Why the controversy with the CBS C699T enzyme defect?

[greenshots]

I have been slowly working through my two known defects, the CBS & the MTHFR A1298C, and have come across some controversy with the CBS C699T enzyme, at least with how Amy Yasko has explained it. I came across an old post from someone on a similar site criticizing the "lack of science" about Dr. Yasko's take on the CBS as he insisted that no one else believes that this is how the CBS enzyme works.

When I was working on recovering my daughter, I had researched methylation quite a bit & read some of the work done by Dr. James, etc. Though I haven't been able to review this recently, I did make notes and while she doesn't comment on CBS activity directly, Dr. James does mention that some of the findings in her study were unexpected. Even though this doesn't prove Dr. Yasko's theories, they were definitely in keeping with what Yasko believed to be true about the MTHFR (that it required the active version of folate as 5 MTHF, not more folate and folinic) and that CBS defects lead to less glutathione rather than more, and that more toxic wastes build up with these faster glitches. But I think whether or not these CBS defects lead to toxic overload or make more or less glutathione is most interesting and important. Then there's the matter of more sulfur and whether taking in more is good or bad since Dr. Cutler's work seems centered on this. But why all the almost angry disagreement?

Since this issue is so important in treatment, I really would like to understand it. I asked my daughter's practitioner almost 2 years ago and it seemed to me that she gave me a few fairly simple opinions but I should have written them down because I can't remember so many things nowadays. I know nothing is super easy or cut & dry like we hope but a basic understanding would help me decide on some things.

I appreciate your time,
Angela

 

[Ahenspry]

I would also like to know more about this. When I was first reading about CBS mutations, on medical sites, the consensus seemed to be that there was reduced enzyme activity http://www.mdl-labs.com/testing/CBSGeneMutation.html. However, because of the previous link, I think that reduced activity is linked to CBS G919A and T833C. Yasko is talking about CBS C699T.

I have many connective tissue symptoms of homocystinuria, but my homocystines are low, which would suggest an up-regulation of my CBS ++. I also had a very bad experience with methylated B vitamins, which increased my systemic inflammation and anxiety. This result makes me think that my CBS is an up-regulation because the methyl donors would have allowed my CBS to turn sulfur into toxins like ammonia.

I'm going to see a geneticist eventually, but in the mean time I've cut out sulfites, eggs, onions, garlic, and reduced meat intake. In just two weeks, I am feeling amazingly better.

 

[dbkita]

I think another key point with CBS is whether we are talking homozygote or heterozygote.
A lot of people (clinicians included) see dysfunctions with a homozygote mutation and then immediately extrapolate
to a heterozygote mutation which simply is WRONG (almost all of the time). Yes multiple heterozygotes across many genes can be a problem but the allele frequencies of some of the heterozygotes that these clinicians focus on are way to prevalent in the population to be smoking guns on their own.

For example the CBS SNP in your post is known (I believe) by rs234706.

According to data online from 1000 genomes here is the frequency date (remember the reverse complement of C->T is G->A):

62.1% G|G (wild type -- no mutation)
32.2% A|G (heterozygous)
5.7 % A|A (homozygous)

I am sorry but there is no way that 32% of the population is being crippled by a CBS polymorphism that is supposedly upregulating the activity of the gene 5-10 fold (maybe that is for the homozygous). Otherwise on its own it would be a MAJOR health factor in this country... I don't buy that.

Having spent now 20+ years in bioinformatics and genomics, I can tell you in all honesty that when the actual functionality is determined by a concert of multiple genes working together in an integrated network of interactions of their expressed protein products, the system behavior is complicated. Often too complicated. So clinicians fall back on the crutch of one or two heterozygous mutations being the culprit. That is simply wrong ...

That being said a person may have reached a state due to metabolics, epigenetics, or many SNPs + exposures to metals, toxins, infections, etc. that their chemical reactions are not properly coupled anymore and they end up with too much say ammonia, etc. Then the important thing is how to treat this clinically. What is not necessarily useful is to see a heterozygous mutation in the CBS gene and then jump to the conclusion the person has a definite problem. Reverse it. What are their symptoms and work back, don't read the genome ticker tape and speculate forward.

Personally I am CBS C699T heterozygote. Based on clinical symptoms and my A1298C mutation in MTHFR, I seem to have a BH4 problem and its repercussions. But... I eat a ton of protein every day and my serum ammonia levels are well within normal bounds. Would it be wise to try to mop up the ammonia? Probably. Should I kill protein? Well whenever I do, I feel like garbage and lose weight rapidly to unhealthy levels which is not surprising given my metabolic type of a strong fast oxidizer.

In the end it all depends on what works clinically.

 

[dbkita]

Wow 522 views and only 2 replies to a very important question by the OP? Eh?

 

[UM MAN]

My 23andme results are not back yet, but, I suspect that I will have a CBS mutation.
My urine sulfate is always above 1200, on the test strips, and my wife's is <400. (we eat the same food)
I'm peeing my sulfate out, where is hers going???????

 

[LaurieL]

I think another key point with CBS is whether we are talking homozygote or heterozygote.
A lot of people (clinicians included) see dysfunctions with a homozygote mutation and then immediately extrapolate to a heterozygote mutation which simply is WRONG (almost all of the time). Yes multiple heterozygotes across many genes can be a problem but the allele frequencies of some of the heterozygotes that these clinicians focus on are way to prevalent in the population to be smoking guns on their own.

I would also like to lend a point of view to this observation. When looking at SNP's quite extensively, you will find that in some cases, +/- is considered the norm and not the variant, outside of the realm of Autism/Yasko parameters. Which is why I have cautioned in the past, that the SNP's are not a definitive diagnoses, but a possibility of dysfunction, and that some of the more common SNP's found in the mass populas, are compensatory for other succedding SNP's. Meaning that quite possibly, a succession in mutations may indeed be needed in order for the organism to survive. Without this succession, the organism wouldn't make it past infancy and in more severe cases, aborted altogether.

Having spent now 20+ years in bioinformatics and genomics, I can tell you in all honesty that when the actual functionality is determined by a concert of multiple genes working together in an integrated network of interactions of their expressed protein products, the system behavior is complicated. Often too complicated. So clinicians fall back on the crutch of one or two heterozygous mutations being the culprit. That is simply wrong ...

For those interested in more information on this particular point, the "concert of multiple genes" is called gene sets.

http://gsaa.unc.edu/login/

Gene Set Association Analysis (GSAA) is a computational method that integrates gene expression analysis with genome wide association studies (GWAS) to determine whether an a priori defined sets of genes shows statistically significant, concordant differences with respect to gene expression profiles and genotypes between two biological states. Gene sets are generally a group of genes that are putatively functionally related, co-regulated, or tightly linked on the same chromosome.

In other words, the mutation alone is an indication, but in tandem with other known associated mutations toward a certain known result, its functionality can change quite dramatically and change again when compared to another known result. So depending on what you are looking for, and then identify its known gene set, and then tandem mutations in that gene set if present all affect the outcome of the mutual gene set. An individual SNP is not entirely indicative of trouble.

What is not necessarily useful is to see a heterozygous mutation in the CBS gene and then jump to the conclusion the person has a definite problem. Reverse it. What are their symptoms and work back, don't read the genome ticker tape and speculate forward.

Very well said.

Now with that all being said, we do not know if Dr. Yasko has or has not done this. I think she would be the one to ask for an explanation. Anybody belong to her forum?

Lauriel

 

[dbkita]

I would also like to lend a point of view to this observation. When looking at SNP's quite extensively, you will find that in some cases, +/- is considered the norm and not the variant, outside of the realm of Autism/Yasko parameters. Which is why I have cautioned in the past, that the SNP's are not a definitive diagnoses, but a possibility of dysfunction, and that some of the more common SNP's found in the mass populas, are compensatory for other succedding SNP's. Meaning that quite possibly, a succession in mutations may indeed be needed in order for the organism to survive. Without this succession, the organism wouldn't make it past infancy and in more severe cases, aborted altogether.

Very well stated. Imo you hit the nail on the head with the BOLDED sentences.

In other words, the mutation alone is an indication, but in tandem with other known associated mutations toward a certain known result, its functionality can change quite dramatically and change again when compared to another known result. So depending on what you are looking for, and then identify its known gene set, and then tandem mutations in that gene set if present all affect the outcome of the mutual gene set. An individual SNP is not entirely indicative of trouble.

It is in fact extremely rare that one or two heterozygote mutations will ever lead to significant dysfunction. I would rather prioritize epigenetic or phenotypic factors due to say enviromental toxins, infections, severe stress, medication usage, etc.

 

[dbkita]

My 23andme results are not back yet, but, I suspect that I will have a CBS mutation.
My urine sulfate is always above 1200, on the test strips, and my wife's is <400. (we eat the same food)
I'm peeing my sulfate out, where is hers going???????

You are probably right.

I am heterozygote CBS and can sometimes get high urine sulfate readings > 1000.

But here is what I learned about myself.

a) if I overmethylate then my sulfates go up
b) if I eat foods with sulfites and then take molybdenum my sulfates go up
c) if I eat too many thiol rich foods my sulfates go up
d) if I have more concentrated urine (i.e. drink less liquids, medication side effects, etc.) my sulfates go up

Now by all rights according to Dr Yasko et al the fact that I get ~2800 calories per day in just meat and nuts (the rest of my diet affords me maybe another 800-900 calories) and hence 250 grams of protein should kill me off.

But if I avoid (a) - (d) above my sulfates with methylation support are at most 600. If I take no methylfolate (i.e. sometimes I forget my FolaPro) my readings are consistently <200. Meanwhile my ammonia is well within normal. So ... yeah it is not simple.

 

[Symptomatic]

I did 23andMe testing, and was hetero for 11 of the "Yasko SNPs" that 23andMe tests for (including CBS 699T and MTHFR C677T).

I decided that for me personally, due to the complexities of the genetics, I wasn't going to start any supplements without doing the HDRI methylation testing (results pending), so I know biochemically what is actually going on in my body - although I am of course curious to see how this compares this to my genetic predispositions.

 

[triffid113]

I have CBS 669 +/+ and one other CBS +/+ but no SUOX. 80g protein/day keeps my ammonia in range. I cannot do Atkins, but that is not a healthy diet anyway. (Atkins causes me low blood sugar (adrenal issues)). W/o methylated supplements my homocysteine is high, but with them it is right on the money. I have a lot of health problems mostly under control with a LOT of pills (vitamins, herbs). BiancaS has genes almost the same as mine (she also has 18 genetic defects) and by the sounds of it she was pretty healthy until she got helminths. It makes me stop and think. I have allergies that she does not and what I am thinking is that allergies and the genes thereof have a greater impact on my health than I ever knew. Just last year I found out they take out my thyroid and my adrenal gland, for example. I think there are a lot of other genes than these that I want to have mapped. Has anyone seen any other good gene panels?? I do not know what my sulfate levels are and I don't really care. I eat eggs and take a broccoil pill (cysteine) and 2g TMG every day and they don't seem to cause any problem. I think high sulfites are a problem but dont worry so much about sulphates which are excreted. I do have high taurine. I have never had glutathione mapped. I have a heck of a time staying replete in zinc because of my allergies (and zinc hurts my stomach). I take 50mg P5P and DHEA which makes testosterone to regulate my CBS and that seems ok as a result. I can't do nothing...in fact I have to struggle pretty hard (I take about 40 pills) but as a result I am functional.

I just want to say that aside from all the research on these genes not being in, there is MUCH less research on COMBINATIONS of genetic defects, of which I have many, and I strongly suggest using your genes to understand which tests might be worthwhile to order and then ordering them (for instance homocysteine, ammonia,...) to see where you REALLY stand.

 

[dbkita]

I have CBS 669 +/+ and one other CBS +/+ but no SUOX. 80g protein/day keeps my ammonia in range. I cannot do Atkins, but that is not a healthy diet anyway. (Atkins causes me low blood sugar (adrenal issues)). W/o methylated supplements my homocysteine is high, but with them it is right on the money. I have a lot of health problems mostly under control with a LOT of pills (vitamins, herbs). BiancaS has genes almost the same as mine (she also has 18 genetic defects) and by the sounds of it she was pretty healthy until she got helminths. It makes me stop and think. I have allergies that she does not and what I am thinking is that allergies and the genes thereof have a greater impact on my health than I ever knew. Just last year I found out they take out my thyroid and my adrenal gland, for example. I think there are a lot of other genes than these that I want to have mapped. Has anyone seen any other good gene panels?? I do not know what my sulfate levels are and I don't really care. I eat eggs and take a broccoil pill (cysteine) and 2g TMG every day and they don't seem to cause any problem. I think high sulfites are a problem but dont worry so much about sulphates which are excreted. I do have high taurine. I have never had glutathione mapped. I have a heck of a time staying replete in zinc because of my allergies (and zinc hurts my stomach). I take 50mg P5P and DHEA which makes testosterone to regulate my CBS and that seems ok as a result. I can't do nothing...in fact I have to struggle pretty hard (I take about 40 pills) but as a result I am functional.

I just want to say that aside from all the research on these genes not being in, there is MUCH less research on COMBINATIONS of genetic defects, of which I have many, and I strongly suggest using your genes to understand which tests might be worthwhile to order and then ordering them (for instance homocysteine, ammonia,...) to see where you REALLY stand.

I agree that exrcreted sulfates are not that huge a deal but they do point to how your trans-sulfuration pathway is working. High sulfites are serious problem. High ammonia is a problem.

I eat a high protein, high fat, low carb diet because it is extremely healthy for me as a fast oxidizer. Too many carbs is very poor for me since they burn through the Krebs cycle way too fast.

Methylation supplements have more impact on my neurotransmitters, thinking ability, mood, and energy (via creatine, etc.) But my homocysteine remains at >9 even if I over-methylate.

2 grams of TMG greatly enhances norepinephrine to dopamine ratio. For you that may good. For me with my autoimmune problems and low BH4 to begin with that is really, really bad.

What do you mean by "take out your thyroid and adrenal gland"? Did you have surgeries? Confused ...

I too have high taurine. That is common for anyone with high inflammation. The body naturally shifts that way. In the same way high inflammation shifts towards neopterin and cytokine signaling and away from biopterin and BH4. Most people on these forums simply ignore one of the 800 lb gorillas in the room --- the immune system. But I am not going to get on my soapbox about that now, I have already posted on that ad nauseum in other threads. Your allergies are one of the expression of your immune system, but they may be just the tip of the iceberg in terms of what else the immune system is doing.

I empathize. I too take a lot of pills. I take about 40-50 pills and 10 powders over five different time slots during the day. But those supplements and medications are based more on clinical symptoms and not on genes. Again heterozygotes are over-blamed for dysfunction. And yes multiple defects are a big deal ... but so are infections, immune system hysteresis, epigenetics, toxins, metals, etc.

 

[JaimeS]

I ended up writing a blog post on this SNP! It is controversial: Yasko believes it's very important, and I can't find any proof to back up that this *particular* homozygous recessive is a problem. In fact, it appears to be slightly beneficial.

Here's my post about genetics in general and beginning to look at 23andme results.
Here's my post about researching the meaning of a SNP, using CBS C699T as an example.

I'm learning this myself, which is why I put the primer and follow-up article together, as a way of keeping track of my thoughts.

-J

 

[adyia]

Thank you, JaimeS, that was immensely enlightening, and since my concern is specifically a homozygous CBS C698T phenotype (which I am), very relevant! I'm examining this in particular, coz I am in fact allergic to sulphate drugs, and sensitive to sulfites.
I'm suspecting that a bit of sulfur foods is fine for me. But the daily onion/tomato masala of Indian food, with garlic and turmeric, then my fondness for spinach, kale, eggs, dairy, and cruciferous veggies has done me in. There was not a meal I ate in recent years which was NOT high in sulfur. I have all kinds of digestive issues (happily on the mend--I hope!), and deep levels of fatigue and moods.
I will be a one rat study to see if I improve on a low sulfur (low thiol) diet. I've already been addressing a hetero MTHFR A1298C phenotype, but am dubious of its significance, since I notice little impact when I take the methyl Bs, vs when I forget. But folic acid in multivitamins does give me flu-like symptoms, so something is going on--I just can't make heads or tails of it.

Thanks for the reminder of my biology classes. I was a cytogenetics tech and your explanation was oddly comforting and familiar. Got through my brain-fogged head somehow.

 

[JaimeS]

@adyia , I'm so glad it was helpful. I was a high school chem teacher in a former life...

-J