The Ehlers–Danlos Syndromes against the Backdrop of Inborn Errors of Metabolism

Abstract

The Ehlers–Danlos syndromes are a group of multisystemic heritable connective tissue disorders with clinical presentations that range from multiple congenital malformations, over adolescent-onset debilitating or even life-threatening complications of connective tissue fragility, to mild conditions that remain undiagnosed in adulthood. To date, thirteen different EDS types have been recognized, stemming from genetic defects in 20 different genes. While initial biochemical and molecular analyses mainly discovered defects in genes coding for the fibrillar collagens type I, III and V or their modifying enzymes, recent discoveries have linked EDS to defects in non-collagenous matrix glycoproteins, in proteoglycan biosynthesis and in the complement pathway. This genetic heterogeneity explains the important clinical heterogeneity among and within the different EDS types. Generalized joint hypermobility and skin hyperextensibility with cutaneous fragility, atrophic scarring and easy bruising are defining manifestations of EDS; however, other signs and symptoms of connective tissue fragility, such as complications of vascular and internal organ fragility, orocraniofacial abnormalities, neuromuscular involvement and ophthalmological complications are variably present in the different types of EDS. These features may help to differentiate between the different EDS types but also evoke a wide differential diagnosis, including different inborn errors of metabolism. In this narrative review, we will discuss the clinical presentation of EDS within the context of inborn errors of metabolism, give a brief overview of their underlying genetic defects and pathophysiological mechanisms and provide a guide for the diagnostic approach.

Children with gene defects are a risk group for the development of abnormalities of the cardiovascular system

“…Для vEDS характерний спонтанний розрив артерій, якому передувала аневризма, артеріовенозна фістула або розшарування. У середньому тривалість життя становить 51 рік [36]. Клінічні критерії hEDS наведено в таблиці 5 [6].…”

Candidate genes for obstructive sleep apnea in non-syndromic children with craniofacial dysmorphisms – a narrative review

“…Ehlers-Danlos syndrome, manifesting through retrognathia, micrognathia, and maxillary constriction, has been previously proposed as a genetic model for pediatric OSA ( 60 , 61 , 132 ). Variants in genes encoding and/or influencing the expression of collagens ( COL gene family) and others (see Supplementary Table S1 in the Supplement) were associated with this rare connective tissue disorder ( 60 , 133 ). The minor allele of SNP rs2249492 in the Collagen type I alpha 1 chain ( COL1A1 ) has been previously associated with the increased risk of a sagittal maxilla-mandibular discrepancy (skeletal class III malocclusion) in non-syndromic children ( 62 ).…”

“…Ehlers-Danlos syndrome, manifesting through retrognathia, micrognathia, and maxillary constriction, has been previously proposed as a genetic model for pediatric OSA (60,61,132). Variants in genes encoding and/or influencing the expression of collagens (COL gene family) and others (see Supplementary Table S1 in the Supplement) were associated with this rare connective tissue disorder (60,133). The minor allele of SNP Clusters of candidate genes for pediatric obstructive sleep apnea (POSA) development in children with craniofacial dysmorphisms and their interactions (created in string, https://string-db.org/cgi/network?taskId = bF5B2GAcAUOE&sessionId = bSUqeCIqj6OL).…”

Lysyl hydroxylase 3–mediated post-translational modifications are required for proper biosynthesis of collagen α1α1α2(IV)

“…Pathogenic variants in genes encoding collagens cause a wide range of disorders affecting almost all tissues and organs ( 3 , 4 ). Type I, type III, and type V collagens form fibrils contributing to structural frameworks and pathogenic variants in these collagens cause connective tissue disorders—osteogenesis imperfecta (OI) and Ehlers–Danlos syndrome (EDS)—that affect fibril-rich tissues, such as bone, skin, and vascular structures ( 5 , 6 , 7 , 8 , 9 , 10 ). In contrast, type IV collagens form flexible networks that are present in the basement membranes of all tissues.…”

“…In the case of OI and EDS, it is well documented that pathogenic variations in genes encoding collagens and genes encoding proteins required for collagen biosynthesis lead to similar clinical outcomes ( 5 , 6 , 7 , 8 , 9 , 10 ). A similar paradigm may also exist for Gould syndrome as pathogenic variants in glycosyltransferase 25 domain containing 1 (GLT25D1), encoded by collagen β (1-O) galactosyltransferase 1 ( COLGALT1 ) cause musculoskeletal ( 36 ) and cerebrovascular ( 37 , 38 ) manifestations similar to those observed in individuals with COL4A1 and COL4A2 pathogenic variants.…”