Immunological and Genetic Aspects of Narcolepsy

Narcolepsy is an increasingly recognized sleep disorder characterized by excessive daytime sleepiness, symptoms of dissociated/abnormal rapid eye movement (REM) sleep, disrupted nocturnal sleep, and cataplexy. Although daytime sleepiness is the most disabling symptom, significantly disrupted sleep at night results in a similar total amount of sleep over 24 hours compared to controls. Many of the hallmark symptoms of narcolepsy [sleep paralysis, hypnagogic hallucinations, sleep-onset REM periods (SOREMPs)] are also seen in the general population, especially in the context of sleep deprivation, however cataplexy (brief episodes of bilateral muscle weakness triggered by emotions) is highly specific to narcolepsy. The most typical triggers for cataplexy are joking, laughter, and to a lesser extent, anger. Attacks may vary in severity ranging from jaw sagging or head dropping, to knees buckling, or total body paralysis lasting up to several minutes, with consciousness preserved throughout the episode. The unifying feature of these symptoms is that they all reflect a fundamental dysregulation of normal transitions between sleep and wake. Disease onset is most often in childhood, peaking between 10 and 25 years of age, and once established, the disease is life-long. Recent work has resulted in substantial insights on key genetic factors contributing to susceptibility and how these relate to the immunological processes underlying the pathophysiology of the disease. Narcolepsy-cataplexy occurs with a fairly consistent prevalence of approximately 0.02-0.03% in various Caucasian groups throughout the world, with a somewhat higher prevalence in Japanese (0.16%) and individuals of African descent, and a lower prevalence in Israeli Jews (0.002%).1,2 These prevalence rates partially correspond with higher frequency of the susceptibility factor DQB1*06:02 (discussed below). This factor has a high frequency in African Americans (38%) and lower frequency in Ashkenazi Jews (3-6%), although not in Japanese (12%). The prevalence of narcolepsy without cataplexy has been difficult to characterize, as the diagnosis lacks specificity (relying primarily on the presence of SOREMPs), and patients are likely to be underdiagnosed or misdiagnosed. Population based studies indicate that 1-3% of the population report sleepiness with multiple SOREMPs detected by mean sleep latency test (MSLT) testing.3,4 Familial occurrence of narcolepsy-cataplexy was reported in the initial 1887 report by Westphal,5 and until recently, it has been considered to be a familial disorder. Many previously reportReceived: July 23, 2011 Accepted: July 23, 2011 Correspondence Emmanuel Mignot, MD, PhD Department of Psychiatry, Stanford University Center for Sleep Sciences and Medicine, 1050 Arastradero Road, Building A Floor 2, Palo Alto, CA 94304, USA Tel +1-650-725-6517 Fax +1-650-725-4913 E-mail [email protected] Immunological and Genetic Aspects of Narcolepsy