Hypocretin Deficiency And Narcoleptic Phenotype

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Human studies have demonstrated that the occurrence of cataplexy is tightly associated with hypocretin deficiency.29 Furthermore, the hypocretin deficiency was already observed at very early stages of the disease (just after the onset of EDS), even before occurrences of clear cataplexy.86 Occurrences of cataplexy are rare in acute symptomatic cases of EDS associated with a significant hypocretin deficiency.87 Thus, it appears that chronic and selective deficit of hypocretin neurotransmission may be required for the occurrence of cataplexy. A possibility of an involvement of a secondary neurochemical change for the occurrence of cataplexy cannot be ruled out. If some of these changes are irreversible, hypocretin supplement therapy may only have limited effects on cataplexy.

Sleepiness in narcolepsy is most likely due to the difficulty in maintaining wakefulness as normal subjects do. The sleep pattern of narcoleptic subjects is also fragmented and they exhibit insomnia (frequent wakening) at night. This fragmentation occurs across 24 hours, and thus, the loss of hypocretin signaling are likely to play a role of this vigilance stage stability (see ref. 88), but other mechanism may also involved in EDS in narcoleptic subjects. One of the most important characteristics of EDS in narcolepsy is that sleepiness is reduced, and patients feel refreshed after a short nap, but this does not last long as they become sleepy within a short period of time. We have observed that hypocretin levels in the extracellular space and in the CSF of rats significantly fluctuate across 24 hours, and build-up toward the end of the active periods.89 Several manipulations (such as sleep deprivation, exercise and long-term food deprivation) are also known to increase hypocretin tonus.89-92 Thus, the lack of this hypocretin build-up caused by circadian time and various alerting stimulations may also play a role for EDS associated with hypocretin-deficient narcolepsy.92

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