Narcolepsy probably results from a combination of genetic and environmental factors, some of which have been identified, but many of which remain unknown. In most cases of narcolepsy with cataplexy, and in some cases without cataplexy, sleep abnormalities result from a loss of particular brain cells neurons in a part of the brain called the hypothalamus. These cells normally produce chemicals called hypocretins also known as orexins , which have many important functions in the body. In particular, hypocretins regulate the daily sleep-wake cycle.
It is unclear what triggers the death of hypocretin-producing neurons in people with narcolepsy, although evidence increasingly points to an abnormality of the immune system.
Researchers have identified changes in several genes that influence the risk of developing narcolepsy. The most well-studied of these genes is HLA-DQB1 , which provides instructions for making part of a protein that plays an important role in the immune system. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses and bacteria. The HLA-DQB1 gene has many different normal variations, allowing each person's immune system to react to a wide range of foreign proteins.
It is unclear how these genetic changes influence the risk of developing the condition. Variations in several additional genes have also been associated with narcolepsy. Many of these genes are thought to play roles in immune system function. However, variations in these genes probably make only a small contribution to the overall risk of developing narcolepsy. Other genetic and environmental factors are also likely to influence a person's chances of developing this disorder.
For example, studies suggest that bacterial or viral infections such as strep throat streptococcus , colds, and influenza may be involved in triggering narcolepsy in people who are at risk. Most cases of narcolepsy are sporadic, which means they occur in people with no history of the disorder in their family.
A small percentage of all cases have been reported to run in families; however, the condition does not have a clear pattern of inheritance. First-degree relatives parents, siblings, and children of people with narcolepsy with cataplexy have a 40 times greater risk of developing the condition compared with people in the general population.
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From Genetics Home Reference. Description Narcolepsy is a chronic sleep disorder that disrupts the normal sleep-wake cycle. This statistic may frighten people with narcolepsy, as it seems like a grim indicator that either your children will inherit it or another family member will later develop the sleep condition. But because narcolepsy is brought on by a unique combination of genetic and environmental factors, the actual risk of inheritance is low.
Narcolepsy is usually divided into two categories , type 1 and type 2. Low levels of hypocretin also called orexin are the main cause of type 1 narcolepsy. Hypocretin is responsible for regulating the sleep cycle, including rapid eye movement or REM sleep — when dreams occur — and the deeper, non-REM sleep that helps you wake up refreshed. Type 1 narcolepsy is diagnosed when a person has low levels of hypocretin, as well as the sleep disturbances and daytime drowsiness most people think of as being part of narcolepsy excessive daytime sleepiness, sleep paralysis, sudden sleep attacks.
Cataplexy — sudden attacks of muscle weakness while awake — is also part of the diagnosis of type 1 narcolepsy. Type 2 narcolepsy has the sleep disturbances of type 1, but not the low hypocretin levels or the cataplexy. Nearly all studies on the genetic inheritance of narcolepsy involve type 1. Specific markers for type 2 have not been found yet.
The rest of this article will discuss type 1 narcolepsy. Inherited conditions are usually thought of as genetic, but the process of inheritance is not clear to most people.
You may remember Punnett squares from biology class and assume all conditions are inherited based on a dominant or recessive gene pattern. In reality, inherited conditions happen in a variety of ways. They can be caused by mutations in a single gene, when a gene from one parent or another mutates before conception in either the sperm or egg or after conception and the trait appears in the child.
Other inherited conditions have a basis in genes, but are dependent on environmental experiences before or after birth that cause the genes to express themselves. The simplest way to see how a trait is inherited is to conduct a survey of monozygotic identical twins and compare them to dizygotic fraternal twins. Identical twins share a genetic code, while fraternal twins are no more alike genetically than any other set of siblings.
So if a condition is as common in identical twins as fraternal ones, it indicates that the environment — more than genetics — plays a factor in its development. There is no clear pattern for the inheritance of narcolepsy. Available research suggests narcolepsy may have a genetic basis, but also requires certain environmental conditions to develop in a person.
One twin study found that just 20 percent to 30 percent of identical twins, who have the same genes, shared a diagnosis of narcolepsy. Specific genetic markers have been found to correlate with a risk of narcolepsy. Researchers currently suspect narcolepsy is an autoimmune disorder in which the immune system attacks the neurons that produce hypocretin, the substance that regulates sleep patterns.
A variant in T-cell receptor genes has also been associated with narcolepsy. For people with narcolepsy, these T-cell receptors are believed to combine with HLA in the nervous system and destroy cells in the brain that produce hypocretin. Having one does not mean a person will develop narcolepsy, and people who do not have any of these genetic variants can still develop narcolepsy. Most cases of narcolepsy are sporadic , meaning they occur without a definitive inherited pattern. There is only a 1 percent chance that a parent with narcolepsy will have a child with narcolepsy.
There seems to be a need for a specific environmental trigger that affects the immune system to make the gene variant express narcolepsy. Our group evaluated Ccr3 knockout mice to elucidate the role of CCR3 in development of the disease. Fragmented sleep patterns were observed in the Ccr3 knockout mice during the light phase.
Interestingly, the number of orexin neurons in the lateral hypothalamus was slightly but significantly decreased in the Ccr3 knockout mice compared with those of the wild-type mice.
When orexin deficiency was first shown to result in NT1, variant screening of the prepro-orexin and orexin receptor genes was performed, as mentioned above. However, common variants of these genes were not significantly associated with the disease in most patients. Only a single severe and early-onset case with a predicted dominant pathogenic variant in the orexin gene was identified p. Leu16Arg This variant was not present in the general population.
The amino-acid encoded by the variant is located in the poly-leucine hydrophobic core of the signal peptide. Functional analyses revealed impaired trafficking and processing of the orexin mutant peptide Recently, advances in next-generation sequencing technologies have had a strong impact on human genetics. Sequencing of all protein coding regions of the human genome exome sequencing has been utilized to identify novel pathogenic variants causing rare Mendelian diseases.
Exome sequencing of familial narcolepsy individuals identified a missense deleterious variant p. SerCys in the myelin oligodendrocyte glycoprotein MOG 61 Table 3 , whereas no control carried the variant. MOG is a key autoantigen for primary demyelination in multiple sclerosis Ectopic clustering of the mutated protein was observed in the cytoplasm, whereas the wild-type protein mainly showed perinuclear and membrane localization.
These results suggest that abnormalities in oligodendrocytes and myelin may play an important role in development of narcolepsy. Another study used exome sequencing and reported rare missense variants in P2RY11 in two narcolepsy families. P2RY11 re-sequencing in sporadic narcoleptic patients revealed six additional missense variants Six of the eight missense variants significantly decreased P2Y11 signaling Table 3. Autosomal dominant cerebellar ataxia, deafness, and narcolepsy ADCA-DN is a neurologic disorder characterized by adult onset of progressive cerebellar ataxia, sensory neuronal deafness, narcolepsy with cataplexy, and dementia AlaVal, p.
GlyAla, and p. ValPhe 65 Table 3 but were not found in the general population. Therefore, these two diseases may have a shared pathogenesis. In contrast to NT1, the genetic backgrounds of other central disorders of hypersomnolence have not been well elucidated, most likely due to difficulty with their diagnoses, their heterogeneity, and their low prevalence compared with those of NT1.
The International Classification of Sleep Disorders, 3rd edition, describes NT2 and idiopathic hypersomnia as central disorders of hypersomnolence other than NT1, but diagnosis is often a challenge In , Honda et al.
The diagnostic criteria for EHS are based on the following three clinical items: 1 recurrent daytime sleep episodes that occur basically every day over a period of at least 6 months; 2 an absence of cataplexy; and 3 the hypersomnia cannot be explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder.
Thus, we focused on patients with EHS. Reduction in the heterogeneity of EHS is required before conducting a genetic study. This enzyme catalyzes the reversible conversion of short-chain acyl-CoA and carnitine to acylcarnitine and free CoA 75 , Aserinsky, E. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep.
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