TY - JOUR
T1 - Drug-Resistant Epilepsy in Tuberous Sclerosis Complex Is Associated With TSC2 Genotype
T2 - More Findings From the Preventing Epilepsy Using Vigatrin (PREVeNT) Trial
AU - PREVENT Study Group
AU - Farach, Laura S.
AU - Richard, Melissa A.
AU - Wulsin, Aynara C.
AU - Bebin, Elizabeth M.
AU - Krueger, Darcy A.
AU - Sahin, Mustafa
AU - Porter, Brenda E.
AU - McPherson, Tarrant O.
AU - Peters, Jurriaan M.
AU - O'Kelley, Sarah
AU - O'Kelley, Sarah
AU - Rajaraman, Rajsekar
AU - Rajaraman, Rajsekar
AU - McClintock, William M.
AU - Koenig, Mary Kay
AU - McClintock, William M.
AU - Werner, Klaus
AU - Nolan, Danielle A.
AU - Wong, Michael
AU - Cutter, Gary
AU - Northrup, Hope
AU - Au, Kit Sing
AU - Bebin, E. Martina
AU - Krueger, Darcy
AU - Flamini, Robert
AU - Sergott, Robert C.
AU - McPherson, Tarrant
AU - Peri, Kalyani
AU - Krefting, Jessica
AU - Porter, Brenda
AU - Taub, Katherine
AU - Litt, Brian
AU - Wu, Joyce
AU - Lagory, Denise
AU - Korf, Bruce
AU - Messiaen, Ludwig
AU - Biasini, Fred
AU - Byars, Anna
AU - Roberds, Steven L.
AU - Rushing, Gabrielle
AU - Griffith, Molly
AU - Davis, Peter
AU - Hansen, Ellen
AU - Arcasoy, Emine
AU - Phillips, Jennifer
AU - Solidum, Rayann
AU - Gulsrud, Amanda
AU - Solis, Natalie
AU - Randle, Stephanie
AU - Patrick, Kristina
AU - Lee-Eng, Jacqueline
AU - Frost, Mike D.
AU - Branson, Janet
AU - Ellis, Sarah
AU - White, Desiree
AU - Novak, Olga
AU - Fasciola, Ashley
AU - Lorenzi, Jill
AU - Layer, Marcus
AU - Thomas, Allison
AU - Chanbers, Emily
AU - Berl, Madison
AU - Elling, Nancy
AU - Kassoff, Bergen
AU - Hardie, Kinaya
AU - Nolan, Danielle
AU - DeBastos, Angela
AU - Batchelder, Christine
AU - Koening, Mary Kay
AU - Au, Kit Su
AU - Pearson, Deborah
AU - Mansour, Rosleen
AU - Farach, Laura
AU - Salazar, Elida
N1 - Publisher Copyright:
© 2024 Elsevier Inc.
PY - 2024/10
Y1 - 2024/10
N2 - 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.
AB - 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.
KW - Drug-resistant epilepsy
KW - Epilepsy
KW - Genotype
KW - Phenotype
KW - Tuberous sclerosis complex (TSC)
KW - Vigabatrin
UR - http://www.scopus.com/inward/record.url?scp=85201115241&partnerID=8YFLogxK
U2 - 10.1016/j.pediatrneurol.2024.06.012
DO - 10.1016/j.pediatrneurol.2024.06.012
M3 - Article
C2 - 39142021
AN - SCOPUS:85201115241
SN - 0887-8994
VL - 159
SP - 62
EP - 71
JO - Pediatric Neurology
JF - Pediatric Neurology
ER -