Activity of Prolyl Hydroxylase

The function of collagen prolyl hydroxylase is dependent upon the two co-factors, vitamin C and iron. Lack of vitamin C is associated with the development of scurvy due to lack of activity of this enzyme. It is also associated with poor wound healing, easy bruising, gingivitis, nosebleeds, myalgia and arthralgia. Low vitamin C is also associated with the production of weaker collagen (DePhillipo etal, 2018; Boverra etal, 1998)

Prolyl Hydroxylase

Functional Iron Deficiency due to vitamin B2 deficiency

Functional vitamin B2 is critical for iron processing in the body, starting with reduction of Fe+++ to Fe++ in the intestine, and to later the release of transferrin-bound Fe+++ within cells. Vitamin B2, as FAD, also is essential for maintaining reduced glutathione with in cells to further add in the solubilization of Fe+++ and conversion to Fe++. Deficiency of reduced glutathione can therefore lead to precipitation of insoluble Fe+++ within cells and a reduced ability to make enzymes containing iron in their active centers, such as prolyl hydroxylase and lysyl hydroxylase. Hence individuals with non-functional B2 are more likely to produce non-hydroxylated collagen, with the result that the rigidity of the normally H-bonded collagen will be reduced thereby increasing the likelihood of hEDS.

Functional Iron Deficiency due to vitamin B12 deficiency

Functional vitamin B2 is critical for maintaining adequate levels of methyl Co(III)B12 within the methylation cycle and ultimately for the production of S-Adenosylmethionine. This in turn is essential for the ultimate conversion of methionine to homocysteine, and the subsequent formation of cysteine, and for the production of glutathione, which is essential for intracellular processing of iron.. Functional vitamin B12 deficiency, therefore can in itself lead to lower levels of intracellular glutathione and hence contribute to the lack of activity of lysyl and prolyl hydroxylases, thereby contributing to the development of "lax collagen" typically described in hEDS.

EDS and POTS

The association of vitamin B12 deficiency and EDS may explain the observation that 80% of people with EDS have POTS. A recent study in children found that vitamin B12 levels were significantly lower in children with POTS (47.2%) when compared to those without (18%) (Oner etal, 2014).

Gastrointestinal issues with EDS

Various intestinal symptoms have been associated with EDS/HDS, which vary from person to person, and include acid reflux, constipation, abdominal bloating, abdominal discomfort. It is, however, hard to determine if these symptoms are a feature of EDS/HDS alone, or if they are features of the potential deficiencies that cause EDS/HDS

Vascular EDS

Disorders of collagen formation can also affect the vasculature, and cause vascular EDS. This is associated with fragile blood vessels, collapsed lung, and heart valve problems.

Current Concepts on EDS

Data suggests that there are two main types of EDS

Type 2 EDS. Environmentally determined EDS. In this from of EDS some environmental or developmental factor changes the availability of iron, functional vitamin B2, or functional vitamin B12. Persons having this form of EDS seem to develop it either in their teenage years, or somewhat later in their 30s or 40s. The resultant deficiency or availability of iron affects the function of prolylhydroxylase and/or lysyl-hydroxylase, leading to a reduced level of hydroxylation of proline and/or lysine, and thereby leading to much weaker strength of collagen, which ultimately causes more frequent dislocations of joints or a higher frequency of ligament damage. The condition potentially is more frequent in women, and the frequency is increasing with the decrease in iron in the community and the increased rate of functional B2 and functional B12 deficiency. The condition is potentially reversible given the proper nutrients.

Type 3 EDS. Ehlers-Danlos syndrome type arthrochalasia (aEDS) is a rare genetic disease characterized by severe generalized joint hypermobility, bilateral congenital hip dislocation, skin hyperextensibility, muscle hypotonia, and mild dysmorphic features (Martin-Martin et al, 2022).

Type VI EDS. Also classified as the kyphoscoliotic type, are clinically characterized by neonatal kyphoscoliosis, generalized joint laxity, skin fragility, and severe muscle hypotonia at birth (Yeowell and Walker, 2000).The condition is characterized by a deficiency in Lysyl Hydroxylase enzyme, normally hydroxylates specific lysine residues in the collagen molecule to form hydroxylysines which have two important functions. The residues serve as attachment sites for galactose and glucosylgalactose and they also act as precursors of the hydrogen-bonding crosslinking process that gives collagen its tensile strength (Arun et al, 2006; Rohrbach et al, 2011).