Two autopsy cases of sudden unexpected death from Dravet syndrome with novel de novo SCN1A variants

2020 ◽  
Vol 42 (2) ◽  
pp. 171-178 ◽  
Author(s):  
Yukiko Hata ◽  
Yuko Oku ◽  
Hiromichi Taneichi ◽  
Tomomi Tanaka ◽  
Noboru Igarashi ◽  
...  
Keyword(s):  
De Novo ◽  
Sudden Unexpected Death ◽  
Dravet Syndrome ◽  
Unexpected Death

scholarly journals Gabra2 is a genetic modifier of Dravet syndrome in mice

2020 ◽  
Author(s):  
Nicole A. Hawkins ◽  
Toshihiro Nomura ◽  
Samantha Duarte ◽  
Robert W. Williams ◽  
Gregg E. Homanics ◽  
...  
Keyword(s):  
Protein Expression ◽  
De Novo ◽  
Genetic Modifier ◽  
Clinical Severity ◽  
Dravet Syndrome ◽  
Unexpected Death ◽  
Increased Risk ◽  
Hippocampal Synapses ◽  
Severe Epilepsy ◽  
Strain Dependent

AbstractPathogenic variants in epilepsy genes result in a spectrum of clinical presentation, ranging from benign phenotypes to intractable epilepsies with significant co-morbidities and increased risk of sudden unexpected death in epilepsy (SUDEP). One source of this phenotypic heterogeneity is modifier genes that affect penetrance, dominance or expressivity of a primary pathogenic variant. Mouse models of epilepsy also display varying degrees of clinical severity on different genetic backgrounds. Mice with heterozygous deletion of Scn1a (Scn1a+/−) model Dravet syndrome, a severe epilepsy most often caused by SCN1A haploinsufficiency. Scn1a+/− heterozygous mice recapitulate key features of Dravet syndrome, including febrile and afebrile spontaneous seizures, SUDEP, and cognitive and behavioral deficits. The Scn1a+/− mouse model also exhibits strain-dependent phenotype severity. Scn1a+/− mice maintained on the 129S6/SvEvTac (129) strain have normal lifespan and no overt seizures. In contrast, admixture with C57BL/6J (B6) results in severe epilepsy and premature lethality in [B6×129]F1.Scn1a+/− mice. In previous work, we identified Dravet Survival Modifier loci (Dsm1-Dsm5) responsible for strain-dependent differences in survival. Gabra2, encoding the GABAA α2 subunit, was nominated as the top candidate modifier at the Dsm1 locus on chromosome 5. Direct measurement of GABAA receptors found lower abundance of α2-containing receptors in hippocampal synapses of B6 mice relative to 129. We also identified a B6-specific single nucleotide intronic deletion within Gabra2 that lowers mRNA and protein by nearly 50%. Repair of this de novo deletion reestablished normal levels of Gabra2 transcript and protein expression. In the current study, we used B6 mice with the repaired Gabra2 allele to validate it as a modifier of phenotype severity in Scn1a+/− mice. Repair of Gabra2 restored transcript and protein expression, increased abundance of α2-containing GABAA receptors in hippocampal synapses, and improved seizure and survival phenotypes of Scn1a+/− mice. These findings validate Gabra2 as a genetic modifier of Dravet syndrome.

scholarly journals Sudden unexpected death in a mouse model of Dravet syndrome

2013 ◽  
Vol 123 (4) ◽  
pp. 1798-1808 ◽  
Author(s):  
Franck Kalume ◽  
Ruth E. Westenbroek ◽  
Christine S. Cheah ◽  
Frank H. Yu ◽  
John C. Oakley ◽  
...  
Keyword(s):  
Mouse Model ◽  
Sudden Unexpected Death ◽  
Dravet Syndrome ◽  
Unexpected Death

scholarly journals Sudden unexpected death in genetic epileptic encephalopathies: a role of neurocardiac genes

2018 ◽  
Vol 10 (3) ◽  
pp. 63-70
Author(s):  
E. D. Belousova ◽  
M. A. Shkolnikova
Keyword(s):  
High Risk ◽  
Sudden Unexpected Death ◽  
Dravet Syndrome ◽  
Unexpected Death ◽  
Sodium Potassium ◽  
Epileptic Encephalopathies ◽  
Increased Risk ◽  
Clinical Conditions ◽  
Cultured Cardiomyocytes

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.

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

2020 ◽  
Vol 12 (558) ◽  
pp. eaaz6100 ◽  
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.

scholarly journals Accurate interpretation of genetic variants in sudden unexpected death in infancy by trio-targeted gene-sequencing panel analysis

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Keita Shingu ◽  
Takehiko Murase ◽  
Takuma Yamamoto ◽  
Yuki Abe ◽  
Yoriko Shinba ◽  
...  
Keyword(s):  
Genetic Analysis ◽  
Cause Of Death ◽  
Genetic Variants ◽  
De Novo ◽  
Sudden Unexpected Death ◽  
Compound Heterozygous ◽  
Unexpected Death ◽  
Accurate Interpretation ◽  
Clinically Significant ◽  
Targeted Gene Sequencing

AbstractIn sudden unexpected death in infancy cases, postmortem genetic analysis with next-generation sequencing potentially can extract candidate genes associated with sudden death. However, it is difficult to accurately interpret the clinically significant genetic variants. The study aim was to conduct trio analysis of cases of sudden unexpected death in infancy and their parents to more accurately interpret the clinically significant disease-associated gene variants associated with cause of death. From the TruSight One panel targeting 4813 genes we extracted candidate genetic variants of 66 arrhythmia-, 63 inherited metabolic disease-, 81 mitochondrial disease-, and 6 salt-losing tubulopathy-related genes in 7 cases and determined if they were de novo or parental-derived variants. Thirty-four parental-derived variants and no de novo variants were found, but none appeared to be related to the cause of death. Using trio analysis and an in silico algorithm to analyze all 4813 genes, we identified OBSCN of compound heterozygous and HCCS of hemizygous variants as new candidate genetic variants related to cause of death. Genetic analysis of these deceased infants and their living parents can provide more accurate interpretation of the clinically significant genetic variants than previously possible and help confirm the cause of death.

scholarly journals Effect of Vagus Nerve Stimulation in an Adult Patient with Dravet Syndrome: Contribution to Sudden Unexpected Death in Epilepsy Risk Reduction?

2013 ◽  
Vol 69 (2) ◽  
pp. 119-121 ◽  
Author(s):  
Marianna Spatola ◽  
Pierre-Yves Jeannet ◽  
Claudio Pollo ◽  
Christian Wider ◽  
Robyn Labrum ◽  
...  
Keyword(s):  
Vagus Nerve ◽  
Adult Patient ◽  
Risk Reduction ◽  
Nerve Stimulation ◽  
Vagus Nerve Stimulation ◽  
Sudden Unexpected Death ◽  
Dravet Syndrome ◽  
Unexpected Death
Sign in / Sign up

Export Citation Format

Share Document