14 Chapter 1 Pathophysiology The discovery of hypocretin (or orexin) in 1998 led to a revolution in sleepwake research and narcolepsy in particular [36, 37]. Hypocretin and orexin were concurrently identified by two independent research groups and later found to be the same peptide. Two types of hypocretin were identified both stemming from the precursor prepro-hypocretin which is exclusively produced in the lateral and posterior hypothalamus [38]. The hypocretins proved vital for adequate sleep-wake control [39], feeding behaviour [37, 40] and reward processing [41, 42]. One year after the discovery of hypocretin, an inheritable mutation encoding the hypocretin-2 receptor was found to cause canine narcolepsy [43]. Two independent research groups identified a slightly different role for hypocretin in human narcolepsy, as they found selective loss of hypocretin-1 neurons in the lateral and posterior hypothalamus [44, 45]. Rodent models have consistently shown that loss of the wake-promoting and stabilizing role of hypocretin-1 leads to a typical narcolepsy type 1 phenotype [39]. Hypocretin-1 can be reliably measured from the cerebrospinal fluid (CSF) and currently serves as the only reliable objective diagnostic biomarker in diagnosing any of the central disorders of hypersomnolence [46]. The role of hypocretin has extensively been investigated in central disorders of hypersomnolence, yet many studies did not specify whether hypocretin-1 and/ or hypocretin-2 were studied. Since most studies likely focused on hypocretin-1, we will henceforth use “hypocretin” to generally denote hypocretin-1, unless stated otherwise. Narcolepsy type 2 and idiopathic hypersomnia have to date been understudied compared to narcolepsy type 1, and due to the multidimensional nature of these disorders, their pathophysiology remains poorly understood. In these two conditions, it has been suggested that endogenous gammaaminobutyric acid (GABA) might promote daytime sleepiness by enhancing GABA-A receptor signalling but this hypothesis was mainly based on a pilot study of a small and heterogeneous sample [47]. Longitudinal studies have uncovered that a proportion of (typically young) individuals with narcolepsy type 2 develop cataplexy within years after onset of excessive daytime sleepiness [48, 49]. Whether these individuals already were hypocretin deficient when the sleepiness symptoms arose and were hereby misclassified, or whether hypocretin deficiency develops closer to cataplexy onset, remains unknown. Reports of delayed development of cataplexy years after confirmed hypocretin deficiency at least suggests frequent misclassification in narcolepsy type 2 [50]. Lack of understanding of underlying pathophysiologies of narcolepsy type 2
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