PURPOSE OF REVIEW: Mendelian disorders that affect cognition provide a unique 
opportunity to study the mechanisms of neurodevelopmental disorders through the 
examination of genetic defects in animals and development of hypotheses that can 
be tested in human beings. Tuberous sclerosis complex (TSC) is a genetic disease 
that presents with epilepsy, autism, and intellectual disability. Here we review 
recent advances in our understanding of TSC pathogenesis and signaling pathways 
that may be modulated to treat the neurological symptoms.
RECENT FINDINGS: Accumulating evidence suggests that TSC patients have nontuber 
abnormalities that contribute to the development of the neurological phenotype- 
in particular, disorganization of axon tracts and deficient myelination. TSC 
mouse models have failed to replicate the human neuropathology entirely, but 
have shed light on the cellular abnormalities and the neurobehavioral 
phenotypes. Most importantly, cell culture and animal models have identified the 
mTORC1 pathway as a therapeutic target in this disease.
SUMMARY: Preclinical data strongly suggest that TSC is a disease of abnormal 
neuronal connectivity. The high incidence of neurodevelopmental deficits, early 
detection of the disease in very young ages, and availability of mTORC1 
inhibitors make TSC a model for other Mendelian disorders of neurocognition and 
an avenue for the mechanism-based treatment trials of neurodevelopmental 
disorders.