![]() NT1 is characterized by a low orexin A level (<110 pg/ml) and cataplexy. In humans, the orexin A level is severely reduced or undetectable in the cerebrospinal fluid (CSF) of approximately 90% of patients with NT1 15. In addition, prepro-orexin knockout mice exhibit narcolepsy-like behaviors and electroencephalographic activity 12. A disruption in the canine orexin receptor-2 gene causes autosomal recessive canine narcolepsy 11. Orexin A and orexin B (also known as hypocretin 1 and hypocretin 2, respectively) are neuropeptides that regulate arousal, wakefulness, and appetite and are produced exclusively by neurons in the lateral hypothalamic area 13, 14. In 1999, two independent groups revealed the pathogenesis of narcolepsy in animals 11, 12. In this review, we focus on genetic research that has elucidated the pathogenesis of narcolepsy (NT1 and NT2). In addition, genetic analyses of NT2 have progressed gradually. Recently, high-throughput technologies have been developed to efficiently obtain genotype data in a genome-wide manner and have identified susceptibility loci for NT1. Fewer studies have been conducted on the epidemiology of NT2 than on NT1. An epidemiological study found that the prevalence of NT2 was 36% of that of NT1, corresponding to a point prevalence of 0.02% 10. NT2 has the same symptoms as NT1 except for cataplexy. Therefore, NT1 is a complex disease with both genetic and environmental risk factors. ![]() The relative risk for first-degree family members of patients with NT1 is approximately 10- to 40-fold higher than that in the general population 6, 9. Approximately 1–2% of first-degree relatives of a person with NT1 are affected by the disease. The concordance rate in monozygotic twins for NT1 is approximately 20–30% 6, 8. The lowest prevalence rate appears to be in Israel (0.0002%) 7. The onset of NT1 usually begins between the ages of 10 and 20 years and affects 0.16–0.18% of the general population in Japan 4, 5 and 0.02–0.06% of the populations in the United States and Europe 6. NT1 is a typical type of hypersomnia that is characterized by excessive daytime sleepiness (intolerable sleepiness in the daytime), cataplexy (sudden loss of muscle tone in response to strong emotion), and pathological manifestation of REM sleep, which includes hypnagogic hallucinations (dream-like experiences occurring at sleep onset), sleep paralysis (feeling of the inability to move while falling asleep), or sleep onset REM sleep (appearance of REM sleep within approximately 5–10 min after sleep onset). Currently, two forms of narcolepsy are recognized: narcolepsy type 1 (NT1) (previously termed narcolepsy with cataplexy) and narcolepsy type 2 (NT2) (previously termed narcolepsy without cataplexy) 3. ![]() Although its symptoms can be managed with appropriate treatment, lifelong treatment is required for most patients. A malfunction of the mechanisms that regulate REM sleep can explain some of the symptoms of narcolepsy. Although healthy individuals typically enter their first REM sleep approximately 90 min after falling asleep, patients with narcolepsy frequently go directly into REM sleep at sleep onset 2. After rapid eye movement (REM) sleep was discovered in 1953 1, several investigators studied sleep onset in patients with narcolepsy. Narcolepsy was first described by Westphal in 1877 and named by Gélineáu in 1880. We expect that future genomic research will provide important contributions to our understanding of the genetic basis and pathogenesis of narcolepsy. The currently identified loci cannot explain the heritability of narcolepsy (NT1 and NT2). However, several studies have revealed loci that increase susceptibility to NT2. NT2 is also a complex disorder, but its underlying genetic architecture is poorly understood. Rare variants associated with NT1 have also been identified by DNA genome sequencing. Genome-wide association studies have uncovered >10 genomic variations associated with NT1. Almost all patients with NT1 carry the specific human leukocyte antigen (HLA) allele HLA-DQB1 * 06:02. NT1 is a multifactorial disease, and genetic variations at multiple loci are associated with NT1. Except for cataplexy, NT2 exhibits most of the same symptoms as NT1. NT1 is characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis and is caused by a marked reduction in neurons in the hypothalamus that produce orexin (hypocretin), which is a wakefulness-associated neuropeptide. Currently, narcolepsy is subdivided into two types according to the International Classification of Sleep Disorders, 3rd edition: narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). Narcolepsy is a term that was initially coined by Gélineáu in 1880 and is a chronic neurological sleep disorder that manifests as a difficulty in maintaining wakefulness and sleep for long periods.
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