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Hyper-mobility, Folate, and the MTHFR Gene Mutation

Updated: Aug 5, 2023

One of the newer discoveries in recent research has been folate-dependent hyper-mobility and the MTHFR gene.

I posted a video about iron and saw some confusion about B9, Folate, Folic Acid, Iron, and supplementing for the MTHFR/hyper-mobility findings.

First, iron is a mineral whereas B9/Folate are the same thing, and are vitamins; folic acid is essentially synthetic folate. It is the intersection of processing folate and the MTHFR mutation where things get interesting. I included one article related to 5- methyl tetrahydrofolate supplementation in pregnancy because it explains the difference between the supplement and regular folic acid.

Second, I wanted to include the research related to this because it's honestly pretty interesting and a lot can get lost in translation online, so bringing the sources straight to you.


Here's what I found to be most important and what I would likely focus on if I were to continue to put this research to use:

"...A key difference between the other 12 subtypes of EDS and hEDS and HSD lies in their molecular bases. The other 12 subtypes of EDS are linked to known mutations in genes encoding the extracellular matrix (ECM) proteins (i.e., collagen), or enzymes and chaperones that facilitate the processing and assembling of ECM proteins [7,8]. However, the molecular bases for hEDS and HSD remain largely unknown. Two studies of two different families have identified genetic polymorphisms linked to hEDS, and Tenascin-X deficiency has been implicated in hypermobility [[9], [10], [11]]. However, none of these findings appear to be pervasive among sufferers of hEDS or HSD. The uncertainty regarding hypermobility's pathophysiology greatly limits the therapeutic options and support available to patients."

Based on observations made in our clinic, we propose that common polymorphisms in a key folate-metabolizing enzyme, methylenetetrahydrofolate reductase (MTHFR), are tied to the development of hypermobility. We notice a consistent pattern arises upon evaluation of our symptomatic hypermobile patients, showing elevated serum folate levels, normal mean corpuscular volume of red blood cells, normal homocysteine levels, and C677T or A1298C MTHFR polymorphisms. These observations raised the possibility that hypermobility symptoms may be dependent on folate status. We propose a folate-dependent hypermobility syndrome (FDHS) model wherein (1) decreased MTHFR activity derepresses the ECM-specific proteinase matrix metalloproteinase 2 (MMP-2), and subsequently, (2) increases MMP-2-mediated cleavage of the proteoglycan decorin. This cleavage destabilizes collagen, leading to laxity and fragility of the ECM. This cleavage also triggers pro-fibrotic pathways downstream of aberrant transforming growth factor β (TGFβ) signaling, resulting in the thickening of fascia and the development of myofascial pain. Based on our FDHS model, we speculate that supplementation with MTHFR's end-product, 5-methyltetrahydrofolate (5-methylTHF), could re-establish methylation of the MMP-2 promoter, preserve decorin-dependent collagen organization in connective tissue, and mitigate the formation of fibrotic adhesions. If this is the case, then 5-methylTHF supplementation could be a viable strategy to lessen impact and progression of hypermobility's manifestations...."

"...5-methylTHF supplementation should be explored as a possible management option for hypermobile patients with an MTHFR polymorphism. Supplementation would bypass the decreased efficacy of the MTHFR enzyme in those with a polymorphism [49]. It has also been shown that 5-methylTHF stabilizes polymorphic MTHFR, thus improving the apo-to-holoenzyme transition and mitigating the polymorphism's impact on enzymatic activity [50]. We have anecdotally observed the benefits of 5-methylTHF supplementation in our hypermobile patients, but additional studies will be needed to empirically determine the efficacy of supplementation in improving folate availability and in clinical endpoints such as decreasing fascial adhesions and fibrosis development."


Do you find this kind of resource farming helpful?

Stay regulated,




I was looking for a new multivitamin because the one I've taken for years has been out of stock for awhile and look what I found!

This single-pill-per-serving (!!!!) multivitamin contains methyl folate.

To be clear, this is not a personal recommendation; just showing you what I found in conjunction with the research so you can make decisions for yourself.

I'm going to try it though - I'm pretty excited and will obviously keep you updated.

Stay regulated,


1 Comment

Sarah Hurtgen
Sarah Hurtgen
Jul 28, 2023

this is super interesting. i appreciate the resources!

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