More than epilepsy—a parent-initiated collaborative analysis of the research landscape and research needs in Dravet syndrome
- Open Access
- 03.11.2025
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Abstract
Dravet syndrome (DS), initially described as severe myoclonic epilepsy of infancy (SMEI), is a genetic, developmental, and epileptic encephalopathy characterized by the early onset of recurrent convulsive seizures, usually within the first year of life in normally developed infants. The mortality rate of DS is high, at 15.84 per 1000 person-years, while the rate of sudden unexpected death in epilepsy (SUDEP) is 9.32 per 1000 person-years [1]. In addition to epileptic seizures, other symptoms such as behavioral problems (aggression, dangerous behavior, impulsivity, hyperactivity, or compulsive habits) motor deterioration, and cognitive deficits emerge during development [2‐4]. Dravet syndrome significantly impacts patients’ and caregivers’ lives [2, 3].
To advance DS research, an innovative approach—landscape analysis—was carried out to depict the global research landscape, identify research obstacles, define priorities for research support, develop a roadmap for future research, and facilitate stakeholder engagement and collaboration.
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Methods
This landscape analysis was initiated and sponsored by three patient and family associations (PFAs) for DS: the Gruppo Famiglie Dravet Associazione APS (Milan, Italy), the Vereinigung Dravet Syndrom Schweiz (Zurich, Switzerland), and the Dravet Syndrom e. V. (Frankfurt a. M., Germany). Commissioned research was carried out by the research consulting agency Science Compass (Milan, Italy), which applied an innovative landscape analysis approach.
A literature search was conducted in February 2021 using both SCOPUS and PubMed databases, searching for the keywords “Dravet OR SCN1a,” which identified 2000 (SCOPUS) and 531 (PubMed) additional publications. A total of 197 reviews published since 2015 were selected as the basis of the landscape analysis. The literature search was repeatedly updated until June 2022, based on the same selection criteria, and ultimately included 3003 publications. Finally, several key opinion leaders were invited to participate in web-based interviews and round-table discussions. The experts were selected with the assistance of each Dravet association’s scientific advisory boards for their central role in DS research. All experts are listed in the Acknowledgments section.
A long version of this manuscript is available as supplementary online material. Materials from the original research report by Science Compass are available upon request by writing to gruppofamiglie@sindromedidravet.org.
Results
Gene, protein, and disease mechanisms
Genetics
Dravet syndrome is primarily linked to mutations in the SCN1A gene, which encodes the NaV1.1 sodium channel. Over 80% of cases involve SCN1A, while other genes such as PCDH19, GABRG2, and SCN2A are implicated less frequently. There is no clear correlation between genotype and phenotype, and about 10% of cases have an unknown genetic cause. Genetic mutations do not always predict the type of disease or disease severity, and SCN1A alterations have been linked to other disorders, such as genetic epilepsy with febrile seizures plus (GEFS+), myoclonic-atonic epilepsy (MAE), and others. SCN1A haploinsufficiency affects not only epilepsy but also motor functions, thermoregulation, and psychomotor development, although the specific mechanisms remain unclear [4].
About 10% of Dravet syndrome cases have an unknown genetic cause
Proteins
The NaV1.1 sodium channel, affected by SCN1A mutations, is crucial for inhibitory GABAergic interneurons. Loss-of-function mutations reduce inhibitory neuron excitability, causing network hyperexcitability and diverse phenotypes influenced by the mutation type and modifying factors. Understanding these mutations is vital for DS research [5].
Expert opinions
Experts emphasize that more basic and preclinical research is warranted in DS. The exact genotype–phenotype correlation remains unclear, and modifying variables such as mosaicism, epigenetics, and environmental factors remain elusive. Examining mosaicism and the whole genome may be worthwhile. At the protein level, the contribution of SCN1A-related dysfunction on ion channels in different types of interneurons, as well as the specific contribution of SCN1A-expressed sodium channels relative to those expressed by SCN2A or SCN8A, is unknown. New technical approaches, such as high-throughput electrophysiology, may allow for quicker and more automated functional studies.
Research infrastructure
In vitro models
Heterologous expression systems.
Electrophysiological studies of SCN1A mutations are conducted in cell lines such as human embryonic kidney (HEK) cells, tsA-201, and Chinese hamster ovary (CHO) cells. These models reveal mutation effects such as gain or loss of function, with loss-of-function mutations linked to severe DS phenotypes. While informative for channel behavior and drug testing, they lack the complexity of neuronal networks and brain-specific interactions. For more details, please refer to the online supplement.
Transfected/transgenic neurons.
Patient mutations can be introduced into neuronal cells or transgenic models to study channel functions, thereby aiding therapy development and personalized medicine.
Patient-derived induced pluripotent stem cells (iPSCs).
The development of pluripotent stem cell technology opens the possibility of designing patient-specific cell models of DS. Pluripotent cells may be derived from fibroblasts by skin biopsy or from blood-derived hematopoietic cells, and can then be reprogrammed through genome editing techniques such as TALEN or CRISPR/Cas9. These iPSCs can help understand disease progression at the cellular, tissue, and organ levels. Furthermore, iPSCs offer insights into disease progression and may clarify non-epileptic dysfunctions in DS.
In vivo models
Rodents.
Various genetically engineered rodent models, such as knockout and knock-in mice, are used to study SCN1A mutations. Knockout mice, like Scn1atm1Kea, display spontaneous seizures, while knock-in models replicate specific human mutations such as R1407X and R1648H, aiding in the understanding of GEFS+ and DS. Conditional mutants, targeting specific neuronal populations, demonstrate the link between SCN1A mutations and increased cortical excitability due to reduced inhibitory interneuron activity.
Zebrafish.
Zebrafish models, with their mammalian-like nervous system subdivisions, are ideal for high-throughput drug screening. Scn1lab zebrafish have been pivotal in identifying antiseizure effects of drugs including clemizole, lorcaserin, and fenfluramine.
Drosophila melanogaster.
Drosophila has one Para gene encoding voltage-gated sodium channels, with structural differences from human nav1.1 channels, raising concerns about transferring findings. Models with human SCN1A K1270T and S1231R mutations exhibit heat-induced seizures, with K1270T showing gain and S1231R showing loss of function. R1648C and R1648H mutations via CRISPR-Cas9 are linked to DS and GEFS+, highlighting the role of differing genetic backgrounds.
Expert opinion
Experts emphasize that iPSC technology enables DS research by replicating human mutations, although doubts remain about its ability to fully capture disease progression. Genetic technologies and in vivo models offer valuable insights into complex neuronal interactions.
Clinical knowledge
Epilepsy
Seizure onset in DS occurs between 1 and 18 months of age, often triggered by hyperthermia from fever or environmental factors. Generalized tonic-clonic or hemiclonic seizures dominate the early stages of DS, with additional seizure types such as absence or myoclonic seizures emerging later. Seizures are frequent, often drug-resistant, and require early diagnosis and proper treatment to prevent complications. Polypharmacy is common, impacting quality of life. For more details, please refer to the online supplement.
Cognitive, behavioral, and social functioning
Neurodevelopment appears normal initially but slows between 12 and 60 months of age, sometimes following episodes of status epilepticus. Most patients develop severe learning disabilities, with autism spectrum disorder present in 31–38% of cases. Cognitive, behavioral, and social issues significantly burden patients and caregivers, impacting their quality of life [2].
Seizure onset occurs between 1 and 18 months of age
Motor development and gait abnormalities
Motor development in DS often shows delays, with crouch gait being common due to increased hip and knee flexion and ankle dorsiflexion [6]. Muscle weakness, spasticity, and contractures worsen gait over time, leading many teenagers to require wheelchairs for long distances. Nevertheless, studies with larger numbers of participants and systematic assessment of therapeutic interventions are still lacking.
Speech and language function
Speech and language issues in DS include imprecise articulation, breathy voice, and language impairment aligned with cognitive skills; however, these areas remain underexplored despite their social importance.
Sleep
Sleep issues are common in DS, with younger children often experiencing sleep–wake transition disorders and older patients facing difficulties in sleep initiation and maintenance. Breathing problems during sleep are prevalent across all ages. Research on the role of SCN1A in sleep regulation is limited, although mouse models reveal abnormalities in sleep architecture. Given the link between sleep deprivation, seizures, and learning challenges, more studies on DS-related sleep disturbances are essential.
Sudden unexpected death in epilepsy
Sudden unexpected death in epilepsy (SUDEP) accounts for up to 50% of deaths in DS, with 73% occurring before age 10 [7]. Studies on cardiac and autonomic functions in DS yield mixed results, with some showing abnormalities [8, 9] and others not [10]. SCN1A-R1407X knock-in mice and DS-derived myocytes suggest a predisposition to cardiac arrhythmia. Other potential mechanisms include intracranial pressure, epilepsy severity, seizure frequency, drug polytherapy, and postictal ventilatory abnormalities. Further research into SUDEP causes and prevention is vital given the high mortality in DS.
DS in adulthood
As patients age, seizure severity and frequency decrease, while Parkinsonian symptoms and behavior issues persist, lowering quality of life. Research and treatment for adults remain limited, with most DS studies focused on children. Although no specific treatment guidelines exist for adults, a treatment algorithm developed in consultation has been suggested [11].
Expert opinion
Early diagnosis and intervention for DS are crucial for better outcomes. More studies are needed to understand the progression of DS symptoms, especially non-epileptic ones such as gait, speech, behavioral issues, and autism spectrum disorder, which are priorities for families. Research should address treatment gaps, especially in adulthood, including pharmacological and behavioral strategies.
Therapeutic pipeline
Approved symptomatic treatments
To date, three antiseizure medications—stiripentol, cannabidiol, and fenfluramine—have been approved in Europe for the treatment of DS. Stiripentol (Diacomid®) was conditionally approved in 2007 and fully authorized in 2014 as an adjunct therapy with valproate and clobazam. It enhances GABA activity, reducing seizures by 70%. Common side effects include weight loss, sedation, and behavioral changes. Cannabidiol (Epidiolex®/Epidyolex®) was approved in 2018 in the United States and 2019 in Europe for children aged 2+. It reduces seizure frequency by 39% and has side effects such as somnolence, diarrhea, and fatigue. Fenfluramine (Fintepla®), developed by Zogenic and UCB, is approved for patients aged 2+ without clobazam. It reduces seizures, may improve cognition, and reduces mortality risks, including SUDEP. Common side effects include anorexia, diarrhea, and sedation. A network meta-analysis shows stiripentol and fenfluramine are more effective than cannabidiol in reducing convulsive seizures [12].
Treatments under development.
Following Mingorance’s suggestion, we categorize treatments into first-in-class, second-in-class, and those targeting SCN1A haploinsufficiency in DS [13]. As most of the treatments under development focus primarily on their anti-epileptic efficacy, it is difficult at this stage to assess their impact on non-epileptic symptoms of DS.
First-generation (first-in-class) treatments.
Soticlestat (TAK-935) inhibits cholesterol-24-hydroxylase, reducing glutamatergic activity. While the phase 3 trial SKYLINE missed its primary endpoint for DS, secondary endpoints were met. Huperzine A (SPN-817), an acetylcholine-esterase inhibitor, showed seizure reduction in a phase 2 trial. BL-001 mimics ketogenic diet effects by modulating the gut microbiome and GABAergic system, with plans for a phase 2 trial. Additional compounds including IAMA‑6, JBPOS-0101, NT102, and ReS3‑T show potential, although their development status remains unclear. For more details, please refer to the online supplement.
Second generation (second-in-class) treatments under development.
Lorcaserin (Belviq®), a serotonin-receptor agonist, was withdrawn in 2020 due to cancer risks. Bexicaserin showed promising phase 2 results and is entering phase 3 trials. Clemizole (EPX-100), lorcaserin (EPX-200), and trazodone (EPX-300) target serotonergic pathways, with results from clemizole trials expected in 2026. BMB-101, also a 5HT2C receptor agonist, is in phase 2 testing. Development of GABAergic compounds such as NCT10004, DSP-0378, and XP-0863 remains unclear. A cannabidiol gel (ZYN002) showed potential in reducing seizures but is now being developed mainly for other syndromes.
Disease-targeting (disease-modifying) therapies.
Disease-modifying therapies for DS focus on SCN1A haploinsufficiency using antisense oligonucleotides (ASOs) and viral vector gene therapy. Zorevunersen (STK-001) boosts Nav1.1 protein through intrathecal injection, showing seizure and cognitive improvements in phase 1/2a trials (MONARCH, ADMIRAL), with phase 3 planned for 2025 (EMPEROR; [14]). ETX101 uses AAV vectors upregulating SCN1A expression in GABAergic cells in three clinical trials: ENDEAVOR, WAYFINDER, and EXPEDITION. EXPEDITION enrolls children in the United Kingdom and is the first study in DS with a primary endpoint on behavioral measures [15].
RT101 (Regel Therapeutics) is also an AAV vector targeting interneurons in DS. The company is preparing an investigational new drug application [13, 16]. Tevard Biosciences is developing mRNA modulators for haploinsufficiency and for nonsense mutations in DS. Viral vectors are used to increase the amount of protein to normal levels or repair the gene’s bad copy by introducing the normal amino acid. There is currently insufficient information to comment on a gene therapy designed to upregulate SCN1A (Sangamo Therapeutics), elevation of gene transcription by CMP-SCN (CAMP4 Therapeutics), and small-molecule ion-channel modulators for Nav1.1 activation (Xenon Pharma). Other companies such as Lundbeck and academic programs such as the Gladstone Institute of Neurological Disease, the Florey Institute of Neuroscience and Mental Health, and the University of Melbourne are also researching Nav1.1. activation [13].
Discussion
The specific relationship between SCN1A-expressed channels and other sodium channels in different types of interneurons remains unknown. The number of patients with DS is relatively high for a rare disease, with approximately 11,000 in Europe [17] and 35,000 in the major markets [13], offering promising economic gain for companies developing effective medications. Dravet syndrome with SCN1A alterations may be considered prototypical for monogenetic brain disorders, although the genotype–phenotype correlation is not yet fully understood. Thus, research results on SCN1A may also inform about other genetically determined diseases.
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There are numerous compelling reasons to optimize treatment for DS. The syndrome has a profound impact on both the patients and their caregivers, significantly affecting quality of life and leading to an increased mortality rate [2, 3]. Many individuals with DS experience challenges in education, social interaction, and mobility, and are often subjected to polypharmacy with uncertain drug interactions and side effects.
Patients experience challenges in education, social interaction, and mobility
For caregivers, the burden is immense. Many report little free time, reliance on family support networks, ongoing emotional stress, and significant concern for their child’s future healthcare needs. The career decisions of up to 80% of caregivers have been influenced by DS, and 28% have missed more than three workdays in the past 4 weeks due to their child’s illness [3]. Additionally, depressive symptoms affect between 47% and 70% of caregivers [2].
From a societal perspective, DS involves substantial direct and indirect costs. Because the number of DS patients is relatively high for a rare disease, pharmaceutical companies are actively investing in the development of effective medications.
In basic and preclinical research, important gaps remain, such as understanding the relationship between genotype and phenotype, as well as the impact of factors such as mosaicism, epigenetics, and environmental influences. The role of SCN1A deficiency and other genetic contributors to non-epileptic symptoms is not yet well understood. From the viewpoint of PCAs, it is crucial to clarify how different symptoms of DS evolve with age. This includes in vitro and in vivo models of epileptic, cognitive, behavioral, social, motor, speech, language, and sleep symptoms. Currently, there is no clear pathophysiological concept explaining the development of motor, cognitive, or behavioral skills and speech, language, or sleep problems. Mortality, especially the heightened risk of SUDEP in DS, remains a significant concern [7]. As such, understanding the mechanisms behind SUDEP and developing effective prevention strategies should be prioritized in preclinical research.
In clinical research, there are also research gaps. The evolution of different DS symptoms during aging—including epileptic, cognitive, behavioral, social, motor, speech and language, and sleep symptoms—requires considerable research efforts. In particular, symptoms in adulthood are not sufficiently studied. Behavioral and social problems are among the most significant concerns for caregivers of DS patients, contributing mainly to their burden of disease. Cognitive and learning impairments limit the patients’ social integration. However, there is no clear pathophysiological concept for these symptoms. The development of motor skills requires much more attention. Speech and language problems are insufficiently explored. Sleep problems require much more attention because they interact with seizures, learning, and the family’s health status. Mortality in DS remains a significant concern, especially concerning the risk of SUDEP, which is exceptionally high in DS [7]. Therefore, SUDEP mechanisms and prevention should also be a focus of clinical research.
There are substantial therapeutic advances in Dravet syndrome
Therapeutic advances in DS are enormous, and the field is very competitive. With stiripentol, cannabidiol, and fenfluramine, three disease-specific symptomatic therapies have been approved in recent years. Several first-generation drugs are currently being researched, e.g., soticlestat, BL-001, SPN-817. Second-generation drugs reproduce the effects of first-generation drugs using novel compounds, e.g., bexicaserin. Most notably, new disease-modifying approaches targeting genetic defects in DS are on the way, e.g., increasing the function of Nav1.1 ion channels by antisense oligonucleotides, viral vectors, or small molecules. Targeting the underlying genetic mechanisms holds the promise of influencing the natural course of the disease and ameliorating development in different domains, including cognitive, behavioral, and motor domains.
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Despite these advances, the burden of disease remains high for patients and caregivers. From the perspective of PFAs, it is essential to consider behavioral, cognitive, and motor measures as well as mortality rates as important endpoints for clinical studies. Standardization of measures would support comparability. Head-to-head comparisons of DS treatments in different populations are greatly needed to develop and validate treatment algorithms and prevent irrational polypharmacy.
Practical conclusion
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This landscape analysis reveals a wealth of knowledge and ongoing research activity in the field of Dravet syndrome (DS).
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It highlights the need for basic and clinical research efforts focused on the development of non-epileptic symptoms.
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The landscape analysis indicates the potential of future symptomatic and disease-modifying treatments in DS.
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As developments continue in the therapeutic pipeline, patient and family associations advocate for all patient-related symptoms to be addressed rather than focusing only antiepileptic properties.
Acknowledgements
We thank the Consultant Scientific Officer Francesca Sofia, Science Compass (Milan, Italy), and Serena Bertoldi, Science Compass, for performing the landscape analysis. We thank the following DS experts for sharing their time and expert opinions in expert interviews: Andreas Brunklaus (University of Glasgow, UK), Daniel Fisher (Tevard Biosciences, Cambridge, Massachusetts, USA), Shinichi Hirose (Fukuoka University, Japan), Jennifer Kearney (Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA), Massimo Mantegazza (Institute of Molecular and Cellular Pharmacology, Nice, France), Miriam Meisler (University of Michigan Medical Center, Ann Arbor, Michigan, USA), Ingrid Sheffer (University of Melbourne, Australia), and Elaine C. Wirrell (Mayo Clinic, Rochester, Minnesota, USA) for sharing their time and expert opinions to support our landscape analysis. We thank the following DS experts for their participation in the round tables and sharing their time and expert opinions to support our landscape analysis: Danielle Andrade (University of Toronto, Toronto, Canada), Scott Baraban (University of California, San Francisco, USA), Andreas Brunklaus (University of Glasgow, Glasgow, UK), Andre Elferink (EMA Medicine Evaluation Board, Amsterdam, The Netherland), Alfred George (Northwestern University, Chicago, USA), Jackie Gofshteyn (Encoded Therapeutics, San Francisco USA), Renzo Guerrini (Azienda Ospedaliero Universitaria Meyer, Florence, Italy), Jennifer Helfer (Encoded Therapeutics, San Francisco, USA), Lori Isom (University of Michigan Medical School, Ann Arbor, USA), Lieven Lagae (UZ Leuven, Leuven, Belgium), Massimo Mantegazza (Institute of Molecular and Cellular Pharmacology, Nice, France), Megan Murphy (Takeda Pharmaceutical Co., Cambridge, USA), Rima Nabbout (Imagine Institute Necker Enfants Malades, Paris, France), Kimberly Parkerson (Stoke Therapeutics, Bedford, USA), Gopi Shanker (Tevard Biosciences, Cambridge, USA), Barry Ticho (Stoke Therapeutics, Bedford, USA), Francoise Truong-Berthoz (Takeda Pharmaceutical Co., Cambridge, US), Konrad Werhahn (UCB, Brussels, Belgium), Elaine Wirrell (Mayo Clinic, Rochester, USA).
Funding
Funding was provided by the Gruppo Famiglie Dravet Associazione APS (Milan, Italy), the Vereinigung Dravet Syndrom Schweiz (Zurich, Switzerland), and the Dravet Syndrom e. V. (Frankfurt a. M., Germany).
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Declarations
Conflict of interest
C. Konrad, S. Borroni, S. Budak, S. Flege and D. Kiper are members of PFAs. C. Konrad has received speakers and advisory honorariums concerning psychiatric topics that do not affect Dravet research. S. Borroni, S. Budak, S. Flege and D. Kiper have no conflicts of interest to declare.
For this article no studies with human participants or animals were performed by any of the authors. All studies mentioned were in accordance with the ethical standards indicated in each case.
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