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C9orf72 - a major cause of MND?

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  • Marc from London
    replied
    Following Wikipedia the grade of C9orf72 mutation worsens from generation to generation. It’s said that the level of mutation in the following generation will trigger an effect approx 10 years earlier the the preceding generation experienced it. So now I look back. My late father who was 57-58 when he started to have first symptoms. I had first symptoms aged 45. Of course that proofs nothing but gave me some confidence that C9orf72 must be a major player in ALS

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  • PaulaF
    replied
    More evidence pointing to 'motor neurone disease' being at least 2 different diseases.
    Big differences were already known between the 2 most common causes, C9orf72 and SOD1 variants:
    1. C9orf72 is strongly inflammatory, SOD1 isn't
    2. C9orf72 increases iron storage, SOD1 doesn't
    3. C9orf72 can sometimes be linked to dementia (often in the absence of any motor neuron damage!), SOD1 can't
    4. C9orf72 onset can be brought forward by strenuous exercise, apparently not in SOD1
    Now we find that although the main point mutation in C9orf72 is linked to a 150% increased risk of osteoporosis (per SAIGE), the Soyocak study recently published reports there is no relationship between SOD1 and osteoporosis.

    If they were to test everyone to properly distinguish which disease they had, they might be able to target their research more effectively and come up with suitable therapies.

    1 in 55 people inherit the point mutation linked to C9orf72 at conception. Most do not get noticeable motor neuron damage. On average, the bodies of those that do seem to be able to hold it at bay often until they are in their 50s or 60s. If our bodies can do this on their own, there is surely some way in which we can tackle this more effectively with some kind of relatively simple pharmaceutical or nutritional interventions?


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  • PaulaF
    replied
    In Reus' study 46% of those with C9orf72 expansions had the genetic variant rs147211831-A, despite this variant only being present in 0.2% of the general population. The variant is inherited at conception - it only exists in people who have certain other variants, so I would say it looks like expansions result from other genetic variations, rather than from the ALS itself.

    An interesting thing is that this variant isn't even on the C9orf72 gene, but on the adjacent gene MOB3B; and a second risk variant sits on another adjacent gene CTAGE12p. My family's readings show that these three genes that affect each other generally seem to be inherited together, so looking at the functions of all three must provide some useful clues to how C9orf72 disorders work. The more clues there are, the greater chance there is of finding a treatment.

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  • PaulaF
    replied
    I hope you don't mind me saying, Johnny5, but a sibling with ALS combined with a read of 18 repeats indicates to me a significant likelihood of a familial C9orf72 disorder. (I dislike the term ALS, as in my case, there is as yet no sclerosis and no fasciculation. Even MND is a misnomer in my view, as plenty of people with malfunctioning C9orf72 have nothing wrong with their motor neurons, and suffer from dementia or schizophrenia instead.)

    The disorder is localised - it can affect one kind of neuron (brain) or another (motor). Many (especially with fewer repeats) aren't symptomatic enough to realise they have it. Most have it for several decades before they notice adverse consequences. There has been masses of research into it, much of it promising. I think this is cause for optimism.

    My view is that it is probably as unrelated to other forms of ALS as hay fever is to the common cold.

    I still think there is a good chance of finding pretty much that a single genetic mutation is the common cause. Reus narrowed this down massively to a single mutation that seems to explain a large proportion of cases. I suspect a mutation just upstream of this one might be the culprit. Then we might find out even more.

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  • EvelynMW
    replied
    Its all getting too technical for me. The 'good' thing about C9orf, is that i got diagnosed very quickly, if we ignore the 20 or so months before that, (no-one got anywhere enough even to refer me on, i had to push for that). As my mum died of MND in 1979, they were immediately convinced that me having this gene repetition, meant....... it MUST be MND. At least i didn't have months of tests to rule everything else out.

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  • Johnny5
    replied
    C9 is also related to schizoprenia. The idea that it is associated with the autoimmune system is not that far out of bounds because a single gene can have an effect on several pathologies. My test came back with 18 repeats and was disqualified for me to have familial even though my brother died from ALS. Too many unknowns still, and the possibility still exists that an unknown player causes repeats. I have heard that C9 repeats can go into the hundreds to thousands in some people and as little as zero to two in others. IMO there is a lot of speculation on this topic.

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  • PaulaF
    replied
    It seems to me that C9orf72 MND is the elephant in the room that most see as only one of many flies buzzing around in it.

    Only a fairly small percentage of people are said to have C9orf72 repeat expansions, but what is defined as a C9orf72 expansion has itself expanded. Originally, you had to have 45 repeats on one allele to be classified as having an expansion. Then they found that 30 repeats was also pathogenic. Then in 2019, based on a study of 8,818 people, Iacoangeli reported that 23-29 repeats were also pathogenic, and were associated with over 4 times the risk of getting MND. Looking at table S1 in Iacoangeli's supplementary materials, we see that the ratio of ALS patients to controls is 12 times higher for people with 16-23 repeats than it is for people with the average 2 repeats. (Iacoangeli presumably does not report this because the numbers are too small for him to prove the link beyond doubt.)

    Rather than a very small minority of MND patients being affected by c9orf72 expansion, my suggestion is that it is endemic. The average number of repeats is 2 on each of the genes inherited from each parent, but 11% of people have a gene with 5 repeats, and nearly 3% have one with 10 repeats. Many people will have expansions like this on the genes inherited from both parents; and as this is an autosomal dominant condition in which both copies of the gene are active, any adverse effect for these people can be doubled.

    Mine is a case in point - one gene is shared with a sibling, meaning there are three independent versions of C9orf72 shared between us, yet our tests show there are expansions on all of them. One has a confirmed 5 repeats, another has at least 11 repeats in one of us and at least 20 in the other (exact number cannot be confirmed without further testing), and not a single read out of about 60 on all our alleles shows 2 or 3 repeats. The genes arrived to us through separate inheritance routes, showing different patterns of C9orf72 mutations, but some degree of expansion is present in all of them.

    Having more than 2 or 3 repeats is almost certainly not optimal, and it seems the more we have, the more likely it is to adversely affect our health. There is a lot of research being done on it, but will it be of any use if few people with MND have been fully tested for it (especially down to the level of 16 repeats) and know the extent to which they are affected by it?


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  • PaulaF
    replied
    I suppose which causes which doesn't matter so much as noticing that they are connected, as this can give clues to how the disease works.

    It looks clear to me that C9orf72 is an immune system gene flanked by other immune system genes that also demonstrate ALS connections. The key to taming the ALS seems to lie in the immume system in some way.

    ALS connected to other genes or no genes at all might work in different ways and be effectively different diseases.

    I still think C9 ALS is far more prevalent than they estimate. Most aren't even tested for it, and as in my case those that are still struggle to get a definite answer. Some simple therapies seem to be able to at least gnaw away at the disease around the edges. I'm not entirely sure why there is virtual silence on them from the medical establishment.

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  • Johnny5
    replied
    One of the world's leading researchers (Prof. Kiernan, Australia, Jun 8 22 Everything ALS ) noted that many genes are associated with ALS, but he could not answer about the possibility of genetic defects causing ALS (not his field) vs ALS causing them. It is a question like what came first, the chicken or the egg.

    About two-thirds of individuals with familial ALS and 10 percent of people with sporadic ALS have a known ALS-associated genetic mutation. The number of familial ALS may be as high as 20% now, so finding genetic mutations in pALS only covers around 20-25% of the population (including C9 repeats). That means 75% of us pALS are the mystery, bringing up the question of which came first, the genetic mutation or the condition (ALS). To date, they have noted that up to 600 genes
    that may be related to ALS, but only around 40 are confirmed (Michael Snyder, Prof of Genetics, Stanford Univ).

    To date, it cannot be noted that any genetic alterations in mice will have the same effect in humans. It is a fact that ALS is a purely human condition, no other species gets it. Mice are genetically altered and given ALS but it barely translates to actual human response in experiments. Labs can double and triple mice's lifespan through genetic studies but have yet to demonstrate the same thing in humans. The greatest success has yet to demonstrate any statistically significant benefit to pALS.

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  • Johnny5
    replied
    Dealing with the brain, it has an enormous ability to modify itself called plasticity. When neurons are damaged, other neurons adapt and attempt to take over the lost capacity. This is well documented in epilepsy where they will literally take out parts of a person's brain. The full function may never be restored, but over time a surprisingly large part of that lost function is restored. Relating it to ALS one would think that if they ever figure out how to stop this condition from progressing, most of us would likely see some restoration of function through plasticity. Another positive note to reflect on is documented ALS reversals. McFinn Lovere is one example.

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  • PaulaF
    replied
    Originally posted by Michael Nicholas View Post
    PaulaF You are dlearly knowledgable about genetics, so I wish to pick your brain, please,

    How can gene editing be undertaken to remedy damage to genes in our brain cells as these cells do not replicate like cells elsewhere in our body?
    I'm not an expert on this, Michael, but so long as the gene editing medications can get through to existing brain cells, replication should not in theory be an issue. Other genetic therapies involve diverting the products of the impaired genes, but as far as I'm aware these have not so far been successful.

    For now, I would mainly focus on simpler therapies - targeting the things that the impaired genes seem to combine with in inflicting damage.

    Just as one example - Burberry's tests from 2020 on C9orf72-impaired mice.

    He pretty much proved that:
    1. C9orf72 is an immune system gene
    2. Knocking it out massively increased inflammatory cytokines & auto-immune antibodies and reduced motor performance
    3. Use of broad spectrum antibiotics in the C9orf72-knockout mice pretty much normalised cytokines, antibodies and motor performance (demonstrating that bacterial infections can have a role in C9orf72 disease)
    4. Faecal transplants from healthy mice partly alleviated the elevation in cytokines and antibodies

    My questions are:
    1. Where is the simple follow up research on the use of antibiotics, faecal transplants and probiotics in C9 MND humans?
    2. Inflammatory C9 MND is clearly a distinct disease that works in a distinctive way, so why are those diagnosed with MND not routinely tested for it and its two genetic biomarkers?
    3. Why are those diagnosed with it not routinely prescribed a short course of antibiotics, followed by at least supplementation with probiotics?




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  • Michael Nicholas
    replied
    PaulaF You are dlearly knowledgable about genetics, so I wish to pick your brain, please,

    How can gene editing be undertaken to remedy damage to genes in our brain cells as these cells do not replicate like cells elsewhere in our body?

    Leave a comment:


  • PaulaF
    replied
    Originally posted by Johnny5 View Post

    At this point, nobody has shown that C9 is the "cause" of ALS. It may be that C9 repeats are the result of ALS as well. I have seen plenty of studies claiming that it "may" cause ALS, but the language is not "does" cause ALS. The majority of studies completely ignore that C9 may be caused by another trigger that is also involved in ALS. If the C9 were the cause, the fact that there are little to no C9 repeat expansions in Asia (0%), Japan (1%), Pacific Islands (0%), and even Italy (0%) in sporadic cases make the claim that C9 is the cause unlikely. Many of these issues are also not addressed in studies attributing the C9 repeats as the possible "cause".

    The percentage of C9 that they attempt to cite as the cause of ALS is actually a small percentage of all pALS. 40% of 10% would be 4% of all pALS. C9 repeats of hundreds of thousands have been seen in people with ALS that lend the idea that ALS may be the cause of expansions, just as zero and two repeats also have been found in pALS which confounds an absolute certainty of cause/effect. Theories abound about what it might be, but none exist that show conclusively that it does. Correlation is not causation.

    IMO, they still do not know what causes ALS. If they did, it would be much easier to find a cure.
    C9 repeats themselves are unstable, so yes, I agree that repeat expansions could potentially be partly the result of ALS, rather than the cause. However, other mutations on C9 that are stable and present from conception are strongly associated with both repeat expansions and later ALS, so the direction of causation for these particular mutations cannot be from ALS to C9.

    As with diseases affecting other areas of the body, there are probably many different causes of diseases of the motor neurons. C9-associated disease of the motor neurons is, in my view, one of the most prevalent ones. I suspect 4% is a gross underestimate, with heritable ALS estimated as something more like 60% (far higher than the 10% clearly proven to be 'familial').

    I also agree it is unlikely that C9 is the sole cause of C9 ALS. A combination of several causes is often required to trigger many diseases, and C9 ALS is probably no exception. Just as a fire requires both tinder and a spark, C9 ALS seems to require both C9 variants and one or more co-causes. It could be very useful to find out what these co-causes are.

    I think we have quite a bit of research information on C9 ALS and how it appears to develop. You're right, they do not know for sure, but I would not wait until we have proven certainty when we already have lots of clues now. And I would not only look for an absolute cure, when effective treatments already look tantalisingly close.

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  • Johnny5
    replied
    Originally posted by PaulaF View Post

    I'm pretty sure it's the C9 genes that cause ...ALS.
    At this point, nobody has shown that C9 is the "cause" of ALS. It may be that C9 repeats are the result of ALS as well. I have seen plenty of studies claiming that it "may" cause ALS, but the language is not "does" cause ALS. The majority of studies completely ignore that C9 may be caused by another trigger that is also involved in ALS, or is caused by ALS. The correlation does not prove causation. If the C9 were the cause, the fact that there are little to no C9 repeat expansions in Asia (0%), Japan (1%), Pacific Islands (0%), and even Italy (0%) in sporadic cases make the claim that C9 is the cause unlikely. Many of these issues are also not addressed in studies attributing the C9 repeats as the possible "cause".

    The percentage of C9 that they attempt to cite as the cause of ALS is actually a small percentage of all pALS. 40% of 10% would be 4% of all pALS. C9 repeats of hundreds of thousands have been seen in people with ALS that lend the idea that ALS may be the cause of expansions, just as zero and two repeats also have been found in pALS which confounds an absolute certainty of cause/effect. Theories abound about what it might be, but none exist that show conclusively that it does. Correlation is not causation.

    IMO, they still do not know what causes ALS. If they did, it would be much easier to find a cure.
    Last edited by Johnny5; 29 May 2022, 16:40.

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  • PaulaF
    replied
    To illustrate my query about C9 being a major cause of MND, take just one of Reus' C9 variants -
    It is estimated that 2% of the population have rs117204439-C, Reus estimates that 18% of these people have expansions and Murphy that 99% of these people will be symptomatic by age 83. This calculates as 1 in 300 people by the age of 83 symptomatic with the variant (not dissimilar to the estimates of MND in total).

    Other C9 ALS research:
    1. Burberry 2020 tests on C9orf72-impaired mice - antibiotic treatment followed by transplantation of healthy gut microflora substantially reduced neuro-inflammation (showing that control of infectious agents can be therapeutic).
    2. Mehta 2021 in vitro and post mortem tests on motor neurons with c9orf72-impaired cells - stimulation of mitochondria increased transport of energy to the neurons and restored some of their axonal length (so remedy of damage is not out of the question).

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