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New insights into the pathogenesis and prevention of tuberous sclerosis-associated neuropsychiatric disorders (TAND)
Tanjala T Gipson1, Michael V Johnston2
1Boling Center for Developmental Disabilities, LeBonheur Children's Hospital, University of Tennessee Health Sciences Center, Memphis, TN, USA.
Abstract:
Tuberous sclerosis complex (TSC) is a multi-system disorder resulting from mutations in either the TSC1 or TSC2 genes leading to hyperactivation of mechanistic target of rapamycin (mTOR) signaling. TSC is commonly associated with autism (61%), intellectual disability (45%), and behavioral, psychiatric, intellectual, academic, neuropsychological, and psychosocial difficulties that are collectively referred to as TSC-associated neuropsychiatric disorders (TAND). More than 90% of children with TSC have epilepsy, including infantile spasms, and early onset of seizures, especially infantile spasms, is associated with greater impairment in intellectual development compared with individuals with TSC without seizures. Development of the mTOR inhibitors everolimus and sirolimus has led to considerable progress in the treatment of renal angiomyolipomata, pulmonary lymphangioleiomyomatosis, and subependymal giant cell astrocytomas in the brain. However, similar therapeutic progress is needed in the treatment of TAND.
Insights
Tuberous sclerosis complex (TSC), a genetic disorder, often causes neurological issues like epilepsy and intellectual disability. While mTOR inhibitors treat some TSC symptoms, new therapies are needed for TSC-associated neuropsychiatric disorders (TAND).
Area of Science:
- Genetics and Neurology
- Molecular Biology
- Developmental Disorders
Background:
- Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in TSC1 or TSC2 genes.
- This leads to hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway.
- TSC is frequently linked with neurodevelopmental and psychiatric conditions, collectively known as TSC-associated neuropsychiatric disorders (TAND).
Purpose of the Study:
- To summarize the current understanding of TAND in TSC.
- To highlight the impact of epilepsy on cognitive development in TSC.
- To underscore the need for targeted therapies for TAND.
Main Methods:
- Review of existing literature on TSC, TAND, and mTOR signaling.
- Analysis of the association between epilepsy, particularly infantile spasms, and intellectual development in TSC.
- Examination of the therapeutic landscape for TSC manifestations.
Main Results:
- Over 90% of children with TSC experience epilepsy, with early-onset seizures correlating with greater intellectual impairment.
- TSC is highly prevalent in individuals with autism (61%) and intellectual disability (45%).
- While mTOR inhibitors (everolimus, sirolimus) are effective for certain TSC-related tumors and lesions, their efficacy for TAND is limited.
Conclusions:
- TAND represents a significant challenge in managing TSC, impacting multiple domains of functioning.
- Early seizure control in TSC is crucial for mitigating intellectual deficits.
- There is an unmet need for novel therapeutic strategies to address the neuropsychiatric manifestations of TSC.
