Phelan McDermid Syndrome: From Genetic Discoveries to Animal Models and Treatment.
Phelan McDermid Syndrome: From Genetic Discoveries to Animal Models and Treatment.
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DOI：
10.1177/0883073815600872
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发表时间：
2015-12
影响因子：
1.9
通讯作者：
Buxbaum JD
中科院分区：
文献类型：
--
作者：
Harony-Nicolas H;De Rubeis S;Kolevzon A;Buxbaum JD
Phelan McDermid综合征（PMS）或22q13.3缺失综合征是一种罕见的神经发育障碍，其特征是广泛性发育迟缓，智力残疾，语言缺失或延迟，癫痫发作，自闭症谱系障碍，新生儿低肌紧张性，身体畸形特征和复发性医学合并症。在大多数情况下，患有PMS的个体在包含SHANK3的染色体22q13.3区域有末端缺失，SHANK3基因编码兴奋性突触的结构成分，对于正常的突触发生和神经元生理是必不可少的。在这里，我们回顾了该综合征的临床方面和遗传发现，揭示了潜在的病因。我们还概述了遗传学研究和小鼠模型的证据，这些证据支持SHANK3单倍缺陷是经前症候群神经行为表现的主要因素。最后，我们讨论了所有这些发现是如何揭示经前症候群的病理生理学，并被转化为临床试验的新疗法，以改善该疾病的核心症状。
Phelan McDermid syndrome (PMS) or 22q13.3 deletion syndrome is a rare neurodevelopmental disorder characterized by generalized developmental delay, intellectual disability, absent or delayed speech, seizures, autism spectrum disorder, neonatal hypotonia, physical dysmorphic features, and recurrent medical comorbidities. In most cases, individuals with PMS have terminal deletions of the chromosomal region 22q13.3 encompassing SHANK3, a gene encoding a structural component of excitatory synapses indispensable for proper synaptogenesis and neuronal physiology. Here, we review the clinical aspects of the syndrome and the genetic findings shedding light onto the underlying etiology. We also provide an overview on the evidence from genetic studies and mouse models that supports SHANK3 haploinsufficiency as a major contributor of the neurobehavioral manifestations of PMS. Finally, we discuss how all these discoveries are uncovering the pathophysiology of PMS and are being translated into clinical trials for novel therapeutics ameliorating the core symptoms of the disorder.