Ehlers-Danlos Syndrome and Folate Deficiency: Is there a link to MTHFR?
Ehlers-Danlos syndrome (EDS) is a group of disorders that affect connective tissue and collagen formation. It affects almost every organ system, but the main complications involve the skin, muscles, bones, and blood vessels. Clinical symptoms include skin hyperelasticity, joint hypermobility, atrophic scarring, and fragile blood vessels. 
In severe cases, complications of EDS can lead to ruptures in the arteries or organs, joint dislocation, chronic pain, and fatigue, among other issues. 
EDS is fairly rare, affecting around one in 5,000 people worldwide. There are 13 subtypes of EDS. The most common form is hypermobile EDS, which comprises more than 90% of cases.
Signs you grew up with Ehlers-Danlos syndrome
• Highly flexible joints and/or double-jointedness
• Frequent joint dislocations, especially of the knee or elbow
• Clumsiness or frequent falls
• Feeling you are double-jointed
• Pain and discomfort in the feet
• Digestive issues like bloating, diarrhea, nausea, acid reflux
• Extreme fatigue
• Migraine or vision issues
• Chronic body pain
• Sensitive skin
What is hypermobile EDS?
People with this form of the syndrome have loose, extremely flexible joints and stretchy skin. Their skin tends to heal poorly, and may be prone to scarring. Although considered the least severe form, hypermobile EDS (hEDS) can lead to significant problems involving the musculoskeletal system. Subluxations and dislocated joints are common, and can be minor or severely painful. Degenerative joint disease is also common.
Other complications include: 
• Chronic pain (separate from joint disorders)
• Tendency to bruise easily
• Functional bowel disorders
• Cardiovascular dysfunction, such as aortic root dilation
• Psychological issues and other emotional problems
• Increased risk for endometriosis or uterine fibroids (women)
Unlike other connective tissue disorders, there is no known genetic cause of hypermobile EDS. This means that diagnosis is usually based on symptoms alone, and patients can only be treated for their individual symptoms. There is also no cure.
Researchers have also noted that diagnostic criteria for hEDS is continuing to evolve, which makes it hard to know how many people may be affected.
The link between EDS and folate deficiency
Until recently, hypermobile EDS was the only subtype without a known genetic cause.
But a recent study from Tulane University has suggested that the condition may be caused by genetic mutations that impair the body’s ability to process folate.
The paper, “Folate-dependent hypermobility syndrome: A proposed mechanism and diagnosis” is based on the researchers’ observations that a large proportion of the hypermobile patients had elevated folate levels. (High folate levels can often mean MTHFR polymorphisms, as decreased MTHFR activity impairs the body's ability to break down folic acid, leading to a buildup of folic acid in the body.)
The researchers found a connection between low intracellular folate and hypermobility, indicating that MTHFR polymorphisms may be involved in EDS.
The theory is that poor folate metabolism in the body leads to high levels of an enzyme called matrix metallopeptidase 2 (MMP2). MMP2 is responsible for cleaving (cutting up) a molecule called decorin. Decorin is a type of protein that acts like the ‘glue’ holding the extracellular matrix (ECM) together. The ECM is the mesh of structural proteins that gives shape to body tissues by providing a scaffolding to hold cells in place. It’s involved in collagen fiber formation of all fibrous connective tissue, including the skin, cornea, tendons, and cartilage.
Higher levels of MMP2 means that cells in the extracellular matrix become disorganized.  Connective tissue is held together more loosely, and there is increased thickening or scarring of the tissue.
According to the researchers, the potential solution may be supplementation with active folate, also known as methylfolate.
Potential solutions for EDS treatment
The high proportion of MTHFR polymorphisms among EDS patients in the above study has led to the theory that poor folate metabolism may play a part. The MTHFR gene mutation impairs the body’s ability to break down folic acid in food and supplements, which leads to low levels of active folate. Previous studies in animals have supported this idea, with evidence that one way to ‘turn off’ the MMP2 enzyme is with 5-methylTHF, or methylfolate.  Other studies have found that folic acid deficiency causes a marked impairment in collagen synthesis. 
For this reason, researchers believe that addressing folate deficiency may help to ease symptoms of hypermobile EDS. While further studies will be needed to test this idea definitively, there are numerous benefits to supplementing with active folate, also known as methylfolate. Methylfolate is an effective way to restore a folate deficiency, including in those with MTHFR mutations.  Active folate is also required for reducing levels of homocysteine in the blood, which in turn reduces homocysteine-related inflammation. 
One highly recommended supplement is Methyl-Life® B-Methylated-II, a scientifically formulated product that contains both methylfolate and methylcobalamin (active vitamin B12). Active B12 is included as it is a vital component of the methylation cycle required for proper folate metabolism.
Those looking for a high therapeutic dose of methylated folate would be best served with L-Methylfolate 15+. Again, this is a scientifically formulated supplement that provides the highest dose of methylfolate (15mg), which is clinically shown to be the most effective in restoring low folate levels.  It also includes 1mg hydroxocobalamin, a form of active B12 shown to assist with nervous system development, myelination, and function. 
Incorporating folate-rich foods into your nutritional plan is a great way to support folate levels.
Folate-rich foods include leafy greens, legumes, dairy products, seafood, eggs, red meat, poultry, and wholegrains. Healthy lifestyle habits such as good sleep hygiene and stress management can also help to support overall wellbeing.
EDS care and nutrition
Folate deficiency can impact a range of bodily systems. Deficiency of folate leads to impairment of cell division, accumulation of toxins, and impaired methylation reactions, which in turn are crucial for proper gene expression. This can result in symptoms such as fatigue, depression, poor cognitive function, and anemia. During pregnancy, low folate can lead to neural tube defects.
Given that a high proportion of EDS patients are found to have MTHFR mutations, it may be important for clinicians to make better recommendations for EDS pain management and care. Testing for an MTHFR polymorphism may be helpful for EDS patients to understand more about their nutritional needs and supplement accordingly. If the MTHFR genetic mutation is indeed involved in EDS, patients can take steps to manage their folate levels. Those with folic acid deficiency should also be tested for vitamin B12 deficiency, as both can lead to macrocytic anemia.
Further research will shed more light on the folate dependency theory.
In the meantime, monitoring folate levels are important to maintain optimal health, especially for those with EDS symptoms. Regular blood tests will help you to keep on top of your folate levels and know when or if you need to adjust your supplementation regime.
The potential link between hypermobility and folate deficiency could open up new possibilities for effective Ehlers-Danlos Syndrome treatment.
By recognizing the impact of folate deficiency on the body, individuals with conditions such as EDS may be better able to develop comprehensive treatment plans that address both the genetic aspects of EDS and their own nutritional requirements.
6. https://www.cambridge.org/core/journals/british-journal-of-nutrition/article/collagen- metabolism-in-folic-acid-deficiency/129447D22C7278E05559A281F06096B9
Updated On: May 26, 2023
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