Mechanistic strategies for secondary prevention of developmental and epileptic encephalopathy in children with tuberous sclerosis complex

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by pathogenic variants in TSC1 or TSC2, leading to mTOR pathway dysregulation and a spectrum of systemic and neurological manifestations. Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder frequently associated with early-onset, drug-resistant epilepsy, intellectual disability, and autism spectrum disorder-collectively known as TSC-associated developmental and epileptic encephalopathy (DEE). Advances in prenatal diagnostics and biomarker research now enable presymptomatic identification of high-risk infants. This review aims to synthesize current evidence on biomarker-informed, mechanism-based strategies for secondary prevention of DEE in TSC, offering a framework for personalized early interventions. Biomarkers, such as interictal epileptiform discharges, pathogenic TSC2 variants, and advanced neuroimaging metrics, predict epilepsy risk and neurodevelopmental trajectories. Preventive approaches include early initiation of vigabatrin and mTOR inhibitors, which show potential in reducing epilepsy severity and improving outcomes. Emerging strategies, including gene therapy, multi-omic profiling, and environmental enrichment, offer promise for disease modification. By linking predictive biomarkers to disease-modifying strategies, this review outlines a proactive and personalised approach to prevent or mitigate TSC-associated DEE. These insights help advance clinical decision-making and promote a shift toward precision prevention in paediatric epilepsy.

Keywords: Biomarkers and precision medicine; Developmental and epileptic encephalopathy (DEE); Presymptomatic intervention; Tuberous sclerosis complex (TSC); mTOR pathway dysregulation.

Fig. 1

Mechanistic model of prenatal and early postnatal brain development in Tuberous Sclerosis Complex (TSC). Genetic mutations in the TSC1 or TSC2 genes lead to hyperactivation of the mTOR signalling pathway, resulting in abnormal cellular processes including differentiation, proliferation, axonal and dendritic growth, oligodendroglial turnover, and glial function. During prenatal development, this dysregulation contributes to formation of cortical tubers, characterized by the emergence of dysmorphic astrocytes by 19–21 gestational weeks (GW), giant cells by 24 GW, and dysmorphic neurons by 36 GW. These cellular abnormalities impair neuronal development, axonal sprouting, and neurogenesis, and lead to an immature GABAergic system. This culminates in an imbalance between excitatory (E) and inhibitory (I) neuronal networks, predisposing the brain to seizures and neuropsychiatric comorbidities, including autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and intellectual disability (ID), observable after birth.