Wurtman Richard J
Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Metabolism. 2006 Oct;55(10 Suppl 2):S36-9. doi: 10.1016/j.metabol.2006.07.011.
Narcolepsy is a chronic neurologic disease characterized by excessive daytime sleepiness and one or more of three additional symptoms (cataplexy, or sudden loss of muscle tone; vivid hallucinations; and brief periods of total paralysis) related to the occurrence of rapid eye movement (REM) sleep at inappropriate times. The daytime sleepiness typically presents as a sudden overwhelming urge to sleep, followed by periods of sleep that last for seconds or minutes, or even longer. During daytime sleep episodes, patients may exhibit "automatic behavior," performing conventionalized functions (eg, taking notes), but not remembering having done so once they are awake. About 10% of narcoleptics are members of familial clusters; however, genetic factors alone are apparently insufficient to cause the disease, inasmuch as the most common genetic disorder, a mutation in chromosome 6 controlling the HLA antigen immune complex, although seen in 90% to 100% of patients, also occurs in as many as 50% of people without narcolepsy. A dog model of narcolepsy exhibits a mutation on chromosome 12 that disrupts the processing of the peptide neurotransmitter hypocretin. No such mutation characterizes human narcolepsy; however, cerebrospinal fluid (CSF) hypocretin levels are profoundly depressed in narcoleptic patients, and a specific reduction in hypocretin-containing neurons has been described. One hypothesis concerning the pathophysiology of narcolepsy proposes that the HLA subtype resulting from the mutation on chromosome 6 increases the susceptibility of hypocretin-containing brain neurons to immune attack. Because hypocretin may normally participate in the maintenance of wakefulness, the loss of neurons that release this peptide might allow REM sleep to occur at inappropriate times, ie, while the patient is awake, in contrast to its normal cyclic appearance after a period of slow-wave sleep. The cataplexy, hallucinations, and/or paralysis associated with REM episodes normally are unnoticed-or, at least, not remembered-when the transition to REM follows slow wave sleep, as is normally the case; however, they are remembered when, in people with narcolepsy, the REM episode starts during a period of wakefulness. The association of narcolepsy with a deficiency in a specific neurotransmitter, in this case, hypocretin, is reminiscent of the associations between Parkinson disease and dopamine, or early Alzheimer disease and acetylcholine.
发作性睡病是一种慢性神经疾病，其特征为日间过度嗜睡，以及出现与快速眼动（REM）睡眠在不适当时间发生相关的三种附加症状中的一种或多种（猝倒，即突然肌肉张力丧失；生动的幻觉；以及短暂的全身麻痹）。日间嗜睡通常表现为突然袭来的强烈睡眠冲动，随后是持续数秒、数分钟甚至更长时间的睡眠期。在日间睡眠发作期间，患者可能会表现出“自动行为”，执行常规功能（如做笔记），但醒来后却不记得做过这些事。约10%的发作性睡病患者属于家族聚集性病例；然而，仅遗传因素显然不足以引发该病，因为最常见的遗传疾病，即控制HLA抗原免疫复合物的6号染色体突变，虽然在90%至100%的患者中出现，但在多达50%没有发作性睡病的人中也会出现。发作性睡病的犬类模型在12号染色体上表现出突变，该突变会破坏肽类神经递质下丘脑分泌素的加工过程。人类发作性睡病并无此类突变；然而，发作性睡病患者的脑脊液（CSF）下丘脑分泌素水平显著降低，且已发现含下丘脑分泌素的神经元有特异性减少。关于发作性睡病病理生理学的一种假说提出，6号染色体突变产生的HLA亚型会增加含下丘脑分泌素的脑神经元对免疫攻击的易感性。由于下丘脑分泌素通常可能参与维持清醒状态，释放这种肽的神经元的丧失可能会使REM睡眠在不适当的时间发生，即当患者清醒时，这与正常情况下在一段慢波睡眠后出现的周期性情况相反。与REM发作相关的猝倒、幻觉和/或麻痹在正常情况下，即当从慢波睡眠过渡到REM睡眠时通常不会被注意到——或者至少不会被记住；然而，当发作性睡病患者在清醒期开始REM发作时，这些症状会被记住。发作性睡病与特定神经递质（在这种情况下是下丘脑分泌素）缺乏的关联，让人联想到帕金森病与多巴胺，或早期阿尔茨海默病与乙酰胆碱之间的关联。
