Answer. Narcolepsy is largely underdiagnosed and its prevalence might be much higher. The delay in diagnosis is around 10 years, leaving many patients without adequate treatment for years. This has a huge impact in terms of its socioeconomic, health and welfare burden.
A. The cause of hypocretin deficiency is unknown but the most plausible explanation is the destruction of hypocretin neurons. Since narcolepsy is strongly associated with specific HLA (Human Leukocyte Antigen) genes regulating the immune system, an autoimmune process targeting hypocretin neurons might be involved. We have shown that narcolepsy patients are positive for anti-Trib2 (Tribbles Homolog 2) antibodies and these antibodies recognise hypocretin neurons. Nevertheless, half of all narcolepsy patients are negative for these antibodies, leaving the question open. Moreover, both we and others have reported a remarkable positive response to IVIg, a typical anti-autoimmune treatment. Taken together the available data strongly suggest that the cause of narcolepsy might be autoimmune.
A. Narcolepsy is a complex disease and like other complex disorders it is influenced by both genetic and environmental factors. The more we learn about the genetic factors, the more the environmental triggers become important. Unfortunately we know little about the environmental factors, although significant life events such as infections or stressful experiences have been reported as relevant. We are beginning to learn more and more about genetic factors, and this will help us to understand the genetic background that predisposes people to narcolepsy. The high rate of discrepancy between monozygotic twins strongly suggests a critical role for an as-yet unknown environmental factor acting on a genetic predisposition to the disease.
A. The diagnosis of narcolepsy is a major problem. In up to 80% of the patients excessive daytime sleepiness appears between one and 10 years before cataplexy. Sleepiness without cataplexy is very difficult to investigate and may be related to many conditions other than narcolepsy. Accordingly, most narcolepsy patients either go undiagnosed or misdiagnosed. Moreover, other comorbid disorders such as sleep apnoea, restless legs syndrome, and depression are frequently found in narcolepsy patients, thus making it very difficult to reach a positive diagnosis in the absence of clear-cut cataplexy. An additional problem is the recognition of cataplexy, since no objective test is available and many patients may have partial cataplexy that goes unnoticed. Diagnostic tools are well-established and standardised, but unfortunately not yet completely appropriate.
A. Treatment remains symptomatic because the cause is still unknown. As mentioned before, if narcolepsy is an autoimmune disease, then immunotherapy may be a first choice but it seems that not all cases turn out to be autoimmune in origin. Since hypocretin deficiency is the best biological marker of narcolepsy, hypocretin replacement is the best therapy to date. Unfortunately hypocretins do not cross the blood-brain barrier and there is a strong need to develop centrally-acting hypocretin agonists. Gene- or cell-based therapies are future directions that need intensive research. The existence of several animal models of narcolepsy is highly valuable in the pharmacology management of the condition.
A. We have known for decades that HLA-DQB1*0602 is strongly associated with narcolepsy but the gene is normal and found in 10-20% of the general population. Therefore the conclusion was that this gene is not sufficient. By comparing European narcolepsy patients with controls matched for this HLA allele, we have found that another HLA allele, present in 10% of controls, is extremely rarely found in patients. This new allele (DQB1*0603) increases the protection against narcolepsy 50 fold in subjects carrying one copy of the susceptibility allele (DQB1*0602). Given that the two proteins produced by these two alleles differ by only two amino acids, our finding strongly suggests that DQB1 is causally involved in narcolepsy. In other words, if DQB1*0602 is found in up to 20% of subjects who are not affected with narcolepsy, one major explanation is that they are protected with another HLA variant.
A. This is a vast question. Until now the molecular genetics of sleep have attracted very little interest. My laboratory is tracking down genes that regulate both normal and disordered sleep. We have already identified several important genes that causally affect the sleep EEG in mice, as well as genes associated with narcolepsy, sleepwalking and Kleine-Levin syndrome. More recently we have initiated a large study that looks at sleep and sleep disorders in the general population. The project, called HypnoLaus, is part of a larger cohort study of the Lausanne general population (CoLaus), where 6600 subjects are investigated for hundreds of metabolic, cardiovascular and neuropsychiatric variables. Additionally, all these subjects have been genotyped with over 500,000 genetic markers. The aim of our study is to record sleep in up to 3000 members of this cohort in order to identify genes involved in both normal and pathological sleep. So far nearly 800 subjects have been investigated.Dr. Rosa Peraita-Adrados