Do we finally have a genetic link for hypermobile Ehlers-Danlos syndrome?

Researchers at Tulane University School of Medicine think so – and it could even point to an effective treatment that’s already available.

A variation of the MTHFR gene that causes a deficiency of folate – the natural form of vitamin B9 – could hold the key to hypermobility and a range of associated connective tissue disorders such as Ehlers-Danlos (EDS), according to preliminary findings published in the journal Heliyon.

“You’ve got millions of people that likely have this, and until now, there’s been no known cause we’ve known to treat,” said Gregory Bix, MD, director of the Tulane University Clinical Neuroscience Research Center. “It’s a big deal.”

People with the genetic variant can’t metabolize folate, which causes unmetabolized folate to accumulate in the bloodstream. The resulting folate deficiency in other parts of the body prevents key proteins from binding collagen to the extracellular matrix, which plays an important role in cell growth. This leads to more elastic connective tissue, hypermobility, and a potential cascade of associated conditions, researchers said.

The discovery could help doctors more accurately diagnose hypermobility and hypermobile EDS by looking for elevated folate levels in blood tests and the MTHFR genetic variant.

“Hypermobility is widespread and unfortunately under-recognized,” said Jacques Courseault, MD, medical director of the Tulane Fascia Institute and Treatment Center. “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.”

Doctors discovered the connection between folate deficiency and the MTHFR gene by working with patients at Tulane’s Hypermobility and Ehlers-Danlos Clinic, the only clinic in the U.S. that focuses on fascia disorders. Blood tests of hypermobile patients revealed elevated levels of unmetabolized folate. Subsequent tests showed that most of those with elevated folate serum levels had the MTHFR genetic variant.

The good news is a treatment already exists. Methylated folate – folate that is already processed – is FDA-approved and widely available.

“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.”

Though more studies and clinical testing needs to be done, researchers say patients who have been treated with folate have shown improvement: less pain, less brain fog, fewer allergies and improved gastrointestinal function.

“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.”

What Is Hypermobile EDS?

For those with hypermobile Ehlers-Danlos syndrome (EDS), the same conditions that create fragile connective tissue can cause a range of other symptoms that, on the surface, can seem unrelated: joint pain, chronic fatigue, thin tooth enamel, dizziness, digestive trouble and migraines, as well as psychiatric disorders such as anxiety and depression. Women with hypermobile EDS may also be at increased risk for endometriosis or uterine fibroids.

For years, researchers have struggled to find the cause of hypermobility and hypermobile EDS. Of the 13 subtypes of EDS, hypermobile EDS comprises more than 90 percent of cases. But until this study, hypermobile EDS was the only subtype without a known genetic correlate. As a result, symptoms have often been treated individually, without EDS being recognized as the likely cause.

Until now, hypermobility could only be diagnosed by the Beighton score, a somewhat controversial physical exam that involves measuring the bend of the spine, fingers and limbs. There has also been a historic lack of acceptance of hypermobility as a disorder that requires specialized treatment.

Many patients with hypermobile EDS never get a proper diagnosis. As a result, the number of people with hypermobility is unclear, though it could comprise more than half the world’s population.

“Hypermobility is not rare,” Courseault said. “Hypermobility is like a Ferrari that requires a lot of maintenance and the best synthetic oil. 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.”