Dravet syndrome with autism inherited from a paternal mosaic heterozygous mutation on SCN1A

Xiong, Zhenzhen; Li, Yi; Cao, Dingya; He, Weiming; Chen, Jiayu; Gao, Shaorong; Sun, Xiaofang

doi:10.1016/j.jns.2016.07.038

Cited by 7 publications

(7 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The important function of Na V 1.1 in the CNS is highlighted by more than 500 mutations in its coding sequence that cause epileptic syndromes (Febrile Seizure, Generalized Epilepsy with Febrile Seizures +, and Severe Myoclonic Epilepsy of Infancy also known as Dravet syndrome) ( Catterall et al, 2010 ). Moreover, three of these mutations are also correlated to familial hemiplegic migraine, and several copy number variants have been linked to neurodevelopmental disorders such as intellectual disability, autism and psychiatric disease ( Dichgans et al, 2005 ; Fry et al, 2016 ; Xiong et al, 2016 ).…”

Section: Voltage-gated Sodium Channels Expressed In Drg Neuronsmentioning

confidence: 99%

The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

et al. 2018

View full text Add to dashboard Cite

Although necessary for human survival, pain may sometimes become pathologic if long-lasting and associated with alterations in its signaling pathway. Opioid painkillers are officially used to treat moderate to severe, and even mild, pain. However, the consequent strong and not so rare complications that occur, including addiction and overdose, combined with pain management costs, remain an important societal and economic concern. In this context, animal venom toxins represent an original source of antinociceptive peptides that mainly target ion channels (such as ASICs as well as TRP, CaV, KV and NaV channels) involved in pain transmission. The present review aims to highlight the NaV1.7 channel subtype as an antinociceptive target for spider toxins in adult dorsal root ganglia neurons. It will detail (i) the characteristics of these primary sensory neurons, the first ones in contact with pain stimulus and conveying the nociceptive message, (ii) the electrophysiological properties of the different NaV channel subtypes expressed in these neurons, with a particular attention on the NaV1.7 subtype, an antinociceptive target of choice that has been validated by human genetic evidence, and (iii) the features of spider venom toxins, shaped of inhibitory cysteine knot motif, that present high affinity for the NaV1.7 subtype associated with evidenced analgesic efficacy in animal models.

show abstract

Section: Voltage-gated Sodium Channels Expressed In Drg Neuronsmentioning

confidence: 99%

The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

et al. 2018

View full text Add to dashboard Cite

show abstract

“…An additional consideration is the recent observation that in cases of Dravet syndrome due to apparently de novo SCN1A mutation, a parent may be a mosaic carrier in up to 10% of cases when deep sequencing is performed . The parent may have a past history of FS only and the mild nature of seizures, if present, may reflect the degree of mosaicism . Other genes are also noted to have a degree of observed mosaicism .…”

Section: Focal Epilepsy Syndromesmentioning

confidence: 99%

“…124,156 The parent may have a past history of FS only and the mild nature of seizures, if present, may reflect the degree of mosaicism. 123,157,158 Other genes are also noted to have a degree of observed mosaicism. 122 All these factors emphasize the potential benefit of familial testing in patients with Dravet syndrome or GEFS+ phenotypes in the context of thorough pre-and post-genetic counseling.…”

Section: Gefs+ and Dravet Syndromementioning

confidence: 99%

Epilepsy genetics: Current knowledge, applications, and future directions

2018

View full text Add to dashboard Cite

The rapid pace of disease gene discovery has resulted in tremendous advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, and genomes are now available and have led to higher diagnostic rates and insights into the underlying disease processes. As such, the contribution to the care of patients by medical geneticists, neurogeneticists and genetic counselors are significant; the dysmorphic examination, the necessary pre- and post-test counseling, the selection of the appropriate next-generation sequencing-based test(s), and the interpretation of sequencing results require a care provider to have a comprehensive working knowledge of the strengths and limitations of the available testing technologies. As the underlying mechanisms of the encephalopathies and epilepsies are better understood, there may be opportunities for the development of novel therapies based on an individual's own specific genotype. Drug screening with in vitro and in vivo models of epilepsy can potentially facilitate new treatment strategies. The future of epilepsy genetics will also probably include other-omic approaches such as transcriptomes, metabolomes, and the expanded use of whole genome sequencing to further improve our understanding of epilepsy and provide better care for those with the disease.

show abstract

“…We used a well-established mouse model of Dravet syndrome (Scn1a+/-mice) in which a loxP-flanked neo cassette replaces exon 1 of the Scn1a gene, creating a null allele [Mistry et al, 2014]. Mice were maintained on a strict 50:50 C57BL6/J:129S6 genetic background (see METHODS for details) which recapitulates salient core features of DS observed in human patients, including temperature-sensitive seizures, early-onset chronic epilepsy (with appearance of seizures at/around post-natal day (P) 18), approximately 30% death from seizure-related causes during early development (compared to 20% lifetime risk in humans) [Cooper et al, 2016], and social recognition and memory deficits consistent with features of ASD [Berkvens et al, 2015, He et al, 2018, Xiong et al, 2016. Cross to double transgenic PV-Cre.tdTomato mice yielded triple transgenic Scn1a.PV-Cre.tdT mice and age-matched wild-type PV-Cre.tdT littermate controls [Favero et al, 2018] and facilitated comparison of PV-INs between genotypes and across development.…”

Section: Resultsmentioning

confidence: 83%

Developmentally-regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome

Kaneko

Currin

Goff

et al. 2021

Preprint

View full text Add to dashboard Cite

Dravet syndrome (DS) is a neurodevelopmental disorder defined by epilepsy, intellectual disability, and sudden death, due to heterozygous variants in SCN1A with loss of function of the sodium channel subunit Nav1.1. Nav1.1-expressing parvalbumin GABAergic interneurons (PV-INs) from pre-weanling Scn1a+/- mice show impaired action potential generation. A novel approach assessing PV-IN function in the same mice at two developmental time points showed that, at post-natal day (P) 16-21, spike generation was impaired all mice, deceased prior or surviving to P35. However, synaptic transmission was selectively dysfunctional in pre-weanling mice that did not survive. Spike generation in surviving mice normalized by P35, yet we again identified abnormalities in synaptic transmission. We conclude that combined dysfunction of PV-IN spike generation and synaptic transmission drives disease severity, while ongoing dysfunction of synaptic transmission contributes to chronic pathology. Modeling revealed that PV-IN axonal propagation is more sensitive to decreases in sodium conductance than spike generation.

show abstract

Dravet syndrome with autism inherited from a paternal mosaic heterozygous mutation on SCN1A

Cited by 7 publications

References 10 publications

The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

Epilepsy genetics: Current knowledge, applications, and future directions

Developmentally-regulated impairment of parvalbumin interneuron synaptic transmission in an experimental model of Dravet syndrome

Contact Info

Product

Resources

About