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Chemical sensitivities, cognitive issues, fatigue: Pseudocholinesterase & Acetylcholinesterase Defic

Discussion in 'General ME/CFS Discussion' started by BeautifulDay, Sep 26, 2017.

  1. BeautifulDay

    BeautifulDay Senior Member

    (edit: @nandixon caught that I was using Acetylcholine Deficiency instead of Acetylcholinesterase Deficiency. I have fixed it below. Thanks @nandixon)

    Chemical sensitivities, cognitive issues, fatigue – Pseudocholinesterase Deficiency (BCHE mutations) and Acetylcholinesterase Deficiency (COLQ mutations)

    There have been several threads and posts here at Phoenix Rising (PR) that hit upon Pseudocholinesterase Deficiency and also Acetylcholinesterase Deficiency as being involved in some PR members’ Chronic Fatigue and various other symptoms.

    In my second post on this topic, I’ll list all the mutations that I am aware of that are pathogenic for Pseudocholinesterase Deficiency (BCHE mutations) and Acetylcholinesterase Deficiency (COLQ mutations).

    Please forgive me for what is likely to be a very long post. It’s a complicated yet important issue and it may turn out that a higher percentage of the population on Phoenix Rising have one of these mutations, than the percent in the general population. For example, Enlis puts the Allele Frequency for the pathogenic BCHE mutation for rs28933390 at .30%. Yes, that is point 3 percent. OpenSNP puts the Allele Frequency for the non-mutation at 100%. With rounding, that is very in-line with Enlis. https://opensnp.org/snps/rs28933390#users

    It’s also interesting to note that Livewello puts the Livewello population for no-mutation at 83%.

    Therefore, the Livewello folks (who are more likely not feeling well and looking for answers among the topics of methylation and detox are more likely to carry this mutation than those in the general population). I find that interesting and in need of further study and research (meaning I have a lot more researching and reading of scientific journals ahead of me).

    p2 + 2pq + q2 = 1 and p + q = 1
    p = frequency of the dominant allele in the population
    q = frequency of the recessive allele in the population
    p2 = percentage of homozygous dominant individuals
    q2 = percentage of homozygous recessive individuals
    2pq = percentage of heterozygous individuals

    Using Enlis’ Allele Frequency for the mutation, q = .003
    p + q = 1 so p = .997
    homozygous dominant should be .994 or 99.4% of the population
    homozygous recessive should be .000009 or .0009% of the population
    2pq = .00598 or .59% of the population

    So 99.4% + .0009% + .59% = 100% (with rounding)

    Therefore, if for this one mutation 83% of the Livewello population is homozygous dominant (no mutation), and if OpenSNP and Enlis both put it at just a smidge under 100% (around 99.4%), then it looks like just for this one BCHE mutation (and of course there are other pathogenic BCHE mutations and other pathogenic Acetylcholinesterase Deficiency (COLQ mutations), that maybe these mutations have a huge impact on the difference in Chronic Fatigue Syndrome symptoms among the PR members.

    While 23andme has a history of being off on some of their calls, usually you can tell when they are way off by comparing Enlis’ Allele Frequency for the mutation versus that reported by OpenSNP. When OpenSNP has a much higher mutation rate, it can be due to a 23andme misread error resulting in more mutations than actually exist.

    While not being a proper scientific study, maybe this discussion will lead more researchers to look into this issue. Of course, with all the scientific experts here on PR, I expect holes to be shot in my theory and math so that I won’t have to look into this issue any further. I’m not perfect. I have my own cognitive issues and I just wanted to share something that’s been bouncing around in my mind.

    I believe there are several avenues leading to being diagnosed with Chronic Fatigue Syndrome. For our family, our CFS turned out to be caused by a mutation that results in us having Mitochondrial Disease. At the same time, some in our family also carry a mutation (heterozygous – one copy) for Pseudocholinesterase Deficiency. In fact we carry the above mutation for rs28933390.

    Most people think of homozygotes (two copies) as having Pseudocholinesterase Deficiency. While heterozygotes for Pseudocholinesterase Deficiency are considered Pseudocholinesterase Deficiency Carriers.

    The NIH states that: “Pseudocholinesterase deficiency is a condition that results in increased sensitivity to certain muscle relaxant drugs used during general anesthesia, called choline esters. These fast-acting drugs, such as succinylcholine and mivacurium, are given to relax the muscles used for movement (skeletal muscles), including the muscles involved in breathing. The drugs are often employed for brief surgical procedures or in emergencies when a breathing tube must be inserted quickly. Normally, these drugs are broken down (metabolized) by the body within a few minutes of being administered, at which time the muscles can move again. However, people with pseudocholinesterase deficiency may not be able to move or breathe on their own for a few hours after the drugs are administered. Affected individuals must be supported with a machine to help them breathe (mechanical ventilation) until the drugs are cleared from the body.

    People with pseudocholinesterase deficiency may also have increased sensitivity to certain other drugs, including the local anesthetic procaine, and to specific agricultural pesticides. The condition causes no other signs or symptoms and is usually not discovered until an abnormal drug reaction occurs.
    When due to genetic causes, this condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. Most often, the parents of an individual with an autosomal recessive disorder have one copy of the altered gene in each cell and are called carriers. They can pass on the gene mutation to their children, but they do not usually experience signs and symptoms of the disorder. In some cases, carriers of BCHE gene mutations take longer than usual to clear choline ester drugs from the body, but not as long as those with two copies of the altered gene in each cell.”


    I want to point your attention to the underlined part. In some cases, carriers (those who are heterozygous) take longer than usual to clear choline ester drugs for the body. I am one of those people. When I was a teenager, having my boney impacted wisdom teeth out, the throat muscle relaxer held too long and I had my throat seize up where I couldn’t breathe and I was gasping for air.

    Therefore, despite only being a carrier (having one mutation), I had the adverse reaction. As I pointed out in another thread, the Mitochondrial Disease doctors believe that people with Mitochondrial Disease impacting every cell in their body can have mutations that are only recessive impact them even though they are only heterozygous because of the defect already going on at the cellular level. It doesn’t mean all heterozygous mutations become homozygous like – it’s just that the doctors see more symptoms in MitoD patients with other pathogenic heterozygous mutations (than normally would impact most people).

    While people think of this mutation as just being important when undergoing surgery, there is research that points to people with these types of mutations as having trouble with clearing away xenobiotic agents. For example, here is a document released by Australia’s Department of Defense.

    Why would a government defense agency be interested in this? I believe @Nielk and @Valentijn got it correct when they posted about Gulf War Syndrome vets with specific mutations being more prone to the disease.

    I can only speak for myself. I have had severe chemical sensitivities in the past. Like all my symptoms, they tend to be intermittent (sometimes hanging around for a long time, sometimes a quick hello goodbye, and sometimes lurking at a low level). I’m wondering if other people with this same (or similar mutations) have fatigue, chemical sensitivities, and/or fatigue. Here is what I found from a quick search of PR members posts regarding Pseudocholinesterase Deficiency and Acetylcholinesterase Deficiency. While acetylcholinesterase and pseudocholinesterase are not the same thing, I’ve found so many similarities, that I thought I’d group this thread with both issues. I do realize they also should be discussed separately when getting down to the nitty gritty of details.

    @richvank had a theory that is related to acetylcholine.
    “if my hypothesis about ME/CFS is valid, it is more likely that there will be a deficiency of acetylcholine, rather than too much, producing toxicity. The reason is that the production of phosphatidylcholine in the body, from which choline can be derived to make acetylcholine, is one of the two main users of methylation, and there appears to be a methylation deficit in most cases of ME/CFS, due to a partial block of methionine synthase in the methylation cycle. I think that a deficiency of acetylcholine is consistent with the high sensitivity to acetylcholine that was observed by Vance Spence's group in Scotland a few years ago. I also think that the MRS experiments that were interpreted as showing elevation of choline in ME/CFS were misinterpreted by assuming that creatine is at normal levels. The problem is that creatine synthesis is the main user of methylation in the body, and creatine is also likely to be low.”

    Several members of Phoenix Rising state they have Pseudocholinesterase Deficiency (or carrier status), including me:

    @kday wrote: “I have found out I have a rare condition called pseudocholinesterase deficiency. I have to be really careful around certain anesthetics during surgery as I could stop breathing, etc with some drugs. This is good to know if I ever have surgery or am intubated - something important the surgeon needs to know.”

    @helen1 wrote: “I too have pseudocholinesterase deficiency, so have had the whole family tested for that, and several have it also. I almost died in surgery because of it.”

    @Theresa_S wrote that: “I have a pseudocholinesterase deficiency, homozygous.
    I came upon this site because of your discussion thread. I believe my pervasive fatigue and diminished cognitive function (I taught grades7&8, all subjects for 25 years) is due to acetylcholine toxicity. There is no family history of Alzheimer's or dementia in my family. I do not have depression. Any thoughts?”

    @wciarci wrote that: “I as well as my family have a rare enzyme disorder called atypical pseudocholinesterase which I find intriguing given the problems found with acetylcholine receptors.”

    If this is representative, then it sure doesn’t sound like it’s 1 in 3200 to 1 in 5000 people as estimated by the NIH. Unless, these mutations really are significantly higher in the Chronic Fatigue Syndrome population (PR population). If they are, then I want to know more. And as always, I reserve the right to be wrong. ;)

    Please forgive typos and any thoughts that were not finished. I’m tired. I’ll come back and list the various pathogenic mutations I know later tonight or tomorrow. You can poke me if I forget. It's part of the cognitive memory issue of forgetting things exist. If I get up from the computer and don't see a note to myself to finish, it's unlikely that I'll remember it exists. I'll have to reread the above before remembering what I'm supposed to do.
    Last edited: Sep 27, 2017
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  2. SilverbladeTE

    SilverbladeTE Senior Member

    Somewhere near Glasgow, Scotland
    hm, would explain the organophosphate link, and the increasing use of those damnable chemicals makes a witch's brew of harm :/

    it's like the DDT issue, DDT *IS* a deadly harmful environmental poison, no matter what those corporate shills say, because it was used in vast, unsafe quantities for agriculture, talking in the tens of thousands of tons.
    where as used in small amounts for Human health and in careful eradication programs, it was extremely useful....but very short lived as resistance becomes inevitable.

    And wouldn't ya know it? the links between the shills and the psychobbablers, SMC and the likes of the "JunkScience" wahoos all desperate to keep links between the harm from the abuse and over-use of chemicals secret.
    "Technology uber alles", so the rich can get richer...no matter the cost.
    And the result of which is, the destruction of the American EPA under the current malignant Adminstration, and so generations of Americans will suffer and die because of that.

    And if the British government's scum, and presumably American, Russians and others too (the Russians sure did), hadn't hushed up the links between workers producing nerve gas and ME/CFS illnesses, we might have had understanding, treatments and bans of those chemicals today.
  3. nandixon

    nandixon Senior Member

    @BeautifulDay, I’m guessing that everywhere you wrote “acetylcholine deficiency” you may have meant “acetylcholinesterase deficiency” instead. (An acetylcholinesterase (AChE) deficiency leads to an excess of acetylcholine, because AChE breaks down acetylcholine.)

    Where @richvank wrote:

    In the 2004 Spence study the conclusion was actually that it was more likely that a deficiency of AChE (i.e., an excess of acetylcholine) was present in ME/CFS, although there must be different subgroups because it's noted in the Spence full text that:

    And indeed, for myself I found that Huperzine A, an AChE inhibitor, made my symptoms much worse. (My red blood cell AChE level measured about 10% below the lowest normal value the only time it was tested early in my illness, so that is seemingly consistent.) I know that other people on this forum have found Huperzine A useful, though.
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  4. Valentijn

    Valentijn Senior Member

    My assumption would be that Livewello messed up - that's usually what happens with SNP interpretation services. The other possibility is that 23andMe messed up on some chips.
  5. BeautifulDay

    BeautifulDay Senior Member

    Thanks @nandixon. I'm going to go fix it now. I'm not sure that I'll be allowed to fix it in the title, but I'll try to fix it there too.
    nandixon likes this.
  6. BeautifulDay

    BeautifulDay Senior Member

    Acetylcholinesterase Deficiency Mutations and related congenital myasthenic syndrome mutations

    I'll do the same thing for Pseudocholinesterase deficiency mutations later (likely tomorrow).

    I don't expect people to look up mutations this way. It's easiest to use something like Enlis. If you don't use Enlis, then rather than looking one up at a time on 23andme, try going to the gene under raw data, and then go down the list for SNPs. Then see if the below SNPs for a gene appear. Since the important ones are going to be very rare, if you were tested for one of the below SNPS, I'd look for heterozygous. If you are heterozygous, only then would I do deep dive research to see if 23andme over-reported mutation in population, etc.....

    Overview - https://www.ncbi.nlm.nih.gov/medgen/C1864233

    Some of the related COLQ gene SNPs


    rs104893735 23andme i5001696 (CC is normal on 23andme) (CC is non-mutation) https://www.ncbi.nlm.nih.gov/clinvar/variation/6657/







    I have no idea what the snp rs# or genomic position is for this one – but it’s called
    COLQ, 215-BP DEL, NT107 RCV000007027

    or for this one
    COLQ, IVS16DS, A-G, +3

    Additional source of info:
    This source is interesting regarding congenital myasthenic syndrome which includes Acetylcholinesterase Deficiency. “Mutations in many genes can cause congenital myasthenic syndrome. Mutations in the CHRNE gene are responsible for more than half of all cases. A large number of cases are also caused by mutations in the RAPSN, CHAT, COLQ, and DOK7 genes. All of these genes provide instructions for producing proteins that are involved in the normal function of the neuromuscular junction. The neuromuscular junction is the area between the ends of nerve cells and muscle cells where signals are relayed to trigger muscle movement.”

    Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency (All on RAPSN gene)











    Myasthenic syndrome, congenital, associated with acetylcholine receptor deficiency





    Not mentioned above is the MUSK gene mutations that also can cause myasthenic syndrome. Specifically MUSK mutations can cause myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency. Here are 3 such mutations.



    Additional resources:

    As always, I reserve the right to be wrong.
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  7. BeautifulDay

    BeautifulDay Senior Member

    Pseudocholinesterase Deficiency

    According to the NIH, “People with pseudocholinesterase deficiency may also have increased sensitivityto certain other drugs, including the local anesthetic procaine, and to specific agricultural pesticides.”

    *I did not know that people with pseudocholinesterase deficiency may also have increased sensitivity to specific agricultural pesticides. Very interesting.*

    Pseudocholinesterase deficiency synonyms: Deficiency of butyrylcholine esterase, Acylcholine acylhydrolase deficiency; BCHE deficiency; BCHE, silent 1; Butyrylcholinesterase deficiency; CHE1 deficiency; Mivacurium response; Succinylcholine response

    Pseudocholinesterase Deficiency (BCHE mutations)



    rs1799807 (TT is the typical/normal on 23andme)
    Per SNPedia, some interesting information:

    Practical consequences of altered substrate affinity from this SNP include:
    · Succinylcholine, commonly used as an anesthetic, depends on BChE hydrolysis for recovery.rs1799807(G;G) homozygotes experience a much delayed return to spontaneous breathing following its use.
    · "Atypical" BChE has a low affinity for CI alkaloids naturally occuring in certain plants, particularly those in the nightshade family (potato, tomato, peppers, eggplant, etc.). rs1799807(G) carriers may be more prone to physiological consequences of AChE inhibition from eating these foods.
    · Many pesticides are CIs, including organophosphates and carbamates. rs1799807(G) carriers may have atypical reactions to pesticide residues on foods and in the environment.
    · Many nerve agents, such as Sarin and VX gas, as well agents used to protect soldiers against them, such as pyridostigmine, are CIs. rs1799807(G) carriers may be more susceptible to exposure to these agents.
    [PMID 15060281[​IMG]] "Atypical" BuChE, rs1799807(G), has 30% lower enzymatic activity than the wild-type enzyme. Homoygous carriers of this polymorphism, rs1799807(G;G), display extreme anxiety after exposure to CIs.


    rs28933389 (GG is normal/typical on 23andme for this one)

    rs1803274 – (CC is normal/typical on 23andme for this one)
    most reports think this one is likely benign, and then there are reports like this:
    “The rs1803274 polymorphism of the BCHE gene is associated with an increased risk of coronary in-stent restenosis”.





    This one without an rs# -- BCHE, VAL142MET

    This one without an rs# -- BCHE Newfoundland AND Bche newfoundland

    This one without an rs# -- BCHE Cynthiana AND Bche Cynthiana

    This one without an rs# -- BCHE Johannesburg AND Bche Johannesburg

    This one without an rs# -- BCHE, ALU INS, EX2 AND Deficiency of butyrylcholine esterase

    This one without an rs# -- BCHE*FS126

    This one without an rs# -- BCHE, GLY115ASP AND IVS3AS, T-C, -14 AND Deficiency of butyrylcholine esterase

    Additional info: https://www.omim.org/entry/177400?search=177400&highlight=177400
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  8. birgitte


    Hi I have rs1799807 hetero - and all the symptoms that goes with it: fatigue, MCS, increased urination, dry mouth, bad regulation of body temperature, weak muscles, apnea, nausea, asthma... you name it. Also sensitive to salicylate - and I have read that NSAIDS (acetylsalicylate) lowers Acetylcholinesterase...

    Also I don't tolerate fish oil - and it is supposed to increase acetylcholine. I would like to share some acetylcholine lowering foods and suppelements, but haven't been able to find any - except perhaps glycine and lipoid acid, but they don't do anything significant I believe.
    Last edited by a moderator: Apr 6, 2018
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  9. BeautifulDay

    BeautifulDay Senior Member

    That's very interesting. I don't tolerate fish oil well.

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