Scientists funded by the National Institutes of Health have identified a gene associated with narcolepsy, a disorder that causes disabling daytime sleepiness, sleep attacks, irresistible bouts of sleep that can strike at any time, and disturbed sleep at night. The gene has a known role in the immune system, which strongly suggests that autoimmunity, in which the immune system turns against the body’s own tissues, plays an important role in the disorder.

“The link between narcolepsy and autoimmunity was proposed decades ago, but efforts to verify it have failed repeatedly. Current findings leave little doubt that autoimmunity plays a role,” says Merrill Mitler, Ph.D., a program director with the National Institute of Neurological Disorders and Stroke (NINDS). The study was funded principally by NINDS, with additional support from the National Institute of Mental Health (NIMH), the National Heart, Lung and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID), all components of NIH.

The new study, which appears today in Nature Genetics, focused specifically on narcolepsy with cataplexy – a sudden loss of muscle tone that can cause a person to collapse, with or without falling asleep. About 1 in 2,000 Americans have narcolepsy-cataplexy. The symptoms of narcolepsy-cataplexy have been shown to result from the death of a small group of brain cells that normally regulate the sleep-wake cycle by releasing chemicals called hypocretins.

Genetic and environmental factors both clearly play a role in narcolepsy-cataplexy. Until now, the best evidence for autoimmunity as a cause of the disorder was the discovery that nearly everyone with the disorder has unique variants of a gene called HLA-DQB1*0602. This is one of the genes that encodes HLA proteins, which dot the surface of the body’s cells and help the immune system identify foreign proteins. Some researchers theorize that the HLA variants found in people with narcolepsy-cataplexy predispose them to an autoimmune reaction that destroys their hypocretin-producing cells.

There are gaps in that theory, however, says Emmanuel Mignot, M.D., Ph.D., director of the Center for Narcolepsy at Stanford University School of Medicine in Palo Alto, Calif. and a Howard Hughes Medical Institute investigator. Dr. Mignot discovered the link between narcolepsy and the hypocretins, and helped establish the link to the HLA system. HLA proteins are found in many tissues including the brain, where they may affect brain development, he says.

HLA variations, however, do not fully account for narcolepsy-cataplexy. Dr. Mignot led a genome-wide association study to search for other genes associated with narcolepsy-cataplexy. These studies involve scanning the genome – the entire set of DNA – for small differences between people who have a disorder and people who do not. Dr. Mignot’s study included more than 4,000 individuals, all of whom had the HLA variants that predispose to narcolepsy-cataplexy but only about half of whom had the disorder. Participants were recruited so that many genetic groups were represented. Subjects were from the United States and eight countries in Europe and Asia; hundreds were African-American, Korean, and Japanese, a group known to have a high incidence of the disorder.

The researchers discovered that in addition to unique HLA variants, people with narcolepsy-cataplexy are also more likely to have unique variants of the TCRA gene, which encodes a receptor protein on the surface of T cells. T cells are the mobile infantry of the immune system. In concert with the HLA proteins, the T cell receptor enables T cells to recognize and attack foreign invaders, such as bacteria and viruses. Changes to the T cell receptor could increase the likelihood that the cells will direct their attack against the body.

The findings of Dr. Mignot’s group indicate that narcolepsy-cataplexy is linked to autoimmunity and involves T-cells. The research could lead to new approaches to prevention and treatment. One possibility may be preventing the disorder by stopping the effects of the autoimmune process. “If we can define the changes in the T cell receptor associated with narcolepsy-cataplexy, we might be able to develop drugs that block the protein’s abnormal activity and prevent the onset of the disorder,” says Dr. Mignot. Current treatments such as stimulant drugs for combating daytime sleepiness and antidepressants for cataplexy are only able to control symptoms, and do not address the underlying loss of hypocretin cells.

It is important to note that this study, like most genome-wide association studies, did not identify genetic variants that directly cause narcolepsy-cataplexy. Instead it identifies groups that are more likely to show narcolepsy-cataplexy and groups that are less likely to show the disorder. In people with the HLA variants that predispose to narcolepsy-cataplexy, there is about a 20-fold higher frequency of the disorder if variants in the TCRA gene are present. It is yet to be known which people with the genetic variants will go on to develop narcolepsy-cataplexy.

Other risk factors for narcolepsy-cataplexy remain to be discovered, and Dr. Mignot’s findings could provide clues to their identity. For example, further studies to characterize the T cells in people with narcolepsy-cataplexy could help reveal whether specific environmental factors – such as infections – contribute to the disorder. Dr. Mignot’s findings also could lead to a better understanding of other autoimmune diseases where HLA genes are known to play a role, such as multiple sclerosis and type 1 diabetes.

NINDS (www.ninds.nih.gov) is the nation’s primary supporter of biomedical research on the brain and nervous system. The mission of NIMH (www.nimh.nih.gov) is to reduce the burden of mental and behavioral disorders through research on mind, brain and behavior. NIAID (www.niaid.nih.gov) conducts and supports research to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. NHLBI (www.nhlbi.nih.gov) plans, conducts, and supports research related to the causes, prevention, diagnosis, and treatment of heart, blood vessel, lung, and blood diseases; and sleep disorders.

The National Institutes of Health (NIH) – The Nation’s Medical Research Agency – includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

For more information about narcolepsy, visit
http://www.ninds.nih.gov/disorders/narcolepsy/narcolepsy.htm or

http://www.nhlbi.nih.gov/health/dci/Diseases/nar/nar_what.html.

Reference:
Hallmayer J et al. “Narcolepsy is Strongly Associated with the TCR alpha locus.” Nature Genetics, published online May 3, 2009.

Source: http://www.ninds.nih.gov/news_and_events/news_articles/pressrelease-narcolepsy-GWAS.htm

Author: Sona Nevsimalova
Sleep Medicine Reviews; Volume 13, Issue 2, Pages 169-180 (April 2009)
Source: http://www.smrv-journal.com/article/S1087-0792%2808%2900050-6/abstract

Conclusions
Our data together with the evidence from the literature cited suggest that: (i) mild OD is a sign of narcolepsy with cataplexies, (ii) the subgroup of narcolepsy patients with cataplexies consists largely of individuals in which the disorder is associated with or caused by decreased CSF orexin, (iii) the anatomical distribution of orexin and orexin-receptors within the entire olfactory path constitute an ideal link between orexin deficiency and OD and (iv) intranasal orexin A administration essentially restores olfactory performance. Hence, there is sound evidence for the hypothesis that pathophysiological mechanisms underlying OD are directly caused by a lack of orexin A.

Further studies are warranted on the one hand to find out whether or not the improvement in the olfactory detection threshold after orexin A application in our narcolepsy patients is clinically significant and for daily life needs and on the other to investigate where in the olfactory tract extrinsic orexin A acts. Moreover, one might speculate that other symptoms of narcolepsy, such as disturbed sleep regulation and cataplexies, are modulated by orexin A.

FULL TEXT ARTICLE
http://brain.oxfordjournals.org/cgi/content/full/131/10/2734

Authors: Paul Christian Baier, Sara Lena Weinhold, Verena Huth, Birgit Gottwald, Roman Ferstl and Dunja Hinze-Selch

Brain 2008 131(10):2734-2741; doi:10.1093/brain/awn193
Brain Advance Access originally published online on August 21, 2008

Methods
Of 228 enrolled patients, 71 discontinued antidepressant therapy. Data from 57 patients were available for analysis: 37 patients discontinued tricyclic antidepressants (TCAs) and 20 discontinued selective serotonin reuptake inhibitors (SSRIs). The trial included a 21-day withdrawal phase followed by 18-day washout and 14-day single-blind treatment phases. Two additional weeks were permitted for withdrawal from fluoxetine due to its long half-life. Weekly cataplexy attacks were recorded throughout the trial. No historical data on the frequency of cataplexy prior to treatment with antidepressants was available.

Results
Among the patients who were and were not withdrawn from antidepressants treatment, the median frequency of baseline weekly cataplexy was similar (17.5 vs. 14.0, respectively). As expected, significant between-group differences emerged by the end of the washout period (52.04 vs. 15.25, respectively; p<0.05); however, the frequency of cataplexy events became similar again by the end of the trial (16.5 vs. 17.5, respectively).

Conclusions
Patients gradually withdrawn from antidepressants experienced a significant increase in cataplexy, but eventually returned to their baseline frequency, comparable to previously untreated control patients. Compared to SSRIs, discontinuation from TCAs was associated with a greater increase in cataplexy attacks.

Sleep Medicine; Volume 10, Issue 4, Pages 416-421 (April 2009).
Authors: Ruzica K. Ristanovic, Howard Liang, Carl S. Hornfeldt, Chinglin Lai
Received 23 February 2007; received in revised form 13 March 2008; accepted 23 April 2008.
Source: http://www.sleep-journal.com/article/S1389-9457%2808%2900115-9/abstract

Methods
Charts from three centers of all patients with narcolepsy who had been using sodium oxybate for at least 3 months were reviewed. Patients in whom anti-cataplexy medications were added or withdrawn or wake-promoting medications added after the start of sodium oxybate were excluded from further analysis. In the remainder, pre-sodium oxybate and, most recently, on-sodium oxybate weights were compared using Student’s t-tests. Sodium oxybate dose and duration of therapy were also noted.

Results
A total of 54 patients meeting inclusion criteria were identified. Of these 54, 33 (61%) were women; the mean age was 48.3 years. The mean dose of sodium oxybate was 6.9g/night and the duration of therapy was 25 months. The mean pre-sodium oxybate weight was 78.3 (±15.7)kg. The most recent on-sodium oxybate weight was 74.9 (±15.1, p=0.003). The average weight loss was 3.4kg, whereas the maximum was 30.9kg.

Conclusions
This study suggests that treatment of patients with narcolepsy with sodium oxybate can result in weight loss.

Sleep Medicine; Volume 10, Issue 6, Pages 661-663 (June 2009).
Authors: Aatif M. Husain, Ruzica K. Ristanovicc, Richard K. Bogand
Received 24 November 2007; received in revised form 26 April 2008; accepted 20 May 2008.
Source: http://www.sleep-journal.com/article/S1389-9457%2808%2900207-4/abstract

Methods
Clinical interviews with the completion of the Stanford questionnaire, Epworth Sleepiness Scale (ESS) and Multiple Sleep Latency Test (MSLT) were evaluated in 105 patients (44 males, 61 females, mean age 45.4±19.2, BMI 29.2±5.8) suffering from narcolepsy.

Results
The severity of the disease was judged by clinical complaints, ESS value and MSLT results. No relations with the age at onset and clinical tetrad were found, however, smoking may be associated with an increased risk of hypnagogic hallucinations. There was no correlation between the number of sleep and cataplectic attacks and the age at onset, nor did subjective ESS show any significant dependence. However, earlier onset of the disease correlated with shorter MSLT mean latency. A correlation was found between the BMI and narcolepsy sleepiness rating in the elderly and between degree of education attained and subjective complaints.

Conclusions
The clinical severity of narcolepsy does not depend on the age at onset.

Publication Information
Sleep Medicine; Volume 10, Issue 9, Pages 967-972 (October 2009).

Authors: Sona Nevsimalovaa, Jitka Buskovaa, David Kemlinka, Karel Sonkaa, Jelena Skibovab

Received 4 December 2008; received in revised form 22 January 2009; accepted 29 January 2009.
Source: http://www.sleep-journal.com/article/S1389-9457%2809%2900056-2/abstract