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

Authors

Laura S Farach
Melissa A Richard
Aynara C Wulsin
Elizabeth M Bebin
Darcy A Krueger
Mustafa Sahin
Brenda E Porter
Tarrant O McPherson
Jurriaan M Peters
Sarah O'Kelley
Katherine S Taub
Rajsekar Rajaraman
Stephanie C Randle
William M McClintock
Mary Kay Koenig
Michael D Frost
Klaus Werner
Danielle A Nolan
Michael Wong
Gary Cutter
Hope Northrup
Kit Sing Au

Language

English

Publication Date

10-1-2024

Journal

Pediatric Neurology

DOI

10.1016/j.pediatrneurol.2024.06.012

PMID

39142021

PMCID

PMC12854254

PubMedCentral® Posted Date

1-30-2026

PubMedCentral® Full Text Version

Author MSS

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

Humans, Tuberous Sclerosis, Tuberous Sclerosis Complex 2 Protein, Drug Resistant Epilepsy, Male, Female, Infant, Genotype, Tuberous Sclerosis Complex 1 Protein, Genetic Association Studies, Vigabatrin

Published Open-Access

yes

Recommended Citation

Farach, Laura S; Richard, Melissa A; Wulsin, Aynara C; et al., "Drug-Resistant Epilepsy in Tuberous Sclerosis Complex Is Associated With TSC2 Genotype: More Findings From the Preventing Epilepsy Using Vigatrin (PREVeNT) Trial" (2024). Faculty, Staff and Student Publications. 5629.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5629