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Advances in the genetics and neuropathology of tuberous sclerosis complex: edging closer to targeted therapy
Paolo Curatolo1, Nicola Specchio2, Eleonora Aronica3
1Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University, Rome, Italy.
Abstract:
Tuberous sclerosis complex is a rare genetic disease associated with mutations in the TSC1 or TSC2 genes, which cause overactivation of the mTOR complex. In the past 5 years, understanding has increased of the cellular consequences of TSC1 and TSC2 genetic variants and the mTORC1 overactivation in neurons and glial cells and their contribution to network dysfunction. Infants and young children (aged 1-5 years) with tuberous sclerosis complex might now benefit from early assessment of gene variant status and mosaicism. In the past 5 years, substantial advances have also been made in our understanding of mTOR-related neuropathology and the molecular aspects of both epileptogenesis and co-occurring neurodevelopmental disorders. Many potential disease-modifying strategies have been identified, including developments in targeted therapies based on molecular findings in epilepsy. Reliable EEG and MRI biomarkers are now available to identify, at a younger age than previously possible, infants with tuberous sclerosis complex who are at risk of epilepsy, autism, and developmental delay. Vigabatrin has been used successfully as a treatment in infants with tuberous sclerosis complex who showed abnormalities on EEG before seizure onset. The scope for mitigation of tuberous sclerosis complex-associated symptoms has expanded, including the use of mTOR inhibitors such as sirolimus and everolimus. Close cooperation between clinical and basic neuroscientists has provided new opportunities for future advances.
Insights
Tuberous sclerosis complex (TSC) research has advanced, focusing on genetic variants and mTORC1 overactivation. Early diagnosis and targeted therapies, including mTOR inhibitors, offer improved outcomes for infants and children with TSC.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Tuberous sclerosis complex (TSC) is a genetic disorder caused by TSC1 or TSC2 gene mutations, leading to mTOR complex overactivation.
- Recent advances have elucidated the cellular effects of TSC gene variants and mTORC1 overactivation in neural cells, contributing to network dysfunction.
- Understanding of TSC-related neuropathology, epileptogenesis, and associated neurodevelopmental disorders has significantly improved.
Purpose of the Study:
- To summarize recent advancements in understanding TSC pathophysiology and identify potential disease-modifying strategies.
- To highlight the importance of early genetic assessment and biomarker identification in TSC management.
- To discuss the therapeutic potential of mTOR inhibitors and other targeted treatments for TSC-associated symptoms.
Main Methods:
- Review of recent scientific literature on TSC genetics, neuropathology, and therapeutic interventions.
- Analysis of cellular consequences of TSC1/TSC2 variants and mTORC1 overactivation.
- Evaluation of diagnostic biomarkers (EEG, MRI) and treatment outcomes (Vigabatrin, mTOR inhibitors).
Main Results:
- Early assessment of gene variant status and mosaicism can benefit infants and young children with TSC.
- Reliable EEG and MRI biomarkers enable earlier identification of infants at risk for epilepsy, autism, and developmental delay.
- Vigabatrin has shown success in treating infants with TSC and pre-seizure EEG abnormalities; mTOR inhibitors like sirolimus and everolimus show promise for symptom mitigation.
Conclusions:
- Substantial progress in understanding TSC neuropathology and molecular aspects of associated disorders has been made.
- Early diagnosis through genetic testing and biomarkers, coupled with targeted therapies, expands mitigation scope for TSC symptoms.
- Collaborative efforts between clinical and basic neuroscientists are crucial for future advancements in TSC research and treatment.
