Unit for Research and Discovery in Neuroscience, IDR Servier, 125 chemin de ronde, 78290 Croissy sur Seine, Paris, France.
Neuropharmacology. 2013 May;68:2-82. doi: 10.1016/j.neuropharm.2012.11.015. Epub 2012 Dec 11.
Neurodevelopmental disorders (NDDs) are characterized by aberrant and delayed early-life development of the brain, leading to deficits in language, cognition, motor behaviour and other functional domains, often accompanied by somatic symptoms. Environmental factors like perinatal infection, malnutrition and trauma can increase the risk of the heterogeneous, multifactorial and polygenic disorders, autism and schizophrenia. Conversely, discrete genetic anomalies are involved in Down, Rett and Fragile X syndromes, tuberous sclerosis and neurofibromatosis, the less familiar Phelan-McDermid, Sotos, Kleefstra, Coffin-Lowry and "ATRX" syndromes, and the disorders of imprinting, Angelman and Prader-Willi syndromes. NDDs have been termed "synaptopathies" in reference to structural and functional disturbance of synaptic plasticity, several involve abnormal Ras-Kinase signalling ("rasopathies"), and many are characterized by disrupted cerebral connectivity and an imbalance between excitatory and inhibitory transmission. However, at a different level of integration, NDDs are accompanied by aberrant "epigenetic" regulation of processes critical for normal and orderly development of the brain. Epigenetics refers to potentially-heritable (by mitosis and/or meiosis) mechanisms controlling gene expression without changes in DNA sequence. In certain NDDs, prototypical epigenetic processes of DNA methylation and covalent histone marking are impacted. Conversely, others involve anomalies in chromatin-modelling, mRNA splicing/editing, mRNA translation, ribosome biogenesis and/or the regulatory actions of small nucleolar RNAs and micro-RNAs. Since epigenetic mechanisms are modifiable, this raises the hope of novel therapy, though questions remain concerning efficacy and safety. The above issues are critically surveyed in this review, which advocates a broad-based epigenetic framework for understanding and ultimately treating a diverse assemblage of NDDs ("epigenopathies") lying at the interface of genetic, developmental and environmental processes. This article is part of the Special Issue entitled 'Neurodevelopmental Disorders'.
神经发育障碍（NDDs）的特征是大脑在生命早期出现异常和延迟发育，导致语言、认知、运动行为和其他功能领域的缺陷，通常伴有躯体症状。围产期感染、营养不良和创伤等环境因素会增加自闭症和精神分裂症等异质性、多因素和多基因疾病的风险。相反，离散的遗传异常涉及唐氏综合征、雷特综合征和脆性 X 综合征、结节性硬化症和神经纤维瘤病、不太熟悉的普氏综合征、索托斯综合征、克莱夫斯特拉综合征、科芬-洛里综合征和“ATRX”综合征，以及印记障碍、安格曼综合征和普拉德-威利综合征。NDDs 被称为“突触病”，是指突触可塑性的结构和功能障碍，其中一些涉及异常的 Ras-激酶信号（“rasopathies”），许多表现为大脑连接中断和兴奋与抑制传递失衡。然而，在不同的整合水平上，NDDs 伴随着异常的“表观遗传”调节，这些调节对于大脑的正常有序发育至关重要。表观遗传学是指在不改变 DNA 序列的情况下，控制基因表达的潜在可遗传（有丝分裂和/或减数分裂）机制。在某些 NDDs 中，DNA 甲基化和组蛋白共价标记的典型表观遗传过程受到影响。相反，其他 NDDs 涉及染色质建模、mRNA 剪接/编辑、mRNA 翻译、核糖体生物发生和/或小核仁 RNA 和 micro-RNA 的调节作用的异常。由于表观遗传机制是可修饰的，这就带来了新疗法的希望，尽管疗效和安全性仍存在疑问。本文批判性地综述了这些问题，提倡一个广泛的表观遗传框架来理解和最终治疗一系列位于遗传、发育和环境过程接口的神经发育障碍（“表观遗传障碍”）。本文是题为“神经发育障碍”的特刊的一部分。
