Genetic Studies in the Sleep Disorder Narcolepsy

Abstract

Narcolepsy is a chronic neurologic disorder characterized by excessive daytime sleepiness and abnormal manifestations of REM sleep including cataplexy, sleep paralysis, and hypnagogic hallucinations. Narcolepsy is both a significant medical problem and a unique disease model for the study of sleep. Research in human narcolepsy has led to the identification of specific HLA alleles (DQB1*0602 and DQA1*0102) that predispose to the disorder. This has suggested the possibility that narcolepsy may be an autoimmune disorder, a hypothesis that has not been confirmed to date. Genetic factors other than HLA are also likely to be involved. In a canine model of narcolepsy, the disorder is transmitted as a non-MHC single autosomal recessive trait with full penetrance (canarc-1). A tightly linked marker for canarc-1 has been identified, and positional cloning studies are under way to isolate canarc-1 from a newly developed canine genomic BAC library. The molecular cloning of this gene may lead to a better understanding of sleep mechanisms, as has been the case for circadian rhythms following the cloning of frq, per, and Clock.Sleep consumes almost one-third of any human lifetime, yet its biological function remains unknown. Electrophysiological studies have shown that sleep is physiologically heterogeneous. Sleep onset is first characterized by light nonrapid eye movement (NREM) sleep (stage I and II), followed by deep NREM sleep or slow-wave sleep (stage III and IV) and finally rapid eye movement (REM) sleep. This sleep cycle is ∼90 min long and is repeated multiple times during nocturnal sleep. REM sleep, also called paradoxical sleep, is characterized by low-voltage fast electroencephalogram activity, increased brain metabolism, skeletal muscle atonia, rapid eye movements, and dreaming. Total sleep deprivation and/ or REM sleep deprivation are both lethal in animals.NREM and REM sleep are mainly regulated by circadian and homeostatic processes. Recent studies have suggested that across the animal kingdom, circadian rhythms are regulated by similar negative feedback loops involving the rhythmic expression of RNAs encoding proteins that act to shut off the genes encoding them (Hall 1995;Dunlap 1996;Rosbash et al. 1996;Young et al. 1996). From a genetic perspective, much less progress has been made in the noncircadian aspects of sleep regulation. This review demonstrates that a genetic approach to narcolepsy will in time provide a novel insight into the molecular basis of sleep control. Narcolepsy, a Disorder of REM Sleep RegulationNarcolepsy most often begins in the second decade of life but may be observed at the age of 5 or younger (Honda 1988). The cardinal symptom in narcolepsy is a persistent and disabling excessive daytime sleepiness. Sleep attacks are unpredictable, irresistible, and may lead to continuing activities in a semiconscious manner, a phenomenon referred to as automatic behavior. Naps are usually refreshing, but the restorative effect vanishes quickly.Sleepiness is not sufficient to diagnose the disorder. N...

HLA-DQ Polymorphism Influences Progression of Demyelination and Neurologic Deficits in a Viral Model of Multiple Sclerosis

“…In some cases mount an immune response against self-antigens. Similar associations have been reported in diseases with neurologic involvement, including Behcet's disease (Alpsoy et al, 1998), narcolepsy (Kadotani et al, 1998;Aldrich, 1998), myasthenia gravis (Tola et al, 1994), Lyme neuroborreliosis (Halperin et al, 1991), and amyotrophic lateral sclerosis (Kott et al, 1979). Several hypotheses have been proposed to explain these associations.…”

Orexin/Hypocretin: A Neuropeptide at the Interface of Sleep, Energy Homeostasis, and Reward System

“…On the contrary, the number of melanin-concentrating hormone containing neurons, which are intermixed with orexin neuron in the normal brain, was similar in control and narcoleptic brains (Peyron et al, 2000;Thannickal et al, 2000). The cause of the specific loss or degradation of orexin neurons in narcolepsy has been unknown so far, but because of its strong association with certain human leukocyte antigen alleles (Kadotani et al, 1998), it is possible that narcolepsy may result from selective immune-mediated degeneration of orexin neurons, although no specific antibody against orexin neurons has been found in serum of the patients. Although the cause of the neuron loss remains to be clarified, the orexin signaling-deficiency in narcolepsy-cataplexy shows that this orexin system plays an important role in the regulation of sleep and wakefulness, especially in the maintenance of long, consolidated awake periods.…”

Orexin deficiency and narcolepsy

“…Because of its strong association with certain human leukocyte antigen (HLA) alleles (15), it has long been speculated that narcolepsy results from an autoimmunemediated mechanism. Recently, Tribbles homolog 2 (Trib2) was reported as a candidate antigen involved in the destruction of orexin neurons (16).…”