What Causes Narcolepsy?
The cause of narcolepsy remains unknown but during the past decade, scientists have made considerable progress in understanding its pathogenesis and in identifying genes strongly associated with the disorder. Researchers have also discovered abnormalities in various parts of the brain involved in regulating REM sleep that appear to contribute to symptom development. Experts now believe it is likely that-similar to many other complex, chronic neurological diseases-narcolepsy involves multiple factors interacting to cause neurological dysfunction and REM sleep disturbances.
A number of variant forms (alleles) of genes located in a region of chromosome 6 known as the HLA complex have proved to be strongly, although not invariably, associated with narcolepsy. The HLA complex comprises a large number of interrelated genes that regulate key aspects of immune-system function. The majority of people diagnosed with narcolepsy are known to have specific variants in certain HLA genes. However, these variations are neither necessary nor sufficient to cause the disorder. Some people with narcolepsy do not have the variant genes, while many people in the general population without narcolepsy do possess these variant genes. Thus it appears that specific variations in HLA genes increase an individual's predisposition to develop the disorder-possibly through a yet-undiscovered route involving changes in immune-system function-when other causative factors are present.
Many other genes besides those making up the HLA complex may contribute to the development of narcolepsy. Groups of neurons in several parts of the brainstem and the central brain, including the thalamus and hypothalamus, interact to control sleep. Large numbers of genes on different Chromosomes control these neurons' activities, any of which could contribute to development of the disease. Scientists studying narcolepsy in dogs have identified a mutation in a gene on chromosome 12 that appears to contribute to the disorder. This mutated gene disrupts the processing of a special class of Neurotransmitters called hypocretins (also known as orexins) that are produced by neurons located in the hypothalamus. Neurotransmitters are special proteins that neurons produce to communicate with each other and to regulate biological processes. The neurons that produce hypocretins are active during wakefulness, and research suggests that they keep the brain systems needed for wakefulness from shutting down unexpectedly. Mice born without functioning hypocretin genes develop many symptoms of narcolepsy.
Except in rare cases, narcolepsy in humans is not associated with mutations of the hypocretin gene. However, scientists have found that brains from humans with narcolepsy often contain greatly reduced numbers of hypocretin-producing neurons. Certain HLA subtypes may increase susceptibility to an immune attack on hypocretin neurons in the hypothalamus, leading to degeneration of neurons in the hypocretin system. Other factors also may interfere with proper functioning of this system. The hypocretins regulate appetite and feeding behavior in addition to controlling sleep. Therefore, the loss of hypocretin-producing neurons may explain not only how narcolepsy develops in some people, but also why people with narcolepsy have higher rates of Obesity compared to the general population.
Other factors appear to play important roles in the development of narcolepsy. Some rare cases are known to result from traumatic injuries to parts of the brain involved in REM sleep or from Tumor growth and other disease processes in the same regions. Infections, exposure to toxins, dietary factors, Stress, hormonal changes such as those occurring during puberty or Menopause, and alterations in a person's sleep schedule are just a few of the many factors that may exert direct or indirect effects on the brain, thereby possibly contributing to disease development.
