The study, “A two-hit story: Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies,” was published in Neurobiology of Disease.
Dravet syndrome is a severe type of epilepsy that usually manifests during the first year of life and is characterized by seizures, cognitive deficits, and increased mortality. In most cases, the disorder is associated with genetic mutations in the SCN1A gene, which encodes for a sub-unit of a sodium channel called NaV1.1, responsible for the transmission of electrical signals in the brain.
Dravet syndrome, together with other milder forms of epilepsy, such as genetic epilepsy with febrile seizures plus (GEFS+), is highly variable among patients. For this reason, it is difficult to define a personalized therapeutic strategy.
Although it has been shown that genetic mutations in SCN1A are associated with Dravet syndrome and other types of epilepsy, it is not clear whether they are truly required for the development of severe forms of the disease, or if they simply increase the frequency of epileptic seizures.
To distinguish the contribution of epileptic seizures and genetic mutations to disease severity, a team of researchers from the Université Côte d’Azur (UCA) in France used a mouse model of Dravet syndrome and GEFS+ carrying a known mutation associated with epilepsy in the SCN1A gene, called R1648H.
To induce recurrent epileptic seizures, researchers treated animals with hyperthermia (high body temperature) or fluorothyl (a stimulant and convulsant agent that induces seizures) for 10 days, starting at 21 days after birth.
These mice, which are normally asymptomatic or have mild disease severity, progressed to a severe disease state resembling Dravet syndrome, with frequent spontaneous seizures and cognitive/behavioral deficits after treatment. The same treatment had no effect on control wild-type (healthy) mice.
Interestingly, researchers found no signs of tissue changes or neuronal death in R1648H mice after treatment. However, they did find that hippocampal granule cells (neurons from the hippocampus, responsible for short-term memory) had increased excitability, suggesting that short-term treatment to induce seizures was able to change disease features.
Of note, excitatory signaling from one nerve cell to the next makes the latter cell more likely to fire an electrical signal. Inhibitory signaling makes the latter cell less likely to fire. This is the basis of communication between nerve cells in the brain.
“[W]e demonstrate for our model that an SCN1A mutation is a prerequisite for a long-term deleterious effect of seizures on the brain, indicating a clear interaction between seizures and the mutation for the development of a severe phenotype [symptoms shown] generated by pathological remodeling. Applied to humans, this result suggests that genetic alterations, even if mild per se, may increase the risk of second hits to develop severe phenotypes,” researchers stated.
“Overall, our results are important for SCN1A-related disorders, but also as a general example for the identification of risk factors in a precision medicine framework,” they concluded.