Will the discovery of hypocretin deficiency in narcolepsy bring new treatments for patients?
The answer is yes, and very soon. The current treatments available, antidepressants, sodium oxybate 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 it is known that having no hypocretin is what is causing narcolepsy in NT1, replacing the missing molecule has been considered the holy grail for these cases, and several companies have been trying to develop hypocretin/orexin agonists, small molecules that can mimic the effects of hypocretin/orexin on their receptor. Indeed, hypocretins themselves cannot be given by mouth or injected in the blood; they are unstable and would be broken down before reaching the brain to do its job. Spectacularly, this has been achieved by several drug companies in animals, and in one case in humans with an intravenous drug called TAK925. This drug, which can only be administered intravenously, reversed the symptoms of type 1 narcolepsy but was not developed because it cannot be taken by mouth. Another drug, TAK994, orally available this time is now undergoing clinical trials at Stanford and elsewhere, with similar promising results.
Will the discovery of hypocretin deficiency in narcolepsy lead quickly to cure for NT1 patients?
The answer is 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.
What types of therapies can be used in patients with narcolepsy and hypersomnia?
The treatment for these diseases is a combination of behavioral changes and medications and depends on the cause. Excluding medical causes, sleep apnea, fatigue or depression is always important, and these diseases may coexist with narcolepsy or hypersomnia. Treatment may involve circadian resetting with light or melatonin, improving sleep at night with sodium oxybate, and increasing wakefulness using dopaminergic stimulants such as modafinil, amphetamine, methyphenidate, or Histamine H3 antagonist such as pitolisant.
Will these recent discoveries be important for the children of NT1 patients?
The answer is maybe, but much more research in the area is needed. Most cases of type 1 narcolepsy do not have a family history for narcolepsy. The risk of developing narcolepsy-cataplexy is only 1-2% for a child of a NT1 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. For narcolepsy type 2 and IH, very little is known, and although familial cases have been reported, no clear causative gene has been identified.
If I have narcolepsy, what is the risk for my child to develop it as well?
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.