Tuberous sclerosis‐associated epilepsy and intellectual disability: what role does the mammalian target of rapamycin pathway play?

The cellular signaling pathway known as mammalian target of rapamycin (mTOR) is a key regulator of many integrated physiological functions, including proper neuronal network development, synaptic plasticity, and cognition. Tuberous sclerosis complex (TSC) is a monogenic disorder of mTOR regulation that provides a mechanistic basis for a direct link between gene mutation and brain pathology. TSC1 and TSC2 mutations, which cause TSC, are associated with overactivation of the mTOR pathway that can lead to epileptogenic cerebral dysplasia and encephalopathy. Increased activation of mTOR complex 1 (mTORC1) has been documented in dysplastic neurons within fetal tubers before the onset of epilepsy. Although cognitive impairment in TSC has a multifactorial origin, intellectual disability is strongly associated with early onset and persistent seizures that can alter brain connectivity in areas that are crucial for cognitive development. In a large prospective study of infants with TSC, seizure severity in the first 2 years of life was associated with impaired intellectual development over long-term follow-up. In the last decade, diagnosis of TSC has increasingly been made prenatally or in early infancy, thanks to improved awareness and access to testing. Earlier presymptomatic diagnosis provides child neurologists with a unique opportunity to follow-up infants with a propensity to have seizures later on. Evidence-based clinical recommendations, recently implemented by a panel of European experts, changed our clinical practice in the management of infants with TSC, improving epilepsy outcome and reducing the rate of profound intellectual disability, which is now rare in recent cohorts. Parental education to recognize subtle focal seizures or infantile spasms and close electroencephalogram (EEG) monitoring to detect epileptiform abnormalities before the occurrence of seizures are of paramount importance to avoid any delay in antiepileptic treatment. Administration of vigabatrin may even be considered in presymptomatic infants as soon as epileptiform EEG discharges are detected. Indeed, vigabatrin may play a role in modulating focal epileptogenesis, preventing the progressive pathological network synchronization and the propagation of seizure discharge to other areas of the brain, and reducing the risk of an epileptic encephalopathy. However, cognitive dysfunction in TSC has also been observed in children without a history of seizures and developmental evaluation occasionally suggests intellectual disability before seizure onset. These findings suggest that TSC-associated neuropsychiatric disorders are not exclusively a consequence of pre-existing seizures, and there is a developmental component in TSC, independent of the epileptic encephalopathy. Intellectual ability correlates with the predicted functional effects of TSC1 and TSC2 mutations. The severity of TSC-related brain pathology is related to the presence of an inactivating TSC2 variant. Children with TSC2 protein truncating mutation are more likely to have progressive worsening of cognitive abilities and severe intellectual disability. A longitudinal study showed that a cascading risk pathway from gene mutation to cortical tubers and seizure severity in infancy, to poor intellectual outcome in late childhood can be a potential pathogenic mechanism. Recently, preclinical evidence suggested that epilepsy severity is directly related to the level of neuronal mTORC1 activity. In a TSC/mTOR-dependent epilepsy mouse model, early treatment with vigabatrin was not able to prevent epileptogenesis, but significantly delayed seizure onset. However, in this preclinical model, epileptogenesis driven by the loss of TSC1 showed a dose-dependent response to the mTORC1 inhibitor, rapamycin. mTOR cascade can be a potential hidden major cause of TSC-associated epilepsy and intellectual disability. Additional research should investigate if early suppression of an abnormal mTOR signal with mTOR inhibitors before the occurrence of seizures can be a more efficient approach and an effective antiepileptogenic and disease-modifying strategy in infants with TSC.