The F.M. Kirby Neurobiology Center, Department of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts, USA.
Curr Opin Neurol. 2011 Apr;24(2):106-13. doi: 10.1097/WCO.0b013e32834451c4.
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.
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.
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.
目的综述：影响认知的孟德尔疾病为通过研究动物中的遗传缺陷并提出可在人类中进行测试的假说，从而研究神经发育障碍的机制提供了独特的机会。结节性硬化症（TSC）是一种具有癫痫、自闭症和智力残疾表现的遗传病。本文综述了我们对 TSC 发病机制和信号通路的最新认识，这些通路可能被调控以治疗神经症状。
最新发现：越来越多的证据表明，TSC 患者存在非结节异常，这些异常导致了神经表型的发展，特别是轴突束的紊乱和髓鞘形成不足。TSC 小鼠模型未能完全复制人类神经病理学，但揭示了细胞异常和神经行为表型。最重要的是，细胞培养和动物模型已将 mTORC1 通路确定为该疾病的治疗靶点。
总结：临床前数据强烈表明 TSC 是一种异常神经元连接的疾病。神经发育缺陷的高发病率、在非常年幼时早期发现该疾病以及 mTORC1 抑制剂的可用性，使得 TSC 成为神经认知的其他孟德尔疾病的模型，并为神经发育障碍的基于机制的治疗试验提供了途径。
