Hypothalamus

What is the role of hypocretin in narcolepsy?

Answer: Hypocretin (orexin) is a neuropeptide that functions in sleep, and low levels are implicated in narcolepsy.

hypocretin orexin narcolepsy sleep

Narcolepsy is a sleep disorder that affects approximately one in 2,000 people across the world. According to estimates from the National Institute of Neurological Disorders and Stroke of the NIH, somewhere between 135,000 and 200,000 Americans are currently living with narcolepsy, but cases are likely under reported.

Most people are able to recognize when they have severe narcolepsy. In less clear cases, a polysomnogram can be used to make a diagnosis. Generally, a polysomnogram is a combination of analytic techniques like electroencephalograms and electromyograms that a person can wear throughout the day. The EEG can help figure out a person’s sleep patterns, and significant deviations from an expected brain wave pattern may contribute to a narcolepsy diagnosis.

Symptoms of narcolepsy

The most common and well-known symptom of narcolepsy is a dysregulation of sleep patterns, resulting in excessive daytime somnolence (EDS). For these people, they experience daily and frequent urges to sleep, no matter how much sleep they had gotten in the night. EDS is a symptom that is found in many other sleep conditions, including sleep apnea or insomnia. What makes EDS different in narcolepsy, their drive to fall asleep comes on rapidly. Patients often describe these events as “sleep attacks.”

A second symptom helps in the diagnosis of narcolepsy, a muscle condition called cataplexy, where a person quickly, over the course of seconds, loses muscle tone. Cataplexy is temporary, and a person generally reverses out of this state over tens of seconds or minutes, rarely longer. There is a broad range of severity of the symptoms seen in cataplexy. In minor cases, a person may feel mild weakness in a localized area, like the forearm or face. In the most severe cases, muscle tone is lost across the whole body, causing a person to potentially collapse. Following a sleep attack, a person may also experience short term memory loss, as they forget what they were doing.

Many times, the presentation of a strong emotion, either positive (like happiness or excitement) or negative (such as stress or fear) can trigger the onset of a sleep attack. Cataplexy is sometimes misdiagnosed as a seizure, contributing to the under diagnosis of narcolepsy. Narcolepsy with cataplexy is categorized as Type I narcolepsy and is significantly more debilitating. In type II narcolepsy, cataplexy is not present.

Causes of narcolepsy

A definitive cause of narcolepsy has not yet been identified, but many clues point towards the action of the naturally-produced neuropeptide hypocretin. Hypocretin was first described by a research lab that identified interesting genes in the hypothalamus, and found one that was remarkably similar to a stomach peptide called secretin. The name “hypocretin” itself is a portmanteau of hypothalamus and secretin. (Confusingly, hypocretin is also called orexin in the literature - both molecules were identified by two different research laboratories around the same time.) In addition to regulation of sleep, hypocretin is known to play a variety of roles, including food intake and mood.

The typical human adult brain has less than 20,000 neurons that produce hypocretin. For some still-unknown reason, these neurons are injured or lost in some people, and the loss of hypocretin likely results in narcolepsy. Levels of hypocretin taken from samples of cerebrospinal fluid taken from a lumbar puncture are low in people with narcolepsy.

One theory has suggested that the loss of hypocretin signaling is an autoimmune disorder, a condition where the body mounts an immune response against itself. In this case, the body may start destroying their own hypocretin receptors, which are expressed at a variety of brain areas. The loss of these receptors may therefore lead to the dysregulation of healthy hypocretin signaling.

Relatedly, there are familial and genetic associations with narcolepsy, as an estimated 10% of people diagnosed with narcolepsy have a family member also with narcolepsy. The gene HLA-DQB1 is heavily implicated in narcolepsy, since certain variants present with elevated risk of narcolepsy over the general population, while other variants produce decreased risk (The impact of the HLA DQB1 gene and amino acids on the development of narcolepsy.)