Let's Talk about Supplementation #5

Genetic Setting vs. Epigenetic Expression: The Power of the Switch, Not Just the Code

Today’s article will focus on supplements that should be part of a regular program designed to support enzymes that belong to the defective variants of MTHFR and Ehlers-Danlos (EDS).

Last week, in the article “The striking similarity of Ehlers-Danlos syndrome with FQAD,” we saw that the toxicity of fluoroquinolones increasingly appears as an acute manifestation of pre-existing genetic deficiencies, solely exacerbated by fluoroquinolones, which target hundreds of enzymatic interactions, including those associated with EDS.

I have read reflections following that article, stating that many FQAD patients do not fall within the scope of EDS because they are not hypermobile. I would like to respond to this here in more detail.

First, as I have written, Ehlers-Danlos syndrome does not limit to hypermobility. It is a set of different pathologies in their symptoms and intensity, and linked by mechanisms that are not yet fully understood. EDS has a genetic component that does not correspond to a single gene, but rather to a cluster of genes affected by mutations on polymorphisms of these genes (called SNPs or Single Nucleotide Polymorphisms). A gene possesses several SNPs, and certain SNPs have a stronger influence on gene activity than others; we then speak of magnitude. If we take the MTHFR gene as an example, certain SNPs of MTHFR have been identified due to their magnitude: rs1801133 (677C>T) and rs1801131 (1298A>C). It is these SNPs that will have the greatest influence on the gene, and therefore on the ability of MTHFR to add a proton and two electrons to 5,10-MTHF from NADPH to form methylfolate.

When these SNPs carry mutant alleles, the gene’s activity is altered. And it is here that one must understand that having mutant alleles does not lead to a single scenario. If we take MTHFR, one can have one or two mutant alleles on the two main SNPs, or alternatively have only wild-type alleles on each SNP, or multiple combinations of these two scenarios. In my own case, I possess a mutant allele on the 677C>T SNP and a mutant allele on the 1298A>C SNP. We call this a doubly heterozygous mutation, and in this case it leads to a reduction of MTHFR activity of about 65%. This doubly heterozygous mutation on the MTHFR gene causes me a risk of hypomethylation, which translates into a high risk of cardiovascular disease, cerebral degeneration, and collagen-related problems.

Yet I consider myself fortunate in my situation, because I could have had a homozygous mutation on rs1801133, which would reduce gene activity by up to 80%. And even worse, I could have been doubly homozygous (677CT + 1299AC), and then my case would have truly been not funny.

All this to say that even for a single gene, one can have a combination of heterozygous or homozygous mutations on each SNP of each gene. The possible combinations for a single gene and two problematic SNPs (as with MTHFR) give three possibilities per SNP (either wild-type, homozygous mutant, or heterozygous), resulting in nine possible genetic configurations for two SNPs. And this is just for a single gene.

Now, if we take the cluster of EDS genes, we know that at least a dozen genes are involved in the syndrome. And certain genes in this cluster, particularly those related to collagen, do not contain two problematic SNPs, but over a dozen! Take the COL3A1 gene, associated with hypermobility. It has more than 60 SNPs with high magnitude. Imagine then the number of possible combinations. Just for this single gene, if we consider only 60 SNPs, this leads to 3^30 possible combinations. That is 205,891,132,094,649 possible combinations in the pathogenesis of hypermobility, ranging from the mildest to the most severe, including asymptomatic cases that became symptomatic precisely on the day fluoroquinolones targeted the enzymes encoded by these genes.

This is the reason why it’s not possible to restrict the diagnosis of EDS to the presence of hypermobility before the collagen issues caused by fluoroquinolones. Only advanced genetic testing can confirm or rule out whether a patient has a predisposition to EDS. And even then, this would require that all the genes in the EDS cluster be identified, which is still far from reality.

Secondly, EDS is not limited to hypermobility. The second form of EDS, and likely the most dangerous one, is the vascular form, labeled vEDS, which can lead to aortic dissections, thus resulting in very severe (even fatal) forms of FQAD. I unfortunately know among my friends many people who exhibit symptoms of vEDS and are not hypermobile.

Then come all the other EDS symptoms related to hypermobility but which do not manifest themselves as such: mast cell activation, tendon pain, fascia pain, histamine excess, brain fog, insomnia, POTS, CFS, and small fiber neuropathy.

Therefore, one cannot reduce EDS to a single symptom of hypermobility, nor can one claim that a person who was not hypermobile before being injured by fluoroquinolones did not have EDS mutations.

With this clarification made, I encourage anyone who can afford it to undergo advanced genetic testing to better understand their situation regarding each of the genes mentioned in EDS. This will allow them to better target their actions in supporting the enzymes associated with these genes.

Let us now address the issue of supplementation and the actions we can undertake within the FQAD. This article will not cover all possible actions and supplements, as that would be too lengthy for a single piece. Today, we will discuss a sort of basic protocol to have permanently at hand or to monitor permanently; as I do, for example, to manage my status as a double heterozygote MTHFR. I do not supplement with methylfolate, methylcobalamin—and other supplements we will discuss below—throughout the entire year, but I test frequently—I test my homocysteine level, and as soon as it rise above a certain threshold (>7), I know I am beginning to revert to hypomethylation, and I resume supplementation. Generally, the need for testing is not high, provided one takes care to supplement without excess but at regular intervals; the body does not need to be overwhelmed daily with supplements, since we also do not know what they do when present in excess (e.g; pyridoxine/NAC/taurine/magnesium and many others). It is therefore important to cycle supplementation and to test every six months or annually to check whether what we are doing is effective.

First, we will discuss the methylation cycle and what we can do to reduce hypomethylation and the issues associated with hypomethylation; then, secondly, we will examine what we can do to support collagen, as well as what we should not do—or simply what serves no purpose.