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Ehlers–Danlos syndromes (EDS) are a group of 13 genetic connective-tissue disorders. Symptoms often include loose joints, joint pain, stretchy velvety skin, and abnormal scar formation. These may be noticed at birth or in early childhood. Complications may include aortic dissection, joint dislocations, scoliosis, chronic pain, or early osteoarthritis. The current classification was last updated in 2017, when a number of rarer forms of EDS were added. EDS occurs due to variations of more than 19 genes that are present at birth. The specific gene affected determines the type of EDS, though the genetic causes of hypermobile Ehlers–Danlos syndrome (hEDS) are still unknown. Some cases result from a new variation occurring during early development, while others are inherited in an autosomal dominant or recessive manner. Typically, these variations result in defects in the structure or processing of the protein collagen or tenascin. Diagnosis is often based on symptoms and confirmed by genetic testing or skin biopsy, particularly with hEDS, but people may initially be misdiagnosed with hypochondriasis, depression, or myalgic encephalomyelitis/chronic fatigue syndrome. Genetic testing can be used to confirm all other types of EDS. A cure is not yet known, and treatment is supportive in nature. Physical therapy and bracing may help strengthen muscles and support joints. Some forms of EDS result in a normal life expectancy, but those that affect blood vessels generally decrease it. All forms of EDS can result in fatal outcomes for some patients. While hEDS affects at least one in 5,000 people globally, other types occur at lower frequencies. The prognosis depends on the specific disorder. Excess mobility was first described by Hippocrates in 400 BC. The syndromes are named after two physicians, Edvard Ehlers and Henri-Alexandre Danlos, who described them at the turn of the 20th century. Types In 2017, 13 subtypes of EDS were classified using specific diagnostic criteria. According to the Ehlers–Danlos Society, the syndromes can also be grouped by the symptoms determined by specific gene mutations. Group A disorders are those that affect primary collagen structure and processing. Group B disorders affect collagen folding and crosslinking. Group C are disorders of structure and function of myomatrix. Group D disorders are those that affect glycosaminoglycan biosynthesis. Group E disorders are characterized by defects in the complement pathway. Group F are disorders of intracellular processes, and Group G is considered to be unresolved forms of EDS. Hypermobile EDS (hEDS) Hypermobile EDS (hEDS, formerly categorized as type 3) is mainly characterized by hypermobility that affects both large and small joints. It may lead to frequent joint subluxations (partial dislocations) and dislocations. In general, people with this variant have skin that is soft, smooth, and velvety and bruises easily, and may have chronic muscle and/or bone pain. It affects the skin less than other forms. It has no available genetic test. hEDS is the most common of the 19 types of connective tissue disorders. Since no genetic test exists, providers have to diagnose hEDS based on what they know about the condition and the patient's physical attributes. Other than the general signs, attributes can include faulty connective tissues throughout the body, musculoskeletal issues, and family history. Along with these general signs and side effects, patients can have trouble healing. Pregnant individuals who have hEDS are at an increased risk for complications. Some possible complications are pre-labor rupture of membranes, a drop in blood pressure with anesthesia, precipitate birth (very fast, active labor), malposition of the fetus, and increased bleeding. Individuals with hEDS may run the risk of falling, postpartum depression (more than the general population), and slow healing from the birthing process. The Medical University of South Carolina discovered a gene variant common with hEDS patients. Genetics of hypermobile EDS While 12 of the 13 subtypes of EDS have genetic variations that can be tested for by genetic testing, there is no known genetic cause of hEDS. Recently, several labs and research initiatives have been attempting to uncover a potential hEDS gene. In 2018, the Ehlers–Danlos Society began the Hypermobile Ehlers–Danlos Genetic Evaluation (HEDGE) study. The ongoing study has screened over 1,000 people who have been diagnosed with hEDS by the 2017 criteria to evaluate their genome for a common mutation. To date, 200 people with hEDS have had whole genome sequencing, and 500 have had whole exome sequencing; this study aims to increase those numbers significantly. Promising outcomes of this increased screening have been reported by the Norris Lab, led by Russell Norris, in the Department of Regenerative Medicine and Cell Biology at Medical University of South Carolina. Using CRISPR Cas-9 mediated genome editing on mouse models of the disease, the lab has recently identified a "very strong candidate gene" for hEDS. This finding, and a greater understanding of cardiac complications associated with the majority of EDS subtypes, has led to the development of multiple druggable pathways involved in aortic and mitral valve diseases. While this candidate gene has not been publicly identified, the Norris lab has conducted several studies involving small population genome sequencing and come up with a working list of possible hEDS genes. A mutation in COL3A1 in a single family with autosomal dominant hEDS phenotype was found to cause reduced collagen secretion and an over-modification of collagen. In 35 families, copy number alterations in TPSAB1, encoding alpha-tryptase, were associated with increased basal serum tryptase levels, associated with autonomic dysfunction, gastrointestinal disorders, allergic and cutaneous symptoms, and connective tissue abnormalities, all concurrent with hEDS phenotype. Lastly, Tenascin X, an extracellular matrix protein important for collagen mutation encoded by the TNXB gene, has been associated with hEDS in patients with Tenascin X deficiency. Another way the Norris lab is attempting to find this gene is by looking at genes involved in the formation of the aorta and mitral valves, as these valves are often prolapsed or malformed as a symptom of EDS. Because hEDS is such a complex, multi-organ disease, focusing on one hallmark trait has proven successful. One gene found this way is DZIP1, which regulates cardiac valve development in mammals through a CBY1-beta-catenin mechanism. Mutations at this gene affect the beta-catenin cascade involved in development, causing malformation of the extracellular matrix, resulting in loss of collagen. A lack of collagen here is both consistent with hEDS and explains the "floppy" mitral and aortic valve heart defects. A second genetic study specific to mitral valve prolapse focused on the PDGF signaling pathway, which is involved in growth f.... Discover the K Grahame popular books. Find the top 100 most popular K Grahame books.