratory Arrest ◽

Sudden Unexpected Death ◽

Unexpected Death

Download Full-text

Antisense oligonucleotides increase Scn1a expression and reduce seizures and SUDEP incidence in a mouse model of Dravet syndrome

Science Translational Medicine ◽

10.1126/scitranslmed.aaz6100 ◽

2020 ◽

Vol 12 (558) ◽

pp. eaaz6100 ◽

Cited By ~ 6

Author(s):

Zhou Han ◽

Chunling Chen ◽

Anne Christiansen ◽

Sophina Ji ◽

Qian Lin ◽

...

Keyword(s):

Mouse Model ◽

Antisense Oligonucleotides ◽

De Novo ◽

Nuclear Gene ◽

Epileptic Encephalopathy ◽

Dravet Syndrome ◽

Unexpected Death ◽

Α Subunit ◽

Gene And Protein Expression ◽

Electrographic Seizures

Dravet syndrome (DS) is an intractable developmental and epileptic encephalopathy caused largely by de novo variants in the SCN1A gene, resulting in haploinsufficiency of the voltage-gated sodium channel α subunit NaV1.1. Here, we used Targeted Augmentation of Nuclear Gene Output (TANGO) technology, which modulates naturally occurring, nonproductive splicing events to increase target gene and protein expression and ameliorate disease phenotype in a mouse model. We identified antisense oligonucleotides (ASOs) that specifically increase the expression of productive Scn1a transcript in human cell lines, as well as in mouse brain. We show that a single intracerebroventricular dose of a lead ASO at postnatal day 2 or 14 reduced the incidence of electrographic seizures and sudden unexpected death in epilepsy (SUDEP) in the F1:129S-Scn1a+/− × C57BL/6J mouse model of DS. Increased expression of productive Scn1a transcript and NaV1.1 protein was confirmed in brains of treated mice. Our results suggest that TANGO may provide a unique, gene-specific approach for the treatment of DS.

Download Full-text