Jülich Kristina, Sahin Mustafa
Department of Neurology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Department of Neurology, F.M. Kirby Center for Neurobiology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
Pediatr Neurol. 2014 Apr;50(4):290-6. doi: 10.1016/j.pediatrneurol.2013.12.002. Epub 2013 Dec 5.
Tuberous sclerosis complex (TSC) is a genetic multisystem disorder that affects the brain in almost every patient. It is caused by a mutation in the TSC1 or TSC2 genes, which regulate mammalian target of rapamycin (mTOR), a key player in control of cellular growth and protein synthesis. The most frequent neurological symptoms are seizures, which occur in up to 90% of patients and often are intractable, followed by autism spectrum disorders, intellectual disability, attention deficit-hyperactivity disorder, and sleep problems. Conventional treatment has frequently proven insufficient for neurological and behavioral symptoms, particularly seizure control. This review focuses on the role of TSC/mTOR in neuronal development and network formation and recent mechanism-based treatment approaches.
We performed a literature review to identify ongoing therapeutic challenges and novel strategies.
To achieve a better quality of life for many patients, current therapy approaches are directed at restoring dysregulated mTOR signaling. Studies in animals have provided insight into aberrant neuronal network formation caused by constitutive activation of the mTOR pathway, and initial studies in TSC patients using magnetic resonance diffusion tensor imaging and electroencephalogram support a model of impaired neuronal connectivity in TSC. Rapamycin, an mTOR inhibitor, has been used successfully in Tsc-deficient mice to prevent and treat seizures and behavioral abnormalities. There is recent evidence in humans of improved seizure control with mTOR inhibitors.
Current research provides insight into aberrant neuronal connectivity in TSC and the role of mTOR inhibitors as a promising therapeutic approach.
结节性硬化症（TSC）是一种遗传性多系统疾病，几乎每位患者的大脑都会受到影响。它由TSC1或TSC2基因的突变引起，这些基因调节哺乳动物雷帕霉素靶蛋白（mTOR），而mTOR是控制细胞生长和蛋白质合成的关键因子。最常见的神经症状是癫痫发作，高达90%的患者会出现癫痫发作，且通常难以控制，其次是自闭症谱系障碍、智力残疾、注意力缺陷多动障碍和睡眠问题。传统治疗方法常常被证明对神经和行为症状，尤其是癫痫控制不足。本综述重点关注TSC/mTOR在神经元发育和网络形成中的作用以及近期基于机制的治疗方法。
我们进行了文献综述，以确定当前的治疗挑战和新策略。
为了让许多患者获得更好的生活质量，目前的治疗方法旨在恢复失调的mTOR信号传导。动物研究深入了解了由mTOR通路的组成性激活导致的异常神经元网络形成，并且在TSC患者中使用磁共振扩散张量成像和脑电图的初步研究支持了TSC中神经元连接受损的模型。雷帕霉素是一种mTOR抑制剂，已成功用于Tsc基因缺陷小鼠，以预防和治疗癫痫发作及行为异常。最近有证据表明，mTOR抑制剂在人类中可改善癫痫控制。
当前的研究深入了解了TSC中异常的神经元连接以及mTOR抑制剂作为一种有前景的治疗方法的作用。
