Mechanisms of neurocognitive dysfunction and therapeutic considerations in tuberous sclerosis complex
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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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Several monogenic causes of ASD, including TSC and Joubert Syndrome, show abnormal axon path finding or migration abnormalities known to lead to altered brain structural connectivity.
“Indeed several of the monogenic causes of ASD, including TSC [56] and Joubert Syndrome [57, 58] show manifestations of abnormal axon path finding or migration abnormalities that are known to lead to alterations in brain structural connectivity.”
From Genetics of autism spectrum disorders (2011) · cites this paper as [56]
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- Authors
- Tsai, P., & Sahin, M.
- Affiliations
- Boston Children's Hospital (US)
- ORCID
- Tsai, Peter
- Venue
- Current Opinion in Neurology
- Published
- 2011-04
- Volume
- 24
- Issue
- 2
- Pages
- 106-113
- ISSN
- 1350-7540 (ISSN-L)
- PMC
- PMC3059306
- OpenAlex
- W2014945127
- Cited by
- 84
- References
- 67
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1 · 2023: 4 · 2022: 2 · 2021: 7 · 2020: 8 · 2019: 3 · 2018: 3 · 2017: 6 · 2016: 5 · 2015: 8 · 2014: 9 · 2013: 13 · 2012: 9
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Current Opinion in Neurology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Nancy Lurie Marks Family Foundation
- Manton Foundation
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R01NS058956, T32NS007473)
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- tuberous sclerosis complex, neurocognitive impairment, mTORC1 signaling, mTORC1 inhibitors, neuronal connectivity, neurodevelopmental disorders, intellectual disability, epilepsy, autism spectrum disorder
- MeSH terms
- Abnormalities, Multiple, Mechanistic Target of Rapamycin Complex 1, Animals, Cognition Disorders, Disease Models, Animal, Humans, Neurons, Proteins, Tuberous Sclerosis, Signal Transduction, Multiprotein Complexes, TOR Serine-Threonine Kinases
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