Narcolepsy: genetic predisposition and neuropharmacological mechanisms

Narcolepsy is a disabling sleep disorder characterized by excessive daytime somnolence (EDS), cataplexy and REM sleep-related abnormalities. It is a frequently-occurring but under-diagnosed condition that affects 0.02 to 0.18% of the general population in various countries. Although most cases occur sporadically, familial clustering may be observed; the risk of a first-degree relative of a narcoleptic developing narcolepsy is 10-40 times higher than in the general population. The disorder is tightly associated with the specific human leukocyte antigen (HLA) allele, DQB1*0602 [most often in combination with HLA-DR2 (DrB1*15)]. Genetic transmission is, however, likely to be polygenic in most cases, and genetic factors other than HLA-DQ are also likely to be implicated. In addition, environmental factors are involved in disease predisposition; most monozygotic twins pairs reported in the literature are discordant for narcolepsy. Narcolepsy was reported to exist in canines in the early 1970s. Both sporadic and familial cases are also observed in this animal species. A highly-penetrant single autosomal recessive gene, canarc-1, is involved in the transmission of narcolepsy in Doberman pinschers and Labrador retrievers. Positional cloning of this gene is in progress, and a human homologue of this gene or a gene with a functional relationship to canarc-1, might be involved in some human cases. Human narcolepsy is currently treated with central nervous system (CNS) stimulants for EDS and antidepressants for cataplexy and abnormal REM sleep. These treatments are purely symptomatic and induce numerous side effects. These compounds disturb nocturnal sleep in many patients, and tolerance may develop as a result of continuous treatment. The canine model is an invaluable resource for studying the pharmcological and physiological control of EDS and cataplexy. Experiments using canine narcolepsy have demonstrated that increased cholinergic and decreased monoaminergic transmission are likely to be at the basis of the pathophysiology of the disorder. Pharmcological studies have shown that blockade of norepinephrine uptake mediates the anticataplectic effect of currently prescribed antidepressants, while blockade of dopamine uptake and/or stimulation of dopamine release mediates the awake-promoting effect of CNS stimulants. Studies in canine narcolepsy also suggest that mechanisms and brain sites for triggering cataplexy are not identical to those regulating REM sleep. It may thus be possible to develop new pharmacological compounds that specifically target abnormal symptoms in narcolepsy, but do not disturb physiological sleep/wake cycles. (See also postscript remarks). (C) 2000 Harcourt Publishers Ltd.