A single-center, retrospective analysis of genotype-phenotype correlations in children with Dravet syndrome

• Published in: Seizure (London, England) Vol. 75; pp. 1 - 6
• Main Authors: Gertler, Tracy S., Calhoun, Jeffrey, Laux, Linda
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2020
• Subjects: Adolescent; Adult; Anticonvulsants - pharmacology; Child; Child, Preschool; Comorbidity; Dravet syndrome; Epilepsies, Myoclonic - drug therapy; Epilepsies, Myoclonic - genetics; Epilepsies, Myoclonic - physiopathology; Epilepsy; Female; Genetic Association Studies; Humans; Infant; Male; NAV1.1 Voltage-Gated Sodium Channel - genetics; Pharmacogenetics; Pharmacogenomics; Precision Medicine; Retrospective Studies; SCN1A; Young Adult; Precision medicine; Epilepsy; Dravet syndrome; SCN1A; Pharmacogenomics
• ISSN: 1059-1311; 1532-2688
• DOI: 10.1016/j.seizure.2019.12.009

•Pathogenic SCN1A missense variants cluster in specific functional channel domains.•The type of pathogenic SCN1A variant does not impact seizures or comorbidities.•Seizures in Dravet syndrome respond to valproic acid, clobazam, and stiripentol.•Levetiracetam and phenobarbital have limited benefit despite frequent use. Dravet syndrome is an early-onset epileptic encephalopathy caused most often by loss-of-function SCN1A variants. Following recognition of its genetic basis and unique clinical features, Dravet syndrome has become one of the most well-studied genetic epilepsies. We sought to evaluate the genetic diversity and correlative seizure phenotype, comorbidities, and response to antiepileptic therapies of patients with clinically-diagnosed Dravet syndrome seen in a tertiary care center. The goal of this study was to examine genotype-phenotype correlations and to ascertain if specific antiepileptic therapies may be more effective on the basis of genetic test result alone. Retrospective chart review of demographics, comorbidities, seizure types, and responses to antiepileptic therapies of all patients (n = 137) with a clinical diagnosis of Dravet syndrome seen at Lurie Children’s Hospital of Chicago from 2008 to 2016. Of the 96% of Dravet syndrome patients with pathogenic SCN1A variants subdivided by missense or truncating variant, there was no difference in clinical presentation. Response to antiepileptic therapies did not differ by genotype with regard to medication class. This is the largest cohort of Dravet patients from within the US to report medication response with respect to genotype. Missense variants in SCN1A were most common in the voltage-sensor and pore domains. All patients were most likely to respond to the recommended medication triad compared to other antiepileptic therapies.