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. 2021 Sep;62(9):2205-2217.
doi: 10.1111/epi.17015. Epub 2021 Aug 2.

Defining Dravet syndrome: An essential pre-requisite for precision medicine trials

Wenhui Li  1   2 , Amy L Schneider  2 , Ingrid E Scheffer  2   3   4
Affiliations

Defining Dravet syndrome: An essential pre-requisite for precision medicine trials

Wenhui Li et al. Epilepsia. 2021 Sep.

Abstract

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.

Keywords: SCN1A; Dravet syndrome; developmental and epileptic encephalopathy; genetics; phenotypic spectrum.

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Conflict of interest statement

I.E. Scheffer has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, BioMarin, Nutricia, Rogcon, Chiesi, Encoded Therapeutics, Xenon Pharmaceuticals, and Knopp Biosciences; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin, and Eisai; has served as an investigator for Zogenix, Zynerba, Ultragenyx, GW Pharma, UCB, Eisai, Anavex Life Sciences, Ovid Therapeutics, Epigenyx, Encoded Therapeutics and Marinus; and has consulted for Zynerba Pharmaceuticals, Atheneum Partners, Ovid Therapeutics, Care Beyond Diagnosis, Epilepsy Consortium, and UCB. She may accrue future revenue on a pending patent WO2009/086591 (filed: 2008); has a patent for SCN1A testing held by Bionomics Inc and licensed to various diagnostic companies (WO/2006/133508), and has a patent for a molecular diagnostic/therapeutic target for benign familial infantile epilepsy (BFIE) [PRRT2] WO/2013/059884. W. Li and A.L. Schneider declare no potential conflict of interest. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

FIGURE 1
FIGURE 1
(A) Age at seizure onset in our cohort of 205 patients with SCN1A‐Dravet syndrome together with published patients with onset after 12 months or with pathogenic mosaic SCN1A variants. (B) First, second, third, and fourth or more seizure type to develop in patients. (C) Duration of first seizure in 164 patients with SCN1A‐Dravet syndrome
FIGURE 2
FIGURE 2
(A) Days between each of the first five seizures. Boxplots show individual data points (dots), median (solid line), interquartile range (boxes), and 1.5× the interquartile range (whiskers). (B) Age at onset of the first three seizure types. Boxplots show individual data points (dots), median (solid line), interquartile range (boxes), and 1.5× the interquartile range (whiskers). Dashed lines denote published upper and lower limits for age of onset of additional seizure types. (C) Average duration of initial hemiclonic, focal impaired awareness seizures, and tonic‐clonic seizures in 33, 35, and 45 patients with available data, respectively
FIGURE 3
FIGURE 3
Age at onset of developmental plateauing in 106 patients with SCN1A‐Dravet syndrome
FIGURE 4
FIGURE 4
Age and cause of death in 25 patients from our cohort with SCN1A‐Dravet syndrome
FIGURE 5
FIGURE 5
Diagnostic algorithm for SCN1A‐Dravet syndrome
See this image and copyright information in PMC

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