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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.
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