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Defining Dravet syndrome: An essential pre-requisite for precision medicine trials
Wenhui Li1,2, Amy L Schneider2, Ingrid E Scheffer2,3,4
1Children's Hospital of Fudan University, Shanghai, China.
Insights
Dravet syndrome, a severe epilepsy, often presents atypically, delaying diagnosis. This study refines the definition of SCN1A-Dravet syndrome to improve early identification and treatment for precision medicine.
Area of Science:
- Epilepsy Genetics
- Developmental and Epileptic Encephalopathies
- Neurology
Background:
- Dravet syndrome, a prototypic developmental and epileptic encephalopathy, classically presents in infancy with prolonged febrile seizures.
- SCN1A pathogenic variants are identified in over 80% of patients, but atypical presentations cause diagnostic delays and inappropriate therapies.
- An evidence-based definition is crucial for advancing precision medicine trials in SCN1A-Dravet syndrome.
Purpose of the Study:
- To provide an evidence-based definition of SCN1A-Dravet syndrome.
- To refine the spectrum of Dravet syndrome presentation for earlier diagnosis.
- To prepare for precision medicine trials by clarifying diagnostic criteria.
Main Methods:
- Retrospective analysis of clinical data from 205 patients with SCN1A pathogenic variants and Dravet syndrome.
- Patients were recruited between 1995 and 2020 through the University of Melbourne Epilepsy Genetics Research Program.
- Analysis focused on seizure onset, type, progression, and developmental course.
Main Results:
- The median seizure onset age was 5.7 months, with initial seizures often being tonic-clonic (52%) or hemiclonic (35%), and fever association in only 55%.
- Status epilepticus occurred in 34% of patients, and significant delays between initial seizures were observed in some cases.
- Developmental slowing before 12 months of age was noted in 27% of patients, challenging the classical description.
Conclusions:
- Refining the definition of SCN1A-Dravet syndrome based on seizure patterns is essential for early diagnosis.
- Understanding the full spectrum of SCN1A-Dravet syndrome presentation is critical for optimizing treatment strategies.
- An accurate definition facilitates timely intervention and eligibility for emerging precision medicine approaches.
Objective:
The classical description of Dravet syndrome, the prototypic developmental and epileptic encephalopathy, is of a normal 6-month-old infant presenting with a prolonged, febrile, hemiclonic seizure and showing developmental slowing after age 1 year. SCN1A pathogenic variants are found in >80% of patients. Many patients have atypical features resulting in diagnostic delay and inappropriate therapy. We aimed to provide an evidence-based definition of SCN1A-Dravet syndrome in readiness for precision medicine trials.
Methods:
Epilepsy patients were recruited to the University of Melbourne Epilepsy Genetics Research Program between 1995 and 2020 by neurologists from around the world. Patients with SCN1A pathogenic variants were reviewed and only those with Dravet syndrome were included. Clinical data, including seizure and developmental course, were analyzed in all patients with SCN1A-Dravet syndrome.
Results:
Two hundred and five patients were studied at a median age of 8.5 years (range 10 months to 60 years); 25 were deceased. The median seizure-onset age was 5.7 months (range 1.5-20.6 months). Initial seizures were tonic-clonic (52%) and hemiclonic (35%), with only 55% being associated with fever. Only 34% of patients presented with status epilepticus (seizure lasting ≥30 minutes). Median time between first and second seizure was 30 days (range 4 hours to 8 months), and seven patients (5%) had at least 6 months between initial seizures. Median ages at onset of second and third seizure types were 9.1 months (range 3 months-25.4 years) and 15.5 months (range 4 months-8.2 years), respectively. Developmental slowing occurred prior to 12 months in 27%.
Significance:
An evidence-based definition of SCN1A-Dravet syndrome is essential for early diagnosis. We refine the spectrum of Dravet syndrome, based on patterns of seizure onset, type, and progression. Understanding of the full spectrum of SCN1A-Dravet syndrome presentation is essential for early diagnosis and optimization of treatment, especially as precision medicine trials become available.
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