Ehlers-Danlos syndrome (EDS) is a group of inherited conditions in which the body’s supporting tissue is built weaker than it should be. In most types, a change in one gene disrupts how collagen, the body’s main structural protein, is made or assembled.1PubMed. The 2017 international classification of the Ehlers-Danlos syndromes The type most people are diagnosed with, hypermobile EDS, has no single known gene, and its causes appear to reach beyond collagen.2PubMed. The 2017 international classification of the Ehlers-Danlos syndromes3Genes. Researchers Identify Previously Unrecognized Genetic Variants, Patterns Associated with Hypermobile Ehlers–Danlos Syndrome So what “a collagen defect” means depends heavily on which type of EDS a person has.
How Healthy Collagen Is Built
Collagen is the most abundant protein in the body. It gives skin, tendons, ligaments and blood vessel walls their toughness, but each tissue uses its own mix of collagen types in its own proportions. Skin needs strength with some give. Ligaments have to resist stretching so that joints stay stable.
Each collagen molecule is three protein strands wound tightly around each other like a rope. The strands can twist into this regular shape because they follow a strict repeating pattern of building blocks.4PubMed Central. Collagen triple-helix formation in all-trans chains proceeds by a nucleation/growth mechanism with a purely entropic barrier The twist starts at a small stretch at one end, then zips closed quickly along the rest of the strand.5PubMed Central. Collagen triple-helix formation in all-trans chains proceeds by a nucleation/growth mechanism with a purely entropic barrier The smallest building block, glycine, sits at every third position, because only that tiny piece fits in the tight center of the rope. If a larger block replaces one of those glycines, it can’t fit, and the rope twists poorly or slowly around that spot. A mistake at one point in the pattern can therefore spoil the whole rope. That is also why changes that swap out one of these key blocks often cause more severe disease than changes that simply stop a gene from working.
Making the rope is only the first stage. Before collagen leaves the cell, enzymes chemically modify some of its building blocks.6Journal of Cell Science / Matrix Biology / Reactome Guide. Collagen biosynthesis and modifying enzymes Pathway These changes hold the triple strand stable and later let neighbouring molecules lock together.7Journal of Cell Science / Matrix Biology / Reactome Guide. Collagen biosynthesis and modifying enzymes Pathway Outside the cell, cutting enzymes trim the loose ends off each molecule.8Journal of Clinical Investigation. The Ehlers-Danlos syndrome: on beyond collagens The trimmed molecules then bundle side by side into fibers, and cross-links between them give collagen its pulling strength.9PubMed. Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI
Classic EDS and the Collagen That Starts Fibers
Type V collagen is a minor collagen that mixes into fibers made mostly of type I, the main collagen in skin and tendons.10PubMed. Type V Collagen in Health, Disease, and Fibrosis Despite its small share, the body needs it to start building those fibers in the first place.11PubMed Central. Molecular alterations due to Col5a1 haploinsufficiency in a mouse model of classic Ehlers–Danlos syndrome The more type V is present, the thinner and more even the fibers turn out.12PubMed. Collagen fibrillogenesis in vitro: interaction of types I and V collagen regulates fibril diameter In mice with no type V at all, fibers hardly form and the embryos don’t survive.13PubMed. Type V collagen controls the initiation of collagen fibril assembly
In most people with classic EDS, one copy of the COL5A1 gene doesn’t work, so they make roughly half the normal type V collagen.14PubMed. Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type In a smaller group, a gene change produces a faulty type V protein instead.15PubMed. Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type In nearly every case, the shared problem is too little usable type V collagen.16PubMed. COL5A1 signal peptide mutations interfere with protein secretion and cause classic Ehlers-Danlos syndrome
Fiber starting is very sensitive to the amount of type V, so the fibers that form grow irregularly. In mice with half the type V collagen, skin had about half the usual number of fibers, and some were large and malformed.17PubMed. Type V collagen controls the initiation of collagen fibril assembly The faulty tissue also sends altered chemical signals to cells, which may help explain poor healing and wide scars.18PubMed Central. Molecular alterations due to Col5a1 haploinsufficiency in a mouse model of classic Ehlers–Danlos syndrome In a person, this shows up as soft, stretchy skin that springs back, skin that splits after minor bumps and heals with wide, thin scars, and joints that bend past the normal range.
Because one faulty gene copy is enough, classic EDS is usually inherited in a dominant pattern. Each child of an affected parent has a 50 percent chance of inheriting it. Severity can differ within a family, so a parent with mild features can have a child with more obvious ones. Sometimes the gene change arises newly in a person with no family history, so a lack of affected relatives doesn’t rule it out.
Vascular EDS and Faulty Type III Collagen
Vascular EDS (vEDS) is caused by changes in COL3A1, the gene for type III collagen, which lines hollow organs like arteries and the bowel. Type III collagen is a rope of three identical strands, so every molecule is built from three copies of the gene’s product. When a faulty strand twists together with normal strands, the whole rope is defective.19PubMed Central. Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome A person can therefore end up with far less working type III collagen than half.20PubMed Central. Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome The faulty collagen also disrupts the elastic fibers that let artery walls stretch and recoil.21PubMed Central. Transcriptome analysis of skin fibroblasts with dominant negative COL3A1 mutations provides molecular insights into the etiopathology of vascular Ehlers-Danlos syndrome
Missing collagen alone can still be serious. Having only one working copy of COL3A1 was once thought to cause mild disease.22European Journal of Human Genetics. Homozygosity for a null allele of COL3A1 results in recessive Ehlers–Danlos syndrome Yet some people with it have symptoms like full vascular EDS, while relatives with the same change stay healthy.23European Journal of Human Genetics. Homozygosity for a null allele of COL3A1 results in recessive Ehlers–Danlos syndrome Mice with half the type III collagen had weaker aorta and bowel walls.24PubMed Central. The Haploinsufficient Col3a1 Mouse as a Model for Vascular Ehlers-Danlos Syndrome
Vascular EDS differs from classic EDS in several ways. Skin is often thin and see-through rather than very stretchy, and joint looseness is usually limited to the fingers. The main danger is sudden tears in arteries or bowel, often in young adults. Because knowing the type changes medical care, genetic testing matters.
Pregnancy shows how fragile these tissues are. In one large group of women with vascular EDS, about 1 in 7 deliveries had a life-threatening complication.25Genetics in Medicine. Pregnancy-related deaths and complications in women with vascular Ehlers–Danlos syndrome These included artery tears and uterine rupture, and about 1 in 15 deliveries ended in the mother’s death.26Genetics in Medicine. Pregnancy-related deaths and complications in women with vascular Ehlers–Danlos syndrome Women with vascular EDS should plan pregnancy with specialists and deliver in a high-risk centre.27PubMed. Pregnancy complications in type IV Ehlers-Danlos Syndrome
Rarer Types Where Collagen Isn’t Finished Properly
Some types come from faults in the enzymes that modify, cross-link or trim collagen, rather than in collagen itself. In one rare type, people lack the enzyme that prepares collagen to cross-link.28PubMed. Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI Without it the molecules can’t be properly riveted together, so fibers can’t lock firmly and lose pulling strength.29PubMed. Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI
If the loose ends of collagen aren’t cut off, the molecules stay bulky and can’t pack properly into fibers.30Journal of Clinical Investigation. The Ehlers-Danlos syndrome: on beyond collagens Some changes in type I collagen genes block trimming and cause very loose joints, a type called arthrochalasia.31Journal of Clinical Investigation. The Ehlers-Danlos syndrome: on beyond collagens Losing the trimming enzyme itself causes extremely fragile skin, called dermatosparaxis.32Journal of Clinical Investigation. The Ehlers-Danlos syndrome: on beyond collagens Fibers in this type look ragged and irregular under a microscope.33PubMed Central. An Adamts2 Knock-In Model of Dermatosparaxis Ehlers–Danlos Syndrome Reveals Defective Collagen Maturation
Enzyme types usually need a faulty copy from both parents. The parents are often healthy carriers, and each of their children has a 1 in 4 chance of being affected.
The 2017 classification lists 13 types. Symptoms overlap between them, which is why genetic testing is usually needed to confirm the type.
Hypermobile EDS and Causes Beyond Collagen
Not all EDS is about collagen. A form of EDS caused by missing tenascin-X, a protein that organises tissue around collagen, showed that EDS isn’t only a collagen disease.34PubMed. Elastic fiber abnormalities in hypermobility type Ehlers-Danlos syndrome patients with tenascin-X mutations When it is missing, the supporting tissue is still built poorly even though the collagen genes are normal. People with this form had loose joints, stretchy skin and easy bruising, but not the wide scars of classic EDS.35PubMed. A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency Having half the normal tenascin-X has also been linked to some cases of the hypermobile type.36PubMed. Elastic fiber abnormalities in hypermobility type Ehlers-Danlos syndrome patients with tenascin-X mutations
Hypermobile EDS is the only type that can’t yet be confirmed with a genetic test.37PubMed. The 2017 international classification of the Ehlers-Danlos syndromes People with it carry more gene differences in collagen-making, immune and cell-energy pathways than people without it.38Genes. Researchers Identify Previously Unrecognized Genetic Variants, Patterns Associated with Hypermobile Ehlers–Danlos Syndrome A large gene study also found a risk region near a gene involved in nerves and pain signalling.39medRxiv. Complex Genetics and Regulatory Drivers of Hypermobile Ehlers-Danlos Syndrome: Insights from Genome-Wide Association Study Meta-analysis Instead of one broken gene, each person may carry a mix of small variations that together nudge tissue toward looseness. That could explain why hypermobile EDS clusters in families without following a clean single-gene pattern, and why relatives can have the same condition with different symptoms.
Tissues still behave differently from normal. People with hypermobile EDS had stiffer-than-normal muscles less often and a softer Achilles tendon than people without it.40PubMed. Muscle-tendon tissue properties in the hypermobility type of Ehlers-Danlos syndrome In classic EDS, though, tendons were about half as stiff as normal, a much bigger change.41PubMed. Low tendon stiffness and abnormal ultrastructure distinguish classic Ehlers-Danlos syndrome from benign joint hypermobility syndrome in patients
For diagnosis, this means hypermobile EDS is identified by a checklist of physical signs and history, not a blood test. A negative gene test doesn’t rule it out, though gene tests can still exclude other types like vascular EDS. Research findings such as immune variants aren’t diagnostic tests yet.
Why EDS Causes Pain, Dizziness and Gut Problems
Loose connective tissue may let veins stretch more, so blood pools in the legs when standing.42PubMed Central. An overview of Ehlers Danlos syndrome and the link between postural orthostatic tachycardia syndrome and gastrointestinal symptoms with a focus on gastroparesis Normally the veins tighten to push blood back up; with looser vein walls, less returns to the heart and brain. The heart speeds up to compensate, which causes the racing pulse, lightheadedness and sometimes a feeling of being close to fainting. Many people get POTS (postural orthostatic tachycardia syndrome) this way.43PubMed. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome About three in four people with hypermobile EDS had trouble standing upright, versus one in three without it.44PubMed. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome Across studies, POTS affects anywhere from about 1 in 6 to 9 in 10 people with EDS, depending on the group.45PubMed. The co-existence of Ehlers-Danlos syndrome and postural orthostatic tachycardia syndrome: A systematic review of the literature
Pain often involves damaged nerves. Small fiber neuropathy, damage to the tiny pain-sensing nerves in the skin, was found in all EDS types in one study.46PubMed Central. Small fiber neuropathy is a common feature of Ehlers-Danlos syndromes In hypermobile EDS, most people showed signs of it, and only about 1 in 10 clearly didn’t have it.47PubMed Central. Small fiber neuropathy in hypermobile Ehlers Danlos syndrome/hypermobility spectrum disorder Pain also comes from unstable joints, muscles and a nervous system that becomes oversensitive.48PubMed Central. Small fiber neuropathy in hypermobile Ehlers Danlos syndrome/hypermobility spectrum disorder In mice with type V collagen loss, pain nerves in the skin were disorganised.49PubMed Central. Tenascin-X as a causal gene for classical-like Ehlers-Danlos syndrome
Gut problems may come from the gut wall too. Slow gut movement in EDS may come from nerve problems or changes in the tissue that holds the gut wall together.50PubMed Central. Prevalence and Predictors of Gastrointestinal Dysmotility in Patients with Hypermobile Ehlers-Danlos Syndrome: A Tertiary Care Center Experience
A few practical steps follow from this. If you get dizzy on standing, ask your doctor about a standing heart-rate test. Fluids, salt and compression garments are common first steps doctors suggest for POTS. Burning or tingling pain may respond to nerve-pain treatments rather than standard painkillers, and a skin biopsy can check for damage to the tiny pain-sensing nerves in the skin.
Why Wounds Heal Poorly
Wound healing is impaired to some degree in every type of EDS.51PubMed. Skin fragility and wound management in Ehlers-Danlos syndromes: a report by the International Consortium on Ehlers-Danlos Syndromes and Hypermobility Spectrum Disorders Skin Working Group Healing needs new collagen to be laid down in an organised pattern, and in EDS the repair tissue is built from the same faulty materials. In mice lacking type V collagen in skin, new fibers ran in random directions instead of lining up.52PubMed Central. Modulating the extracellular matrix to treat wound healing defects in Ehlers-Danlos syndrome About a quarter of wounds were still open after nearly three weeks, and scars were larger.53PubMed Central. Modulating the extracellular matrix to treat wound healing defects in Ehlers-Danlos syndrome Even a small cut can take longer to close and may reopen. Thin, shiny, wide “cigarette paper” scars are typical of classic EDS.
Tell surgeons and dentists about EDS beforehand. Wounds often need more stitches left in longer, or adhesive strips. Protect shins and knees, where splits are common, and expect scars to widen over months.
Treatments Aimed at the Cause
Collagen defects can’t be fixed yet. Researchers are developing gene-editing tools that could correct or silence a faulty collagen gene.54PubMed Central. Gene editing for collagen disorders: current advances and future perspectives One approach would use a harmless virus or tiny particles to deliver the correction for vascular EDS.55Journal of Rare Diseases Research & Treatment. Vascular Ehlers-Danlos Syndrome: Current Understanding and Treatment Strategies In mice with vascular EDS, existing drugs that block an overactive signal raised survival from about half to about nine in ten.56The Journal of Clinical Investigation. Targetable cellular signaling events mediate vascular pathology in vascular Ehlers-Danlos syndrome These results are in mice, and none is an approved EDS treatment.
Fixing collagen genes is hard. Collagen is made in many tissues and the body needs very precise amounts, so a treatment has to correct the fault without disrupting normal collagen. In dominant conditions the faulty copy can harm the healthy one, so silencing the faulty copy may matter more than adding a good one. Delivering a treatment to the right tissues, such as artery walls, is a major challenge.
Care today is about managing symptoms: physiotherapy to strengthen muscles around loose joints, blood pressure control and regular scans in vascular EDS, pain and POTS management tailored to the person, and genetic counselling for family planning. A confirmed type allows testing of relatives, and research trials usually require one.