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(Abst. 2.116), 2019

Delineating the Phenotypic Limits of Dravet Syndrome Due to SCN1A Pathogenic Variants
Authors: Wenhui Li, Children’s Hospital of Fudan University; Ingrid E. Scheffer, The University of Melbourne; Amy L. Schneider, The University of Melbourne
Content: Rationale: Dravet syndrome is the prototypic developmental and epileptic encephalopathy, typically beginning with prolonged febrile hemiclonic or generalized tonic-clonic seizures (GTCS) at around 6 months of age in a normally developing infant. Multiple seizure types evolve between one and five years. Historically, a diagnosis of Dravet syndrome was often delayed until the typical phenotype developed after age 3 years. Earlier diagnosis allows optimization of anti-epileptic therapy, particularly with the promise of precision therapies which will alter the trajectory of this devastating disorder. With next generation sequencing, earlier molecular diagnosis is possible and may be achieved in the first year of life. Understanding the Dravet phenotype is critical for accurate diagnosis, however, the phenotypic spectrum of Dravet syndrome may be subtly nuanced and lack of specific features may prevent early diagnosis. We aimed to delineate the phenotypic spectrum observed early in the disease course of patients with SCN1A positive Dravet syndrome. Methods: The clinical histories of patients with Dravet syndrome and a pathogenic SCN1A variant were analysed for the median and range of variables related to seizure type, onset age and seizure duration. Results: 188 patients were studied; median age at study was 16 years (range 0.9 to 61 years). 22 patients were deceased. 4/188 (2.1%) patients had developmental delay prior to the onset of their seizures. Age at seizure onset ranged from 1.5 to 20 months (median 5.75 months). The first seizure type could be classified in 179/188 (95%) patients: 96/179 (54%) GTCS, 57/179 (32%) hemiclonic seizure, 13/179 (7%) myoclonic seizure, 7/179 (4%) focal impaired awareness seizure (FIAS) and 1/179 (0.6%) absence seizure at onset. 2/179 (1%) patients presented with both hemiclonic and myoclonic seizures and 3/179 (2%) had both GTCS and myoclonic seizures at onset. The exact duration of the first seizure was known for 135186 (73%) patients, with a median duration of 15 minutes (range 1 second – 3 hours). Only 91/168 (54%) patients were febrile during their first seizure. Median time between seizures reduced with increasing seizure number: first to second seizure 29 days (data available for 124/188 [66%] patients); second to third seizure also 28 days (data available for 101/188 [54%] patients), third to fourth seizure 18 days (data available from 82/188 [44%] patients) and fourth to fifth seizure 17 days (data available from 73/188 [39%] patients). 186/188 (99%) patients developed multiple seizure types. Median age at onset of the second and the third seizure types were 9 months (range 2 months – 10 years) and 16 months (range 4 months – 6 years), from data available on 111/187 (59%) and 71/186 (38%) patients respectively. Considering the first 3 seizure types to present in patients, most had GTCS (96/179, 54%), myoclonic seizures (41/135, 30%) and FIAS (27/95, 28%). Conclusions: Subtle differences in presentation of children with Dravet syndrome may lead to delay in diagnosis when rigid definitions are used. Understanding the gestalt of Dravet syndrome is critical, including patterns of seizure onset, type and progression. Only half of the patients present with a fever-related initial seizure; onset can occur before 5 months and after 18 months, and additional seizure types typically begin months after seizure onset. Understanding key features within the phenotypic spectrum will assist clinicians in evaluating whether a child has Dravet syndrome, facilitating early diagnosis for precision therapies. Funding: No funding