Abstract
Musculocontractural Ehlers–Danlos Syndome (mcEDS) is a type of EDS caused by biallelic pathogenic variants in the gene for carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase 1 (CHST14/D4ST1, mcEDS-CHST14), or in the gene for dermatan sulfate epimerase (DSE, mcEDS-DSE). Thus far, 41 patients from 28 families with mcEDS-CHST14 and five patients from four families with mcEDS-DSE have been described in the literature. Clinical features comprise multisystem congenital malformations and progressive connective tissue fragility-related manifestations. This review outlines recent advances in understanding the pathophysiology of mcEDS. Pathogenic variants in CHST14 or DSE lead to reduced activities of relevant enzymes, resulting in a negligible amount of dermatan sulfate (DS) and an excessive amount of chondroitin sulfate. Connective tissue fragility is presumably attributable to a compositional change in the glycosaminoglycan chains of decorin, a major DS-proteoglycan in the skin that contributes to collagen fibril assembly. Collagen fibrils in affected skin are dispersed in the papillary to reticular dermis, whereas those in normal skin are regularly and tightly assembled. Glycosaminoglycan chains are linear in affected skin, stretching from the outer surface of collagen fibrils to adjacent fibrils; glycosaminoglycan chains are curved in normal skin, maintaining close contact with attached collagen fibrils. Homozygous (Chst14−/−) mice have been shown perinatal lethality, shorter fetal length and vessel-related placental abnormalities. Milder phenotypes in mcEDS-DSE might be related to a smaller fraction of decorin DS, potentially through residual DSE activity or compensation by DSE2 activity. These findings suggest critical roles of DS and DS-proteoglycans in the multisystem development and maintenance of connective tissues, and provide fundamental evidence to support future etiology-based therapies.
Highlights
Musculocontractural Ehlers–Danlos Syndome is a type of EDS, caused by biallelic pathogenic variants in the gene for carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase 1(CHST14/D4ST1, mcEDS-CHST14) (MIM#601776), or in the gene for dermatan sulfate epimerase (DSE, mcEDS-DSE) (MIM#615539) [1,2,3]. mcEDS-CHST14 was originally described as three independent conditions: A rare type of arthrogryposis syndrome “adducted thumb-clubfoot syndrome” [4];a specific type of EDS “EDS, Kosho type” [5,6]; and a subset of kyphoscoliosis type without lysyl hydroxylase deficiency [7]
P.(Gly19Trpfs*19) and p.(Lys26Alafs*16) variants have been detected in patients with features similar to those of mcEDS, among patients with hereditary connective tissue disorders and skeletal dysplasia, respectively (Figure 2A) [25,26]
CHST14, showed a marked reduction in D4ST1 activity (Figure 3B); this change in activity resulted in a negligible amount of DS and an excessive amount of chondroitin sulfate (CS) (Figure 3C) [6]
Summary
Musculocontractural Ehlers–Danlos Syndome (mcEDS) is a type of EDS, caused by biallelic pathogenic variants in the gene for carbohydrate sulfotransferase 14/dermatan 4-O-sulfotransferase 1. McEDS-DSE was identified in a patient with a phenotype similar to that of patients with mcEDS-CHST14 [23], as well as in four additional patients from three families [18,24]. These disorders were defined as subtypes of EDS, based on the International Classification of the EDSs [3]. 1. Clinical photographs and radiological images of patients with mcEDS-CHST14. Radiological image of a patient with heterozygous variants Pro281Leu /Try293Cys at6age 6. (U, reproduced from Kosho et al Am J Med Genet Part A 2005, 138A, 282−287, with permission from
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