Genetics, narcolepsy

Chemelli, R. M., Willie, J. T., Sinton, C. M. et al. (1999). Narcolepsy in orexin knockout mice molecular genetics of sleep regulation. Cell 98, 437-51. 

The phenotypic characterization of genetically modified rodents has advanced the understanding of both the basis of narcolepsy-cataplexy and the functions of the orexin system in the normal animal. Here we review the... 

Table 15.2 Genetic modifications of orexin in rodents and studies of narcolepsy-cataplexy. ... 

Although human narcolepsy is not typically associated with orexin gene mutations, the orexin / model is most similar to the case of a narcoleptic-cataplectic child, severely symptomatic from infancy, who has a genetic defect in orexin production and release (Peyron et al., 2000). Thus, constitutive orexin deficiency alone in the presence of otherwise histologically normal orexin neurons... 

Hara, J., Beuckmann, C. T., Nambu, T. et al. (2001). Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30, 345-54. 

Honda, Y., Takahashi, Y., Honda, M. et al. (1997). Genetic aspects of narcolepsy. In Sleep and Sleep Disorders from Molecules to Behavior, ed. O. Hayaishi S. Inoue,... 

Mignot, E. (1998). Genetic and familial aspects of narcolepsy. Neurology 50, S16 S22. 

The main risk factor appears to be a genetic susceptibility to the illness. The majority of narcolepsy patients, particularly those with cataplexy, have a genetic marker known as HLA-DQB1 0602. Recent evidence indicates that the key dysfunction in narcolepsy is diminished activity of a newly discovered neurotransmitter known as hypocretin. This new evidence has led to the development of a new diagnostic test for narcolepsy and may ultimately lead to new treatments that act directly on hypocretin systems in the brain. 

To help the reader understand the reasons for this emphasis on the brain, we now turn our attention to two specific disorders of sleep and dreaming that illustrate, respectively, a genetically determined predisposition to experience dreamlike consciousness in waking (narcolepsy) and an acquired tendency to express dream behavior in sleep (REM sleep behavior disorder). The existence of these clear abnormalities emphasizes what we have learned earlier in the chapter about the normal difficulty we have in containing dreaming to consciousness within sleep. 

Nishino S, Okura M, Mignot E (2000) Narcolepsy genetic predisposition and neu-ropharmacological mechanisms. Sleep Med Rev 4 57-99... 

Mignot E, Lin L, Rogers W, HondaY, Qiu X, Okun M, Hohjoh H, Miki T, Hsu S, Leffell M et al (2001) Complex HLA-DR and DQ interaction confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet 68 686-699... 

Chabas D, Taheri S, Renier C, Mignot E (2003) The genetics of narcolepsy. Annu Rev Genom Hum Genet 4 459-483... 

Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY, Marcus JN, Lee C, ElmquistJK, Kohmeier KA et al. (2003) Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice molecular genetic dissection of non-REM and REM sleep regulatory processes. Neuron 38 715-730... 

Narcolepsy genetic characteristics. Rare, disabling sleep disorder of unknown origin. Characterized by sudden attacks of flaccid paralysis (cataplexy), extensive daytime sleepiness, sleep paralysis, hypnagogic hallucinations and rapid onset of rapid eye movement (REM) phase of sleep. 

The whole field of research can reasonably be described as being revolutionized over a few years at the turn of the century through the discovery of two neuropeptide transmitters produced by cells of the hypothalamus. These hypocretins (Hcrt-1 and Hcrt-2), which are also known as orexins, are clearly the key to understanding narcolepsy, and a good deal of the normal sleep mechanism. The familial canine narcolepsy cases are associated with genetic mutations of this system, mice with targeted deletions of the gene for the precursor of these peptides display symptoms of narcolepsy, and the majority of humans with narcolepsy and the associated HLA characteristics have no detectable hypocretins in their cerebrospinal fluid. 

In some dog families narcolepsy is caused by a gene mutation. In humans there may be a genetic susceptibility in some people, but an autoimmune causation - presumably with an environmental trigger involved - is the most likely explanation for most human cases. If... 

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