Chapter 39 - Immunologic and Genetic Aspects of Type 1 Narcolepsy

Abstract

In international classifications, narcolepsy is subdivided into types 1 and 2. Type 1 narcolepsy is caused by the destruction of about 70,000 hypothalamic neurons that produce the wake-promoting neurotransmitter hypocretin (orexin). Symptoms include daytime sleepiness, abnormalities in sleep architecture and REM sleep, and episodes of loss of muscle tone triggered by positive emotions (cataplexy). The diagnosis of type 1 narcolepsy can often be made based on the presence of cataplexy alone, which is almost pathognomonic for the disorder. Sleep tests such as nocturnal polysomnography followed by the multiple sleep latency test are typically performed to confirm the diagnosis. In difficult cases, measuring hypocretin-1 in the cerebrospinal fluid can also be conducted, with low (≤110-pg/mL) levels indicating hypocretin deficiency. Patients with type 2 narcolepsy are not associated with hypocretin abnormalities but have abnormal REM sleep patterns. Indirect evidence suggests that type 1 narcolepsy is an autoimmune disease targeting hypocretin cells. First, as for many other autoimmune diseases, narcolepsy is strongly associated with human leukocyte antigen (HLA) polymorphisms. Most strikingly, about 97% of patients carry a specific HLA class II allele, HLA-DQB1∗06:02, compared with 25% of the general population. Additional effects of other HLA-DQ alleles and of HLA-DP and class I alleles modulate susceptibility. Second, although these associations are weak comparison with HLA-DQB1∗06:02, genome-wide association studies have identified polymorphisms known to be involved in HLA-mediated adaptive immune responses (T-cell receptor [TCR] α and TCRβ) or in susceptibility to other autoimmune diseases (CTSH, TNFSF4, ZF365, and IL10RB-IFNAR1) as susceptibility risks. Finally, as suspected for many other autoimmune diseases, narcolepsy onset can be precipitated by infections, notably Streptococcus pyogenes and seasonal influenza infections. This was mostly notably shown after the 2009 H1N1 swine flu pandemic infection and after vaccinations with Pandemrix, an AS03-adjuvanted H1N1 vaccine that was used in Europe. In addition to type 1 narcolepsy of autoimmune origin and type 2 cases of unknown etiologies, there are also rare cases of narcolepsy resulting from genetic abnormalities, or that are part of a more complex syndrome. Our understanding of narcolepsy is rapidly improving knowledge regarding how the brain regulates wakefulness and REM sleep.