The genetics of narcolepsy.
Human narcolepsy is a genetically complex disorder. Family studies indicate a 20-40 times increased risk of narcolepsy in first-degree relatives and twin studies suggest that nongenetic factors also play a role. The tight association between narcolepsy-cataplexy and the HLA allele DQB1*0602 suggests that narcolepsy has an autoimmune etiology. In recent years, extensive genetic studies in animals, using positional cloning in dogs and gene knockouts in mice, have identified abnormalities in hypothalamic hypocretin (orexin) neurotransmission as key to narcolepsy pathophysiology. Though most patients with narcolepsy-cataplexy are hypocretin deficient, mutations or polymorphisms in hypocretin-related genes are extremely rare. It is anticipated that susceptibility genes that are independent of HLA and impinge on the hypocretin neurotransmitter system are isolated in human narcolepsy.
Chabas
Dorothee
D
Federation de neurologie, Batiment Paul Castaigne, Hopital Salpetriere, 47-83 Boulevard de l'hopital, 75 013 Paris, France. dorothee.chabas@psl.ap-hop-paris.fr
Taheri
Shahrad
S
Renier
Corinne
C
Mignot
Emmanuel
E
D000818:Animals; D015551:Autoimmunity; D002352:Carrier Proteins / Q000235:genetics; D004195:Disease Models, Animal; D004285:Dogs; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D009290:Narcolepsy / Q000235:genetics*; D009479:Neuropeptides / Q000235:genetics; D000068797:Orexins
D002352:Carrier Proteins; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins