Ryan Jones

Introduction. Dravet Syndrome (DS) is a severe epileptic encephalopathy characterized by seizures triggered by fevers within the first year of life⁷. Infants present after normal health with prolonged seizures within first year, resulting in developmental delays². Approximately 80% of DS cases are related to a mutation in the gene SCN1A, which encodes for the alpha subunit of the voltage-gated sodium channel². Studies have shown that certain SCN1A mutations cause a significantly reduced nerve transient current amplitude at high temperatures and other SCN1A mutations cause reduced excitability of inhibitory interneurons^4,6. Other studies have found genes known as Dravet Survival Modifying genes (Dsm) that modify the severity of DS and create new targets for improved treatments^1,3,5. One study showed that Fenfluramine, formerly used in Fen-Phen, had potential therapeutic effects in DS patients⁹. Methods. Inbred strains of mice were generated to allow for prominence of genetic mutations^1,3,4,5. RNA-sequencing was performed using TruSeq RNA sample prep kit^3,5. Whole-cell patch-clamp recordings of inhibitory neurons were performed at 34°C using Axopatch 200B, Multiclamp 700B, or BVC 700A amplifiers⁴. Video-EEG was used to monitor seizure activity¹. All drugs were dissolved in DMSO and diluted in embryo medium to achieve a final DMSO concentration of 1% w/v, which served as a vehicle control⁹. Results. Recordings from mutant mice showed reduced firing in all studied inhibitory interneurons⁴. Modifier genes were identified on chromosomes 5, 7, 8 and 11 that influence the early lethality of the Scn1a+/-  DS mouse model⁵. Cacna1g was found to influence the DS phenotype severity, mainly a lesser severity was seen at reduced levels of Cacna1g¹. Gabra2 was identified as a putative modifier gene, showing that higher levels correlated with prolonged survival. Clobazam was found to offer therapeutic benefit in DS patients due to its preferential binding to Gabra2 subunit³. Using a zebrafish model of DS, it was shown that Fenfluramine significantly reduced convulsions and epileptic activity at high doses⁹. Conclusions. These modifier genes may suggest new targets for the improved treatment of epilepsy. The discovery of these genes provides information that may help predict the risk of SUDEP (Sudden Unexplained Death in Epilepsy) and the clinical course of epilepsy due to sodium channel mutations and the associated modifier genes.

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