From genes to joints: how Ehler-Danos Syndrome is shaped by genetics

09/01/25, 12:17

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Mutations in collagen and related proteins are the primary cause of EDS

Ehlers-Danlos Syndrome (EDS) is a group of 13 inherited disorders that affect connective tissues, particularly collagen. Collagen is a crucial protein in the body that provides structure and strength to skin, joints, and blood vessels. Mutations in collagen or collagen-modifying proteins are the primary cause of the types of EDS.

EDS manifests through a range of symptoms that vary significantly depending on the specific type of EDS. However, there are common symptoms that many individuals with EDS experience, particularly related to joint and skin issues. For instance, joints can move beyond the normal range, leading to frequent dislocations and subluxations, also called joint hypermobility. Additionally, the skin can be stretched more than usual, which creates a soft and velvety appearance known as skin hyperextensibility. As mentioned in Figure 1, skin bruising, scarring and tearing are common symptoms, leading to individuals often experiencing chronic pain.

Life expectancy for individuals with EDS varies depending on the type of disorder an individual has. This is due to how specific forms can have structural changes in organs and tissues, which can lead to serious life-threatening complications. For example, vascular EDS (vEDS) is associated with a significantly reduced life expectancy due to the risk of spontaneous rupture of major blood vessels, intestines, and other hollow organs. Most other forms of EDS, such as classical EDS (cEDS), hypermobile EDS (hEDS), and kyphoscoliotic EDS (kEDS), generally do not significantly affect life expectancy. However, the health complications that patients have can substantially impact their quality of life.

Genetic basis

As stated, the various types of EDS encompass many genetic defects, for example, cEDS is linked to mutations in the COL5A1 or COL5A2 genes, which encode the α1 and α2 chains of type V collagen. Following an autosomal dominant inheritance pattern, 50% of cEDS diagnoses inherit the condition from an affected parent, while the other half from a new (de novo) pathogenic variant. Diagnosing EDS encompasses a variety of methods. Firstly, differential diagnosis may be used to distinguish between subtypes like cEDS and hEDS by evaluating clinical features such as the presence of joint hypermobility, skin characteristics, and scarring patterns. Clinicians use these specific symptoms along with family history to differentiate between the subtypes since some, like hEDS, lack identified genetic markers, making this clinical assessment essential for accurate diagnosis and management. This process helps exclude other conditions and accurately identify the EDS subtype. Also, suggestive clinical features identifying pathogenic or likely pathogenic variants in the COL5A1 or COL5A2 genes can be done through molecular genetic testing. This testing can be approached in two ways: targeted multigene panels, which focus on specific genes like COL5A1 and COL5A2. Alternatively, comprehensive genomic testing, such as exome or genome sequencing, does not require preselecting specific genes and is useful when the clinical presentation overlaps with other inherited disorders.

Mutations in COL5A1 and COL5A2 can include missense, nonsense, splice site variants, or small insertions and deletions, all of which impair the function of type V collagen. Missense mutations result in the substitution of one amino acid for another, disrupting the collagen triple helix structure and affecting its stability and function. On the other hand, nonsense mutations lead to a premature stop codon, producing a truncated and usually non-functional protein. Splice site mutations interfere with the normal splicing of pre-mRNA, resulting in aberrant proteins. These mutations in COL5A1 and COL5A2 lead to the characteristic features of cEDS, such as highly elastic skin and joint hypermobility.

Furthermore, different types of EDS are caused by specific genetic mutations, each affecting collagen in distinct ways and necessitating varied treatment approaches. VEDS is caused by mutations in the COL3A1 gene, which affects type III collagen and leads to fragile blood vessels and a higher risk of organ rupture. kEDS results from mutations in the PLOD1 or FKBP14 genes, impacting collagen cross-linking, and presents with severe scoliosis and muscle hypotonia. Arthrochalasia EDS (aEDS), due to mutations in the COL1A1 or COL1A2 genes that affect type I collagen, features severe joint hypermobility and congenital hip dislocation. Dermatosparaxis EDS (dEDS) is caused by mutations in the ADAMTS2 gene, which is crucial for processing type I collagen, leading to extremely fragile skin and severe bruising. Each type of EDS highlights the critical role of specific genetic mutations in the structural integrity and function of collagen, which consequently influences treatment approaches.

Treatment

Treatments for EDS primarily focus on managing symptoms and preventing complications due to the underlying genetic defects affecting collagen. Pain relief through nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and sometimes opioids is common, addressing chronic pain related to joint and muscle issues. Moreover, physical therapy may help strengthen muscles around hypermobile joints, reducing the risk of dislocations and improving stability. Orthopaedic interventions, such as braces and orthotics, are also used to support joint function, and surgery may be considered in severe cases. Cardiovascular care is crucial, especially for vEDS, involving regular monitoring with imaging techniques to detect arterial problems early. Preventive vascular surgery might be necessary to repair aneurysms or other vascular defects. Wound care includes using specialised dressings to handle fragile skin and prevent extensive scarring, relevant to mutations in genes like COL5A1 and COL5A2 in classical EDS. Understanding the specific genetic mutations helps tailor these treatments to address the particular collagen-related defects and associated complications in different EDS types.

Moreover, clinical trials for treating EDS have shown both positive and negative results. For example, trials investigating the efficacy of physical therapy in strengthening muscles around hypermobile joints have shown positive outcomes in reducing joint instability and improving function. On the other hand, trials aiming to directly modify the underlying genetic defects in collagen production have faced significant challenges. Gene therapy approaches and other experimental treatments targeting specific mutations, such as those in COL5A1 or COL3A1 genes, have shown limited success and faced hurdles in achieving sufficient therapeutic benefit without adverse effects. This is evident as in mouse models the deletion of COL3A1 resulted in aortic and gastrointestinal rupture meaning that simply restoring one functional copy may not be sufficient to prevent the disease. Moreover, the unknown and partial success in identifying mutations responsible for all EDS cases has further bolstered the struggle for researchers to establish comprehensive treatment strategies.

In vEDS, as it is a dominantly inherited disorder, adding a healthy copy of the gene (a common strategy in gene therapy) is ineffective because the defective gene still produces harmful proteins. Research has highlighted, however, that the combination of RNAi-mediated mutant allele-specific gene silencing and transcriptional activation of a normal allele could help as a promising strategy for vascular Ehlers-Danlos Syndrome. In the experiment, researchers used small interfering RNA (siRNA) to selectively reduce the mutant COL3A1 mRNA levels by up to 80%, while simultaneously using lysyl oxidase (LOX) to boost the expression of the normal COL3A1 gene. This dual approach successfully increased the levels of functional COL3A1 mRNA in patient cells, suggesting a potential therapeutic strategy for this condition.

Conclusion

In conclusion, EDS represents a diverse group of inherited connective tissue disorders, primarily caused by mutations in collagen or collagen-modifying proteins. These genetic defects result in a wide range of symptoms, including joint hypermobility, skin hyperextensibility, and vascular complications, which vary significantly across the 13 different types of EDS. Diagnosing and treating EDS is complex and largely dependent on the specific genetic mutations involved. While current treatments mainly focus on managing symptoms and preventing complications, advances in genetic research, such as RNAi-mediated gene silencing and transcriptional activation, show promise for more targeted therapies, especially for severe forms like vascular EDS. However, challenges remain in developing comprehensive and effective treatments, underscoring the need for ongoing research and personalised medical approaches to improve the quality of life for individuals with EDS.

Written by Imron Shah

REFERENCES

Malfait, F., Wenstrup, R.J. and De Paepe, A. (2010). Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type. Genetics in Medicine, 12(10), pp.597–605. doi:https://doi.org/10.1097/gim.0b013e3181eed412.

Miklovic, T. and Sieg, V.C. (2023). Ehlers Danlos Syndrome. [online] PubMed. Available at: https://www.ncbi.nlm.nih.gov/books/NBK549814/.

Sobey, G. (2014). Ehlers–Danlos syndrome – a commonly misunderstood group of conditions. Clinical Medicine, [online] 14(4), pp.432–436. doi:https://doi.org/10.7861/clinmedicine.14-4-432.

Watanabe, A., Wada, T., Tei, K., Hata, R., Fukushima, Y. and Shimada, T. (2005). 618. A Novel Gene Therapy Strategy for Vascular Ehlers-Danlos Syndrome by the Combination with RNAi Mediated Inhibition of a Mutant Allele and Transcriptional Activation of a Normal Allele. Molecular Therapy, [online] 11, p.S240. doi:https://doi.org/10.1016/j.ymthe.2005.07.158.

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Figure 1- How symptoms are commonly viewed in EDS

Figure 3- Normal knee joint vs one with EDS