The Genetics of Narcolepsy

Abstract

Human narcolepsy is not a familial or classic genetic disorder. However, autosomal recessive canine narcolepsy and genetic manipulation models in rodents have identified the hypothalamic perifornical hypocretin (orexin) neuropeptidergic system as key to the disease. In humans, no functionally important genetic abnormities in the hypocretin gene or genes for hypocretin peptide receptors have been observed, but human narcolepsy is associated with hypocretin cell loss and reduced hypocretin levels in the cerebrospinal fluid. The causes of hypocretin cell loss in humans are undetermined, but genetic studies have suggested an autoimmune aetiology. Narcolepsy has a close association to the human leukocyte antigen class II antigen HLA DQB1*0602 present in the majority of cases with narcolepsy with cataplexy. Furthermore, recent studies have identified a narcolepsy-associated polymorphism in the TRA@ (T-cell receptor alpha) gene. HLA class II antigens on antigen-presenting cells present antigens (foreign and self) to the T-cell receptor, with subsequent immune system mobilisation against the specific antigen and cells that express it. Other polymorphisms identified in narcolepsy include those affecting key processes that are important in the immune response. Thus, the genetic case for an autoimmune basis for narcolepsy with cataplexy is compelling. Nonimmune system genes have also been implicated in narcolepsy whose influence appears to be more physiological, but may shed light to the aetiology of narcolepsy without cataplexy and other hypersomnias. The increased availability of more advanced genetic techniques is likely to shed further light on narcolepsy development, progression and treatment.