Correspondence

Narcolepsy and the HLA System

N Engl J Med 2001; 344:692March 1, 2001

Article

To the Editor:

In the second part of their review of the HLA system (Sept. 14 issue),1 Klein and Sato state that the HLA class II association in human narcolepsy is due to linkage disequilibrium with mutations in the gene coding for the hypocretin type 2 receptor (HCRTR2). HCRTR2 is located on human chromosome 6, but at a very large genetic distance from the HLA loci; there is no linkage disequilibrium between the HLA alleles and HCRTR2 over a distance of more than 30 million base pairs and 33.4 centimorgans. However, there is a different association between narcolepsy and the HLA system. Microsatellite-marker and sequencing studies of the HLA class II region have shown that HLA-DQ is the primary susceptibility locus for human narcolepsy in the HLA region.2-4

We have recently shown that most cases of narcolepsy in humans do not involve mutations in the hypocretin-system genes but, rather, involve a loss of hypocretin-containing neurons in the perifornical hypothalamus.5 On the basis of current data, the most likely hypothesis is that human narcolepsy is an autoimmune disorder targeting hypocretin-containing cells.

Emmanuel Mignot, M.D., Ph.D.
Stanford University School of Medicine, Stanford, CA 94305-5485

Erik Thorsby, M.D., Ph.D.
National Hospital, N-0027 Oslo, Norway

5 References

1. 1

   Klein J, Sato A. The HLA system: second of two parts. N Engl J Med 2000;343:782-786
   Full Text | Web of Science | Medline

2. 2

   Ellis MC, Hetisimer AH, Ruddy DA, et al. HLA class II haplotype and sequence analysis support a role for DQ in narcolepsy. Immunogenetics 1997;46:410-417
   CrossRef | Web of Science | Medline

3. 3

   Mignot E, Kimura A, Latterman A, et al. Extensive HLA class II studies in 58 non-DRB1*15 (DR2) narcoleptic patients with cataplexy. Tissue Antigens 1997;49:329-341
   CrossRef | Web of Science | Medline

4. 4

   Mignot E, Lin L, Risch N, et al. Identification of a novel HLA narcolepsy susceptibility subtype, HLA-DQB1*0301. Sleep 1999;22:Suppl 1:S121-S122
   

5. 5

   Peyron C, Faraco J, Rogers W, 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;6:991-997
   CrossRef | Web of Science | Medline

Citing Articles (5)

Citing Articles

1. 1

   M. López, R. Nogueiras, M. Tena-Sempere, C. Diéguez. (2010) Orexins (hypocretins) actions on the GHRH/somatostatin-GH axis. Acta Physiologica 198:3, 325-334
   CrossRef

2. 2

   Jiaqiang Cai, Fiona E Cooke, Bradley S Sherborne. (2006) Antagonists of the orexin receptors. Expert Opinion on Therapeutic Patents 16:5, 631-646
   CrossRef

3. 3

   LUIGIA BRUNETTI, RUGGIERO FRANCAVILLA, VITO LEONARDO MINIELLO, MADDALENA LEONE, MICHELE RANA, DAMIANO COLAZZO, PAOLO LOGRILLO, BIAGIO FAVOINO, LUCIO ARMENIO. (2005) Influence of HLA antigens and OSAS in childhood: a preliminary report*. Journal of Sleep Research 14:2, 157-162
   CrossRef

4. 4

   Laura C McAtee, Steven W Sutton, Dale A Rudolph, Xiaobing Li, Leah E Aluisio, Victor K Phuong, Curt A Dvorak, Timothy W Lovenberg, Nicholas I Carruthers, Todd K Jones. (2004) Novel substituted 4-phenyl-[1,3]dioxanes: potent and selective orexin receptor 2 (OX2R) antagonists. Bioorganic & Medicinal Chemistry Letters 14:16, 4225-4229
   CrossRef

5. 5

   Neil T. Feldman. (2003) Narcolepsy. Southern Medical Journal 96:3, 277-282
   CrossRef