ABSTRACT
Since the first HLA association study in 1983, we know that narcolepsy has a genetic component and that HLA-DQB10602 confers an increased risk of the disease in all ethnic groups. However, no other gene has yet been unequivocally associated with narcolepsy. We also know that mutations in hypocretin/orexin ligands or receptors cause narcolepsy in animal models and that hypocretin/orexin deficiency characterizes human narcolepsy, although without any identified mutation in the hypocretin/ orexin gene system. Narcolepsy is mainly sporadic, its clustering in families is rare, and the concordance rate in monozygotic twins is low. Therefore no convincing evidence for major non-HLA genetic factors is available. Thus, narcolepsy should be considered a complex disorder where many genes might be involved, each exerting a small effect. To fully understand the pathogenic mechanisms, a comprehensive knowledge of the effect of the individual genes and environmental factors is needed.
