DC 17: Association of metabolic markers and neurological manifestations in patients with mTOR pathway related epilepsy

Project part of Work Package 3

Objectives: The mTOR pathway regulates essential cellular functions, such as protein synthesis, cell growth, and synaptic plasticity, potentially impacting neuronal excitability and epileptogenesis. Genetic variants in pathway-related genes lead to neurological issues, including epilepsy and neurodevelopmental disorders. DC17 will focus on two genetic conditions: tuberous sclerosis complex (TSC) with TSC1 or TSC2 gene variants and GATOR 1 epilepsy with DEPDC5, NPRL2, and NPRL3 gene variants. The main objective is to improve our understanding of altered metabolism in TSC or GATOR1 epilepsy patients and the interplay between altered metabolism, mTORC1, and clinical manifestation. The ultimate goal is to identify novel targets and approaches for therapeutic intervention. Specifically, DC17 will assess blood amino acid levels and glucose after fasting in patients with TSC or GATOR1 epilepsy and associate alterations with neurological manifestations assisted by magnetic resonance spectroscopy. We will investigate amino acids and glucose levels in TSC patients under ketogenic diet or mTOR inhibitor treatment and study the relations with efficacy, tolerance and response to treatment. Finally, we will identify possible targets for nutritional interventions and conduct a proof-of-principle n of 1 trial.

Expected Results: We will improve the current understanding of the role of metabolism on neurological manifestations in patients with TSC or GATOR 1 epilepsy. We will identify patients who may benefit from nutritional intervention or other targeted treatments developed in this consortium (e.g. inhibition of mTOR/PI3Ka or S6K kinases).

Prospects of career development: Over the past decades, alumni from the dept of neurology and pediatrics form the UMCU became clinical scientists, group leaders/tenured researchers in Academia, and University teaching professors. The job opportunities for the Doctoral Candidates will be expanded by the multidisciplinary nature of the Research and Educational program, leading to potential recruitments in new fields (genetic tests, biomarkers analysis, drug/ treatment discovery and development) in both Academia and Industries.

Planned secondments: 3 months at PD-value for modelling drug response across blood brain barrier, 3 months at Institut du Cerveau for DNAsequencing of patient samples