Thread by @chronicallyadyk

1st, what a sloppy claim. The hypothesis that intracellular folate deficiency can cause symptomatic elements of #EDS is not new, but I think it's wrong. The #MTHFR polymorphism is SO common and we've gone down the MTHFR rabbit hole before. /1

https://twitter.com/FasciaInstitute/status/1597595646177021954

You hypothesis is that decreased activation of decorin causes structural differences in collagen making it loose enough to cause hypermobility. I find it interesting that other, peer-reviewed studies say that "decorin promot[es] inflammatory activity" science.org/doi/abs/10.112… /2

suggesting that a decrease in decorin could actually be protective in disease associated with an inflammatory state, such as #EhlersDanlos. That is not to say that treating patients with the MTHFR polymorphism with methylfolate couldn't cause improvement, but /3

I believe that improvement has nothing to do with your hypothesis. /3

First, let's talk about the cytoskeleton. These are the interlocking proteins, filaments, and tubules that gives cells their shape. The way that the cytoskeleton is organized is critical to cell function, /4

just like the way the fibers within collagen are organized are critical to its strength and rigidity or flexibility. Of course, the fibers that make up collagan are made up of cells that have a cytoskeleton. /5

There are these things called αβ-tubulins, which are responsible for structural support and transporting things between cells, these things called actins, which are proteins that form around cell movement. /6

The activity of these cytoskeletal proteins can cause activation of mast cells that is accompanied by changes in cell morphology. /7

To put it simply, mast cell activity can change the shape of collagen cells. "Dramatic reorganization of actin cytoskeleton has been observed in mast cells activated by FcεRI aggregation."
ncbi.nlm.nih.gov/pmc/articles/P… /8

So yeah... Just because there is symptom improvement with methylfolate supplementation, does not mean that deactivated decorin is causing collagen elasticity. /9

This study postulates deactivated or downregulated decorim causes a lack of cell adhesion to the ECM and that since binding of decorin to TGF-B is necessary in order to downregulate the inflammatory properties of TGF-B, that is the crux of immflammation? /10

In another peer-reviewed study, "We report that hEDS and HSD skin fibroblasts exhibit in vitro a similar myofibroblast-like phenotype characterized by the organization of α-smooth muscle actin cytoskeleton [and a bunch of other stuff]..." pubmed.ncbi.nlm.nih.gov/29309923/ /11

"The indistinguishable phenotype identified in hEDS and HSD cells resembles an inflammatory-like condition... and suggests that these multisystemic disorders might be part of a phenotypic continuum rather than representing distinct clinical entities." /12

Like so many patients in #NEISVoid and #DisabilityTwitter keep saying, we don't fit into diagnostic boxes. Most patients don't and never did. Moreover, to reduce complex disease to singular factors like a gene (though sometimes that's the cause) completely /13

overlooks the fact that nonwhite folks are disproportionately affected by environmental factors and epigenetics that play huge parts in these multi-systemic disorders. Black folks are left out of EDS research despite being extremely affected and under-diagnosed. /14

I am going to stop here, but will just say. Do better. You're a medical institution and I am just a patient, yet I have a better big-picture grip on this than you seem to. /15

Okay, so side note:

When i@was in methotrexate and having a mast cam reaction, i thought maybe it’s due to the folate-depletion and started researching the molecular structure of mast cells and their patterns of degranulation and figured out that /15

the de-folating effect of methotrexate likely increases IL-10 which then increased mast cell activation. There are a ton of other complicated factors, but long story short, thought about adding folinic acid /16

to enhance the binding of BH4 (Tetrahydrobiopterin) to NOS (nitric oxide synthase) and hopefully reduce the mast cell activation caused by reduced folate. /17

So maybe there’s something about increasing folate as a mast cell stabilizer in there. /18