Bridging the Diagnostic Gap for Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders: Evidence of a Common Extracellular Matrix Fragmentation Pattern in Patient Plasma as a Potential Biomarker

Am J Med Genet A. 2025 Jan;197(1):e63857. doi: 10.1002/ajmg.a.63857. Epub 2024 Sep 3.

Abstract

Diagnosing hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD), common overlapping multisystemic conditions featuring symptomatic joint hypermobility, is challenging due to lack of established causes and diagnostic tools. Currently, the 2017 diagnostic criteria for hEDS are used, with non-qualifying cases classified as HSD, although the distinction remains debated. We previously showed extracellular matrix (ECM) disorganization in both hEDS and HSD dermal fibroblasts involving fibronectin (FN), type I collagen (COLLI), and tenascin (TN), with matrix metalloproteinase-generated fragments in conditioned media. Here, we investigated these fragments in patient plasma using Western blotting across diverse cohorts, including patients with hEDS, HSD, classical EDS (cEDS), vascular EDS (vEDS), rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA), and healthy donors, uncovering distinctive patterns. Notably, hEDS/HSD displayed a shared FN and COLLI fragment signature, supporting their classification as a single disorder and prompting reconsideration of the hEDS criteria. Our results hold the promise for the first blood test for diagnosing hEDS/HSD, present insights into the pathomechanisms, and open the door for therapeutic trials focused on restoring ECM homeostasis using an objective marker. Additionally, our findings offer potential biomarkers also for OA, RA, and PsA, advancing diagnostic and therapeutic strategies in these prevalent joint diseases.

Keywords: fibronectin fragments; hypermobile Ehlers‐Danlos syndrome/hypermobility spectrum disorders; osteoarthritis; psoriatic arthritis; rheumatoid arthritis; tenascin fragments; type I collagen fragments.

MeSH terms

  • Adult
  • Arthritis, Psoriatic / blood
  • Arthritis, Psoriatic / diagnosis
  • Arthritis, Psoriatic / pathology
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / diagnosis
  • Arthritis, Rheumatoid / pathology
  • Biomarkers* / blood
  • Collagen Type I / blood
  • Collagen Type I / genetics
  • Ehlers-Danlos Syndrome* / blood
  • Ehlers-Danlos Syndrome* / diagnosis
  • Ehlers-Danlos Syndrome* / genetics
  • Ehlers-Danlos Syndrome* / pathology
  • Extracellular Matrix* / metabolism
  • Extracellular Matrix* / pathology
  • Female
  • Fibronectins* / blood
  • Fibronectins* / genetics
  • Humans
  • Joint Instability* / blood
  • Joint Instability* / diagnosis
  • Joint Instability* / genetics
  • Joint Instability* / pathology
  • Male
  • Middle Aged
  • Osteoarthritis / blood
  • Osteoarthritis / diagnosis
  • Osteoarthritis / genetics
  • Osteoarthritis / pathology
  • Tenascin* / blood
  • Tenascin* / genetics

Substances

  • Biomarkers
  • Fibronectins
  • Tenascin
  • Collagen Type I

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