Folate-dependent hypermobility syndrome: A proposed mechanism and diagnosis

Jacques Courseault; Catherine Kingry; Vivianne Morrison; Christiania Edstrom; Kelli Morrell; Lisa Jaubert; Victoria Elia; Gregory Bix

doi:10.1016/j.heliyon.2023.e15387

Folate-dependent hypermobility syndrome: A proposed mechanism and diagnosis

Heliyon. 2023 Apr 9;9(4):e15387. doi: 10.1016/j.heliyon.2023.e15387. eCollection 2023 Apr.

Authors

Jacques Courseault¹, Catherine Kingry¹, Vivianne Morrison², Christiania Edstrom¹, Kelli Morrell¹, Lisa Jaubert¹, Victoria Elia¹, Gregory Bix²

Affiliations

¹ Tulane University School of Medicine, Department of Orthopedics, The Fascia Institute and Treatment Center 7030 Canal Blvd, New Orleans, LA 70124, USA.
² Tulane University School of Medicine, Departments of Neurosurgery and Neurology, Clinical Neuroscience Research Center, 1430 Tulane Avenue, New Orleans, LA 70112, USA.

Abstract

Hypermobility involves excessive flexibility and systemic manifestations of connective tissue fragility. We propose a folate-dependent hypermobility syndrome model based on clinical observations, and through a review of existing literature, we raise the possibility that hypermobility presentation may be dependent on folate status. In our model, decreased methylenetetrahydrofolate reductase (MTHFR) activity disrupts the regulation of the ECM-specific proteinase matrix metalloproteinase 2 (MMP-2), leading to high levels of MMP-2 and elevated MMP-2-mediated cleavage of the proteoglycan decorin. Cleavage of decorin leads ultimately to extracellular matrix (ECM) disorganization and increased fibrosis. This review aims to describe relationships between folate metabolism and key proteins in the ECM that can further explain the signs and symptoms associated with hypermobility, along with possible treatment with 5-methyltetrahydrofolate supplementation.

Keywords: Ehlers-danlos syndrome; Folate deficiency; Folate hypermobility; Hypermobility spectrum disorder; Hypermobility syndrome; MTHFR Gene polymorphism.