Imagine standing in line at the supermarket when a sudden, irresistible bout of sleep — a “sleep attack” — that lasts anywhere from a few seconds to several minutes, overtakes you. Next, imagine this happening as you ride the train home from work. Painfully, such uncomfortable scenarios may be common to people who suffer from narcolepsy. Now European researchers have discovered that a specific allele or variant of a particular gene, which is within the human leukocyte antigen (HLA) system and related to immune function, is connected to this unusual brain disorder. "This almost 100 percent association with HLA is somehow unique to narcolepsy and suggests a causal implication," lead author Mehdi Tafti, professor at the University of Lausanne, stated in a press release. The ground-breaking research appears in the current issue of Sleep.
A rare but often disabling brain disorder, narcolepsy with cataplexy is estimated to affect about one in every 3,000 Americans while additional cases of the disorder without the cataplexy component may also exist. People with narcolepsy experience repeated daily episodes of an irrepressible need to sleep or lapses into sleep, which may occur suddenly. Cataplexy is another common symptom of the disorder and involves sudden muscle weakness — usually in the legs but also in the face and neck — that is caused by strong emotions such as laughter. Narcolepsy affects both males and female equally and appears throughout the world, though unevenly. It is most common in Japan, for instance, while being very rare in Israel. The condition is life-long and symptoms, including “sleep attacks” and cataplexy, generally start in childhood or adolescence, though in some cases they begin later in life.
Narcolepsy is considered to be both underrecognized and underdiagnosed, in part due to the difficulty of finding an appropriate diagnostic test. It is known, for example, that most patients with narcolepsy do not produce hypocretin in a deep part of the brain called the hypothalamus; prior studies have also identified five common genetic variants linked to narcolepsy with cataplexy. “Because of the discovery of the HLA association, narcolepsy is believed to be an autoimmune disease,” wrote the authors in their study. “The discovery of hypocretin (orexin) deficiency in narcolepsy with cataplexy raised the possibility that hypothalamic hypocretin-producing neurons might be the target of an autoimmune attack, motivating the search for potential genetic mechanisms.”
Seeking, then, a more precise explanation of the condition, a team of European researchers investigated HLA-DQB1, the previously identified five variants linked to the condition as well as 10 other potential variants in a sample of 1,261 European patients who have narcolepsy with cataplexy symptoms. These same patients also made their complete diagnostic work-up and their DNA freely available to the study effort. After matching these patients with 1,422 controls, the researchers began high-resolution genotyping to identify genetic variants including those in the HLA system.
Remarkably, they discovered a more definite relationship between the disorder and the genetic variants than they expected. Their results showed that participants with the HLA allele DQB1*06:02 were 251 times more likely to have narcolepsy with cataplexy than participants without the allele. In fact, the scientists discovered that DQB1*06:02 had a negative predictive value of 99.32 percent. This means that nearly 100 percent of patients who suffer narcolepsy with cataplexy are DQB1*06:02 positive. “An overwhelming portion of genetic risk for narcolepsy with cataplexy is found at DQB1 locus,” wrote the authors in their study. “Since DQB1*06:02 positive subjects are at 251-fold increase in risk for narcolepsy … DQB1 genotyping may be relevant to public health policy.” More proof, then, that as human genome studies unfold, the more personal — and more effective — medicine should soon become.
Source: Tafti M, Hor H, Watson N, et al. DQB1 Locus Alone Explains Most of the Risk and Protection in Narcolepsy with Cataplexy in Europe. Sleep. 2014.