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Molecular EPISTOP, a comprehensive multi-omic analysis of blood from Tuberous Sclerosis Complex infants age birth to
Franz Huschner1, Jagoda Głowacka-Walas2,3, James D Mills4,5,6
1Proteome Factory AG, Berlin, Germany.
Insights
This study analyzed biomarkers in infants with Tuberous Sclerosis Complex (TSC) to predict epilepsy development. Early intervention with vigabatrin showed significant metabolic changes, aiding in identifying predictive biomarkers for epilepsy.
Area of Science:
- Biochemistry
- Genetics
- Clinical Medicine
Background:
- Tuberous Sclerosis Complex (TSC) is a genetic disorder associated with a high risk of epilepsy.
- Early intervention strategies are crucial for managing TSC-related epilepsy.
- Identifying reliable biomarkers for epilepsy development in TSC is a significant clinical challenge.
Purpose of the Study:
- To conduct a comprehensive multi-omic analysis of the EPISTOP clinical trial.
- To identify biomarkers for predicting epilepsy development in infants with TSC.
- To evaluate the effects of early vigabatrin intervention on molecular profiles.
Main Methods:
- Prospective follow-up of 93 infants with TSC from birth to age 2.
- Multi-omic analysis including serum proteins, metabolites, and blood RNA.
- Multivariate analysis to identify predictors of epilepsy development.
Main Results:
- Vigabatrin significantly altered metabolite levels, notably increasing deoxycytidine monophosphate (dCMP).
- Significant differences in proteins, metabolites, and genes were observed between control and TSC infants.
- Six molecular features showed progressive differences across control, TSC without epilepsy, and TSC with epilepsy groups.
- A 3-variable model achieved a high positive predictive value (0.987) for epilepsy prediction using enrollment samples.
Conclusions:
- Multi-omic data from the EPISTOP trial provides valuable insights into epilepsy development in TSC.
- Biomarkers for epilepsy prediction in TSC infants can be identified through comprehensive molecular analysis.
- This dataset supports further research into developmental effects and seizure associations in TSC.
Abstract:
We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age. Thirty-nine proteins, metabolites, and genes showed significant differences between age-matched control and TSC infants. Six also showed a progressive difference in expression between control, TSC without epilepsy, and TSC with epilepsy groups. A multivariate approach using enrollment samples identified multiple 3-variable predictors of epilepsy, with the best having a positive predictive value of 0.987. This rich dataset will enable further discovery and analysis of developmental effects, and associations with seizure development in TSC.
