Child Neurology and Psychiatry Unit, Systems Medicine Department, Tor Vergata University, Rome, Italy.
Rare and Complex Epilepsy Unit, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Lancet Neurol. 2022 Sep;21(9):843-856. doi: 10.1016/S1474-4422(22)00213-7.
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.
结节性硬化症是一种罕见的遗传疾病，与 TSC1 或 TSC2 基因突变有关，这些突变导致 mTOR 复合物的过度激活。在过去的 5 年中，人们对 TSC1 和 TSC2 基因突变以及神经元和神经胶质细胞中 mTORC1 过度激活的细胞后果有了更多的了解，并认识到其对网络功能障碍的贡献。现在，患有结节性硬化症的婴儿和幼儿（1-5 岁）可能会受益于早期评估基因变异状态和嵌合体。在过去的 5 年中，我们对 mTOR 相关神经病理学以及癫痫发生和同时发生的神经发育障碍的分子方面的理解也取得了重大进展。已经确定了许多潜在的疾病修饰策略，包括基于癫痫分子发现的靶向治疗的发展。现在已经有可靠的 EEG 和 MRI 生物标志物可用于识别以前不可能识别的在更年轻时患有结节性硬化症的婴儿，这些婴儿有癫痫、自闭症和发育迟缓的风险。加巴喷丁已成功用于在癫痫发作前 EEG 显示异常的结节性硬化症婴儿的治疗中。结节性硬化症相关症状的缓解范围已经扩大，包括使用 mTOR 抑制剂，如西罗莫司和依维莫司。临床和基础神经科学家之间的密切合作为未来的进展提供了新的机会。
