13 March 2022

Epilepsy Awareness: A spotlight on Dravet Syndrome

 

Background

Epilepsy is a chronic neurological condition that affects approximately 50 million people worldwide. It is characterised by recurrent seizures due to excessive electrical discharges in the brain [1]. Seizures experienced by individuals with epilepsy can be categorised as generalised (affecting both sides of the brain) or focal (located in one specific area of the brain) and can vary in severity from an individual being dazed/confused and twitching to experiencing muscle jerks/spasms and loss of consciousness [2].

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterised by frequent and difficult-to-treat seizures [3]. Dravet syndrome (DS) is a genetic form of epilepsy within this group that represents an estimated 0.17% of all epilepsies in the U.S. [4]. A frequent trigger of seizures in DS is high temperatures, such as those experienced while taking a warm bath or during an infection [3, 4]. Onset of DS usually occurs between 4 and 8 months of age but can occur up to the age of 18 months and typically becomes apparent because of significant developmental delays [3, 5]. The effect of DS on cognitive function varies widely among individuals; however, most adults with the condition are dependent on caregivers despite the decline in the number and duration of seizures usually seen with age. Individuals with DS also experience changes in eating, appetite, balance, and a crouched walk [6].

Pathophysiology of Dravet Syndrome (DS)

DS is considered a genetic form of epilepsy and globally more than 80% of DS cases are associated with a mutation in the sodium voltage-gated channel alpha subunit 1 gene (SCN1A) [3–5]. In general, more than 1,800 mutations in SCN1A have been identified, with 90% being de novo (mutation that develops in a family member for the first time) [7]. These mutations can result in loss of function of sodium channel protein type 1 subunit alpha (SCN1A; the protein encoded by SCN1A) and, as only one copy of SCN1A is typically affected in cases of de novo mutations, haploinsufficiency (50% less functioning SCN1A in the body) [7]. It must then be considered how such mutations can cause seizures.

Neurons are cells of the nervous system that transport electrical signals via action potentials. When an excitatory neuron becomes activated, an action potential is generated through the influx of positive ions into the neuron (Figure 1; A) [7]. This ultimately results in the release of the neurotransmitter glutamate into the synapse (the junction between neurons) [7]. Glutamate then binds to the receptors on the neighbouring excitatory neuron(s), resulting in the influx of positive ions and triggering an action potential, which continues the electrical signal (Figure 1; B) [7].

However, an excess of glutamate in the synapse can result in neurons becoming hyperexcitable, which can result in seizures [8]. Inhibitory neurons are present within the nervous system to prevent this. Glutamate also binds to receptors on these inhibitory neurons, causing sodium ion channels such as SCN1A to open and an influx of sodium ions to occur (Figure 1; C) [8, 9]. This activates the inhibitory neurons, resulting in the release of the neurotransmitter gamma-aminobutyric acid (GABA) into the synapse [8]. GABA binds to receptors on excitatory neurons, resulting in the influx of negative ions and the cessation of neuronal activation (Figure 1; D) [8, 9].

Most cases of DS occur because of haploinsufficiency of SCN1A leading to reduced levels of SCN1A on inhibitory neurons in the brain [9]. This results in reduced activation of inhibitory neurons, leading to reduced release of GABA. Consequently, excitatory neurons are not inhibited and so experience hyperexcitability, which can result in seizures [10].

Treatment for Dravet Syndrome (DS)

There is currently no cure for DS and most available treatments only aim to reduce seizure frequency. The current global standard of care for children with DS is sodium valproate with stiripentol and clobazam [12, 13]. In a randomized trial, 71% of 21 children with DS treated with stiripentol were seizure-free or experienced a decrease of at least 50% in the frequency of seizures. This was versus 5% of 20 children with DS receiving placebo who experienced a decrease of at least 50% in the frequency of seizures [14].

In 2018, a purified oral solution form of cannabidiol (a compound isolated from the Cannabis sativa plant) was approved for DS by the Food and Drug Administration (FDA) in the USA [12]. In a clinical trial of this drug in combination with standard antiepileptic treatment, 43% of patients with DS experienced a decrease of at least 50% in convulsive seizure frequency compared to 27% of those treated with placebo [12, 15]. Additionally, fenfluramine was approved for DS in 2020 by the European Medicines Agency (EMA) and the FDA and in 2022 by the National Institute for Health and Care Excellence (NICE) [12, 16, 17]. Fenfluramine has demonstrated a median decrease in seizure frequency of 74.9% in a randomized clinical trial [13, 18]. As not all treatments will work for individuals, the development and innovation of treatments allows for more options for patients with DS.

Gene therapy has been shown to be effective in other genetic neurological disorders and so may provide a cure for DS, with several gene therapies for DS currently in the pipeline stage. As the SCN1A gene is too large to be delivered directly into neurons via viral vectors, the focus of gene therapy for DS is to increase the production of the healthy copy of the SCN1A gene and reduce production of the mutated gene [19].

Conclusion

Dravet Syndrome (DS) is a severe form of epilepsy that has a poor prognosis. Although there are several therapies that reduce the symptoms of DS, they only focus on reducing seizure frequency. Therefore, the shift in focus towards genetic therapies that could potentially cure DS has a promising outlook for patients.

The information in this article is not intended or implied to be a substitute for professional medical advice, diagnosis or treatment. All content is for general information purposes only. Always seek the guidance of your doctor or other qualified healthcare professional with any questions you may have regarding your health of medical condition.

 

References

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  2. Centers for Disease Control and Prevention. Types of seizures. Available at: https://www.cdc.gov/epilepsy/about/types-of-seizures.htm. Accessed December 2022.
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  4. National Organization for Rare Disorders. Rare disease database: Dravet syndrome. Available at: https://rarediseases.org/rare-diseases/dravet-syndrome-spectrum/. Accessed December 2022.
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