New insights into the pathogenesis and therapeutics of episodic ataxia type 1.
New insights into the pathogenesis and therapeutics of episodic ataxia type 1.
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DOI：
10.3389/fncel.2015.00317
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发表时间：
2015
影响因子：
5.3
通讯作者：
Franciolini F
中科院分区：
文献类型：
--
作者：
D'Adamo MC;Hasan S;Guglielmi L;Servettini I;Cenciarini M;Catacuzzeno L;Franciolini F
发作性共济失调1型（EA1）是一种以广谱症状为特征的K+通道病。一般来说，患者可能会经历持续的肌肉震颤和头部、手臂和腿部骨骼肌痉挛性收缩的剧烈发作，同时失去运动协调和平衡。在发作期间，可能报告其他症状，如眩晕、视力模糊、复视、恶心、头痛、出汗、笨拙、身体僵硬、构音障碍和呼吸困难。这些发作可能是由焦虑、情绪紧张、疲劳、惊吓反应或突然的姿势变化引起的。癫痫在EA1中的比例过高。该疾病以常染色体显性方式遗传，并且对几个家族的遗传分析导致在染色体12p13上的电压依赖性K+通道基因KCNA1（Kv1.1）中发现了许多点突变。迄今为止，KCNA1是唯一已知与EA1相关的基因。功能研究表明，这些突变损害Kv1.1通道功能，对通道组装、运输和生物物理学有不同的影响。尽管获得了关于EA1分子机制的确凿证据，但这些如何导致中枢和外周神经系统回路功能障碍仍然难以捉摸。本文综述了EA1的主要突破性发现，讨论了疾病的神经生理机制，目前的治疗方法，未来的挑战，并打开了一个窗口，Kv1.1通道在中枢神经系统（CNS）和外周神经系统（PNS）功能的作用。
Episodic ataxia type 1 (EA1) is a K+ channelopathy characterized by a broad spectrum of symptoms. Generally, patients may experience constant myokymia and dramatic episodes of spastic contractions of the skeletal muscles of the head, arms, and legs with loss of both motor coordination and balance. During attacks additional symptoms may be reported such as vertigo, blurred vision, diplopia, nausea, headache, diaphoresis, clumsiness, stiffening of the body, dysarthric speech, and difficulty in breathing. These episodes may be precipitated by anxiety, emotional stress, fatigue, startle response or sudden postural changes. Epilepsy is overrepresented in EA1. The disease is inherited in an autosomal dominant manner, and genetic analysis of several families has led to the discovery of a number of point mutations in the voltage-dependent K+ channel gene KCNA1 (Kv1.1), on chromosome 12p13. To date KCNA1 is the only gene known to be associated with EA1. Functional studies have shown that these mutations impair Kv1.1 channel function with variable effects on channel assembly, trafficking and biophysics. Despite the solid evidence obtained on the molecular mechanisms underlying EA1, how these cause dysfunctions within the central and peripheral nervous systems circuitries remains elusive. This review summarizes the main breakthrough findings in EA1, discusses the neurophysiological mechanisms underlying the disease, current therapies, future challenges and opens a window onto the role of Kv1.1 channels in central nervous system (CNS) and peripheral nervous system (PNS) functions.