Mutations that impair folate processing may be cause of hEDS

Methylfolate supplements could help with hypermobility symptoms

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Hypermobile Ehlers-Danlos syndrome (hEDS) may be caused by genetic mutations that impair the body’s ability to process folate, the natural form of vitamin B9.

That’s the idea put forward by scientists at Tulane University, in the paper “Folate-dependent hypermobility syndrome: A proposed mechanism and diagnosis,” which was published in the journal Heliyon.

The scientists said that this might mean supplementation with pre-processed forms of folate could help to ease symptoms of hEDS, though they stressed that further studies will be needed to test this idea definitively.

“Hypermobility is widespread and unfortunately under-recognized,” said Jacques Courseault, MD, a professor at Tulane and the study’s lead author, said in a press release. “I’m excited about being able to treat the masses where people aren’t going their whole lives being frustrated and not getting the treatment they need.”

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Millions of people affected by hypermobility

Gregory Bix, MD, PhD, another study author at Tulane, added: “You’ve got millions of people that likely have this, and until now, there’s been no known cause we’ve known to treat. It’s a big deal.”

Hypermobile EDS is the most common form of EDS, characterized by symptoms like unusually mobile joints and fragile skin. Unlike other forms of EDS, there is no known genetic cause of hypermobile EDS, or the related hypermobility spectrum disorders.

Without a known cause, clinicians have to rely on relatively subjective tests to diagnose these conditions based on what symptoms a person is experiencing. The researchers noted that diagnostic criteria for hEDS are “relatively new, unstable, and evolving,” which makes it hard to estimate just how common hypermobility is — though Courseault notes that it is “not rare.”

“Hypermobility is like a Ferrari that requires a lot of maintenance and the best synthetic oil,” Courseault  said. “After knowing a patient’s name and date of birth, I think it’s prudent for clinicians to know which of these body types they have.”

Over the course of treating people with hEDS at their clinic, the scientists observed that the patients had abnormally high levels of folate in their blood. This nutrient, which is in the B9 family of vitamins, plays important roles in a wide array of biological processes.

High folate levels in these hEDS patients were typically accompanied by mutations in the gene MTHFR. This gene codes for an enzyme that converts a form of folate into another molecule called 5-methyltetrahydrofolate (5-methylTHF), the primary form of folate found in blood.

The researchers proposed that MTHFR mutations might reduce the amount of 5-methylTHF, ultimately resulting in higher levels of unprocessed folate in the bloodstream, which would explain these results.

In addition to these observations in their patients, the researchers noted studies done in animal models have suggested 5-methylTHF is needed to “turn off” an enzyme called MMP-2.

MMP-2 (matrix metalloproteinases 2) is responsible for cutting up a molecule called decorin. Decorin normally acts as the “glue” that holds together the mesh of structural proteins called the extracellular matrix, which gives shape to body tissues by providing a scaffold that holds cells in place.

When MMP-2 cuts decorin, it results in the connective tissue being held together more loosely. Cutting of decorin by MMP-2 also activates molecular signaling pathways that trigger scarring.

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‘Hypermobility symptoms could be mitigated by supplementation’

Taking all these data together, the researchers proposed that MTHFR mutations could lead to reduced levels of 5-methylTHF. Low levels of 5-methylTHF, in turn, lead to increased activity of the MMP-2 enzyme. The MMP-2 enzyme then cuts up decorin, resulting in looser connective tissue and more scarring that gives rise to hEDS symptoms.

“If this model and mechanism are supported by future research … then it raises the possibility that hypermobility symptoms could be mitigated by supplementation with 5-methylTHF,” the researchers wrote, calling for further studies to test this idea.

“It’s an innocuous treatment,” Bix said. “It’s not dangerous, and it’s a vitamin that can improve people’s lives. That’s the biggest thing: We know what’s going on here, and we can treat it.”

The scientists noted that, since the late 1990s, grain products in the U.S. have been required to be supplemented with folic acid, which is the oxidized form of folate that needs to be processed inside the body before it can be turned into 5-methylTHF. As such, supplements of 5-methylTHF, also known as methylfolate, may be more beneficial for people with hEDS.

“We’ve discovered something in medicine that can help, not a small group of people, but potentially many across the world,” Courseault said. “This is real, it’s been vetted out well and clinically we’re noticing a difference.”