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Review
. 2011 Apr;24(2):106-13.
doi: 10.1097/WCO.0b013e32834451c4.

Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex

Peter Tsai  1 , Mustafa Sahin
Affiliations
Review

Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex

Peter Tsai et al. Curr Opin Neurol. 2011 Apr.

Abstract

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.

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Figures

Figure 1
Figure 1
TSC mediated signaling in the central nervous system. This cartoon of TSC mediated signaling has been simplified to highlight the demonstrated biologic roles for TSC mediated mTOR signaling in the nervous system. Among the upstream signaling pathways, only the growth factors and ephrins have been shown to modulate TSC-mTOR pathway in neurons (growth factors, ephrins) while others (e.g. Wnts) have been implicated, but not proven to regulate TSC signaling in the nervous system.
See this image and copyright information in PMC

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