Being able to move like a rubber band and showing off how you can manipulate your joints to your will can be a neat party trick. And while for some, this Gumby-like level of joint movement is a fun icebreaker, for others, double-jointedness (aka hypermobility) can come with more serious health concerns and disorders.

A new paper published by Tulane University may offer hope for those who suffer from joint hypermobility syndrome, identifying a potential underlying reason for joint hypermobility and associated connective tissue disorders like hypermobile Ehlers-Danlos Syndrome (hEDS).

Based on observations made in their clinic, the researchers at Tulane have suggested a connection between hypermobility and a genetic variant of the MTHFR gene—a variant that is characterized by the inability to properly metabolize and process the B vitamin folate properly, leading to potential deficiency of usable folate inside cells and other issues.

According to Dr. Gregory Bix, director of Tulane University's Clinical Neuroscience Research Center, up to this point, research into the underlying cause of hypermobility has largely been under-recognized, making it difficult to inform treatment in patients. By identifying the potential role of folate metabolism in hypermobility, treatments that already exist and are readily available—like dietary methylated folate—can be used on hypermobile patients to hopefully start providing relief to those suffering from these conditions.

What are some of the symptoms and types of hypermobility?

When you were a kid, you probably had at least one classmate that liked to show off and push the boundaries of their flexibility—seemingly able to extend their joints beyond a typical range of motion, usually painlessly, and position their joints right back into place.

While some may experience harmless joint flexibility (sometimes referred to as benign hypermobility syndrome), it is still considered a hypermobility spectrum disorder, an umbrella term for a variety of connective tissue disorders that run the gamut when it comes to the specific symptoms a patient might experience.

Hypermobility symptoms can range from joint pain, including frequent full or partial dislocations, to severe injury in the bones, tendons, ligaments, muscles and skin. Some of the most severe cases of hypermobility syndromes can also contribute to:

• Chronic pain
• Psychological disorders, like anxiety and depression
• Migraines
• Gastrointestinal distress and disorders
• Pelvic and bladder disfunction
• In women, increased risk of endometriosis and other gynecological concerns

There are several severe joint hypermobility syndromes, but one of the most well-known is a type of Ehlers-Danlos Syndrome (EDS), a condition that affects connective tissue to an extreme degree.

What is the connection between folate and hypermobility?

Hypermobility is common and estimated to affect over half of the population, and although it's often hereditary, it has been difficult to pinpoint exactly how the condition develops. The researchers at Tulane have aimed to better understand the development of hypermobility in their patients.

Basing their hypothesis on observations made at Tulane's Hypermobility and Ehlers-Danlos Clinic, the researchers performed blood tests on hypermobile patients to assess elevated folate serum levels and subsequently performed genetic tests for signs of polymorphisms (variant forms of a specific DNA sequence). These tests allowed them to identify the presence of a methylenetetrahydrofolate reductase (more commonly known by its abbreviation MTHFR) gene mutation in many of their hypermobile patients.

Why is this important? People with MTHFR polymorphisms are unable to metabolize or convert either of the traditional vitamin B9 forms (folate and folic acid), often found in food, into its metabolically active form, L-methylfolate (you might also see this form called 5-methyltetrahydrofolate or 5-MTHF).

This means several things: unmetabolized folate can accumulate in the blood, and metabolically active L-methylfolate is not readily available to epigenetically regulate the expression of certain proteins involved in maintaining the extracellular matrix. This can destabilize the "glue" that holds collagen fibers together in connective tissues.

Since collagen is an integral component of strength and flexibility in your joints, skin, tendons and ligaments, if these proteins can't perform their primary function, it can lead to things like more elastic tissue and joint hypermobility, and even fibrosis.

But there is good news! Dietary L-methylfolate is available as an option to counter altered folate metabolism and potentially offer a means to help better manage some of the more severe symptoms of joint hypermobility syndromes.

Pro-tip: Folate goes beyond hypermobility. Like other forms of vitamin B (from vitamin B1 all the way to vitamin B12), the body relies on these vitamins to perform metabolic processes and even make new red blood cells and DNA. So getting enough of this vitamin and avoiding deficiency truly is essential!

How do I know if I have a folate deficiency?

The best way to know if you're experiencing any sort of deficiency is through testing. There are lab tests that can measure your serum folate levels, but if you're experiencing hypermobility, it may be better to check if your serum levels are elevated. It may be a sign you're not properly metabolizing folate, rather than specifically identifying traditional deficiency.

If you really want to identify if you have specific genetic mutations like MTHFR, it might be worth getting a genetic test. This is the best way to get a more concrete diagnosis about what might be going on and how to address anything testing uncovers.

References

• Blagowidow, Natalie. "Obstetrics and gynecology in Ehlers-Danlos syndrome: A brief review and update." Am J Med Genet C Semin Med Genet. December 2021. https://pubmed.ncbi.nlm.nih.gov/34773390/
• Courseault, Jacques, et al. "Folate-dependent hypermobility syndrome: A proposed mechanism and diagnosis." Heliyon. April 2023. https://www.sciencedirect.com/science/article/pii/S240584402302594X
• Yawn, Andrew J. "Could a vitamin deficiency cause 'double-jointedness' and troubling connective-tissue disorder?" Tulane News. April 2023. https://news.tulane.edu/pr/could-vitamin-deficiency-cause-%E2%80%98double-jointedness%E2%80%99-and-troubling-connective-tissue-disorder
• Yew, Kenneth S., et al. "Hypermobile Ehlers-Danlos Syndrome and Hypermobility Spectrum Disorders." Am Fam Physician. April 2021. https://pubmed.ncbi.nlm.nih.gov/33856167/
• "Ehlers-Danlos syndromes." NHS. https://www.nhs.uk/conditions/ehlers-danlos-syndromes/

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