(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%. https://livewello.com/snp/rs28933390 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). HARDY-WEINBERG LAW 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.” https://ghr.nlm.nih.gov/condition/pseudocholinesterase-deficiency#synonyms 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. http://dspace.dsto.defence.gov.au/dspace/handle/1947/10114 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. http://forums.phoenixrising.me/inde...genetics-anti-nerve-agent-pills-to-gwi.35237/ 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.” http://forums.phoenixrising.me/inde...acetylcholine-toxicity-the-cause-of-cfs.9757/ 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.” http://forums.phoenixrising.me/index.php?threads/is-23andme-worth-it.19320/#post-391821 @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.” http://forums.phoenixrising.me/index.php?threads/is-23andme-worth-it.19320/#post-391821 @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?” http://forums.phoenixrising.me/inde...city-the-cause-of-cfs.9757/page-6#post-416947 @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.” http://forums.phoenixrising.me/inde...ere-had-to-leave-my-old-site.2413/#post-57586 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. https://ghr.nlm.nih.gov/condition/pseudocholinesterase-deficiency#synonyms 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.