Murine and canine narcolepsy can be caused by mutations of the hypocretin (Hcrt) (orexin)
precursor or Hcrt receptor genes. In contrast to these animal models, most human narcolepsy
is not familial, is discordant in identical twins, and has not been linked to mutations
of the Hcrt system. Thus, the cause of human narcolepsy remains unknown. Here we show
that human narcoleptics have an 85%-95% reduction in the number of Hcrt neurons. Melanin-concentrating
hormone (MCH) neurons, which are intermixed with Hcrt cells in the normal brain, are
not reduced in number, indicating that cell loss is relatively specific for Hcrt neurons.
The presence of gliosis in the hypocretin cell region is consistent with a degenerative
process being the cause of the Hcrt cell loss in narcolepsy.