Mechanisms and therapeutic challenges in autism spectrum disorders: Insights from Rett syndrome

Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
Current opinion in neurology (Impact Factor: 5.31). 04/2013; 26(2):154-9. DOI: 10.1097/WCO.0b013e32835f19a7
Source: PubMed


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.

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    • "Besides also operating as a splicing modulator of RNA, MECP2 acts as a transcriptional activator by binding to the cAMP response element-binding (CREB) protein (Young et al. 2005; Chahrour et al. 2008) and playing a role in regulating the expression of microRNAs that are important for brain development and brain plasticity (Wu et al. 2010; Urdinguio et al. 2010). Studies have shown that through its different means of regulation, MECP2 is capable of indirectly controlling a range of molecules responsible for local protein synthesis and synaptic plasticity, which would be involved in RTT (Castro et al. 2013). "
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    ABSTRACT: Autism spectrum disorder (ASD) is multifactorial and complex condition, with a marked genetic influence, as evidenced by the high heritability (around 80—90%). Additionally, both common and rare genetic variants have an influence on the etiology and development. Several genetic syndromes are described in ASD, and they are present in approximately 10% of cases. Different genetic approaches are described in studies with ASD samples. Linkage studies mainly identify regions in chromosomes 2 and 7 which are involved in ASD. Genetic association studies, which aim to identify genes or genomic regions influencing ASD, involve the analysis of candidate genes or genome scan. The genes analyzed in these studies encode components related to neurotransmitter metabolism, neural migration, neuronal cell adhesion, apoptosis, and cell proliferation. Other methodologies have been used to complement genetic investigations, for example, exome and copy number variation (CNV) studies. Epigenetic studies indicate an important environmental influence on these disorders. The genetic evaluation of all patients with ASD is now required due to recent advances in knowledge regarding the genetic factors involved in the etiology of autism. Definitions of key terms and concepts used throughout this chapter are presented in Fig.3.1.
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    • "animal models. Strategies to alleviate abnormal phenotypes include genetic manipulation, cellular therapy, pharmacological intervention and environmental stimulation (Wang and Doering, 2012; Zoghbi and Bear, 2012; Castro et al., 2013; Chapleau et al., 2013a; Delorme et al., 2013; Ebert and Greenberg, 2013). Most encouraging, some of these fundamental studies have led to the development of drugs that are in clinical trials. "
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