84 Rubin studied a large number of autoimmune markers, including rheumatoid factor, Sjogren’s syndrome B antigen, Smith antigen, antinuclear antibodies, anti-DNA and anti-histone antibodies, but found no differences between patients and controls. time just before the first onset of symptoms. Often pointed out events include major psychological stress, major familial events, sleep deprivation or other changes in sleep/wake schedules, and head trauma.16 However, these types of studies are hampered by several methodological issues, such as recall-bias. Studies on diseases associated with narcolepsy are also rare.17 There have been reports on an increased frequency of migraine. Furthermore, as HLA-DQB1*0602 is usually protective for type I diabetes and there is a high prevalence of obesity in narcoleptic patients, it Rabbit polyclonal to ANKMY2 is likely that there is an large discrepancy between the co-occurrence of type I versus type II diabetes with narcolepsy. However, this has not been studied. There have been several case reports of secundary narcolepsy NVP-LCQ195 in patients with auto-immune neurological disorders such as multiple sclerosis and acute disseminated encephalomyelitis.18C 21 These disorders caused focal lesions in the hypothalamic area, showing that autoimmune mechanisms can damage the hypocretin system. Large epidemiological studies on co-occurrence with other confirmed autoimmune disorders, including non-neurological ones, are lacking however. FAMILY AND TWIN STUDIES Depending on the exact definition of narcolepsy, in about 1C4 % of cases, narcolepsy occurs in families. Although some early reports might have mistaken other sleep disorders for narcolepsy, numerous familial cases have been reported. Genuine multiplex (i.e. more affected generations) families are very rare. If narcolepsy runs in families, it typically shows an autosomal dominant mode of inheritance.22C24 The majority of patients suffer from non-familial (sporadic) narcolepsy, but genetic factors are still important in those cases. Prevalence studies have shown that the risk for any first-degree relative of a patient with narcolepsy is usually 1 to 2 2 percent.25 This risk, although small, is still 30 to 40 times higher than the estimated prevalence in the general population, suggesting the existence of genetic factors that predispose to the development of narcolepsy. Although genetic factors play a role in sporadic narcolepsy, these are neither necessary, nor sufficient to cause narcolepsy. Twin studies showed that only 25 to 31% of monozygotic twins are concordant for the disease (for references observe 26), suggesting a major contribution of environmental factors. In familial cases and concordant twin pairs, there is a much less strong association with either HLA-DQB1_*0602 or hypocretin deficiency, indicating the presence of additional disease influencing genes. THE ROLE OF THE HYPOCRETIN SYSTEM Animal models A cloning effort was initiated in the early 1990s to identify the NVP-LCQ195 gene responsible for the autosomal recessive form of narcolepsy in the dog, designated was cloned, Yanagisawas group reported around the phenotype of preprohypocretin knockout mice. Using a combination of infrared video recordings during the active period and sleep recordings, they convincingly showed that these animals develop narcolepsy, including cataplexy-like behavior, sleep fragmentation and sleep-onset REM periods. 30 More recent rodent models for narcolepsy include transgenic mice in which the hypocretin promotor drives the expression ataxin-3, a truncated Machado-Joseph disease gene, causing a post-natal degeneration of the hypocretin neurons and consequently symptoms of narcolepsy.31 Hypocretin defects in human narcolepsy A large body of evidence shows that the hypocretin system is also critically involved in NVP-LCQ195 human narcolepsy. Shortly after the seminal papers around the pathophysiology of narcolepsy in dogs and mice, it was reported that this sporadic form NVP-LCQ195 of narcolepsy in humans is associated with absent levels of the hypocretin-1 peptide in the cerebrospinal fluid (CSF).32 Subsequent studies confirmed the association, and also showed that hypocretin defiency in the CSF is highly specific for HLA-DQB1*0602 positive narcolepsy with cataplexy.33,34 Besides case-reports,35,36 so far only a few disorders have been found in which undetectable CSF hypocretin levels can be present; two of them are autoimmune in nature: Guillain-Barr syndrome and anti-Ma2 associated limbic encephalitis.37 In healthy subjects CSF hypocretin-1 levels in the CSF are highly constant over a large age-range.38 In.