Stanford University
Palo Alto, CA 94305, USA
arcolepsy is a disabling disorder characterized by sleepiness and abnormal REM sleep. It affects 0.05% to 0.16% of the general population in Europe, North America and Japan. The development of human narcolepsy involves environmental factors on a specific genetic background. The importance of environmental factors can be illustrated by the fact that most (65-83%) monozygotic twins reported in the literature are discordant for narcolepsy. One of the predisposing genetic factors is located in the HLA DQ region. Ninety-five percent of all narcoleptic patients share a specific MHC class II allele, HLA DQB1*0602 (most often in combination with HLA DR2) versus 20% of the general population. Genetic factors other than HLA are also likely to be involved. Even if genuine multiplex families are rare, 1-2% of the first degree relative of a patient with narcolepsy are affected by the disorder (versus 0.05-0.16% in the general population). We also have found a few multiplex families with numerous affected members and no apparent haplotype linkage with HLA.
Studies using a canine model of the disorder also illustrate the importance of non MHC genes in disease predisposition. In this model, narcolepsy is transmitted as a single autosomal recessive trait. This high penetrance narcolepsy gene is unlinked to MHC class II but cosegregates with a DNA segment with high homology to the human immunoglobulin m-switch sequence, thus suggesting immunopathology in both human and canines.
Narcolepsy is currently treated using tricyclic antidepressants for the REM related symptoms and amphetamine-like stimulants for sleepiness. Using the canine model, we have studied the effects of over 150 compounds on cataplexy, a pathological symptom of narcolepsy akin to REM sleep atonia. Our results indicate that the pharmacological control of cataplexy, is similar but not identical to the pharmacological control of REM sleep. In both cases, monoaminergic and cholinergic systems are involved but the adrenergic is more critical for cataplexy and thus presumably REM sleep atonia. Other results suggest that stimulants are acting via presynaptic stimulation of dopaminergic systems.
Using in vivo dialysis and local injection studies, we are also trying to establish a neuroanatomical and neurochemical map of the structures that are important for the regulation of narcolepsy. Our results indicate that narcoleptic canines are hypersensitive to M2 cholinergic stimulation in the Pontine Reticular Formation and the Basal Forebrain. This is likely to mediate abnormal REM sleep in narcolepsy. We have also found that dopaminergic autoreceptor stimulation (D3) in the Ventral Tegmental Area (VTA) induces cataplexy and sleepiness in narcoleptic but not control canines. This suggests that narcolepsy may result from abnormal interactions between REM-on cholinergic and mesocorticolimbic dopaminergic systems.
In spite of this association with immune-related genes, narcolepsy does not seem to be a classical autoimmune disease. The role of the immune system in generating abnormal monoaminergic and cholinergic reactivity remains to be determined. Pathophysiological models involving the microglia, HLA class II expression and the release of specific cytokines in the brain are being explored. This approach, together with positional cloning studies in humans and canines, should at last reveal the cause of narcolepsy and open novel therapeutic avenues for the disorder.
