Entrevista
Interview with Prof. Mehdi Tafti for European Narcolepsy Day 2011
Fecha de publicación de la entrevista 18/03/2011 | Nº de lecturas de la entrevista 50.375
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Dr. Mehdi Tafti
Center for Integrative Genomics (CIG), University of Lausanne and Center for Investigation and Research on Sleep (CIRS), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
Question. We know that narcolepsy is a chronic disabling sleep disorder affecting 1 out of every 2000 individuals, but what exactly is the impact of narcolepsy in the European population?
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.
Q. It has been proved that narcolepsy is related to a severe hypocretin-1 deficiency (De Lecea, 1998), and since hypocretin has been reported to be undetectable in the cerebrospinal fluid (CSF) of most narcoleptic patients with cataplexy, is there any autoimmune mechanism explaining the destruction of the hypocretin neurons in the lateral hypothalamus?
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.
Q. We know that the majority of cases of narcolepsy are sporadic, 1-10% of cases are familiar and studies with twins show that only 25-31% of monozygotic twins are concordant for the disease. So, what is the role played by genetic and environmental factors?
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.
Q. We know that symptoms develop gradually. Cataplexy is often the second symptom to occur, although it appears years after the onset of sleep attacks and some cases remain undetected and misdiagnosed. Do you think that the diagnostic tools currently in use are appropriate?
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.
Q. So far treatment has been symptomatic with stimulants and antidepressants: are there any new perspectives in the pharmacological therapy of narcolepsy?
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.
Q. You are a member of the Board of the European Narcolepsy Network (EU-NN), founded in 2007. One of the first results of this European collaboration is the recent paper in Nature Genetics, Hor et al., 2010, which is the first study to identify a genetic protective factor. Could you please summarise the main points of your study?
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.
Q. You are a Professor of the on-line Master Sleep: Medicine and Physiology, which is now in its fifth edition, with a chapter entitled Genetics of Sleep. What are the actual goals of the research in this topic? We know that your team is doing translational research, so could you please give us an overview of your work?
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.
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