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Drug-Resistant Epilepsy in Tuberous Sclerosis Complex Is Associated With TSC2 Genotype: More Findings From the
Laura S Farach1, Melissa A Richard2, Aynara C Wulsin3
1Department of Pediatrics, McGovern Medical School at the University of Texas Health Science Center at Houston (UTHealth Houston) and Children's Memorial Hermann Hospital, Houston, Texas.
Insights
Children with tuberous sclerosis complex (TSC) have high epilepsy risk. TSC2 gene variants, especially those causing no protein, strongly predict drug-resistant epilepsy (DRE) and earlier onset in these children.
Area of Science:
- Pediatric Neurology
- Genetics
- Epilepsy Research
Background:
- Tuberous sclerosis complex (TSC) presents a significant risk for drug-resistant epilepsy (DRE) in children.
- Early identification of children at high risk for DRE is crucial for neurocognitive outcomes.
- The PREVeNT cohort provides extensive phenotypic and genotypic data for TSC research.
Purpose of the Study:
- To investigate the association between TSC genotype and the risk of DRE in children.
- To correlate specific TSC gene variants with epilepsy severity and onset.
- To inform clinical management and counseling strategies for pediatric TSC.
Main Methods:
- Analysis of genotypic and phenotypic data from 70 infants with TSC enrolled in the PREVeNT trial.
- Comparison of genotype-phenotype correlations for DRE, EEG abnormalities, and epilepsy onset.
- Utilized Fisher exact test and regression models for statistical analysis.
Main Results:
- A significant association was found between TSC2 pathogenic variants and DRE.
- All participants with DRE possessed a TSC2 pathogenic variant; variants predicted to cause no protein product showed higher DRE risk.
- TSC1 pathogenic variants were linked to later epilepsy onset compared to other genotypes.
Conclusions:
- This study establishes genotype-phenotype correlations for epilepsy in TSC patients from infancy.
- Children with TSC2 pathogenic variants, particularly those leading to absent protein, face the highest risk of DRE and earlier epilepsy onset.
- Findings support targeted counseling and management for high-risk TSC patients.
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.
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