Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland; Neuroscience Center Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland; Drug Discovery Network Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
Institute of Pharmacology and Toxicology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland; Neuroscience Center Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland; Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH), Vladimir-Prelog-Weg 10, 8023 Zurich, Switzerland.
Neuropharmacology. 2018 Jul 1;136(Pt A):46-55. doi: 10.1016/j.neuropharm.2017.07.030. Epub 2017 Jul 29.
Animal studies of several single-gene disorders demonstrate that reversing the molecular signaling deficits can result in substantial symptomatic improvements in function. Focusing on the ratio of excitation to inhibition as a potential pathophysiological hallmark, seven single-gene developmental CNS disorders are reviewed which are characterized by a striking dysregulation of neuronal inhibition. Deficits in inhibition and excessive inhibition are found. The examples of developmental disorders encompass Neurofibromatosis type 1, Fragile X syndrome, Rett syndrome, Dravet syndrome including autism-like behavior, NONO-mutation-induced intellectual disability, Succinic semialdehyde dehydrogenase deficiency and Congenital nystagmus due to FRMD7 mutations. The phenotype/genotype correlations observed in animal models point to potential treatment options and will continue to inspire clinical research. Three drugs are presently in clinical trials: acamprosate and ganoxolon for Fragile X syndrome and SGS-742 for SSADH deficiency. This article is part of the "Special Issue Dedicated to Norman G. Bowery".
对几种单基因疾病的动物研究表明，纠正分子信号缺陷可以显著改善功能的症状。本文以兴奋与抑制的比值为潜在的病理生理学标志，综述了七种以神经元抑制显著失调为特征的单基因发育性中枢神经系统疾病。发现抑制不足和过度抑制。发育障碍的例子包括神经纤维瘤病 1 型、脆性 X 综合征、雷特综合征、包括自闭症样行为的 Dravet 综合征、NONO 突变引起的智力障碍、琥珀酸半醛脱氢酶缺乏症和 FRMD7 突变引起的先天性眼球震颤。在动物模型中观察到的表型/基因型相关性为潜在的治疗选择指明了方向，并将继续激发临床研究。目前有三种药物正在进行临床试验：用于脆性 X 综合征的 acamprosate 和 ganoxolon 以及用于 SSADH 缺乏症的 SGS-742。本文是“献给 Norman G. Bowery 的特刊”的一部分。
