Cause of Ehlers-Danlos Syndrome
Ehlers-Danlos syndrome is caused by genetic mutations affecting collagen synthesis and structure, with 19 different causative genes identified across 13 recognized subtypes, though the genetic basis of the most common hypermobile type remains unknown. 1, 2
Genetic Basis by Subtype
Classical EDS (Types I and II)
- Approximately 50% of classical EDS cases are caused by mutations in COL5A1 and COL5A2 genes, which encode the α1 and α2 chains of type V collagen respectively 3
- The majority of molecularly characterized classical EDS results from mutations creating a nonfunctional COL5A1 allele, leading to haploinsufficiency of type V collagen 3
- A smaller proportion harbor structural mutations in COL5A1 or COL5A2 that produce functionally defective type V collagen protein 3
- Rare cases involve arginine-to-cysteine substitutions in type I collagen (COL1A1), causing intermolecular disulfide bridges and collagen aggregates 4
Vascular EDS (Type IV)
- Caused by mutations in the COL3A1 gene, which encodes type III collagen 5
- These mutations result in structurally abnormal collagen type III production by fibroblasts 5
- Mutations are widely distributed throughout this large, fragmented gene with no specific clustering patterns 5
Hypermobile EDS (Most Common Type)
- The genetic cause remains unidentified despite being the most common subtype, accounting for 80-90% of all EDS cases 1, 6, 7
- The connective tissue shows disorganization of collagen and elastin fibers, resulting in softer and less rigid tissue than normal 8, 6
- Skin biopsies reveal altered collagen fibril structure that triggers fibroblast dysfunction within connective tissue with abnormal adhesion and cytoskeletal response 5
Molecular Mechanisms
Collagen-Related Genes
- The majority of the 19 identified causative genes encode fibrillar collagen types I, III, and V, or their modifying and processing enzymes 2
- Additional genes encode enzymes that modify glycosaminoglycan chains of proteoglycans 2
- Type V collagen functions as a regulator of type I collagen fibrillogenesis, explaining why its deficiency causes disease 4
Pathophysiological Consequences
- Most identified mutations result in reduced amounts of functional collagen available for fibrillogenesis in connective tissues 3
- The altered collagen structure affects mechanical stiffness, with evidence showing connective tissue in hEDS is softer and less stiff than in controls 5
Inheritance Patterns
- Classical EDS and vascular EDS follow autosomal dominant inheritance 5
- Genetic heterogeneity exists, with some patients showing recessively inherited presentations with apparently normal collagen III metabolism 5
- Almost every family has its own specific mutation, making genetic testing challenging 5
Clinical Caveat
No genotype-phenotype correlations have been established, meaning the specific mutation does not predict disease type, course, or severity 5, 3. Inter- and intrafamilial phenotypic variability is common, likely depending on age, gender, lifestyle, and expression domains of EDS genes during development and postnatal life 7.