Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

Ehlers-Danlos Syndrome (EDS) - Overview [Q79.6]

OMIM numbers: 130000 (Typ I), 130010 (Typ II), 130020 (Typ III), 130050 (Typ IV), 130060 (Typ VIIA/B), 225400 (Typ VIA), 601776, 614557 (Typ VIB), 606408, 225410 (Typ VIIC)

Dr. rer. nat. Karin Mayer

Scientific Background

Ehlers-Danlos syndrome (EDS) is a clinically and genetically heterogeneous group of connective tissue disorders based on different molecular defects of the collagen metabolism. EDS can be divided into 13 subtypes based on clinical, biochemical and molecular genetic data as well as inheritance (autosomal dominant, autosomal recessive, or X-linked). According to the Villefranche classification, these groups are subdivided into 6 main types. Key symptoms are hyperelastic skin, tissue fragility, joint hypermobility and various skeletal, cardiovascular, and gastrointestinal symptoms as well as involvement of lung and eyes. Although the estimated prevalence is between 1 in 5,000-150,000 depending on the severity of the symptoms, EDS seems to be the most common inherited connective tissue disorder. 

Biosynthesis of the dermal collagen fibrils that is impaired in the following stages in different EDS subtypes:

a) Synthesis, stability: haploinsufficiency of mutated COL5A1 mRNA, which leads to a decreased synthesis of ?1 procollagen (V), is causal for classical EDS syndrome type I and II in 40-50% of all cases. 

b) Hydroxylation of lysine and proline residues in the procollagen chains: missing hydroxylation due to a lysyl hydroxilase deficiency is causal for kyphoscoliosis EDS type VIA.

c) Processing and secretion: mutations in COL3A1 that affect the triple-helical domain of procollagen-?-chains inhibit normal processing in the rough endoplasmic reticulum (RER) and the following secretion of homotrimers. They are causal for the vascular EDS type IV.

d) Cleavage of N-terminal propeptides in the extracellular matrix (ECM): dominant mutations in COL1A1 and COL1A2 which eliminate the cleavage site for the removal of the N-terminal propeptides are causal for arthrochalasis EDS types VIIA and VIIB . Recessive mutations in the gene for procollagen N-peptidase lead to the dermatosparaxis EDS type VIIC. 

e) Fibril formation: dominant negative mutations in COL5A1 and COL5A2 can inhibit the aggregation of collagen molecules into heterotopic fibrils and are in some cases causal for classical EDS type I and II.

f) Interaction with extracellular matrix proteins: disruption of the tissue-specific structure of collagen fibrils and the interaction with extracellular matrix proteins, for example TenascinX, can lead to an EDS phenotype (EDS hypermobility type III).