Genetic variants affecting folate metabolism common in hEDS: Study

Hypermobility linked to changes in how body processes folate

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Most people with hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorder (HSD) carry genetic variations that affect the amount of folate available in their blood, according to a study.

These findings support earlier work suggesting changes in how the body processes folate, also known as vitamin B9, may cause the connective tissue that normally binds structures together to become loose and scarred, leading to symptoms.

The study, “Prevalence of MTHFR Polymorphisms in Patients With Hypermobile Ehlers-Danlos Syndrome and Hypermobile Spectrum Disorders in a US Hypermobility Clinic,” was published as a brief report in ACR Open Rheumatology.

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Mutations that impair folate processing may be cause of hEDS

Differentiating hypermobility disorders challenging due to similar symptoms

Both hEDS and HSD are conditions of the body’s connective tissue that manifest as overly elastic skin and hypermobile joints, or joints that stretch farther than normal. Distinguishing hEDS from HSD is challenging because their symptoms largely overlap.

When testing patients at the Tulane Fascia Institute and Treatment Center, affiliated with Tulane University, the researchers observed high levels of unprocessed folate in the blood of people with hEDS or HSD. This suggests hypermobility may be linked to MTHFR gene-mediated folate metabolism, they said.

This gene codes for an enzyme that converts a form of folate into another one, called 5-methyltetrahydrofolate, which is the main form of folate found in blood. Lack of this converted form of folate may prevent key proteins from binding collagen to the extracellular matrix, a scaffolding for cells.

Now, the researchers checked how common it is for people with hEDS or HSD to carry two polymorphisms, or variations at a single DNA base position, in the MTHFR gene, called C677T and A1298C. It’s estimated these polymorphisms may reduce the enzyme’s activity down to 30% of normal, which may affect the amount of 5-methyltetrahydrofolate in the blood.

The study included 157 patients, ages 13 to 70, of whom 82 (52.2%) had hEDS and 75 (47.8%) had HSD. Most patients (93%) were female. Some 133 (84.7%) carried either one or two copies of the C677T and/or A1298C polymorphisms.

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Significant involvement of MTHFR gene in development of HSD, hEDS

“High prevalence [commonness] of MTHFR polymorphisms in patients with hypermobility suggests significant involvement of MTHFR in the development of HSD and hEDS,” the researchers wrote.

The C677T polymorphism was more common in people with hEDS than in those with HSD (57.3% vs. 48%), whereas A1298C was less common in people with hEDS (46.3% vs. 53.3%). C677T is linked to a greater reduction of the enzyme’s activity compared to A1298C, which could be a reason for the often severe symptoms of hEDS.

“High prevalence of MTHFR polymorphism in patients with hypermobility underscores the gene’s potential role in the maintenance of connective tissue integrity,” the researchers wrote, and “supports our hypothesis that hypermobility may be dependent on folate status.”

“However,” they added, “further research is needed to comprehensively understand the mechanisms involved and potential therapeutic implications.”