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KMID : 0894720000020010014
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Korean Journal of Sleep Medicine
2000 Volume.2 No. 1 p.14 ~ p.22
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Genetic Predisposition and Neurochemical Mechanisms of Narcolepsy
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Hong Seung-Chul
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Abstract
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Narcolepsy is both a common neurological disorder and a model disorder to further our understanding of REM sleep and sleepiness regulation. Research in the area is greatly facilitated by the existence of a unique animal model, canine narcolepsy. The mode of action of stimulant medication was shown to be mediated by presynaptic stimulation of dopaminergic transmission while anticataplectic compounds were suggested to exert their therapeutic effects via adrenergic uptake inhibition. Abnormally sensitive cholinergic transmission and depressed dopaminergic transmission are believed to underly abnormal REM sleep and daytime sleepiness in canine narcolepsy. The abnormalities are however unlikely to be the primary cause of narcolepsy. Genetic studies in narcolepsy have already led to the identification of a predisposing genetic factor in narcolepsy, the HLA allele DQB1*0602, a result that suggests an involvement of the immune system in the pathophysiology of narcolepsy. HLA-DQB1*0602 has however a low penetrance since a large portion of the normal population carries an identical HLA allele but does not have narcolepsy. Twin studies and the examination of multiplex narcoleptic families suggest the existence of non-HLA factors in narcolepsy predisposition, both of environmental and genetic origin. In the canine model, the study of the positional cloning lead to identify the mutated gene which encode the receptor 2 (Hcrtr2) for hypocretin. Hypocretin is suggested as a major neuromodulator of sleep in interaction with aminergic and cholinergic systems. We need to study the effects of hypocretins on sleep behaviour and development of therapeutic avenues in narcolepsy and other sleep disorders, using novel
neuropeptides like the hypocretin and their analogues appears to be the direction of furture research.
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KEYWORD
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