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Nature Medicine 6, 991 - 997 (2000)
doi:10.1038/79690

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

Christelle Peyron1,8, Juliette Faraco1,8, William Rogers1, Beth Ripley1, Sebastiaan Overeem1,2, Yves Charnay3, Sona Nevsimalova4, Michael Aldrich5, David Reynolds6, Roger Albin5, Robin Li1, Marcel Hungs1, Mario Pedrazzoli1, Muralidhara Padigaru6, Melanie Kucherlapati6, Jun Fan7, Richard Maki7, Gert Jan Lammers2, Constantin Bouras3, Raju Kucherlapati6, Seiji Nishino1 & Emmanuel Mignot1

We explored the role of hypocretins in human narcolepsy through histopathology of six narcolepsy brains and mutation screening of Hcrt, Hcrtr1 and Hcrtr2 in 74 patients of various human leukocyte antigen and family history status. One Hcrt mutation, impairing peptide trafficking and processing, was found in a single case with early onset narcolepsy. In situ hybridization of the perifornical area and peptide radioimmunoassays indicated global loss of hypocretins, without gliosis or signs of inflammation in all human cases examined. Although hypocretin loci do not contribute significantly to genetic predisposition, most cases of human narcolepsy are associated with a deficient hypocretin system.