ABSTRACT
Narcolepsy is a disabling neurological disorder characterized by excessive daytime sleepiness and abnormal rapid eye movement (REM) sleep manifestations. A genetic predisposition with Human Leucocyte Antigen (HLA) DQB10602 has been evidenced as well as a strong association with absent or abnormally low cerebrospinal fluid (CSF) levels of the neuropeptide hypocretin. Several lines of evidence from family and twin studies are in favour of environmental factors in the development of narcolepsy. Family members of a narcoleptic subject may have the same haplotype as their relative and yet not be narcoleptics (Fig. 1). Also of 16 monozygotic twin pairs reported in the literature, five were presumably concordant and eleven discordant for narcolepsy (1). Moreover a recently reported HLA DQB10602 positive monozygotic twin discordant for narcolepsy was shown to be also discordant for CSF hypocretin-1 (2). This is clear evidence that the genetic background is not a sufficient condition to develop abnormality in the hypocretin system. Thus narcolepsy appears to result from the interaction of environmental factors acting on a specific genetic background. In a large study of adult-like sexed Finnish twin pairs it was shown that the best-fitting additive genetic components effects due to dominance and nonshared environmental components (ADE) model estimated that 34.7% of total variance was attributable to genetic effects among men and 39.4% among women, while over 65% was accounted for by environmental effects among men and 60% among women (3). In regard to these data it is striking that the literature should be so rich on genetic factors and so poor on environmental factors, probably due to the present aura of genetic research and the complexity and cost of relevant approaches to environmental factors. This is detrimental both in view of the understanding of the pathophysiology of narcolepsy and in view of its prevention. Thus we thought it valuable to review the present state of knowledge on environmental factors and to formulate proposals for the future. The issue of so-called symptomatic narcolepsies in relation with brain tumors, inherited disorders, vascular disorders, encephalopathies, multiple sclerosis, paraneoplastic syndromes is treated in another chapter (4) and will not be addressed.
