Investigators at the National Institute of Allergy and Infectious Diseases (NIAID), a division of the National Institutes of Health (NIH), have uncovered a genetic explanation for a syndrome characterized by multiple frustrating and difficult-to-treat symptoms, including dizziness, skin flushing and itching, gastrointestinal complaints, chronic pain, and bone and joint problems. The investigators summarized their results in a study that was published recently in the journal Nature Genetics, in an article entitled, “Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number.”
The researchers found that some individuals who experience these diverse symptoms have elevated levels of the enzyme tryptase—a protein in the blood often associated with allergic reactions. The scientists surmised that multiple copies of the alpha tryptase gene are driving the tryptase elevations and may contribute to the experienced symptoms.
"This work suggests that multiple alpha tryptase gene copies might underlie health issues that affect a substantial number of people," explained NIAID director Anthony Fauci, M.D., who was not directly involved in the study. "Identifying one genetic cause for high tryptase opens the door for us to develop strategies for diagnosing and treating people carrying this genetic change."
Previous studies revealed that a combination of chronic and sometimes debilitating symptoms, such as hives, irritable bowel syndrome, and overly flexible joints, ran in some families and was associated with high tryptase levels. Interestingly, many affected family members with high tryptase also reported symptoms consistent with disorders of autonomic nervous system function (dysautonomia), including postural orthostatic tachycardia syndrome (POTS)—dizziness, faintness, and an elevated heartbeat when standing up.
In the current study, the NIAID researchers were able to identify a genetic cause of high tryptase by studying these severely affected families. Initial work pointed the researchers to the alpha tryptase gene, for which they designed a novel laboratory test to detect the number of alpha tryptase gene copies. Analysis of 96 affected and 41 unaffected members from 35 families confirmed that all affected family members had inherited multiple copies of the alpha tryptase gene. These results led the research team to conclude that the additional copies were causing increased production and release of alpha tryptase protein from immune cells.
Additionally, the scientists found that extra gene copies were associated with more severe effects. Family members with three copies of the alpha tryptase gene had higher tryptase levels and reported experiencing more symptoms than those who had two copies.
"These families had gone for years without a medical diagnosis, and many had been told that some of their symptoms were 'all in your head.' These results not only provide a genetic explanation for the combination of symptoms that these patients experience, but also point the way to a potential solution," noted senior study investigator Joshua Milner, M.D., chief of the Genetics and Pathogenesis of Allergy Section in NIAID's Laboratory of Allergic Diseases. "If we can devise a way to block alpha tryptase, we might be able to alleviate some or all of the symptoms related to elevated tryptase levels."
The researchers felt it essential to investigate these genetic changes among a general population. They assessed a group of NIH patients who had their DNA sequenced for reasons unrelated to tryptase, as well as a group of unrelated healthy volunteers—172 people in total. To the scientists' surprise, all those with high blood levels of tryptase also had duplications of the alpha tryptase gene. Many individuals with the duplicate gene reported experiencing symptoms similar to those seen in the original group of severely affected families, including irritable bowel syndrome, skin flushing, and itching.
"The families we originally studied may be among the more severely affected on a spectrum of disease, while some people with alpha tryptase gene duplications experience few or mild symptoms," remarked lead study author Jonathan Lyons, M.D., an assistant clinical investigator in NIAID's Laboratory of Allergic Diseases. "Additionally, it's important to note that many people with normal tryptase levels also suffer from these problems. We hope that our study opens the door for future work to understand the cause of their symptoms as well."