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EDS Now is an initiative of the Rare Disease United Foundation. The sole purpose of EDS Now is to fund promising research into Hypermobile EDS and its comorbids. All funding will go directly to research and research related expenses. No salaries. No awareness campaigns. No conferences. No education. We are grateful there are so many wonderful organizations doing this work and don’t wish to duplicate efforts.
Recently there was some exciting research coming out of the NIH about hEDS and its comorbids. To learn more about this study, please click here.
EDS Now is working to fund this study. We have been working with the NIH to evaluate their findings and future plans regarding this study. We are very excited about this research and believe this is the link that millions of us have been looking for. The NIH is working globally with researchers in Italy, Slovenia and the UK. Below is a summary from the NIH outlining plans for the future of this study:
Through the study of genetic causes for allergy, we and others have made the observation that many inherited and severe allergic disorders are associated with connective tissue abnormalities; examples of these abnormalities include scoliosis (abnormal curvature of the spine), retained primary teeth, congenital malformations (such as abnormally shaped or forms bones and joints), joint hypermobility, and recurrent dislocation or ligament rupture.
One of the recent genetic disorders we discovered is caused by structural changes in the genome (as opposed to mutations). In this disorder we have called hereditary alpha tryptasemia (which means inherited high alpha-tryptase in the blood) individuals from affected families were identified with high basal serum tryptase levels in association with the connective tissue changes described above, but also in association with functional gastrointestinal (GI) disorders (such as irritable bowel syndrome or IBS), allergic-type symptoms both locally in the skin (such as flushing, swelling, or hives) and systemically (such as anaphylaxis) and symptoms of altered autonomic nervous system function, which often is referred to as positional orthostatic tachycardia syndrome, or POTS – reported symptoms included episodic racing heartbeat, low blood pressure, and even recurrent loss-of-consciousness.
In order to identify these individuals –now over 46 families and counting – we created a new genetic test using a technique called digital droplet PCR (ddPCR) to show that patients with this disorder were inheriting extra genetic copies of the alpha-tryptase gene (at TPSAB1). Interestingly, we also found that the more copies the patients had, the higher patients’ tryptase levels were, and the more severe patients’ symptoms were.
We have since found that having alpha-tryptase duplications is quite common among Caucasians (~5.5%), while up to 30% don’t have any alpha-tryptase. For reasons we do not yet know, the number of people with any alpha-tryptase is much lower in other ethnic groups.
Currently we are working towards two primary goals in the lab: 1) to determine the genotype tryptase genes in individuals with medical problems that we would have associated with the symptoms seen in our families, and 2) to determine how alpha- tryptase can lead to the clinical problems we observed.
To accomplish the first goal we are in the process of setting up a number of collaborations with researchers from academic centers around the world (including Italy, Slovenia, and the UK) and in the US that study specific disorders such as Ehlers-Danlos syndrome (EDS) type III or hypermobility sub-type or other similar connective tissue disorders and certain kinds of allergic disorders which cause anaphylaxis or skin symptoms. Using our genetic test we can determine how frequently these individuals have alpha-tryptase or extra alpha-tryptase genes.
Tryptase proteins, like their genetics, are complicated and incompletely understood. In addition to alpha-tryptase, a highly similar group of beta-tryptases, constitute the measureable tryptase in blood. Tryptase can exist as two different versions – pro- tryptase, a single protein (monomer) that we know very little about, or mature tryptase, a tetramer (or combined four protein structure) that is an enzyme, which cuts other proteins. Mature tryptases are better studied, and we know some of what the enzyme’s activity is normally, and how long it is stable in the body. All tryptases are made primarily in mast cells – allergic cells that reside in body tissues. These cells can become activated a number of ways in different people, and in addition to tryptase contain compounds like histamine. When mast cells are activated they can degranulate – a process during which they release tryptase and histamine. Mast cell activation and degranulation is a major component of immediate hypersensitivity allergic reactions, sometime called type I hypersensitivity reactions.
We hypothesize and have preliminary data suggesting that mast cell alpha-tryptase functions differently than beta-tryptases. Studying patients with extra alpha- tryptase copies and how alpha-tryptase behaves in a test tube will allow us gain insights into how alpha-tryptase may alter connective tissues. We also have reason to believe that alpha-tryptase, even in the absence of extra copies, may have physiologic effects. Consistent with this finding, in a small cohort of individuals with connective tissue abnormalities, we found that nearly all of the individuals had at least one alpha-tryptase copy. Through these studies we will identify the role that alpha-tryptases may play in patients with connective tissue abnormalities, characterize the mechanism by which this may occur, and lay the groundwork for future interventional studies, such as treatment trials targeting tryptase.
• We will perform tryptase genotyping using our novel genetic (ddPCR) test to determine genotype/phenotype correlations among patients with EDS type III (hypermobility type) and related disorders (CT)
• We will measure tryptase gene expression from CT patients using our novel gene expression test
• Through work with collaborators, we will characterize any differences in clinical symptoms based upon tryptase genotype and gene expression
• We will measure biomarkers to characterize turnover of connective tissues (eg. tendons, ligaments, and bone) in patients with extra alpha-tryptase copies and controls with known tryptase genes
• We will characterize collagen, a primary building block of connective tissues, from patient samples and control samples treated with tryptases • Finally, we will treat human collagen with mature mast cell tryptases to determine how collagen may be cleaved by enzymes that contain alpha- tryptase