Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Curr Opin Neurol. 2013 Apr;26(2):154-9. doi: 10.1097/WCO.0b013e32835f19a7.
A major challenge for understanding neurodevelopmental disorders, including autism spectrum disorders (ASDs), is to advance the findings from gene discovery to an exposition of neurobiological mechanisms that underlie these disorders and subsequently translate this knowledge into mechanism-based therapeutics. A promising way to proceed is revealed by the recent studies of rare subsets of ASDs. In this review, we summarize the latest advances in the mechanisms and emerging therapeutics for a rare single-gene ASD, Rett syndrome.
Rett syndrome is caused by mutations in the gene coding for methyl CpG-binding protein 2 (MeCP2). Although MeCP2 has diverse functions, examination of MeCP2 mutant mice suggests the hypothesis that MeCP2 deficiency leads to aberrant maturation and maintenance of synapses and circuits in multiple brain systems. Some of the deficits arise from alterations in specific intracellular pathways such as the PI3K/Akt signaling pathway. These abnormalities can be at least partially rescued in MeCP2 mutant mice by treatment with therapeutic agents.
Mechanism-based therapeutics are emerging for single-gene neurodevelopmental disorders such as Rett syndrome. Given the complexity of MeCP2 function, future directions include combination therapeutics that target multiple molecules and pathways. Such approaches will likely be applicable to other ASDs as well.
综述目的：理解神经发育障碍（包括自闭症谱系障碍（ASD））的一个主要挑战是将基因发现的结果转化为神经生物学机制的阐述，这些机制是这些疾病的基础，并随后将这些知识转化为基于机制的治疗方法。一个有希望的方法是通过最近对 ASD 的罕见亚群的研究揭示的。在这篇综述中，我们总结了 Rett 综合征（一种罕见的单基因 ASD）的机制和新兴治疗方法的最新进展。
最新发现：Rett 综合征是由编码甲基化 CpG 结合蛋白 2（MeCP2）的基因突变引起的。尽管 MeCP2 具有多种功能，但对 MeCP2 突变小鼠的检查表明，MeCP2 缺乏会导致多个脑系统中的突触和回路异常成熟和维持的假说。一些缺陷是由于特定细胞内途径（如 PI3K/Akt 信号通路）的改变引起的。在 MeCP2 突变小鼠中，通过用治疗剂治疗，这些异常至少可以部分得到挽救。
总结：针对 Rett 综合征等单基因神经发育障碍的基于机制的治疗方法正在出现。鉴于 MeCP2 功能的复杂性，未来的方向包括针对多个分子和途径的联合治疗。这些方法可能也适用于其他 ASD。
