![]() ![]() However, it is not known if impairments of the hypocretin neurotransmission instantly lead to occurrences of cataplexy or if any secondary changes are required to develop cataplexy. Thus, cataplexy may now appear to be a hypocretin-deficient pathological phenomenon. In these conditions, the degree of hypocretin deficiency is modest compared to most idiopathic cases (undetectably low), but projection and projection sites of the hypocretin system may also be damaged in these secondary cases. Moderate hypocretin deficiency is also reported in cataplexy associated with some secondary narcolepsy cases with brain tumors or vascular diseases. Archives of Neurology 59: 1553–1562.Ī significant degree of hypocretin deficiency already occurs around the disease onset and, in some case, before the onset of cataplexy. (2002) The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Adapted from Mignot E, Lammers GJ, Ripley B, et al. CSF, cerebrospinal fluid HLA, human leukocyte antigen. The number of patients with hypocretin values below or equal to 110 pg ml −1, above 200 pg ml −1, and between these two values is indicated for each category. Concentrations above 200 pg ml −1 best determined healthy control values. Hypocretin-1 values below 110 pg ml −1 were determined to be diagnostic for narcolepsy. Cerebrospinal fluid hypocretin-1 levels across various disease categories. (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Adapted from Peyron C, Faraco J, Rogers W, et al. C1/2, controls f, fornix N1/2, narcopleptic patients. In (b) preprohypocretin transcripts are detected in the hypothalamus of control (left) but not narcoleptic (right) subjects. two controls) was more pronounced in the pons where high concentrations are observed in the control subjects. The difference in hypocretin concentrations (two narcoleptic subjects vs. In (a), cortical hypocretin-1 and hypocretin-2 (data not shown) concentrations were detectable in all controls (- indicates mean) and undetectable (- indicates the detection limit, 332 pg/g brain) in five of the six narcoleptic subjects. Absence of hypocretin signals and peptide in the hypothalamus of narcoleptic patients: (a) brain hypocretin levels in narcoleptic and control subjects (b) hypocretin mRNA signal in the lateral hypothalamic area of control and narcoleptic subjects. Hypocretin replacements are expected to be a new treatment for hypocretin-deficient narcolepsy, but this is not available due to low penetration (of the brain) of hypocretin peptides the development of synthetic agonists are likely to be needed.įigure 3. ![]() A positive reading for HLA is also tightly associated with hypocretin deficiency. Extended human studies further suggested that hypocretin deficiency is tightly associated with the occurrence of cataplexy and that most patients with narcolepsy without cataplexy and idiopathic hypersomnia and secondary excessive daytime sleep disorders (such as obstructive sleep apnea) have normal CSF hypocretin levels ( Figure 4). However, cerebrospinal fluid (CSF) measures (and a small number of postmortem brain studies) found hypocretin ligand deficiency in most idiopathic narcolepsy–cataplexy cases (∼90%) ( Figures 3 and 4). Subsequent human studies revealed that the mutation in the hypocretin-related gene is extremely rare, and only one case of early-onset narcolepsy to date was identified as having a mutation in the preprohypocretin gene. Hypocretin neurons are exclusively located in the lateral hypothalmic area, but project to most brain areas. The hypocretin/orexin system is a recently discovered hypothalamic neuropeptidic system. Mutation of one of the two hypocretin/orexin receptors and knockout of the hypocretin/orexin gene (preprohypocretin) causes narcolepsy in dogs and mice, respectively. Studies in these animals (familial canine narcolepsy in narcoleptic Dobermans and gene-knockout mice) led to the discovery of the etiology of narcolepsy in animals. The identification of cataplexy in these animals led to the discovery of narcolepsy in these animal species. Cataplexy is also a hallmark symptom of narcolepsy in animals, such as dogs and mice.
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