Differential ultrastructural aberrations of collagen fibrils in Ehlers-Danlos syndrome types I?IV as a means of diagnostics and classification

Abstract

Among the different subtypes of Ehlers-Danlos syndrome (EDS), the dominant types I-III have, so far, been uninformative biochemically and molecular genetically, and diagnostic problems with subgroup boundaries often arise. We have investigated the ultrastructural pattern of connective tissue macromolecules in skin biopsy specimens of some 85 patients aged 4 months-54 years who exhibit clinical symptoms or the suspicion of EDS I-IV. Based on the differential features of collagen fibrils and ground substance material, four distinct groups could be established. Group I (clinically EDS type I) showed disorganized collagen bundles and dense aggregations of collagen fibrils with bizarre shapes. Group II (clinically varying from EDS types I-III) revealed collagen bundles that regularly contained numerous "composite collagen fibrils" with enlarged "flower-like" cross-sections and rope-like longitudinal sections, often associated with increased amounts of matrix substances in the form of electron-dense irregular strands and filaments in a branched network. Group III (clinically EDS types II-III) presented smaller isolated collagen flowers and ropes associated with excessive filamentous ground substance material and flocculent material. Group IV (with clinical symptoms of EDS type IV) had a dermis thinned to one third of the normal and a reduced number of collagen bundles with small diameter fibrils. In 13 patients, the abnormal ultrastructural dermal architecture did not coincide with any of these four groups or with the pattern of any other inherited connective tissue disorder. In 16 additional patients with mostly mild clinical symptoms, such as muscle weakness and small joint hyperlaxity, no ultrastructural aberrations could be found. Even though the primary defects underlying the respective aberration of the collagen fibrils are still unknown, the differential ultrastructural changes of the collagen fibrils together with clinical symptoms should, as in other heterogeneous genetic disorders, facilitate the (provisional?) classification of EDS and permit the diagnosis of individual cases.

Clinical and genetic aspects of Ehlers-Danlos syndrome, classic type

“…A "cauliflower" deformity of collagen fibrils is characteristic. 48 However, these findings are not specific for EDS and, therefore, not diagnostic. Furthermore, ultrastructural changes, usually most pronounced in the central parts of the reticular dermis, may be missed if the skin biopsy is not of full thickness.…”

Collagen V is a dominant regulator of collagen fibrillogenesis: dysfunctional regulation of structure and function in a corneal-stroma-specificCol5a1-null mouse model

“…The most common reported molecular mechanism in classic EDS is the functional loss of one COL5A1 allele (Schwarze et al, 2000;Wenstrup et al, 2000), with a haplo-insufficiency for collagen V. Abnormal fibril formation is seen in the classic EDS and the dermis of EDS patients contains large, irregular collagen fibrils (Hausser and Anton-Lamprecht, 1994;Vogel et al, 1979). Studies using fibroblasts from EDS patients with characterized mutations in COL5A1 and a mouse Col5a1 +/2 model of classic EDS have demonstrated that heterotypic collagen I and V interactions are involved in the regulation of fibril diameter and fibril number (Segev et al, 2006;Wenstrup et al, 2004a;Wenstrup et al, 2004b;Wenstrup et al, 2006).…”

Broadened and Elevated Humoral Immune Response to Ebna1 in Pediatric Multiple Sclerosis

“…The skin biopsies of all four twin brothers did not show any severe connective tissue abnormalities. 5 The figure, A, shows the structurally intact arterial wall of the STA of a control subject (control C2 4 ). Vascular smooth muscle cells (SMC) were of the physiologic contractile phenotype and neither fresh nor degraded erythrocytes or other cellular debris were found.…”