Ehlers-Danlos Syndrome (EDS) is a heterogeneous group of hereditary connective tissue disorders characterized by hyperextensible skin, hypermobile joints, and tissue fragility. The underlying pathophysiology of EDS is primarily due to mutations in genes responsible for the biosynthesis, processing, or structure of collagen, which is the most abundant protein in the extracellular matrix of connective tissues. Collagen provides essential tensile strength and elasticity to tissues, and defects in its production or assembly can lead to the diverse clinical manifestations observed in EDS.

The pathophysiology of EDS is rooted in mutations in various genes responsible for the structure and function of collagen and other proteins critical to connective tissue integrity. The most common forms of EDS are linked to mutations in the COL5A1 and COL5A2 genes, which code for type V collagen, a crucial component of the collagen fibrils that provide structural support to tissues. These mutations result in abnormal collagen fibril formation, leading to increased elasticity and fragility of the connective tissues. Additionally, certain types of EDS involve mutations in the COL1A1, COL1A2, and COL3A1 genes, affecting type I and type III collagen, respectively, and further compromising tissue integrity. The hypermobility and fragility seen in EDS patients are due to the resultant faulty collagen matrix, which fails to provide adequate mechanical strength and stability. Furthermore, defects in the enzymes involved in post-translational modification of collagen, such as lysyl hydroxylase (encoded by the PLOD1 gene in the kyphoscoliotic type of EDS), impair the cross-linking of collagen fibers, exacerbating tissue weakness. The vascular type of EDS, caused by mutations in the COL3A1 gene, is particularly severe due to the critical role of type III collagen in blood vessel walls, predisposing patients to life-threatening vascular complications. Understanding the molecular basis of EDS highlights the importance of collagen in maintaining connective tissue integrity and provides insight into potential therapeutic targets for managing this complex and varied group of disorders.

The most common forms of EDS, such as the classical type, are typically associated with mutations in the COL5A1 and COL5A2 genes. These genes encode the α-chains of type V collagen, a regulatory fibrillar collagen that co-assembles with type I collagen, which is critical for the formation of mature collagen fibrils. Mutations in these genes can result in the production of structurally abnormal collagen fibrils, leading to skin that is excessively stretchy, fragile, and prone to bruising. Joints may be hypermobile due to the insufficient structural support provided by the defective collagen, leading to frequent dislocations and chronic joint pain.

In the vascular type of EDS, which is one of the most severe forms, mutations in the COL3A1 gene are responsible. This gene encodes type III collagen, which is essential for the integrity of hollow organs and blood vessel walls. Defective type III collagen in vascular EDS patients leads to significant risks of arterial, intestinal, and uterine rupture, often manifesting in spontaneous, life-threatening bleeding episodes and organ perforations. This underscores the critical role of type III collagen in maintaining the structural integrity of major blood vessels and other hollow structures in the body.

Additionally, kyphoscoliotic EDS, a rarer type, is associated with mutations in the PLOD1 gene, which encodes lysyl hydroxylase 1, an enzyme involved in the hydroxylation of lysine residues in collagen. This post-translational modification is crucial for the proper cross-linking of collagen fibers, which imparts additional tensile strength and stability. Mutations in PLOD1 lead to deficient cross-linking, resulting in collagen that is more elastic and less resistant to mechanical stress, contributing to severe kyphoscoliosis (curvature of the spine), ocular fragility, and other systemic manifestations.

Other rare forms of EDS can involve mutations in genes such as ADAMTS2, which is responsible for the cleavage of procollagen to collagen, and TNXB, which encodes tenascin-X, a glycoprotein that interacts with collagen fibrils and influences their organization and stability. Deficiencies or abnormalities in these proteins further illustrate the complexity and variability of the pathophysiology underlying EDS.

Overall, the diverse genetic mutations in EDS converge on a common theme of disrupted collagen synthesis, structure, or function, leading to compromised integrity of connective tissues throughout the body. This not only elucidates the critical role of collagen in maintaining normal tissue function but also highlights potential molecular targets for future therapeutic interventions aimed at correcting or mitigating the effects of these genetic defects. Current management strategies focus on symptomatic relief and preventing complications, but ongoing research into the molecular mechanisms of EDS holds promise for more targeted and effective treatments in the future.