Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, Zayed Centre for Research into Rare Disease in Children, London, United Kingdom.
Department of Neurology, Great Ormond Street Hospital, London, United Kingdom.
Mov Disord. 2021 May;36(5):1104-1114. doi: 10.1002/mds.28495. Epub 2021 May 2.
Adenylyl cyclase 5 (ADCY5)-related phenotypes comprise an expanding disease continuum, but much remains to be understood about the underlying pathogenic mechanisms of the disease. ADCY5-related disease comprises a spectrum of hyperkinetic disorders involving chorea, myoclonus, and/or dystonia, often with paroxysmal exacerbations. Hypotonia, developmental delay, and intellectual disability may be present. The causative gene encodes adenylyl cyclase, the enzyme responsible for the conversion of adenosine triphosphate (ATP) to cyclic adenosine-3',5'-monophosphate (cAMP). cAMP is a second messenger that exerts a wide variety of effects via several intracellular signaling pathways. ADCY5 is the most commonly expressed isoform of adenylyl cyclase in medium spiny neurons (MSNs) of the striatum, and it integrates and controls dopaminergic signaling. Through cAMP pathway, ADCY5 is a key regulator of the cortical and thalamic signaling that control initiation of voluntary movements and prevention of involuntary movements. Gain-of-function mutations in ADCY5 have been recently linked to a rare genetic disorder called ADCY5-related dyskinesia, where dysregulation of the cAMP pathway leads to reduced inhibitory activity and involuntary hyperkinetic movements. Here, we present an update on the neurobiology of ADCY5, together with a detailed overview of the reported clinical phenotypes and genotypes. Although a range of therapeutic approaches has been trialed, there are currently no disease-modifying treatments. Improved in vitro and in vivo laboratory models will no doubt increase our understanding of the pathogenesis of this rare genetic movement disorder, which will improve diagnosis, and also facilitate the development of precision medicine approaches for this, and other forms of hyperkinesia. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
腺苷酸环化酶 5（ADCY5）相关表型构成了一个不断扩大的疾病连续体，但对于该疾病的潜在发病机制仍有许多需要了解的地方。ADCY5 相关疾病包括一系列涉及舞蹈症、肌阵挛和/或肌张力障碍的多动障碍，常伴有阵发性恶化。可能存在张力减退、发育迟缓以及智力障碍。致病基因编码腺苷酸环化酶，该酶负责将三磷酸腺苷（ATP）转化为环腺苷酸-3'，5'-单磷酸（cAMP）。cAMP 是一种第二信使，通过几种细胞内信号通路发挥广泛的作用。ADCY5 是纹状体中型多棘神经元（MSNs）中表达最广泛的腺苷酸环化酶同工型，它整合并控制多巴胺能信号。通过 cAMP 途径，ADCY5 是控制起始自主运动和预防不自主运动的皮质和丘脑信号的关键调节剂。ADCY5 的功能获得性突变最近与一种称为 ADCY5 相关运动障碍的罕见遗传疾病有关，其中 cAMP 途径的失调导致抑制活性降低和不自主多动。在这里，我们介绍了 ADCY5 的神经生物学更新，以及报告的临床表型和基因型的详细概述。尽管已经尝试了一系列治疗方法，但目前尚无疾病修饰治疗方法。改进的体外和体内实验室模型无疑将增加我们对这种罕见遗传性运动障碍的发病机制的理解，这将改善诊断，也有利于为这种疾病和其他形式的多动症开发精准医学方法。© 2021 作者。运动障碍由 Wiley 期刊代表国际帕金森病和运动障碍协会出版。
