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I have a lot of BHMT and AHCY mutations, among others. Can you advise me?

Discussion in 'Genetic Testing and SNPs' started by Tom_Nightingale, Feb 19, 2013.

  1. Tom_Nightingale

    Tom_Nightingale

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    Hi everyone,

    I have recently gotten my genetics testing done thru 23andMe, and I have reason to believe my symptoms have something to do with the methylation cycle. Thing is, I don't really understand it too well, and most people I talk to seem to know about undermethylation. From my experience, supplementing with many things that increase methylation quickly cause negative effects. I wonder if I am overmethylated, but no one I know has that problem. I've learned that mutations in the AHCY gene will lead to overmethylation.

    Let's take a look at my Genetic Genie results:

    [​IMG]

    As you can see, I also have a lot of BHMT mutations, which I don't totally understand yet. What I do know is that my homocystine level is normal.

    I suffer from mental illness, mostly depression but also psychosis. My COMT and MAO A genes can probably take some of the blame.

    I recently bought a fancy supplement that a friend of mine is taking who is undermethylated and having great success on.
    http://www.thorne.com/Products/Mens-Health/prd~VMX.jsp
    Yet, when I tried it at small doses, I was unable to tolerate the excitability/anxiety that it induced. It contains some nice methyl donors (Calcium Folinate, L-5-Methyltetrahydrofolate, Methylcobalamin). Dissapointing :( It felt a lot like when I was taking Wellbutrin, a norepinephrine and dopamine reuptate inhibitor. Edgy and nervous. From what I understand, the chatecholamines (serotonin, domanine, norepinephrine, etc.) are end products of the methylation cycle.

    What could I do today to try and treat my methylation issues? The only thing I have found was a suggestion to take slow release niacin with this supplement, so that it can soak up some of the methyl groups. But isn't that defeating the point of taking it?

    Thank you!
    Tom
     
  2. kgg12003

    kgg12003

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    Hi, Tom~ I hate to see someone not receive a reply when so many have looked at a post! I am not an expert at this stuff but a newbie. But I think, if I were you, and had the sensitivity to supplements you seem to have that I would work with an expert opposed to asking on line. Especially because of the mental illness. You need something to help you feel better faster not make you feel worse. It has been my experience that I would much rather have pain than the neuropsych stuff that can happen. Hate that!

    Have you looked for a local expert? This link should take you to a "find a doctor" page. If it does not come up with someone, perhaps on their forum you could ask if they know of someone in your area. http://mthfr.net/mthfr-resources/

    Hope this helps you start to find some answers,
    Karen
     
  3. Hip

    Hip Senior Member

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    For excess methylation, this webpage recommends: fish oil (omega 3 fatty acids), manganese, zinc, DMAE, choline (or alpha GPC), vitamin B12, niacinamide, vitamin E, and vitamin C.

    I guess you could try a few of these supplements taken together, and see if you feel better.
     
  4. caledonia

    caledonia

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    You may have to treat CBS first so you can tolerate methyl groups. The Heartfixer page explains what to do about CBS. Once you get past that, COMT will limit the amount of methyl groups you can tolerate.

    As the CBS thing can make you anxious and stressed and COMT makes mood swings, I would say your symptoms match with CBS.

    AHCY is supposed to clear as you work generally on the methylation cycle. Nothing specific is needed for it.

    BHMT is the shortcut secondary pathway through the middle of the cycle. It's good to get this running first, just to get some kind of methylation going. You would take TMG for that. Yasko's multi has TMG and some other general stuff in the right amounts to help with the shortcut pathway.

    If you're on any psych drugs, you may no longer need them, or need less of them. There could be implications with serotonin syndrome, I'm not sure. However, getting off psych drugs can be really tricky, with horrible withdrawal syndromes. I had this happen to me with Zoloft. I call it my "lost year".

    So what I've chosen to do is gradually taper off Zoloft while I'm gradually ramping up methylation supplements. It's going to take me about 2 years. See the Paxil Progress forum for info on how to taper off psych drugs.
     
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  5. Tom_Nightingale

    Tom_Nightingale

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    Thank you everyone for pitching in! I live on disability and have depleted a lot of my family's resources by having to deal with my mental health. I hesitate to find another provider, but it could be worth it. I'd like to think I can understand this on my own and avoid spending money that I really don't have.

    Those supplements for overmethylators look to be useful. I still need to establish if I really am overmethylated, or if I should try something like TMG.

    I have had some tough years myself. I have a tremendous appreciation for how powerful psychiatric medications are. I agree, I think I will be able to resolve my mental health issues through nutrigenomic methods, but I currently depend on psychotropic meds to get by. Any transition will be made slowly and with the supervision and knowledge of my docs.

    I got results for my amonia level test in today, and my doc says they're normal. I don't have any values, but I trust him. I was hoping I could just chow down on more molybdenum and feel better. I have more results coming, including heavy metals and phenylaline (to gauge my BH4 levels)

    I continue to read more, Heartfixer is such a huge help!
     
  6. LaurieL

    LaurieL Senior Member

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    Wow....these are difficult combo's you have and all will have some bearing on the other.

    Give me a few hours and I will try to wrap my brain around these specific combo's. I am not an expert but I am sure willing to help get you some more info.

    Lauriel
     
    merylg likes this.
  7. LaurieL

    LaurieL Senior Member

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    Hi Tom,

    For newer folks to this arena, I would like to first clarify the terminology of undermethylated vs. overmethylation. This is a particular occurence having to do with methyl donors and their effects due to not enough or too many methyl donors in those with mutations within the methylation cycle. With some mutations, one may find they cannot tolerate larger quantities of methyl donors, and in others, one may find they are indeed in need of many sources of methyl donors.

    Tolerance to methyl donors is referenced by Yasko, and determined to be centered around COMT status. COMT +/+ is a downregulation, in that +/+ is sluggish essentially slowing the methylation of brain neurotransmitters (this mutation will not break down the neurotransmitters as efficiently). The COMT enzyme uses methyl groups to help inactivate dopamine and nor-epi. Since a +/+ is a downregulation, then this particular individual may not be using up methyl groups, since it slows down methylation at this particular point, and so they wouldn't tolerate the addition of methyl groups like a -/- or a +/-. And a +/- not as much as a -/-. Excess methyl groups or the terminology, "overmethylation" would then equate to erratic behaviour, mood swings, hyperactivity, and irritability.

    -/- individuals will deplete methyl donors and can tolerate more methyl donors.

    COMT is involved in the breakdown of dopamine as well as nor-epi and also estrogen, and pain tolerance.

    Dopamine: Is a neuotransmitter linked to motor/movement disorders, ADHD, addictions, paranoia, and schizophrenia. It strongly influences both motor and thinking areas of the brain.

    Low levels are associated with muscle stiffness, stooped/unstable posture, loss of balance/coordination, gait disturbances, tremors, fixed, mask like expressions, slow speech, impaired fine motor skills, falling when walking, and impaired cognition. Low levels would impair the ability to focus or lock on to tasks, activities, or conversations.

    As dopamine levels rise, we would become energized and excited, then suspicious and paranoid, and then finally hyperstimulated by the environment.

    Nor-Epinephrine (Nor-epi): Is a neurotransmitter associated with the fight or flight response. Mood swings, anxiety, and depression are related to nor-epi levels, as it is this neurotransmitter that maintains the balance between agitation and depression. Because it is strongly involved in physical reactions, moderate increases create worry, increased startle reflex, jumpiness, fear of crowds and tight places, impaired concentration, restless sleep, rapid fatigue, muscle tension/cramps, irritability, and a sense of being on edge. Panic attacks are sudden and severe increases in nor-epi.

    So in the context of this entire conversation and your particular COMT status +/-, and remember, +/+ is a downregulation, you may very well have elevated levels of these neurotransmitters, but that is not accounting for the combination of mutations, just this single particular one.

    Vitamin D receptors or VDR bsm-taq also relate to dopamine and nor-epi levels. Vitamin D increases the enzyme involved in synthesizing these. I believe the VDR bsm-taq can compensate for COMT mutations as from what I have read, vitamin D levels correlate directly with dopamine levels ( ^ levels of Vitamin D = ^ levels of dopamine). Sensitivity to methyl donors are equated to individuals in which have higher levels of dopamine. Higher levels of these neurotransmitters are equated to -/- individuals. You have a +/+ mutation which is thought to be equated to lower levels of Vitamin D, and thus lower levels of the enzyme involved in synthesizing these neurotransmitters. These could very well compensate for each other in your case. The fact that you are having trouble would then justify investigation into bacterial and toxic metals in your case, in which could very well lead to the experiences you are describing.

    Something of addittional interest to you, in the book, Genetic Bypass, by Dr. Amy Yasko...

    MAO-A: (personally I think this one should be renamed to something more derogatory like the MTHFR enzyme is to some.) :D And of which you also seem to be blessed with a single point mutation in the A1298C incidently. But I digress for the moment....

    Again, MAO-A: This is the warrior mutation and is involved in the breakdown of Serotonin. This is the bliss to despair neurotransmitter and has been identified in multiple pyschiatric disorders including depression, OCD, anorexia, bulemia, body dysmorphia, social anxiety, and phobia's. It is involved in processes such as sleep, libido, and body temperature.

    When serotonin is low, we experience problems with concentration and attention. We can become scatterbrained, and poorly organized. Routine responsibilities will seem overwhelming. We lose our car keys, and put odd things in the refrigerator. (Personally, I have put the peanut butter in the fridge and the milk in the cupboard..:confused:) When we are driving, we forget where we were going, when we call someone, we forget why we called them in the first place, when we go grocery shopping, we forget the list, or forget what we needed in the first place. We also tell people the same thing two or three times.

    As serotonin levels decrease, we can become more depressed. At moderately low levels, major changes in bodily functions can occur. Such as...

    Chronic Fatigue. Despite sleeping extra hours and naps, we remain tired.
    Sleep disturbances, can't get to sleep or early morning waking and then can't fall back asleep.
    Appetite disturbances. Either a loss of appetite and weight loss, or weight gain due to the bodies craving for carbs in an attempt to make more serotonin.
    Loss of sexual interest, loss of interest in general.
    Social withdrawal is common, not answering the phone, rarely leaving the house, stop calling friends and family, and withdrawal from social activities.
    Emotional sadness and frequent crying spells are common.
    Self-esteem and self-confidence is low.
    Body sensations, due to serotonins role as a body regulator, include hot flashes, and temp changes, headaches, and stomach aches.
    Outbursts will begin. Typically two types. Crying and behavioral.
    Thinking speed will increase.
    Memory torture. Your brain at 100 mph, will search your memories for your most traumatic or unpleasant experiences. You will suddenly become pre-occupied with horrible experiences that may have happened ten, twenty, or even thirty years ago. You will relive the death of loved ones, divorce, child abuse, whatever the brain can find to torture you with, and you will feel as though it happened yesterday.
    Loss of personality, a sense that our sense of humor has got up and left us, personality changes.
    And we begin taking everything very personally. Comments, glances, and situation are viewed personally and negatively. If someone talks to you, it irritates you, and it irritates you if they don't and become angry because you are ignored.
    This is the neurotransmitter in which your family will notice first, in that your behavior is odd, or have the sense that you have faded away. You talk less, smile less.

    Very low levels will bring this particular individual to the attentions of others, doctors, etc. Severe depletion also affects the brains ideation/thinking, and becomes very uncomfortable and even torturing in thoughts. Symptoms are very difficult to ignore by others. When you reach the bottom of the severely low, the "garbage truck" will arrive. Everyone with severely low levels will experience family members telling them they are a bad spouse, husband, wife, daughter, son, employee, etc.

    The other end of this spectrum is too high levels of serotonin. This is called serotonin syndrome.

    I have had the extreme pleasure of experiencing both sides of this neurotransmitter. MAO-A + is a decreased enzyme activity mutation and many with this will experience cycle fluctuations in serotonin. There for experiencing both sides of it. This cycling from low to high levels results in extreme mood swings and/or aggressive behaviors (where the "warrior" term was coined). Again, infections can deplete tryptophan, and also affect MAO-A status. A double whammy if you like and hence why I think it needs to be renamed....

    More on next post.....
     
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  8. LaurieL

    LaurieL Senior Member

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    You have a single point mutation in CBS A360A, which is an upregulation, but not as high of an up-regulation as the CBS C699T (40 times that of the A360A).

    The CBS enzyme is the "gate" between Hcy(homocystiene) and the trans-sulfuration pathway in which can generate ammonia in the body. Mutations in the CBS enzyme act like a "gate" is left open, and any support that has been added to the methylation cycle will be depleted, including any B12 that is used to address MTRR, a consideration for you. This is one of three first priority mutations in which should be addressed prior to specific methylation supplementation. While glutithione is generated from the downstream portion of the trans-sulfuration pathway, if cysteine is high, it will favor Taurine and not glutithione. Increased CBS activity, can release toxic sulfites into the body. Sulfites can cause chest tightness, nausea, hives, and in rare cases, more severe allergic reactions.

    The net effect of high CBS activity is to take sulfur and nitrogen groups that are complexed in the methionine cycle and free them up. Having relatively free sulfur and nitrogen can have downstream consequences in that sulfur is able to directly activate the stress cortisol response, which then can also affect dopamine and nor-epi levels. Another result of chronic high levels of sulfur, is the activation of the sympathetic nervous system. The cortisol response can then go on to affect magnesium/calcium levels, serotonin and dopamine levels, changes in GABA and glutamate, and depletion of G6PDH, causing blood sugar issues.

    AHCY is the enzyme that converts SAH (s-adenosyl homocysteine) to adenosine and Hcy. Your levels of HCY may be due to this enzyme, as HCY levels with AHCY mutations are related to lower levels of Hcy. AHCY is a down-regulation and is also associated with inhibition of MTRR. From what I have read, the AHCY mutation is not very straight forward, and its reactions with CBS, SAH, SAMe, and MTRR are hard to predict.

    Additonally, if your Hcy levels are normal, even with your BHMT and AHCY mutations, then your normal MTHFR 677T may help to explain this as well, as the 677 pulls Hcy into its cycle.

    BHMT: This is the shortcut from Hcy to methionine. Again CBS, excess sulfur, and its effects on cortisol, in which cortisol can also affect the activity of this enzyme. BHMT 2, 4 can result in higher intermediates in the transulfuration pathway.

    MTHFR A1298C has pretty abundant info out there.

    Hope this is helpful and my best to you.

    Lauriel
     
  9. kgg12003

    kgg12003

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    Wow, Lauriel. Thank you so much for this lengthy explanation. In spite of this not being my post, I appreciate you taking the time to respond.

    Best,
    Karen
     
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  10. Sea

    Sea Senior Member

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    Thanks LaurieL for your detailed reply. I am just trying to get my head around my own results which are somewhat similar to Tom's except that our homo (red) and hetero (yellow) versions are opposite
     
  11. LaurieL

    LaurieL Senior Member

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    Very welcome, and a pleasure to be helpful.
     
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  12. Tom_Nightingale

    Tom_Nightingale

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    Thank you LaurieL for your helpful post. I got some blood tests done a few days ago. I didn't know all of the ones I should do, but these are the results I've gotten:

    • Aresnic: <3, ref range <10 (good)
    • Mercury: <4, ref range <10 (good)
    • Lead: <2, ref range <10 (good)
    • Ammonia: 24, ref range 11-51 (good)
    So nothing sticks out there. I recently read on Heartfixer that "Mood swings (suggesting excessive dopamine) will prompt a treatment shift away from methyl-B12 and towards more hydroxy-B12." I have so many signs that point to excess dopamine, I think I will find some hydroxy-B12 and try that. Interestingly though, I have taken a 3000 iu methyl-B12 losenge and not had ill effects, nor did I experience remission of my symptoms. For some gene mutations Heartfixer says that you can take a combination of hydroxy and methyl B12. I'll see how I feel on the hydroxy-B12 first though.
    The AHCY issue still puzzles me, and it seems like you too... I just see those 3 red +/+ and think "that's got to be messing something up." I just don't really know how to address it.
    I am going to buy urine strips for sulfer testing. What other tests should I have done? I keep reading aluminum is important to check, so is copper. What is the test called that measures these? What other basic levels tests should I consider? I am still waiting on my Phenylaline level, to see if I can convince my doc to let me try Kuvan, the prescription BH4.
     
  13. Tom_Nightingale

    Tom_Nightingale

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    So I just realized something important about AHCY! Homocystine is one of the products of SAH (s-adenosyl homocysteine)'s reaction with AHCY, but adenosine is too! AHCY (+) would lower my levels of homocystine, but I have normal homocystine levels. This could easily be because my many BHMT mutations are not breaking down homocystine, masking the effects of the AHCY mutations.

    But back to adenosine. Adenosine "is also an inhibitory neurotransmitter, believed to play a role in promoting sleep and suppressing arousal, with levels increasing in the brain with each hour an organism is awake. Generalized, adenosine has an inhibitory effect in the central nervous system (CNS). Caffeine's stimulatory effects, on the other hand, are primarily (although not entirely) credited to its inhibition of adenosine by binding to the same receptors, and therefore effectively blocking adenosine receptors in the CNS. This reduction in adenosine activity leads to increased activity of the neurotransmitters dopamine and glutamate." (Wikipedia)

    This is really significant to my situation! I have problems with anxiety and nervousness, and I respond extremely well to benzodiazepines (Clonipin), which I just read is an adenosine reuptake inhibitor, along with a variety of other meds. There is actually a synthetic adenosine either in the pipe or available for prescription.

    I think the takeaway here is I have a high sensitivity to upregulation of dopamine, and a lot of supplements that are taken by people to treat their methylation problems increase production of dopamine. Reduced adenosine could explain why I can't tolerate methyl donors well, and it could neatly explain my mental health issues! I have to take an antipsychotic who's job is to block dopamine receptors, and I have found Clonipin to be a life-saver at keeping me from becoming panicked and edgy. I've seen only a few suggestions of how to supplement for AHCY, but I think that there is promise in finding help on this from my doctor and meds.
     
  14. ktred

    ktred

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    Thanks Tom for this interesting post. This is the first I have read about benzodiazepine's effect on adenosine. I feel like I bounce between too much dopamine and not enough, but maybe I should really be looking into my adenosine levels. Amongst my many mutations, I am +/- for all of the AHCY and BMHT mutations but haven't started any supplements to treat them.

    At this point, what are your thoughts on treating your AHCY and BMHT mutations?
     
  15. Tom_Nightingale

    Tom_Nightingale

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    I have taken the supplement TMG to try and correct my BHMT mutations. Again, like with most methyl donors, I did not tolerate it well and I had to stop after one dose of 1000mg (I felt nervous and agitated). I keep hearing how BMHT is the "short cut" of the methylation cycle, and it can help you get your cycle back in gear if other pathways aren't working well.

    Treating AHCY is not easy from what I am finding. There is a product that is a copy of adenosine (comes up when I search "adenosine" on Google), but that means you'd have to convince a doctor to prescribe it to you. The indications for adenosine usage are kind of scary, it can cause some quick and powerful effects. I am still looking into this, and will update here if I find something.

    The best bit of info I've found is this: " mutation in the human AHCY results in AHCY deficiency with increase of plasma creatine kinase, methionine, S-adenosylmethionine and AdoHcy, delay of myelination, myopathy and psychomotor retardation."

    Getting levels checked of creatine kinase, methionine, SAM or AdoHcy can help your doctor see if you need adenosine
     
  16. Valentijn

    Valentijn Activity Level: 3

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    The AHCY SNPs shown don't have any known relation to any dysfunction, and the +/+ variations are fairly common.

    So basically the AHCY results don't mean anything.

    If you search your 23andMe results, rs13043752 (AA, AG, or GA) and rs1205366 (TT) are associated with abnormal vitamin levels according to http://repository.ubn.ru.nl/bitstream/2066/80617/1/80617.pdf#page=52

    rs41301825 (TT, CT, or TC) is also extremely rare, practically nonexistent, and causes a missense mutation (wrong amino acid gets inserted into proteins), which is usually bad news. http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=rs41301825
     
  17. Bluebell

    Bluebell Senior Member

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    Valentijn, what are the vitamins which have abnormal levels associated with these 2 rs numbers? I have skimmed over the link you provided, and clicked on some of the usual reference links listed in the raw data area of 23andme, but I'm afraid I'm none the wiser.

    On the first rs number, I've got "AG", which it seems nearly no one in the world but Craig Venter and myself have (and I assure you we are not the same person :lol: ).

    I exaggerate slightly -- Craig and I have a little company -- it looks like about 2% of people have it.

    Un-click-on-able articles cited by Google Scholar in relation to this SNP mention early Crohn's disease/IBD and hypermethylation....

    I don't know how all this stuff relates yet [is it just me, or is the Higgs boson easier to comprehend than this methylation tangle?! ;-) ] so I don't know what that means, really.

    What does the Dutch paper indicate is the impact on a person's health of having this rare allele variation?
     
  18. Valentijn

    Valentijn Activity Level: 3

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    Whoops. For the first rs it's just showing that there's a mutation in the protein which the gene produces. Combined with the extreme rarity of the heterozygous mutation and the non-existance of the homozygous mutation, it seems very likely that this SNP is relevant to the functioning of the gene.

    And for the second rs, it's associated with homocysteine levels rather than vitamins - though vitamins are the subject of the study, thus the likely cause of my confusion :p

    Whatever you say, Craigbell :D
    There's no concrete information that rs13043752 is pathological, even though it causes a documented protein mutation. But when a mutation is so very rare (and you're ill), I think there's a strong possibility that it causes problems. Is it rare because it's just a random mutation that almost no one has? Or is a mutation rare because it's causing problems to the extent that someone with that mutation can't pass on their genes? I think it certainly merits further investigation into your functioning of that gene, at the very least.
     
  19. Beyond

    Beyond 10% of discount in iHerb!--> PEZ915

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    Thorne MethylGuard also resulted in my case in severe side effects - in the psychiatrically pathological side of side effects. I suspect some similarites in our genetic profiles. We will see in a month or less.

    In case Valentijin and caledonia arent right about the ACHY genes, which would be strange... Cordyceps contains both adenosine and cordycepin, an adenosine analogue. I have taken it and it worked as an aphroisiac and lung booster. This stuff also helps with adrenal fatigue and the chinese are crazy about it. Worth a shot! Look for one with high nucleotides.

    http://www.scirp.org/journal/PaperInformation.aspx?paperID=7997

    OH and to REALLY get out of the doubt zone with the Adenosine stuff you can get a methylation cycle test, it measures valuable markers like that one and glutathione.
     
  20. Bluebell

    Bluebell Senior Member

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    Maybe I've found the secret to why no fella has married me!

    To paraphrase the tv/film character Ali G, "Is it 'cause I is rs13043752?"
     
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