Hypocretin/orexin and narcolepsy: new basic and clinical insights.
Hypocretin/orexin and narcolepsy: new basic and clinical insights.
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DOI：
10.1111/j.1748-1716.2009.02012.x
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发表时间：
2010-03
期刊：
影响因子：
--
通讯作者：
Kanbayashi T
中科院分区：
文献类型：
--
作者：
Nishino S;Okuro M;Kotorii N;Anegawa E;Ishimaru Y;Matsumura M;Kanbayashi T
发作性睡病是一种慢性睡眠障碍，其特征是白天过度嗜睡（EDS）、昏厥、临睡幻觉和睡眠麻痹。发作性睡病的散发（95%）和家族（5%）形式存在于人类中。人类发作性睡病的主要病理生理学最近已经基于动物中发作性睡病基因的发现而被发现;所述基因参与下丘脑泌素/食欲素配体及其受体的病理学。下丘脑泌素相关基因的突变在人类中是罕见的，但下丘脑泌素配体缺乏症在绝大多数发作性睡病中被发现。人发作性睡病中下丘脑泌素配体缺乏可能是由于下丘脑泌素神经元的出生后细胞死亡。虽然人类白细胞抗原（HLA）的关联和人类嗜睡症与cataerosis之间的紧密联系表明，自身免疫机制的参与，这尚未得到证实。下丘脑泌素缺乏症也见于发作性睡病和EDS的症状性病例中，所述发作性睡病和EDS具有各种神经病症，包括免疫介导的神经病症，如格林-巴利综合征、MA 2阳性副肿瘤综合征和视神经肌萎缩症（NMO）相关病症。这些发现可能具有重要的临床意义，并了解下丘脑泌素细胞死亡的机制和治疗方案的选择。这些在人类中的一系列发现导致了发作性睡病的新诊断测试的建立（即，对于具有癫痫发作的发作性睡病和由于医学状况引起的发作性睡病，脑脊液[CSF]下丘脑泌素-1水平较低）。由于大多数人类发作性睡病患者是配体缺乏的，下丘脑泌素替代疗法可能是一种有前途的新的治疗选择，并且使用基因疗法和细胞移植的动物实验正在进行中。
Narcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, and sleep paralysis. Both sporadic (95%) and familial (5%) forms of narcolepsy exist in humans. The major pathophysiology of human narcolepsy has been recently discovered based on the discovery of narcolepsy genes in animals; the genes involved in the pathology of the hypocretin/orexin ligand and its receptor. Mutations in hypocretin-related genes are rare in humans, but hypocretin-ligand deficiency is found in a large majority of narcolepsy with cataplexy. Hypocretin ligand deficiency in human narcolepsy is likely due to the postnatal cell death of hypocretin neurons. Although tight association between human leukocyte antigen (HLA) association and human narcolepsy with cataplexy suggests an involvement of autoimmune mechanisms, this has not yet been proven. Hypocretin deficiency is also found in symptomatic cases of narcolepsy and EDS with various neurological conditions, including immune-mediated neurological disorders, such as Guillain-Barre syndrome, MA2-positive paraneoplastic syndrome and neuromyelitis optica (NMO) related disorder. These findings likely have significant clinical relevance and for understanding the mechanisms of hypocretin cell death and choice of treatment option. These series of discoveries in humans lead to the establishment of the new diagnostic test of narcolepsy (i.e. low cerebrospinal fluid [CSF] hypocretin-1 levels for narcolepsy with cataplexy and narcolepsy due to medical condition). Since a large majority of human narcolepsy patients are ligand deficient, hypocretin replacement therapy may be a promising new therapeutic option, and animal experiments using gene therapy and cell transplantations are in progress.
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