National Sleep Foundation

Chapter 4: Primary Hypersomnias

Etiology and Risk Factors

Narcolepsy affects both genders and typically begins between age 15 and 24, although it has been found in children as young as 5 years old. Age at onset has a bimodal distribution, with higher rates of onset between 15 and 36 years of age.29  Narcolepsy rarely develops after age 40.

Specific genetic factors are thought to contribute to narcolepsy. First-degree relatives of narcoleptic patients have a 20-40-fold increased risk of experiencing narcolepsy with cataplexy, indicating that it has a genetic component.30

The vast majority (90 – 100%) of individuals with narcolepsy with cataplexy have the human leukocyte antigen (HLA) allele DQB1*0602, most often in combination with HLA DR2. In comparison, only 12 – 38% of the general population has this HLA combination.31, 32, 33

It is thought that narcolepsy may be caused by an autoimmune destruction of hypocretin (also called “orexin”) cells, mainly occurring in adolescence. Current evidence demonstrates the loss of some or all of the almost 100,000 hypocretin-containing hypothalamic neurons in patients who have narcolepsy with cataplexy.34, 35, 36, 37, 38 “The hypothesis …is that there is a genetic predisposition to autoimmune attack on the hypocretin-producing neurons in the lateral hypothalamus, triggered by environmental factors, such as infective agents.”39


References

  1. Dauvilliers Y, Montplaisir J, Molinari N, et al. Age at onset of narcolepsy in two large populations in France and Quebec. Neurology 2001;57:2029–33.
  2. Mignot E. Genetic and familial aspects of narcolepsy. Neurology. 1998;50:S16-22.
  3. Juji T, Satake M, Honda Y, Doi Y. HLA antigens in Japanese patients with narcolepsy: all the patients were DR2 positive. Tissue Antigens. 1984;24:316-319.
  4. Mignot E, Hayduk R, Black J, Grumet FC, Guilleminault C. HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients. Sleep. 1997;20:1012-1020.
  5. Mignot E, Lin L, Rogers W, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet. 2001;68:686-699.
  6. Nishino S, Ripley B, Overeem S, et al. Hypocretin (orexin) deficiency in human narcolepsy (letter). Lancet. 2000;355:39-40.
  7. Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002;59:1553-1562.
  8. Thannickal TC, Moore RV, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27:469-474.
  9. Hungs M, Lin L, Okun M, Mignot E. Polymorphisms in the vicinity of the hypocretin/orexin are not associated with human narcolepsy. Neurology. 2001;57:1893-1895.
  10. Leschziner, G, Narcolepsy: a Clinical Review, Pract Neurol 2014; 0:1–9. doi:10.1136/practneurol-2014-000837.
  11. Leschziner, G, Narcolepsy: a Clinical Review, Pract Neurol 2014; 0:1–9. doi:10.1136/practneurol-2014-000837.