Collagen Ehlers-Danlos syndrome

A number of rare genetic diseases involve collagen abnormalities, including Marfan s syndrome and the Ehlers-Danlos syndromes, which result in hyperextensible joints and skin. The formation of atheroselerotie plaques, which cause arterial blockages in advanced stages, is due in part to the abnormal formation of collagenous structures in blood vessels. 

Silk fibroin and collagen illustrate the close linkage of protein stmcture and biologic function. Diseases of collagen mamration include Ehlers-Danlos syndrome and the vitamin C deficiency disease scurvy. 

Diseases associated with impaired synthesis of collagen include scurvy, osteogenesis imperfecta, Ehlers-Danlos syndrome (many types), and Menkes disease. 

Ehlers-Danlos syndromes Mutations in collagen genes and lysine hydroxylase gene Hyperextensible, fragile skin HypermobUe joints, dislocations, varicose veins, ecchymoses, arterial, intestinal ruptures... 

Defects in collagen synthesis, structure, or assembly Into fibers are the principal basis for a group of connective tissue disorders called Ehlers-Danlos syndrome (EDS). 

Ehlers-Danlos syndrome type V, is due to a deficiency in lysyl oxidase and results in hypermobile joints and hyperextensibility of the skin. The India-rubber man found in circuses probably had such a collagen deficiency. 

COL1A2 null allele mutations produce collagen that has three al(I>chains rather than two al(I> and one a2(I>chains (50% of all type I collagen in heterozygous and 100% in homozygous cases).The al(I>homotrimer does have a normal role, but only as a minor collagen in fetal tissues. Mutations that result in exclusive synthesis of al(I>homotrimers cause rare recessive forms of OI and Ehlers-Danlos syndrome (Schwarze et al., 2004). 

Ehlers-Danlos syndrome is actnaUy the name associated with at least ten distinct disorders that are biochemically and chnically distinct, yet all manifest structural weakness in connective tissne as a resnlt of defective collagen strncture. 

B. A defect in the synthesis or processing of collagen causes Ehlers-Danlos syndrome. 

Who would dream of doing a phenol peel on a woman who is pregnant or breastfeeding Or on a patient with an obvious malign lesion Or a patient recovering from a serious illness A patient with immunodeficiency On a patient with Ehlers-Danlos syndrome On one with scleroderma or collagen disease The doctor must use his professional skill and experience to rule out any patient who poses an increased risk. 

Other mutations of fibrillar collagen, or mutations that affect collagen-processing, cause Ehlers-Danlos syndrome (EDS), a group of heritable connective tissue disorders causing skin hyperextensibility, articular hypermobility, and tissue fragility. The 3 major types are classic (EDS-I and EDS-II), hypermobility (EDS-III) and vascular (EDS-IV). 

The importance of lysyl hydroxylation is seen in patients with the type VI variant of Ehlers-Danlos syndrome (Table 25-5). The collagen in these individuals has a decreased fibril diameter and profound changes in mechanical properties. Skin fibroblasts show virtually no lysyl hydroxylase activity. Furthermore, hydroxylysine formation can be severely affected in some tissues, mildly affected in others, and unaffected in still others (e.g., cartilage). These observations suggest the presence of tissue-specific lysyl hydroxylases. 

The conversion of procollagen to collagen by removal of propeptides seems to be essential for the formation of collagen fibrils. This supposition is supported by studies of two heritable diseases, one found in humans and the other in cattle, sheep, and cats. In both, the defect lies in the removal of N-terminal propeptides and results in impaired fibril formation. The human disorder is the type VII variant of Ehlers-Danlos syndrome (Table 25-5). Affected individuals exhibit marked joint hypermobility, dislocation of joints, short stature, and minor changes in skin elasticity. Their skin fibroblasts show normal... 

Several collagen disorders result from defects in the formation of cross-links (Chapter 11). The cross-linking disorders can be due to a hereditary deficiency of lysyl oxidase, inhibition of lysyl oxidase, deficiency of copper, defects in the formation of cross-links, or defects in their stabilization. The genetic deficiency of lysyl oxidase is characterized by Ehlers-Danlos syndrome type IX (Table 25-5) and some forms of cutis laxa. Type IX Ehlers-Danlos syndrome patients exhibit extreme extensibility of the skin, cigarette-paper scarring, and easy bruisability. In cutis laxa, the skin is loose and inelastic and appears to be too large for the surface it covers. Some affected individuals exhibit deficiency of lysyl oxidase, presumably... 

Cyanoalanine is an unusual amino acid derived from cysteine that is produced in the seeds of Lathyris odoratus. Animals consuming these seeds develop defects in their collagen. In humans the disease is associated with consumption of / -cyanoalanine is called Ehlers-Danlos syndrome and it manifests itself as curvature of the spine and heart problems. 

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