Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Oct:159:62-71.
doi: 10.1016/j.pediatrneurol.2024.06.012. Epub 2024 Jul 4.

Drug-Resistant Epilepsy in Tuberous Sclerosis Complex Is Associated With TSC2 Genotype: More Findings From the Preventing Epilepsy Using Vigatrin (PREVeNT) Trial

Laura S Farach  1 , Melissa A Richard  2 , Aynara C Wulsin  3 , Elizabeth M Bebin  4 , Darcy A Krueger  3 , Mustafa Sahin  5 , Brenda E Porter  6 , Tarrant O McPherson  7 , Jurriaan M Peters  5 , Sarah O'Kelley  8 , Katherine S Taub  9 , Rajsekar Rajaraman  10 , Stephanie C Randle  11 , William M McClintock  12 , Mary Kay Koenig  13 , Michael D Frost  14 , Klaus Werner  15 , Danielle A Nolan  16 , Michael Wong  17 , Gary Cutter  18 , Hope Northrup  13 , Kit Sing Au  13 ; PREVeNT Study Group
Collaborators, Affiliations

Drug-Resistant Epilepsy in Tuberous Sclerosis Complex Is Associated With TSC2 Genotype: More Findings From the Preventing Epilepsy Using Vigatrin (PREVeNT) Trial

Laura S Farach et al. Pediatr Neurol. 2024 Oct.

Abstract

Background: Children with tuberous sclerosis complex (TSC) are at high risk for drug-resistant epilepsy (DRE). The ability to stratify those at highest risk for DRE is important for counseling and prompt, aggressive management, necessary to optimize neurocognitive outcomes. Using the extensively phenotyped PREVeNT cohort, we aimed to characterize whether the TSC genotype was associated with DRE.

Methods: The study group (N = 70) comprised participants with TSC enrolled at age less than or equal to six months with detailed epilepsy and other phenotypic and genotypic data, prospectively collected as part of the PREVeNT trial. Genotype-phenotype correlations of DRE, time to first abnormal electroencephalography, and time to epilepsy onset were compared using Fisher exact test and regression models.

Results: Presence of a TSC2 pathogenic variant was significantly associated with DRE, compared with TSC1 and participants with no pathogenic mutation identified. In fact, all participants with DRE had a TSC2 pathogenic variant. Furthermore, TSC2 variants expected to result in no protein product were associated with higher risk for DRE. Finally, TSC1 pathogenic variants were associated with later-onset epilepsy, on average 21.2 months later than those with other genotypes.

Conclusions: Using a comprehensively phenotyped cohort followed from infancy, this study is the first to delineate genotype-phenotype correlations for epilepsy severity and onset in children with TSC. Patients with TSC2 pathogenic variants, especially TSC2 pathogenic variants predicted to result in lack of TSC2 protein, are at highest risk for DRE, and are likely to have earlier epilepsy onset than those with TSC1. Clinically, these insights can inform counseling, surveillance, and management.

Keywords: Drug-resistant epilepsy; Epilepsy; Genotype; Phenotype; Tuberous sclerosis complex (TSC); Vigabatrin.

PubMed Disclaimer

Conflict of interest statement

Declaration of competing interest Dr. Krueger has received consulting fees from Biocodex, Jazz Pharmaceuticals, and Longboard Pharmaceuticals. He also serves on the Board of Directors of the TSC Alliance and the Science and Medical Advisory Committee of the Smith Kingsmore Syndrome Foundation. Mustafa Sahin reports grant support from Biogen, Astellas, Bridgebio, and Aucta. He has served on Scientific Advisory Boards for Roche, SpringWorks Therapeutics, Jaguar Therapeutics, Noema, and Alkermes. No other authors have conflicts of interests to disclose.

LinkOut - more resources