23andme & Chronic insomnia and family history of psychiatric/CNS disorders

[futuritycarpaccio]

I will then consolidate all the ideas I've been having here... My own conclusions are in orange and at the end. Everything else has the references to scientific articles or wiki. let me know if you find something wrong or don't agree.

Finasteride Metabolism

Finasteride's metabolism is hepatic. It's metabolites are excreted through feces (39%) and urine (57%). [1]
In Phase I of liver detoxification, finasteride is primarily metabolised through CYP3A4, through Oxidative Metabolism, into:
- Hydroxy-Finasteride, which isn't found in Plasma bile or urine [2]
- Carboxy Finasteride~oic finasteride, which is then found in Plasma, Bile and Urine. [2]

In Phase II
Hydroxy Finasteride is metabolised into Omega-Hydroxy-Finasteride [3] through Gluthatione S Transferase Omega 1 (GSTO1 gene).
Carboxy Finasteride, which is +- oic finasteride, is then metabolised into Omega-oic-Finasteride [3] through Gluthatione S Transferase Omega 1 (GSTO1 gene).

Glucuronidation:
In Vitro, Omega-Hydroxy-Finasteride is metabolised into omega-hydroxy-finasteride-glucunoride, by UGT1A4. This metabolite was not detected in vivo. [3]
In vivo, omega-oic-finasteride is transformed in omega-oic-finasteride glucuronide and was found in the bile of a few individuals. [3]

Other metabolites
In vitro, but also in urine and bile, 2 other Hydroxy Finasteride compounds were identified. [3]

-----------------

CYP, UGT and Finasteride

Finasteride is primarily detoxified through CYP3A4.[1]
However, finasteride can also be an inhibitor of CYP3A4 [4]:
- Finasteride's Ki for 5Beta Reductase is less than an order of magnitude higher than that for 5Alpha Reductase I [4]. Finasteride inhibits 5AR II = 10nM Ki, 5AR I = 300nM, 5breductase AK1RD1 = 2100nM.
- Finasteride's acts upon 5beta reductase as a competitive inhibitor, not a mechanical based inactivator (irreversible enzyme inhibitor).[4]
- 5beta reductase is involved in bile acid synthesis. [4]
- 5beta reductase is responsible for generating 5beta-pregnanes,which are natural ligands for the pregnane-X receptor (PXR) in the liver. 4]
- PXR is involved in the induction of CYP3A4. [4]

This means that high dosage of finasteride might inhibit CYP3A4, which means that finasteride might prevent its own metabolism [4], thus promoting drug accumulation.

Inhibition of hepatic UGT isozymes by finasteride has not been explored before 2014. In vitro, of the seven hepatic UGTs, finasteride potently and selectively inhibited UGT1A4, finasteride did not inhibit hepatic UGT1A1, 1A3, 1A6, 1A9, 2B7, and 2B15 activities. However, the C max of finasteride in patients is much lower than K i of finasteride for UGT1A4, finasteride is unlikely to cause clinically significant drug–drug interactions via UGTs inhibition. [5]

However, Cmax of finasteride seems to be able to change based on other factors. [6]
In this case

Cmax and AUC0-24 of finasteride were significantly higher after coadministration with terazosin.

. Even though finasteride and terazosin are not substrates for the same enzyme (CYP3A4).

That could mean there is a metabolite of finasteride that is detoxified by another CYP enzyme, or UGT enzyme, that terazosin either induces or inhibits. This could mean there is a method of detoxification of finasteride that has not been yet identified. It could be a metabolite that has not been yet identified and uses enzymes other than UGT1A3 or CYP3A4.

-------

Conclusion

Genetic polymorphisms in the detoxification elements of the liver, unique to each person, promoted accumulation of high dosages of the drug. This in turn lead to all sorts of problems, some of which are not identified yet.

I think we have a genetic predesposition, be it through methylation blocks, reduced amounts of CYP3A4, UGT1A3, or other enzymes necessary by the metabolites, which were already present or that were latent and were then triggered by the hormonal changes imposed by finasteride. This induced enough drug accumulation that finasteride started inhibiting CYP3A4, preventing it's metabolism and promoting huge quantities of the drug in the liver. This had lead to the following:
-> Bile acid synthesis problems
-> Liver endoplasmatic reticulum stress
-> Hepatotoxicity
-> Leyidig Cell hyperplasia and adenomas [7]
-> others unidentified

And to it's consequences:
- Liver problems (bile acid problems, liver endoreticulum stress) could be accountable for low vitamin d, high cholesterol, problems with glucuronidation, endoplasmatic reticulum stress, low 3adiolG, digestion issues, high crp, adrenal problems, malabsorption of nutrients and minerals, pancreatitis...

- Endoreticulum Stress may have triggered Dolichol Deprivation, as outlined by TryingNotToWorry [8], or could be the other way around.


In rats, finasteride was randomly associated with Leydig Cell hyperplasia and adenomas, as outlined by Vicentv in PropeciaHelp.[7]

The fact that in the mitotane study, the person doesn't get back the full amount of the CYP3A4 activity, probably could be further indicative of an epigenetic change in that enzyme's activity. [9]


[1] http://en.wikipedia.org/wiki/Finasteride
[2] http://www.diva-portal.org/smash/record.jsf?pid=diva2:174003&dswid=-4682
[3] http://www.researchgate.net/publica...Liquid_ChromatographyTandem_Mass_Spectrometry
[4] http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2740403/
[5] http://www.ncbi.nlm.nih.gov/pubmed/25448279
[6] http://www.ncbi.nlm.nih.gov/pubmed/9824790
[7] http://www.ncbi.nlm.nih.gov/pubmed/8005373
[8] http://propeciahelp.com/forum/viewtopic.php?f=27&t=4892
[9] http://press.endocrine.org/doi/full/10.1210/jc.2012-2851

 

[drob31]

I ordered:

Glucose tolerance test (challenge test)
pregnenelone
DHT
DHEA-S
Estrogen e1, e2, and total estrogens
Prolactin
Urine album and creatinine ratio

I forgot to get myogobulin, phosphorus and c-peptide antibodies.


Also got a referral for an allergist to try testing for food sensitivities.

 

[futuritycarpaccio]

I am curious to see your results.

I think finasteride triggered some sort of choleostasis drug induced liver injury in many people.

I think people have a conjugation of severeal polymorphisms, which lead to hepatotoxicity.

The clinical studies on finasteride announced a rate of hepatotoxicity similar to placebo but it is obvious that if there is such a small percentage of population in which finasteride will induce it, then it is for sure possible that it is masked in those values. the fact that placebo and finastrride groups have the same percentage is irrelevant when considering a very rare case...the proof are 2 cases i found in a spanish medical literature of finasteride induced elevation of trasaminases

I have many rare reactions to some meds, and i have several polimorphisms in several areas of the liver detox.. I think thats the reason...


I want to alert the authorities in my country for this. This drug is an overkill for such a condition like MPB, which is not life threatening

 

[futuritycarpaccio]

ahh...let me see if i can summarize this...tomorrow ill perfect it and put in all the references...still i miss one connection which i couldn't find anywhere: finasteride and foxa2

So.. Consider a person with a rare subset of polimorphisms on several steps of the liver detoxification process. Let's say:
Phase I: -/- for CYP2D6 (this leads to increased estrogen)
Phase II: -/- for GSTO1 (this metabolises a finasteride metabolite), -/- for UGT1A3(this metabolises a finasteride metabolite's metabolite)
Others: -/- for Pregnane X Receptor (which I am btw...this is affected by fin in high dosages), -/- for SOD2 (this leads to increase of super oxide, which is a ROS), Methylation block SNPs

This very unlucky person, takes a few mgs of finasteride:


Finasteride------------->Carboxy-Finasteride---------------->Omega Oic Finasteride------------------>Omega Oic Finasteride Glucuronide
____________CYP3A4_______________________GSTO1__________________________UGT1A3

Omega Oic Finasteride Glucuronide is found in human bile.

GSTO1 reaction takes place in the mitochondria of hepatocytes. GSTO1 generates ROS.
In a person with mitochondrial detoxification polimorphisms. In this case lets consider SOD2. This leads to impaired reduction of Super Oxide because of low presence of Super Oxide Dismutase. This directly leads to higher presence of Super Oxide because it's not being reduced properly and Super Oxide is a ROS. So this leads to increase in ROS in the mitochondria.

SOD2 -/- -->Impaired reduction of Super Oxide-->ROS accumulation in Mitochondria-->Imbalance between Antioxidats/ROS->Oxidative stress ----> Mytochondrial Dysfunction


Increased ROS in the mitochondria will decrease glutathione. This will contribute to a depletion of glutathione.

Methylation blocks will contribute to the person's inability to replenish glutathione properly in order to go on with the correct metabolism of finasteride.

Finasteride is an inducer of GST pi in the prostate, which means it probably increases ROS and this is a compensatory mechanism. Could be that this happens as well in the liver. If so, it means finasteride increases ROS in the liver.

Increased ROS mitochondria------->Decreased Glutathione
Methylation Blocks------------------>Decreased Glutathione
Finasteride induces ROS-----------.>Decreased Glutathione

Decreased Glutathione----------------------------------------> Depleted glutathione
given enough time leads to

Depleted Glutathione------------>Problems in Krebs Cycle
leads to

A dysfunctional mitochondria cross talks with Endoplasmatic Reticulum and indirectly makes it elevate the generation of ROS. This leads to ER Stress which is involved in thousands of gene changes!!!!

A dysfunctional mitochondria will create an accumulation of Carboxy Finasteride.
A high level of Carboxy Finasteride maybe (or finasteride itself???) is the factor that makes high dosage finasteride inhibit 5beta reductase.
5 beta reductase inhibition inhibits Pregnane X receptor. This in turn leads to lowered CYP3A4 expression (maybe this is helpful??)
5 beta reductase inhibition impairs bile acid synthesis.
Glucocorticoid receptor is involved in a cross talk with Pregnane X Receptor. So that dexamethasone is modulating PXR as well as GCR.

High levels of Carboxy Finasteride-->inhibition of 5beta reductase-->inhibition of PXR-->decrease of CYP3A4--->accumulation of finasteride
High levels of Carboxy Finasteride-->inhibition of 5beta reductase-->impaired bile acid synthesis---->impaired bile flow--->high bilirubin

UGT1A3 mutations can also lead to impaired bile flow which lead to high bilirubin.
Could be that a Foxa2 defect is present as well and this will lead to Bile acid homeostasis dysregulation lead to ER Stress.

Bile Acid Problems, Homeostasis Dysregulation ------------------> ER Stress
lead to

Accumulation of finasteride together with CYP2D6 -/-, will lead to higher estrogen. Higher estrogen is associated with cholestasis. Highish concentrations of finasteride in rats, sometimes leads to leydig cell hyperplasia.

ER stress ties in with the Dolichol Deprivation Theory made by TNTW, which in turn ties in with 5AR3 inhibition.
Dolichol Deprivation Theory (due to inhibition of 5AR3??)-->UnfoldedProtein Response problem--->ER Stress

ER Stress leads to Drug Induced Liver Injury. This leads to systemic ROS production and systemic oxidative stress state.

Over time the drug exits the system, and the liver recovers. But maybe somewhere along the above process of damage, some organs were damaged, some genes methylated due to ER stress and/or hormonal changes, and mitochondrias become dysfunctional, leading to a host of problems. The PXR is involved with glucocorticoids as well and maybe this lead to the adrenal problems. I won't theorize so much more as this is obviously an impossible exercise with such few data. I will perfect this as time goes by. I'm positive liver has had much influence in our condition and I will prove it is dysfunctional upon quitting.


Ideas on how to address this (this is not an advice on what to do! Follow this at your own risk and responsibility if you want):
----> PXR agonist
----> CYP inducer
----> UGT inducer
----> P450scc inducer (still have to check this one out too..forgot)
-----> Foxa2 inducer (impossible, there's no data in this)
-----> ER stress killer
-----> Increasing Glutathione
-----> Helping dysfunction mytochondria
-----> Helping SOD2
-----> Possibly supporting the gut, pancreas, bile (???), adrenals, thyroid...

How to know if this is working out fine:
- Check LDL and HDL for positive changes
- Check D3 for positive changes
- Monitorize liver enzymes and bilirubin
- Check 3adiolG for increases and 3adiol for decreases
- check cortisol for normalization
- check improved thyroid function
- check improved testestore
- check improved estrogens

anyway, just my contribute. i'm not sure any of this makes any sense. But I will try it out. I hope when my vitamin D3 reaches 80, and my thyroid and cortisol normalise, I will solve my insomnia.

I will now buy supplements/drugs.

 

[futuritycarpaccio]

I ordered:

Glucose tolerance test (challenge test)
pregnenelone
DHT
DHEA-S
Estrogen e1, e2, and total estrogens
Prolactin
Urine album and creatinine ratio

I forgot to get myogobulin, phosphorus and c-peptide antibodies.


Also got a referral for an allergist to try testing for food sensitivities.

@drob31 what do you expect tonfind with these? myogobulin, phosphorus and c-peptide antibodies.

 

[drob31]

@drob31 what do you expect tonfind with these? myogobulin, phosphorus and c-peptide antibodies.

Myoglobulin was for rhabdomyolysis, phosphorus was something I wanted to check, and C-pep was for diabetes. I think now I've put allot of peices of the puzzle together. I'm going to make a thread on it soon.

 

[futuritycarpaccio]

Myoglobulin was for rhabdomyolysis, phosphorus was something I wanted to check, and C-pep was for diabetes. I think now I've put allot of peices of the puzzle together. I'm going to make a thread on it soon.

cool, let me know when you make a thread on it! I'm very curious about it

Regarding finasteride, basically I think there is a chance it made a drug-drug interaction with itself by inhibiting 5beta reductase. I found evidence of hepatotoxicity in people and even 2 documented cases, even though they state in the leaflet that finasteride is not associated with hepatotoxicity

 

[ppodhajski]

Hello xptriado,

I was looking at your MTHFRSupport report and would like to add my ideas and what helped me and ask you a few other questions.

First, did you run your genes through Promethease?
https://promethease.com/ondemandlicense

There are a lot of other important genes that all of these sites do not look at. And I feel as well that these sites look at genes that are not important to healing.

However, on what you presented:

First, your CBS A13637G rs2851391 SNP. This is important to take care of because it is where homocysteine gets stopped from turning into a few things: sulfate, an important transporter of minerals, as well as taurine and glutathione, both antioxidants.

Also, I see you have a SOD2 SNP. Taking manganese for that is good but if you do not have enough glutathione from the CBS SNP you will get a build up of H2O2 because your body will get rid of superoxides (SOD2) effectively but will turn them into hydrogen peroxides. If your glutathione perioxidase gene (GPx) is bad you will get damage from those. Not as bad as superoxides but still bad. (See my attachments for the pathways involved)



I am wondering if you have/had early grey hair?

Next, your MAO-A SNP makes you leave behind more H2O and O2 in the presynaptic nerve . Here is the formula:

RCH2NHR' + H2O + O2 = RCHO + R'NH2 + H2O2 (http://www.uniprot.org/uniprot/P21397)

That first part is the catecholamine, like serotonin or dopamine. MAO is the catylst for this reaction and uses FAD (an end product of Riboflavin or Flavin Mononucleotide) as a cofactor. (This SNP will cause a riboflavin deficiency.)

So when we have MAOA SNPs, that O2 and H2O is left around in the cell and forms superoxides. Those superoxides hand around and damage the nerves, or the skin, or any of the many other places the MAOA enzyme is active.
http://www.cvphysiology.com/Blood Flow/BP016 ROS formation.gif

Also, when under stress we release cortisol (a glucocorticoid) and that inhibits our MAOA gene even more, making us feel worse.
http://www.ncbi.nlm.nih.gov/pubmed/8749044

So we get anxiety and insomnia from the epinephrine that is not being broken down and also free radical damages to the nerves and other cells that use MAOA. You will also see low blood sugar or reactive hypoglycemia.

I did not see your GPx SNPs, there are four of them you can see in promethease (GPX1, GPX2, GPX3, GPX4) and it uses selenium as a cofactor.

Their are other genes , like DAO (Diamine Oxidase) that play a role in all this as well but that should be enough for you right now.

I take Flavin Mononucleotide for my homozygous MAOA and MAOB SNPs and Magnesium for my homozygous COMT SNPs. And I take B6 for my homozygous CBS SNP, and infrequently, Manganese for my homozygous SOD2, Zinc/Copper for my heterozygous SOD1 and SOD3, and selenium for my homozygous GPX SNPs. This has removed my anxiety/sleep issues and all of my other health related issues.

Understand that this is an inflammation issue, and that the inflammation is caused by too many free radicals.
Insomnia and Free Radicals
http://link.springer.com/article/10.1134/S0362119709040100
Seizures and Free Radicals
http://journals.lww.com/neurosurger...nd_Free_Radicals___the_Antioxidant_May.3.aspx

You need to limit reactive oxygen production and support their complete removal.

 

[Valentijn]

First, your CBS A13637G rs2851391 SNP. This is important to take care of because it is where homocysteine gets stopped from turning into a few things: sulfate, an important transporter of minerals, as well as taurine and glutathione, both antioxidants.

rs2851391 probably isn't anything to worry about. I've only found one study where any significant association was found, and it was a tiny increase in a folate-related birth defect. It's also extremely common to be +/+ for that one.

I also haven't seen any indication as to whether it's an up-regulation or down-regulation. The assumption would be a down-regulation, based on other CBS SNPs causing similar mild elevations in disease risk for fetuses. I honestly would not worry about that one unless homocysteine is elevated, or if getting pregnant. In which case, a small/normal dose of B6 should help speed up the enzyme created by the CBS gene.

 

[ppodhajski]

rs2851391 probably isn't anything to worry about. I've only found one study where any significant association was found, and it was a tiny increase in a folate-related birth defect. It's also extremely common to be +/+ for that one.

I also haven't seen any indication as to whether it's an up-regulation or down-regulation. The assumption would be a down-regulation, based on other CBS SNPs causing similar mild elevations in disease risk for fetuses. I honestly would not worry about that one unless homocysteine is elevated, or if getting pregnant. In which case, a small/normal dose of B6 should help speed up the enzyme created by the CBS gene.

I feel like CBS rs2851391 is important because two autistic children I know have it homozygous.

I think I know why there is confusion about weather this is an up regulation or a down regulation since fixing CBS by taking pyridoxal phosphate can cause issues downstream, like with sulfites or hypotaurine if someone had GAD1 or SUOX SNPs and they are not taken care of first. But I have not seen any evidence that there can be an up regulation of the CBS gene.

I feel that if there is some evidence that a SNP causes issues it is important enough to treat, since research move slowly and is incomplete. In another post I will explain the way I look at promethease that helped me.

Thans Valentijn.

 

[Valentijn]

I feel like CBS rs2851391 is important because two autistic children I know have it homozygous

Well, that's not surprising. Approximately 1.04 billion people are homozygous for it. I'd be much more shocked if you didn't know a lot of people who happened to have it.

 

[futuritycarpaccio]

Hi @ppodhajski ! Thank you for your help!

I did ran Promethease but I have not given it too much credit because it has too much information and I saw things like: reduced risk of male pattern baldness..uhhhh...i'm loosing hair since 17-18. This may answer your other question. I'm loosing hair, but I have probably 2 grey hairs in my head lol. I do have a few grey (or unmatured thanks to finasteride?!) hairs in my beard.

How have you filtered the important info on promethease? I could upload it...
Some SNP's i feel are active, particularly the ones about dopamine and D2 receptors, where it says I have increased risk for restless legs, parkinson and adhd. I have experienced something like periodic limb movement for more than one year, I'm slightly sluggish and at times I feel I can't focus on conversations as I don't always take pleasure in them. Agomelatine which disinhibits dopamine at presynaptic 5ht2c receptors (if i remember correctly) cured me those points from one day to the next, one pill..but unfortunately it further indered my sleep. Libido has taken a hit too since a long time. But I'm so worried it was because of finasteride. I'm doing more exams on tuesday which will help me rule out post finasteride syndrome, according to my analysis of PFS. I do think I might have ADHD but it's not so bad as I have finished university...

I also thought about the riboflavin deficiency but not because of the reason you gave me. That's a really good reason and I will check for that on tuesday as well!

Is there an easy way to rise glutathione?

Low blood sugar or reactive hypoglycemia is somethign I have given some thought. In prometeashe I also have a higher risk of low blood sugar but somehow it is connected to a positive SNP.

How can I find GPX1/2/3/4 in promethease? I am also curious about the SNPs for those genes but I am not sure I was tested for them A SNP in those genes would be another staple to my finasteride theory.

How to further limit ROS? I will follow your plan on these cofactors. Also, could you let me know the dosages?

One last thing: my homocysteine wasn't high, it was actually below the lower limit!! at the time I was taking adb12, but after reading Amy Yasko I may have understood why I had low homocysteine. I am pouring everything to the CBS pathway because of some other mutations. And this leads to increased excretion of taurine and some other stuff. Anyway, I think I will buy SAM-e to supplement the methionine cycle.
Do you think it would hurt?

 

[ppodhajski]

Well, that's not surprising. Approximately 1.04 billion people are homozygous for it. I'd be much more shocked if you didn't know a lot of people who happened to have it.

Maybe you are misunderstanding me on this medium. I am not saying that that SNP alone causes autism, but it might be one gene in many that can be a factor autism or other illnesses.

I cannot see how a SNP in rs2851391 would not, sooner or later, cause some sort of condition. Besides, all of these 1.04 billion people might have varying states of disease but that would be a complicated survey. But combine this SNP (or any homozygous CBS SNP) with pesticide and heavy metal exposure and other oxidative stress and I can see this causing the rising rates of neurological diseases.

Mexicans have the highest prevalence of this SNP, nearly 40%. I think this is the reason they have a higher rate of neural tube defects and heart disease than other nationalities.

I have the following three SNPs. I take P5P as needed for them as part of my treatment.

 

[Valentijn]

I cannot see how a SNP in rs2851391 would not, sooner or later, cause some sort of condition. Besides, all of these 1.04 billion people might have varying states of disease but that would be a complicated survey. But combine this SNP (or any homozygous CBS SNP) with pesticide and heavy metal exposure and other oxidative stress and I can see this causing the rising rates of neurological diseases.

You seem to be equating a distant possibility with a sure thing. This is completely nonsensical, since there are billions of SNPs which "might" be causing something. Assuming that every SNP does the worst thing possible, in a complete absence of evidence, is insanity.

 

[ppodhajski]

Hi @ppodhajski ! Thank you for your help!

I did ran Promethease but I have not given it too much credit because it has too much information and I saw things like: reduced risk of male pattern baldness..uhhhh...i'm loosing hair since 17-18. This may answer your other question. I'm loosing hair, but I have probably 2 grey hairs in my head lol. I do have a few grey (or unmatured thanks to finasteride?!) hairs in my beard.

How have you filtered the important info on promethease? I could upload it...
Some SNP's i feel are active, particularly the ones about dopamine and D2 receptors, where it says I have increased risk for restless legs, parkinson and adhd. I have experienced something like periodic limb movement for more than one year, I'm slightly sluggish and at times I feel I can't focus on conversations as I don't always take pleasure in them. Agomelatine which disinhibits dopamine at presynaptic 5ht2c receptors (if i remember correctly) cured me those points from one day to the next, one pill..but unfortunately it further indered my sleep. Libido has taken a hit too since a long time. But I'm so worried it was because of finasteride. I'm doing more exams on tuesday which will help me rule out post finasteride syndrome, according to my analysis of PFS. I do think I might have ADHD but it's not so bad as I have finished university...

I also thought about the riboflavin deficiency but not because of the reason you gave me. That's a really good reason and I will check for that on tuesday as well!

I made a video that I will upload to show you how I use promethease. But it is important that you save your promethease results as a full webpage so you can keep the search functionality. Using just the download they provide is useless.

It is not useful to me to waste time looking at the receptors since we cannot change them. Most times with people I see a receptor SNP with with a SNP in the enzyme that makes the product; like a MAO SNP with a DRD SNP. This is why I think these receptor blocking drugs work but we are stuck with the side effects.

Is there an easy way to rise glutathione?

Low blood sugar or reactive hypoglycemia is somethign I have given some thought. In prometeashe I also have a higher risk of low blood sugar but somehow it is connected to a positive SNP.

How can I find GPX1/2/3/4 in promethease? I am also curious about the SNPs for those genes but I am not sure I was tested for them A SNP in those genes would be another staple to my finasteride theory.

You need to know your transulfuration pathway SNPS to know what you need to do to raise glutathione and if you even need to. CBS, CTH, GCL, GS, and GPX will all play a role, as well as SNPs in the Methionine cycle.

I do not worry about raising Glutathione, I only look at the SNPs and their cofactors and I take the cofactors. I have BHMT, CBS, and GPX SNPs. I take Zinc/Copper, P5P, TPP (Thiamine) and Selenium. Here are my GPX SNPs.

How to further limit ROS? I will follow your plan on these cofactors. Also, could you let me know the dosages?

This will also depend on your genes. I have MAOA and MAOB SNPs. Taking riboflavin corrects the epigenetic transcription and makes them work well again. This removes the O2 and H2O from my cells and reduces ROS creation. (Every wonder why people with heart disease get edema? This is why)

One last thing: my homocysteine wasn't high, it was actually below the lower limit!! at the time I was taking adb12, but after reading Amy Yasko I may have understood why I had low homocysteine. I am pouring everything to the CBS pathway because of some other mutations. And this leads to increased excretion of taurine and some other stuff. Anyway, I think I will buy SAM-e to supplement the methionine cycle.
Do you think it would hurt?

My homocysteine was low normal when I was ill. Homocysteine does not tell the whole story. It is only one part in the cycle. A low methane diet will lower your homocysteine rapidly without helping the disease state much. You do not want below normal homocysteine, it is as bad of a marker as high homocysteine.

Yasko is wrong on blaming all low homocysteine on an "upregulated" CBS SNP. I used to think the same thing and I did not get better treating it that way. I was pretty much vegan because that helped me feel the best, but unfortunately it was causing other issues.

I do not take anything that is a product of enzyme metabolism, like SAMe. I only take cofactors that help the genes which have SNPs. I think it makes sense this way because you let the body decide how much product it needs (although this can be overdone as well but is quickly reversed).

This way of thinking about epigenetic treatment of disease led to my complete recovery with no side effects. It has done the same for three of my friends as well who have different types of issues. One of them had fibromyalgia and CFS which is now completely resolved.

 

[ppodhajski]

You seem to be equating a distant possibility with a sure thing. This is completely nonsensical, since there are billions of SNPs which "might" be causing something. Assuming that every SNP does the worst thing possible, in a complete absence of evidence, is insanity.

Valentijn, I need you to slow down in your interpretation of what I am saying because what you are replying is not what is in my head. This could be the medium that we are on as well that leads to the confusion.

I am saying that people with the rs2851391 SNP will have slower CBS enzyme function. That is all. The disease state will depend on other factors like diet and chemical exposure and other SNPs.

However, and this might seem controversial to you but I have seen it in my recovery as well as others, I think there are very few genes that we need to correct with cofactors in order to recover. This has worked on every single person I know who has tried it. It takes some dose manipulation, but it works.

A friend of mine has the SNPS in CBS and CTH you see below. Her hip arthritis is completely resolved when she takes P5P twice a day. (Note she also had high enough homocysteine that she could not donate blood)

 

[ppodhajski]

@xptriado Here is how I look for SNPs of interest in Prometheus:

 

[futuritycarpaccio]

@xptriado Here is how I look for SNPs of interest in Prometheus:

That's great, thank you so much!

I'm a bit confused with the frequency: is it the frequency of this SNP in the population? Maybe I could just filter out the good SNPs and just check supplement according to the bad SNPs? So you are saying even if the frequency is high, as they contribute to the problem, I should not ignore them?

These are my GPX's.

My biggest confusion is on the transsulfuration pathway. These are the CBS mutations. I have that CBS configuration that Yasko says it leads to increased excretion of taurine. I'm thinking of analysing taurine in urine on tuesday... this also leads to low homocysteine. she recommends low protein diet, which I suppose was your vegan diet?
in this pathway I basically have mutations everywhere, except MTRR. But many are just +/- and not -/-.
How did you get the dosages for the cofactors right? Experimentation?
How long did this supplementation took to work in your experience?

Honestly I think my bigest problems are at receptor level..but as you said, that can't be fixed. I found I have an SNP that is correlated with vitamin D deficiency and I have as well a vitamin D receptor problem. Vitmain D and insomnia are strongly correlated... Then there's the D2 receptor problem.

So I will look at the cofactors for those enzymes and supplement accordingly...

By the way, do you have any idea why AdenosylCobalamin sublingual after waking (early morning insomnia), helps me fall back asleep?

 

[ppodhajski]

That's great, thank you so much!

I'm a bit confused with the frequency: is it the frequency of this SNP in the population? Maybe I could just filter out the good SNPs and just check supplement according to the bad SNPs? So you are saying even if the frequency is high, as they contribute to the problem, I should not ignore them?

When the frequency is low that means the SNP is kind of rare. So far the research I have seen associates rare SNPS with disease states.

I am saying that if you have a low occurring SNP (low frequency) you should seek the cofactor and take it.

For looking up cofactors for genes I use this:
http://www.uniprot.org

Just put the gene in the top and look for the gene make "HUMAN" in the results.

These are my GPX's.
SNIPPED

Yes, I would look at taking selenium if I had those. But I think selenium needs thiamine as well but I am unclear on this right now. Selenium lowers my blood sugar if I take too much for too long which increases my epinephrine levels, so go low and slow. I do not take this everyday but I do eat brazil nuts often.

My biggest confusion is on the transsulfuration pathway. These are the CBS mutations. I have that CBS configuration that Yasko says it leads to increased excretion of taurine. I'm thinking of analysing taurine in urine on tuesday... this also leads to low homocysteine. she recommends low protein diet, which I suppose was your vegan diet?
in this pathway I basically have mutations everywhere, except MTRR. But many are just +/- and not -/-.
How did you get the dosages for the cofactors right? Experimentation?
How long did this supplementation took to work in your experience?

Yasko, eh, well, I think she helped to start all this but afraid she is over complicating it all and I would recommend you abandon her. CBS may lead to more taurine if you do not have a GAD1 SNP, but more taurine might not be a problem. There is no one answer, you just need to look at your own genes. (Yakso thinks Autism is one set of factors but I think it is three and each one can be at different levels.)

High taurine MAY have something to do with homocysteine but taurine does not raise or lower homocysteine, it ONE end product of homocysteine metabolism. You can actually have any combination of homocysteine and taurine so a taurine test is mostly useless. I never had any of these test done, I think they can help but they are unnecessary to healing. I am proof of that.

Low protein worked for me, kind of. It lessened my symptoms but did not get rid of them. I think it creates other problems. Eating less overall will lower reactive oxygen species.

Yes, it was experimentation that got my doses right for me. Low and slow and one at a time. This reaction should happen immediately. You know how magnesium can make you sleepy? That is how fast it works. Magnesium increases COMT activity in a few hours.

Honestly I think my bigest problems are at receptor level..but as you said, that can't be fixed. I found I have an SNP that is correlated with vitamin D deficiency and I have as well a vitamin D receptor problem. Vitmain D and insomnia are strongly correlated... Then there's the D2 receptor problem.

So I will look at the cofactors for those enzymes and supplement accordingly...

I think vitamin D supplementation is unnecessary based on my own experience. I could not get my vitamin D levels up no matter how much D3 I took so I stopped taking it. Not that I treated all these other genes my D levels are normal. Again, a lot of these low nutrients I think are not the cause of problems, but symptoms of other problems. I will have a longer post on this soon.

By the way, do you have any idea why AdenosylCobalamin sublingual after waking (early morning insomnia), helps me fall back asleep?

AdoB12 is turned into MethylB12 by MTRR. Funny that the is the only SNP you do not have an issue with, but it makes sense that taking AdoB12 helps you. I have that SNP and the only form of B12 that helped me was MethylB12. But I no longer take B12 because I fix the MTRR with FMN (B2) instead. The B12 worked but then it did not.

As far as to why it helps with sleep, I can see it pushing your Krebs cycle by creating more Succinyl COA and therefor pushing the Urea Cycle through Furmarate.

Urea cycle disorders are associated with sleep disturbances and seizures:
http://www.rarediseasesnetwork.org/ucdc/learnmore/

 

[ppodhajski]

@xptriado Looking at your SNPs:

A question for anyone. I have seen this in other peoples promethease reports and do not know what it means when we see a "-" where an allele is supposed to be. Is it a deletion, like the gene is broke or is it a problem with the DNA report, that they just could not read it. Or is it that it is on the X chromosome and these are just two different ways it reads the report. We are both male. Hmm, maybe I have some extra X chromosomes?

This is my MAOA SNP:

And this is xptriado's: