DNA Narcolepsy Test
What is narcolepsy?
Narcolepsy is a neurological disorder characterized by extreme daytime sleepiness and uncontrollable episodes of falling asleep during the day. This excessive daytime sleepiness should not be mistaken for the afternoon slump, since neurological defects are responsible for narcolepsy, rather than just sleep deprivation or lack of caffeine!
Who is at risk of narcolepsy?
Family members of an affected individual have a 20X – 40X increased risk of developing narcolepsy, indicating a strong genetic basis for the disorder. The genetic variant most closely associated with narcolepsy is HLA-DQB1*06:02. Individuals with this variant have a 7X to 25X increased risk of developing narcolepsy, although one recent European study indicates a much higher odds ratio of approximately 250-fold! Multiple other HLA-DQB1 variants also exist, and many of these provide some protection from narcolepsy, complicating the risk analyses.
What are the symptoms of narcolepsy?
Narcolepsy is often incorrectly diagnosed because it involves a wide variety of neurological symptoms. The symptoms include:
- Excessive daytime sleepiness (100% of affected individuals)
- Cataplexy – a sudden loss of voluntary muscle tone (70% of affected individuals)
- Sleep paralysis and/or vivid hallucinations (10 to 20% of affected individuals)
- Microsleep (sleep episodes that only last a few seconds)
- Nighttime wakefulness
- Atonia (loss of muscle strength)
- Involuntary leg muscle contractions
- Rapid entry into REM sleep
How common is narcolepsy?
Between 1 in 2000 and 1 in 5000 people are thought to be affected by narcolepsy. However, only about 25% are correctly diagnosed, and often people are instead mistakenly diagnosed with psychiatric or emotional problems. Family members of an affected individual also have a 20X – 40X increased risk of developing narcolepsy, indicating a strong genetic basis for the disorder.
Genetics of narcolepsy
90-99% of individuals with narcolepsy carry a variant of the HLA-DQB1 gene known as the HLA-DQB1*06:02 allele. Approximately 15 – 25% of the unaffected worldwide population, also have HLA-DQB1*06:02, so other factors must also contribute to this disease.
- Two copies of HLA-DBQ1*06:02 = 7X – 25X increased risk of narcolepsy (or potentially up to 250X increased risk!)
- One copy of HLA-DBQ1*06:02 + an alternative HLA-DBQ1 allele = >3X increased risk (depending on the risk or protective affect of the alternative allele)
- Absence of HLA-DBQ1*06:02 = Low risk of narcolepsy
This genetic analysis detects the HLA-DQB1*06:02 allele associated with narcolepsy. It is a useful tool, in conjunction with other clinical symptoms, for an accurate narcolepsy diagnosis.
The autoimmunity theory of narcolepsy
About 70% of people with narcolepsy also suffer from cataplexy, which is caused by lower levels of a neurotransmitter named hypocretin (also called orexin). However, no genetic changes have been observed in the hypocretin gene. The neurons that produce hypocretin gradually die off in individuals with narcolepsy. Given the role of HLA-DQ proteins in immunity, it is believed that they play a role in this cell death; supporting the hypothesis that narcolepsy is an autoimmune disease. Celiac disease is another autoimmune disease that occurs due to changes in the HLA-DQ genes. The HLA-DQ changes in celiac disease cause an aberrant immune response and severe intestinal lining damage, triggered by the consumption of gluten. The trigger (if any) for narcolepsy is currently unknown, but a similar aberrant autoimmune response occurs, this time resulting in the destruction of healthy (and essential) hypocretin-producing neurons.
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