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Objectives: Several recent studies have suggested that the altered sleep-stage transitions of rapid eye movement (REM) sleep is a novel characteristic of REM-NREM sleep dysregulation in narcolepsy.In this study, we aimed to determine a series of characteristics of this novel sleep stage sequence marker, including the diagnostic properties, HLA association, longitudinal stability, and familial transmission.Methods: This study consisted of two sub-studies, an observational case-control family study to investigate the diagnostic value and familial patterns and a longitudinal follow-up study of the subjects to determine the stability of sleep-stage transition.In order to compare the sleep-stage transition to REM, all participants were required to have at least one sleep onset REM period (SOREMP) during MSLT.Finally, 78 narcoleptic patients (36 with cataplexy (N+C) and 42 without cataplexy (N-C)), 26 unaffected relatives, and 160 non-narcoleptic controls were recruited from January 2001 to September 2013.The sleep stages were scored according to AASM criteria (2007).Among them, 57 subjects had DBQ1*0602 typing and 33 subjects had DRB1*1501 typing.Twenty-five N+C, 21 N-C, and 56 controls were reassessed with a mean follow-up period of 37.6 months (SD: 28.0).Results: N+C patients had the highest prevalence rate of transition of REM period directly from wakefulness during any nap of MSLT and NPSG (57.0% and 47.1%), followed by N-C patients (17.4% and 5.6%), controls (3.8% and 0%), and unaffected relatives (0% and 0%).Unaffected relatives of narcolepsy patients had a higher rate of transition of REM sleep from stage NREM1 (N1) (53.7% vs 28.9%, p<0.05) but lower rate of transition of REM sleep from stage N2 (43.9% vs 67.2%, p<0.05) than controls.The REM sleep-stage transition from wakefulness had reasonably sensitivity (77.8%) and high specificity (95.6%) in differentiating N+C from controls, but low sensitivity (21.4%) and high specificity(95.6%) in differentiating N-C from controls.Both positive typing of DBQ1*0602 and DRB1*1501 were highly associated with sleep-stage transition of REM sleep from wakefulness (OR: 8.3 vs 7.5 in MSLT and OR: 14.4 vs 2.7 in NPSG).The sleep-stage transitions patterns were rather stable in 3-yr longitudinal follow-up.Thirteen out of 17 N+C patients (76.5%) with "any nap transition of REM sleep directly from wakefulness" persisted at follow-up.Two out of 3 N-C patients persisted to have this phenomenon at follow-up.While none of the controls had this phenomenonat baseline, only 1 of them (8.3%) developed this phenomenon at follow-up.For NPSG, 50% of N+C patients with transition of first REM period from wakefulness persisted at follow-up, while one N-C patient (100%) persisted to have this transition at follow-up.None of controls had a transition from wakefulness or N1 at either baseline or follow-up NPSG.Conclusions: Transition of REM sleep directly from wakefulness is a significant and a stable marker of narcolepsy, especially those with cataplexy.The high sensitivity and specificity of sleep-stage transition in both MSLT and NPSG suggested clinical utility in the differential diagnosis of SOREMPs.Its Iongitudinal stability, association with HLA typing especially DBQ1*0602 and probable familial predisposition suggest a vulnerable REM-NREM sleep dysregulation trait of narcolepsy.