Age at onset of narcolepsy in two large populations of patients in France and Quebec

Dauvilliers, Yves; Montplaisir, J; Molinari, Nicolas; Carlander, Bertrand; Piotin, Michel; Besset, A; Billiard, Michel

doi:10.1212/wnl.57.11.2029

Cited by 373 publications

(165 citation statements)

References 29 publications

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“…This finding is reminiscent of the clinical observations made in T1N patients, which may result from a chronic multistep process. Indeed, most patients first develop excessive daytime sleepiness, whereas cataplectic episodes appear months or years later (40).…”

Section: Discussionmentioning

confidence: 99%

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Bernard‐Valnet

Yshii

Quériault

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

120

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Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin + neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin + neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin + neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin + neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin + neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.arcolepsy with cataplexy, referred to as type 1 narcolepsy (T1N), is a rare and chronic neurological disease characterized by excessive daytime sleepiness, sudden loss of muscle tone triggered by emotions (cataplexy), sleep paralysis, hypnagogic hallucinations, and fragmented nocturnal sleep (1). T1N is caused by a defective neurotransmission by the orexin/hypocretin neuropeptide and is associated with a selective and almost complete loss (85-100%) of orexinergic neurons in the hypothalamus (2, 3). The mechanisms leading to this neuronal loss are not yet elucidated, although current evidence points to an autoimmune process. Indeed, T1N is tightly associated with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, carried by 98.4% of patients vs. 17.7% of the general European population (4). An independent association with HLA class I alleles was recently revealed in two independent studies (5, 6). Additionally, an association with polymorphisms in the T-cell receptor (TCR) α chain locus was found and replicated (7,8). Moreover, autoantibodies recognizing different antigenic targets expressed in the central nervous system (CNS) have been identified in the serum and cerebrospinal fluid (CSF) of narcoleptic patients (9-11)....

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Section: Discussionmentioning

confidence: 99%

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Bernard‐Valnet

Yshii

Quériault

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

120

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“…Narcolepsy with cataplexy, narcolepsy without cataplexy, and idiopathic hypersomnia patients were included based on diagnostic criteria of the International Classification of Sleep Disorders (ICSD-2). The frequency of cataplexy was assessed by a scale from 1 to 5, reporting rare to very frequent cataplexy attacks (29). Healthy controls were recruited in affiliated sleep centers and had full clinical and, in more than half, polysomnography investigations.…”

Section: Rt-pcr and Real-time Rt-pcr Experimentsmentioning

confidence: 99%

Elevated Tribbles homolog 2–specific antibody levels in narcolepsy patients

Cvetkovic-Lopes¹,

Bayer²,

Dorsaz³

et al. 2010

J. Clin. Invest.

281

177

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Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataplexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder.

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“…12 , 64 Globally, the prevalence varies from highest in Japan (0.16%) to lowest in Israel (0.0002%). 65 Th e age of onset in clinical populations appears to be bimodal, with the fi rst peak at 15 years and the second at 35 years, 66 although a population-based study demonstrated a single large peak between ages 10 and 19, with gradual tapering off with increasing age. 12 Th ere are no populationbased prevalence estimates for IH using the second edition of ICSD or ICSD-3 classifi cations, 1 so prevalence estimates are extrapolations from sleep disorders clinics.…”

Section: Epidemiologymentioning

confidence: 99%

Central Disorders of Hypersomnolence

Khan¹,

Trotti²

2015

Chest

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The central disorders of hypersomnolence are characterized by severe daytime sleepiness, which is present despite normal quality and timing of nocturnal sleep. Recent reclassifi cation distinguishes three main subtypes: narcolepsy type 1, narcolepsy type 2, and idiopathic hypersomnia (IH), which are the focus of this review. Narcolepsy type 1 results from loss of hypothalamic hypocretin neurons, while the pathophysiology underlying narcolepsy type 2 and IH remains to be fully elucidated. Treatment of all three disorders focuses on the management of sleepiness, with additional treatment of cataplexy in those patients with narcolepsy type 1.Sleepiness can be treated with modafi nil/armodafi nil or sympathomimetic CNS stimulants, which have been shown to be benefi cial in randomized controlled trials of narcolepsy and, quite recently, IH. In those patients with narcolepsy type 1, sodium oxybate is eff ective for the treatment of both sleepiness and cataplexy. Despite these treatments, there remains a subset of hypersomnolent patients with persistent sleepiness, in whom alternate therapies are

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Age at onset of narcolepsy in two large populations of patients in France and Quebec

Abstract: Bimodal distribution of age at onset of narcolepsy was found in two independent patient populations. Our data suggest that age at onset is genetically determined.

Cited by 373 publications

References 29 publications

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Elevated Tribbles homolog 2–specific antibody levels in narcolepsy patients

Central Disorders of Hypersomnolence

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