1. Home>
2. Specialty Care>
3. Neurology>
4. Summary and Comment

Hypocretin Deficiency Important in Narcolepsy-Cataplexy Syndrome

Using sophisticated molecular neurobiologic techniques, researchers have recently unraveled the exciting story of hypocretins (or orexins) -- their discovery and their functional role in narcolepsy-cataplexy syndrome. Two lines of evidence have been developed: (1) animal models of narcolepsy (a canine model produced by hypocretin receptor 2 (Hcrtr2) gene mutation and a mouse model produced by preprohypocretin knockout) and (2) discovery of low cerebrospinal fluid hypocretin-1 in humans with narcolepsy. To investigate the role of the hypocretin system in the pathophysiology of human narcolepsy, these authors used (1) mutation screening and sequencing of 3 hypocretin loci (Hcrt, Hcrtr1, Hcrtr2) in 74 Caucasian patients who had a family history of narcolepsy or who lacked the human leukocyte antigen HLA-DQB1*0602, and (2) histopathologic examination of 6 narcoleptic brains.

DNA analysis revealed one Hcrt mutation, found in a 2-year-old boy with severe narcolepsy beginning at 6 months of age. In situ hybridization and peptide radioimmunoassays found global loss of concentrations of Hcrt1 and Hcrt2 peptides without signs of inflammation or gliosis in all studied areas of the narcoleptic brains. The authors concluded that hypocretin neurotransmission plays a central role in the etiology of human narcolepsy.

Comment: The evidence for a loss of Hcrt1 and Hcrt2 peptides in the brains of narcoleptic patients extends the authors' previous discovery of low levels of hypocretins in cerebrospinal fluid. Because the loss is not associated with inflammation or gliosis in the hypothalamus, it is unlikely that an autoimmune process is responsible for hypocretin destruction. As the authors' series suggests, a genetic cause is also unlikely because most human narcolepsy cases are sporadic.

Although hypocretin deficiency does seem to be a significant factor in narcolepsy-cataplexy syndrome, it would be naive to conclude that human narcolepsy is simply a hypocretin-deficiency disease. Its linkage to HLA and its complex inheritance suggest that other factors must be at issue. The next challenge is to find out what causes hypocretin deficiency. The answer to this question will provide the key to discovering a cure for narcolepsy. In the meantime, vigorous attempts should be made to find a pharmacologic agent to promote hypocretin neurotransmission, so that preventive or curative therapy can be designed for this disabling illness.

— S Chokroverty

Sudhansu Chokroverty, MD, FRCP, FACP, is Professor of Neurology, New York Medical College, New York, NY.

Published in Journal Watch Neurology November 22, 2000

Citation(s):

Peyron C et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000 Sep 6 991 -997.

• Medline abstract (Free)