Recent studies have shown that narcolepsy with cataplexy is usually caused (>90%) by the lack of two related brain chemicals called "hypocretin-1" and "hypocretin-2". The cause of narcolepsy without cataplexy is still under investigation.
Hypocretins (orexins) were discovered by two groups of researchers almost simultaneously, hence the two names "hypocretins" and "orexins". The first group called them "hypocretin-1" and "hypocretin-2" after discovering that the molecules were found only in the hypothalamus and had some weak resemblance with the gut hormone secretin. Only 10,000-20,000 cells in the entire human brain (out of many billions) secrete these specific hypocretin molecules. The hypothalamus, a region localized deep in the base of the brain, regulates many basic functions such as the release of hormones, blood pressure, sex, food intake regulation and sleep. The subregion of the hypothalamus containing the hypocretin cells was known to be especially important for the regulation of feeding. These molecules were thus first hypothesized to be important in feeding regulation. In fact, the second group that discovered the hypocretin molecules called them "orexin A and orexin B" (from orexis=appetite in grec) and suggested that they stimulated appetite. Orexins and hypocretins are thus interchangeable terms and the scientific community is divided on what is the best name to use.
Hypocretin-1 (but not 2) can be measured in the cerebrospinal fluid (CSF) but not in the blood or in any other peripheral tissue. A lumbar puncture is required to collect CSF. Most patients with narcolepsy-cataplexy have no hypocretin-1 molecules in their CSF. Unfortunately, this testing is not commercially available and as of 1/1/2017 we no longer do this test through the Mignot Lab. We are not aware of another center that offers this service.
To draw CSF requires a lumbar puncture (spinal tap). This is a safe but not completely insignificant procedure (the main problem is that temporary headaches can occur in about 5% of the cases following the procedure). The procedure is a little similar to an epidural anesthesia (actually safer and easier), is used a lot by neurologists to exclude many neurological problems such as brain hemorrhage, brain infections, multiple sclerosis, etc... We have tried to measure hypocretins in other tissues such as blood but this molecule probably exists in sufficient amount only in the brain and the CSF. Clearly, some effort should be devoted in measuring hypocretin levels more easily.
HLA stands for " Human Leukocyte Antigens". HLA antigens are molecules produced by the HLA genes. HLA molecules are expressed on the surface of white blood cells to coordinate the immune response. DR and DQ are two different types of HLA molecules. HLA genes are very important systems to keep the immune system in check. The HLA molecules are very particular in that different individuals generally carry different HLA "subtypes" (for example DR1, DR2, subtypes of HLA-DR; DQ1, DQB1*0602, subtypes of HLA-DQ). The fact HLA molecules are slightly different from one individual to another makes our immune system slightly different from each other.
The best HLA marker for narcolepsy is HLA-DQB1*0602. Over 90% of patients with narcolepsy-cataplexy carry HLA-DQB1*0602. This marker is more specific and sensitive than the old marker HLA-DR2, especially in African Americans.
Absolutely not. About 20% of the general population carry the exact same HLA subtypes (HLA-DR2, DQB1*0602, etc.). Furthermore, many patients without cataplexy do not have HLA-DQB1*0602. The HLA subtypes are only predisposing factors but are not sufficient by themselves to cause narcolepsy.
No one knows for sure. A large number of other diseases (>80) like Multiple sclerosis or Juvenile Onset (type I) Insulin Dependent Diabetes Mellitus are also associated with specific HLA subtypes. Most of these diseases are autoimmune disorders.
An autoimmune disease is a disorder where the immune system turns against one's own body instead of fighting an external infection. In Multiple Sclerosis for example, the immune system attacks the surface of the nerves that facilitates nerve conduction. The nerves then don't function very well, resulting in symptoms such as muscle weakness. Most autoimmune disorders are associated with specific HLA subtypes. About 70% of the patients with multiple sclerosis have HLA-DR2, for example.
Recent studies have shown that the hypocretin-containing cells are missing in the brain of narcoleptic patients. The most likely explanation may be that the cells are destroyed by an autoimmune attack.
Most cases of narcolepsy have no other family members affected with narcolepsy and the risk is very small. If you have narcolepsy-cataplexy, the risk for your child to develop narcolepsy-cataplexy is only 1-2%. The risk of developing daytime sleepiness without cataplexy may be slightly higher (4%). These risks are probably smaller if you carry the HLA-DQB1*0602 subtype and have no other family member with narcolepsy.
Yes, but with a caveat. No single test will ever be 100% specific for narcolepsy but this test is clearly much more specific than HLA typing. Approximately 90% of the narcoleptic patients we have tested to date have undetectable hypocretin levels in their cerebrospinal fluid (CSF). All the normal individuals (with or without HLA-DR2 or DQB1*0602) we have tested have detectable hypocretins in their CSF. Having undetectable levels (independently of any other severe medical condition) is thus clearly a strong signature for narcolepsy. We however still need to extend the study before fully assessing the value of the test. For example, we don't know if patients without cataplexy also have abnormal hypocretin levels. Furthermore, it is likely that some (probably rare) patients with narcolepsy will have normal CSF hypocretin levels. In narcoleptic dogs for example, hypocretin CSF levels are normal even so the animals have all the symptoms of narcolepsy. In this case, the receptors for hypocretins are the problem, not the hypocretin molecules (receptors are proteins on which the hypocretins act to produce their effect on cells, like a lock -receptor- and a key -hypocretin-). In the narcoleptic dogs, the hypocretin is present but cannot produce its effect on cells in the brain.
The answer is most probably yes, but is it difficult to tell when. The current treatments available, antidepressants, GHB and stimulants including modafinil do not act directly on the hypocretin system. Rather, they act on a group of molecules called monoamines (especially dopamine, serotonin and norepinephrine). These treatments correct the symptoms rather than the cause of the problem. Now that we know that having no hypocretin is what is causing narcolepsy in most patients, replacing the missing molecule is probably going to be the best treatment. Unfortunately however, hypocretins probably cannot be given by mouth or injected in the blood. Hypocretins are unstable and would be broken down before reaching the brain to do its job. Very high doses maybe effective but its should first be tried animal models (e.g. mouse without the hypocretin gene, unavailable to us). Most likely, this would not work well and be too expensive anyway. A probably better option will be to create an artificial drug with brain penetration that can "replace" the missing hypocretin molecule. This is perfectly doable (but not easy). The fact that the narcolepsy market is small is a drawback but other indications for these "hypocretin" drugs are possible. Because drugs take a long time to go to the market however, it is likely an hypocretin stimulating drug will occur at best in 5 years and probably in more than 10 years (personal opinion).
The answer is probably no. Even though we have now discovered that not to have hypocretin causes narcolepsy, this does not mean we will be able to reverse the process. Recent studies in postmortem brain tissue indicate that the hypothalamic cells that secrete the hypocretins are destroyed in most human patients. The HLA association in narcolepsy suggests that maybe the immune system destroys the cells that secrete hypocretins early in adolescence. In this case, narcolepsy would be very similar to HLA associated juvenile onset insulin dependent diabetes mellitus where the immune system destroys the pancreatic cells that synthesize insulin. In this condition, it is possible to replace insulin to alleviate the symptoms but obviously it does not replace the missing insulin producing cells so it is not a long term cure. A cure for narcolepsy may rather involve new breakthroughs, for example transplanting cells that could produce hypocretins in the brain. These protocols are explored in other similar clinical conditions, for example in Parkinson disease where dopamine is the missing molecule and where cells synthesizing dopamine are being transplanted. Efficacy is controversial and a lot of work needs to be done before these protocols are operational. Narcoleptic patients may one day benefit from similar protocols or from another breakthrough such as gene therapy or another major advance.
The answer is maybe, but much more research in the area is needed. Most cases of narcolepsy do not have a family history for narcolepsy. The risk developing narcolepsy-cataplexy is only 1-2% for a child of a narcoleptic patient. Still, 1-2% is 20-40 fold the general population risk (0.05%) and some families clearly have a high incidence of narcolepsy. Using the test, it may be possible to better identify family members with high risk and maybe one day to prevent the development of narcolepsy.
Patients, friends, and professionals can help in many ways. These include participating to research protocols and/or educating the public and our political representatives about narcolepsy. Financial contributions to patient support groups such as the Narcolepsy Network also go a long way in helping patients in need of assistance. Contributions to our center are also essential to our research, especially at the present time (see funding section).