Congenital Disorders of Deficiency in Glycosaminoglycan Biosynthesis

Glycosaminoglycans (GAGs) including chondroitin sulfate, dermatan sulfate, and heparan sulfate are covalently attached to specific core proteins to form proteoglycans, which are distributed at the cell surface as well as in the extracellular matrix. Proteoglycans and GAGs have been demonstrated to exhibit a variety of physiological functions such as construction of the extracellular matrix, tissue development, and cell signaling through interactions with extracellular matrix components, morphogens, cytokines, and growth factors. Not only connective tissue disorders including skeletal dysplasia, chondrodysplasia, multiple exostoses, and Ehlers-Danlos syndrome, but also heart and kidney defects, immune deficiencies, and neurological abnormalities have been shown to be caused by defects in GAGs as well as core proteins of proteoglycans. These findings indicate that GAGs and proteoglycans are essential for human development in major organs. The glycobiological aspects of congenital disorders caused by defects in GAG-biosynthetic enzymes including specific glysocyltransferases, epimerases, and sulfotransferases, in addition to core proteins of proteoglycans will be comprehensively discussed based on the literature to date.

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Transcriptome Profiling of Primary Skin Fibroblasts Reveal Distinct Molecular Features Between PLOD1- and FKBP14-Kyphoscoliotic Ehlers–Danlos Syndrome

Genes ◽

10.3390/genes10070517 ◽

2019 ◽

Vol 10 (7) ◽

pp. 517 ◽

Cited By ~ 3

Author(s):

Lim ◽

Lindert ◽

Opitz ◽

Hausser ◽

Rohrbach ◽

...

Keyword(s):

Extracellular Matrix ◽

Protein Trafficking ◽

Treatment Strategies ◽

Transcriptome Profiling ◽

Joint Hypermobility ◽

Skin Fibroblasts ◽

Ehlers Danlos Syndrome ◽

Molecular Features ◽

Extracellular Matrix Components ◽

Danlos Syndrome

Kyphoscoliotic Ehlers–Danlos Syndrome (kEDS) is a rare genetic heterogeneous disease clinically characterized by congenital muscle hypotonia, kyphoscoliosis, and joint hypermobility. kEDS is caused by biallelic pathogenic variants in either PLOD1 or FKBP14. PLOD1 encodes the lysyl hydroxylase 1 enzyme responsible for hydroxylating lysyl residues in the collagen helix, which undergo glycosylation and form crosslinks in the extracellular matrix thus contributing to collagen fibril strength. FKBP14 encodes a peptidyl-prolyl cis–trans isomerase that catalyzes collagen folding and acts as a chaperone for types III, VI, and X collagen. Despite genetic heterogeneity, affected patients with mutations in either PLOD1 or FKBP14 are clinically indistinguishable. We aim to better understand the pathomechanism of kEDS to characterize distinguishing and overlapping molecular features underlying PLOD1-kEDS and FKBP14-kEDS, and to identify novel molecular targets that may expand treatment strategies. Transcriptome profiling by RNA sequencing of patient-derived skin fibroblasts revealed differential expression of genes encoding extracellular matrix components that are unique between PLOD1-kEDS and FKBP14-kEDS. Furthermore, we identified genes involved in inner ear development, vascular remodeling, endoplasmic reticulum (ER) stress, and protein trafficking that were differentially expressed in patient fibroblasts compared to controls. Overall, our study presents the first transcriptomics data in kEDS revealing distinct molecular features between PLOD1-kEDS and FKBP14-kEDS, and serves as a tool to better understand the disease.

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Molecular alterations due to Col5a1 Haploinsufficiency in a mouse model of classic Ehlers Danlos syndrome

Human Molecular Genetics ◽

10.1093/hmg/ddab323 ◽

2021 ◽

Author(s):

Keren Machol ◽

Urszula Polak ◽

Monika Weisz-Hubshman ◽

I-Wen Song ◽

Shan Chen ◽

...

Keyword(s):

Extracellular Matrix ◽

Type I Collagen ◽

Lysyl Oxidase ◽

Type I ◽

Ehlers Danlos Syndrome ◽

Type V Collagen ◽

Molecular Alterations ◽

Extracellular Matrix Components ◽

Type V ◽

Danlos Syndrome

Abstract Type V collagen is a regulatory fibrillar collagen essential for type I collagen fibril nucleation and organization and its deficiency leads to structurally abnormal extracellular matrix. Haploinsufficiency of the Col5a1 gene encoding α(1) chain of type V collagen is the primary cause of classic Ehlers Danlos Syndrome (EDS). The mechanisms by which this initial insult leads to the spectrum of clinical presentation is not fully understood. Using transcriptome analysis of skin and Achilles tendons from Col5a1 haploinsufficient (Col5a1+/−) mice, we recognized molecular alterations associated with the tissue phenotypes. We identified dysregulation of extracellular matrix components including thrombospondin-1, lysyl oxidase, and lumican in the skin of Col5a1+/− mice when compared to control. We also identified upregulation of Tgf-β in serum and increased expression of pSmad2 in skin from Col5a1+/− mice suggesting Tgf-β dysregulation as a contributor for abnormal wound healing and atrophic scaring seen in classic EDS. Together, these findings support altered matrix to cell signaling as a component of the pathogenesis of the tissue phenotype in classic EDS and point out potential downstream signaling pathways that may be targeted for treatment of the disease.

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Genetic testing for vascular Ehlers-Danlos syndrome and other variants with fragility of the middle arteries

The EuroBiotech Journal ◽

10.2478/ebtj-2018-0034 ◽

2018 ◽

Vol 2 (s1) ◽

pp. 42-44

Author(s):

Yeltay Rakhmanov ◽

Paolo Enrico Maltese ◽

Alice Bruson ◽

Marco Castori ◽

Tommaso Beccari ◽

...

Keyword(s):

Extracellular Matrix ◽

Clinical Trials ◽

Vascular Involvement ◽

Molecular Testing ◽

Connective Tissue Disorders ◽

Ehlers Danlos Syndrome ◽

Recurrent Mutations ◽

Gene Test ◽

Danlos Syndrome

Abstract Ehlers-Danlos syndrome (EDS) is an umbrella term for various inherited connective tissue disorders associated with mutations in genes involved in extracellular matrix formation. “The 2017 International Classification of Ehlers-Danlos Syndromes and related disorders” identifies 13 clinical types with mutations in 19 distinct genes. The present module focuses on forms with major vascular involvement: vascular EDS (vEDS) caused by heterozygous mutations in COL3A1, “vascular-like” EDS (vlEDS) caused by recurrent mutations in COL1A1, classical EDS with vascular fragility associated with heterozygous mutations in COL5A1, and kyphoscoliotic EDS associated with recessive variations in PLOD1 and FKBP14. The overall prevalence of EDS is estimated between 1/10,000 and 1/25,000 and vEDS accounts for about 5 to 10% of all EDS cases. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. Molecular testing is useful for diagnosis confirmation, as well as differential diagnosis, appropriate genetic counselling and access to clinical trials.

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Psychiatric Manifestations of Ehlers-Danlos Syndrome in Adolescents: A Case Report and Literature Review

Current Psychiatry Research and Reviews ◽

10.2174/2666082216999201126165311 ◽

2020 ◽

Vol 16 ◽

Author(s):

Daisy Vyas Shirk ◽

Sarah D. Williams

Keyword(s):

Chronic Pain ◽

Literature Review ◽

Literature Search ◽

Web Search ◽

Psychiatric Symptoms ◽

Connective Tissue Disorders ◽

Ehlers Danlos Syndrome ◽

Symptoms Of Depression ◽

Psychiatric Manifestations ◽

Danlos Syndrome

Background: Ehlers-Danlos Syndromes (EDS) comprise a group of heterogeneous hereditary connective tissue disorders [1, 2]. Psychiatric disorders such as depression, anxiety, panic disorder, agoraphobia, schizophrenia, neurodevelopmental disorders, personality disorder, eating disorders, substance misuse and interpersonal issues have been reported in the literature to be associated with EDS [1-3]. Objectives: The case of a 15-year -old male who was hospitalized after a suicide attempt by gunshot was discovered to have symptoms suggestive of EDS is presented in this paper along with the results of a literature search of psychiatric manifestations of EDS in children and adolescents. Methods: Literature review was conducted on the UpToDate website on March 11, 2020 to review symptoms of EhlersDanlos Syndrome for the purpose of preliminary diagnosis of this patient. Additional literature search was conducted on PubMed on 4/2/20 at 12:10 P.M. and on 4/9/20 at 10:51 P.M. and on the search engine Google on 4/2/20 at 12:25 P.M. On May 11, 2020 at 2 P.M., another web search was conducted with review of 6 different websites pertaining to EhlersDanlos Syndrome. Results: A systematic review of psychiatric manifestations of Ehlers-Danlos Syndromes revealed a strong incidence of psychiatric symptoms. Conclusion: Our patient’s psychiatric symptoms of depression, suicidal ideations, anxiety and social and educational struggles may have been at least partially due to chronic pain- abdominal, headache and musculoskeletal, and social ostracization associated with Ehlers-Danlos Syndrome. Education regarding this illness helped our patient’s recovery as he came to understand why he was so “odd” and the cause of his multisystemic chronic pain.

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Pain Symptomatology and Management in Pediatric Ehlers–Danlos Syndrome: A Review

Children ◽

10.3390/children7090146 ◽

2020 ◽

Vol 7 (9) ◽

pp. 146

Author(s):

Estée C. H. Feldman ◽

Daniel P. Hivick ◽

P. Maxwell Slepian ◽

Susan T. Tran ◽

Pradeep Chopra ◽

...

Keyword(s):

Quality Of Life ◽

Psychological Interventions ◽

Pediatric Pain ◽

Connective Tissue Disorders ◽

Ehlers Danlos Syndrome ◽

Major Criterion ◽

Pain Characteristics ◽

The Relationship ◽

Danlos Syndrome

Ehlers–Danlos syndromes (EDS) are a group of connective tissue disorders that manifest with hyperextensibility of joints and skin, and general tissue fragility. While not a major criterion for clinical diagnosis, pain is a frequently endorsed symptom across subtypes of EDS. As such, the present review aims to summarize research to date on pain characteristics and management, and the relationship between such pain symptomatology and quality of life in pediatric EDS. Characteristics of pain, including theorized etiology, relative intensity and extent of pain are described, as well as descriptions of frequently endorsed pain sites (musculoskeletal, and non-musculoskeletal). Interventions related to the management of musculoskeletal (e.g., pharmaceutical intervention, physical therapy) and non-musculoskeletal pain (e.g., pharmaceutical and psychological interventions) are discussed, highlighting the need for additional research related to pediatric pain management in the context of hypermobility syndromes. In addition, the relationship between pain in pediatric EDS and quality of life is described. Finally, limitations of literature to date are described and recommendations for future lines of research are outlined.

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Hereditary Connective Tissue Diseases in Young Adult Stroke: A Comprehensive Synthesis

Stroke Research and Treatment ◽

10.4061/2011/712903 ◽

2011 ◽

Vol 2011 ◽

pp. 1-18 ◽

Cited By ~ 4

Author(s):

Olivier M. Vanakker ◽

Dimitri Hemelsoet ◽

Anne De Paepe

Keyword(s):

Connective Tissue ◽

Metabolic Disorders ◽

Type Iv Collagen ◽

Connective Tissue Diseases ◽

Haemorrhagic Stroke ◽

Monogenic Disease ◽

Connective Tissue Disorders ◽

Ehlers Danlos Syndrome ◽

Type Iv ◽

Danlos Syndrome

Though the genetic background of ischaemic and haemorrhagic stroke is often polygenetic or multifactorial, it can in some cases result from a monogenic disease, particularly in young adults. Besides arteriopathies and metabolic disorders, several connective tissue diseases can present with stroke. While some of these diseases have been recognized for decades as causes of stroke, such as the vascular Ehlers-Danlos syndrome, others only recently came to attention as being involved in stroke pathogenesis, such as those related to Type IV collagen. This paper discusses each of these connective tissue disorders and their relation with stroke briefly, emphasizing the main clinical features which can lead to their diagnosis.

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Ehlers–Danlos syndrome: how to diagnose and when to perform genetic tests

Archives of Disease in Childhood ◽

10.1136/archdischild-2013-304822 ◽

2014 ◽

Vol 100 (1) ◽

pp. 57-61 ◽

Cited By ~ 40

Author(s):

Glenda Sobey

Keyword(s):

Genetic Basis ◽

Correct Diagnosis ◽

Clinical Signs ◽

Accurate Diagnosis ◽

Connective Tissue Disorders ◽

Internal Organs ◽

Ehlers Danlos Syndrome ◽

Starting Point ◽

Life Threatening ◽

Danlos Syndrome

The term Ehlers–Danlos syndrome (EDS) encompasses a group of inherited connective tissue disorders. The manifestations of EDS can be seen in skin, joints, blood vessels and internal organs and vary from mild to severe and life threatening. Each subtype is a separate and different condition. The genetic basis of many subtypes has now been elucidated, confirming heterogeneity. An awareness of the different conditions within this group is the starting point towards accurate diagnosis. Accurate elicitation of history and clinical signs is vital in selecting the correct confirmatory investigation. Skin biopsy with electron microscopy can be helpful in the decision process of whether and when to perform genetic testing. Correct diagnosis within the EDSs allows targeted management, family screening and prenatal diagnosis.

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