TMG/Methylation

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TMG is a supplement that can be purchased. As I understand it, TMG is supposed to promote methylation. Methylation should dial down/turn off genes. This might be a good thing if your child has PWS UPD because your child has received a double dose of mom's genes and a double dose of those genes has been linked to autistic tendencies, so maybe it is good to suppress their expression/dial them down.

Note from Theresa the geneticist: I will say that I don¹t really agree with this point that it might be beneficial to increase methylation in those with PWS by UPD as a means to downregulate expression of maternally expressed genes ­ unless you could do that very specifically. I think the bigger problem probably is the inactive paternally expressed genes, which are methylated, and you wouldn¹t want to add to that.

UPD

Interesting bit of information relating to Danny’s TMG - I had stopped giving him the TMG and folic acid simply because I ran out and kept forgetting to order it. A couple weeks ago his therapist asked me if anything had changed in Danny’s diet or medication, etc because he was really not acting himself.. He had some weird ‘autistic’ tendencies – going off by himself, not listening to the teachers, very obstinate and not wanting to do what he was told.. Slightly disruptive. I told her that he hadn’t been getting those supplements but I was going to refill and get him back on it.. well, he’s back on it and believe it or not, completely back to normal. Totally focused again and doing what is asked of him, etc etc.. so.. you may be right about the TMG and kids with UPD.

Deletion

In contrast to UPD, kids with PWS deletion do not have any extra genetic material. Instead, they are just missing Dad's contribution. In the best possible world, you would like to dial up expression of mom's turned off (methylated) genes. Therefore logic (if it applies!) would suggest that TMG is not a good idea for kids with PWS deletion.

Also see Leaky Genes


Technical Discussion of Methylation and PWS

Including large amounts of TMG strikes me as a rather odd way to go about changing gene expression, given that high amounts of methyl donors promote DNA hypermethylation, which silences gene expression. (See, e.g., Maternal Methyl Supplements in Mice Affect Epigenetic Variation and DNA Methylation of Offspring <http://jn.nutrition.org/cgi/content/full/132/8/2393S> (2002), in which high levels of maternal dietary methyl donors (choline, betaine (TMG), folic acid, B-12, L-methionine and zinc) were used to down-regulate expression of the agouti gene in offspring.)

As I noted previously, there are some serious concerns with the idea of trying to influence gene expression through the use of methyl donors to silence genes or acetyl group donors to try to demethylate genes and thereby increase their expression. What is getting left out of the discussion is the very important fact that DNA methylation is a genome-wide process, that is, using large amounts of methyl or acetyl group donors to manipulate gene expression has the potential to affect genes on every chromosome, not just those in the PWS region on chromosome 15. A good review article in Nature (2003), Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals <http://www.nature.com/ng/journal/v33/n3s/full/ng1089.html>, addresses some of the unknowns:

'Epigenetic changes' include the silencing of tumor suppressor genes by hypermethylation, the loss of imprinting and, less likely, the activation of oncogenes by demethylation. Of these, the most important epigenetic change leading to a selective growth advantage of tumor cells is likely to be the hypermethylation-mediated silencing of tumor suppressor genes. [appears about 1/3 of the page, just below Table 2]
[...]
Even though the epigenetic misregulations that are involved in the etiology of diseases such as imprinting disorders, RTT [Rett syndrome], ICF or cancers are potentially reversible, a key issue of any therapeutic strategy that attempts to remedy the abnormal epigenetic state is that of specificity. Interfering with the activity of factors that modify the chromatin state is likely to affect the expression of unwanted genes such as endogenous retroviruses. Before intervening we will need to understand better how the components that establish and maintain different chromatin conformations cooperate to ensure proper gene expression patterns, and how the genome integrates this information with signals from the environment. [emphasis added; second paragraph from the end]

(In case you want to explore this further, the "See all related articles" <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Display&itool=abstractplus&dopt=pubmed_pubmed&from_uid=12610534> link for the Nature article's PubMed abstract lists several hundred related articles.)

As the Nature article notes, DNA methylation-mediated gene silencing is likely to be at least in part an evolutionarily-evolved process that serves to protect the integrity and stability of the genome while still allowing for flexibility in responding to environmental changes. As such, it is part of a vast, delicately balanced dance of gene promoters, suppressors, signalers, transcribers, transporters, etc., that we are just barely beginning to understand and still constantly being surprised by. There is great wisdom in the genome - it is what billions of years of evolution has found to "work." As a result, my inclination is to be rather cautious when contemplating grabbing one of the threads in that intricate web and tugging on it, especially when we don't know what other threads connect to the one in our hand.

As far as I can determine, there have been no human studies of the use of methyl donors to down-regulate gene expression and a search on "gene expression methyl" at clinicaltrials.gov returns only one result (a trial of L-arginine supplementation to treat pre-eclampsia, which doesn't seem to be relevant to this discussion). It may be that the use of methyl donors to silence gene expression will "work" in those situations where it might be appropriate (such as perhaps Down syndrome) and there won't be any significant adverse consequences down the road. At this point, though, it is most certainly an experiment. My approach in such a situation would be to explain to parents the theory behind the use of methyl donors, that it is an experimental approach with many unknowns and what the possible risks are, and let them decide if they want to proceed or not. The fact that that apparently isn't done regarding the Nutrivene formula suggested to me that the TMG in it is not being used to attempt to down-regulate gene expression, especially since there are other rationales for its presence (e.g., to increase the production of S-adenosylmethionine) and that the amounts of zinc and choline were both reduced by half compared to the autism formula, not to mention the fact that methyl donors silence gene expression, which is the exact opposite of what we would want to happen in PWS. In addition, the information on the Down's version of Nutrivene <http://www.altonweb.com/cs/downsyndrome/index.htm?page=ntdrda.html> at the Riverbend Downs Syndrome Group web site states (click on the yellow question mark):

The purpose [of TMG] is to attempt to force methionine resynthesis pathway from homocysteine by an alternative mammalian pathway to the 5-methylfolate-B12-methionine synthase pathway before cystathionine beta synthase (CBS) can convert homocysteine. Methionine levels tend to be deficient in Down syndrome and is necessary for the production of S-adenosylmethionine (SAM) which is a precursor to serotonin and crucial for countless metabolic reactions. The byproduct is dimethylglycine. The purpose of this addition is to try to keep homocysteine, in the form of methionine, to rob CBS of substrate for overproduction of cysteine. This is essentially a backup pathway, and is meant to complement the folate route for remethylation, rather than supplant it. It does not interfere with the folate route.

However, given what Nutrivene has told you and others, it seems I was wrong in thinking that the purpose of the TMG is not to influence gene expression. At any rate, I am not aware of any research that would provide a basis for determining how much TMG (either alone or in combination with other methyl donors) would be needed to down-regulate gene expression in humans and have no idea if the amount of methyl donors in the Nutrivene formula is enough to actually accomplish that. However, if it is assumed the amounts are sufficient and we are willing to accept the risk of unwanted consequences from possibly down-regulating an unknown number of genes across the entire genome, then I would say it is still not an appropriate approach for those with PWS due to either deletion or UPD.

The fact that the paternal copy of the genetic information in the PWS region is missing and the maternal genes are silenced due to methylation-mediated imprinting means we would want to try to demethylate the maternal genes in order to restore at least some gene expression from the PWS region, not make them even more methylated as would be done by methyl donors.

In PWS due to UPD, there are two silenced copies of the PWS region and the suggestion has been made that a very low level of expression of one or more of the genes in the PWS region may manage to "leak" through the imprinting, thereby possibly accounting for the supposedly somewhat less severe phenotype in UPD. Even if that were true, I think that as with PWS due to deletion, with UPD we would also want to increase the expression of the genes in the PWS region, but only partially because of the risk of over-expression due to the fact that there are two copies of the PWS region in UPD. In other words, with UPD we would also want to (partially) demethylate the PWS region genes, not make them hypermethylated as would be done by methyl donors.

(Another potential concern in terms of up-regulating gene expression in UPD is the issue of X-chromosome inactivation skewness (see, e.g., X-chromosome inactivation patterns in females with Prader-Willi syndrome <http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17036338&query_hl=1&itool=pubmed_docsum> (2006)).)