A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains

We explored the role of hypocretins in human narcolepsy through histopathol ogy of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcr tr2 in 74 patients of various human leukocyte antigen and family history st atus. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization o f the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human case s examined. Although hypocretin loci do not contribute significantly to gen etic predisposition, most cases of human narcolepsy are associated with a d eficient hypocretin system.