C9orf72 - a major cause of MND?

[PaulaF]

This would make sense.
At least for late-onset diseases like MND, genetic mutations are like chinks in our armour. They don't seriously affect us until we are put under stress - viral or otherwise.
We can target this by finding other ways of stimulating functions that the gene weakens. And this suggests another approach - acting against potential viral stressors. Do we know if there are HSV1 therapies, and whether they have been tested at all on MND?

[Johnny5]

C9 genes may be a cause, trigger point, or the repeats may be caused by ALS. C9 is has a large body of research behind it which may be why we are much more aware of it than other genes. They got excited at the discovery and it triggered a rush of exploration.

At this point, science does not know how to detect ALS at its earliest onset. The best guess would have to think that onset may be innocuous while it sets up the conditions for it to do actual damage and be noticed. The thing is they do not know enough about ALS to rule that out because there are no known biomarkers. Of the many genes we acknowledge at this time, onset may be caused by any or all of them, or none. We may not have yet identified the actual genetic path ALS takes. There is a lot of guesswork at this time.

Dr. Snyder from Stanford University in the Everything ALS Zoom from 11 May this month explained the new DNA sequencing program they use and that there may be more than 600 genes involved with ALS. Cause and effect though is still a mystery.

[Michael Nicholas]

PaulaF There are as yet no specific therapy for HSV1, but research is proceeding. A problem is that any viable therapy may eradicate the virus yet not remedy the damage to the genes which cause the disease; on the othe hand, maybe it would halt progression of the disease.
It seems to me important to establish how many sufferers of MND have the HSV1.

[PaulaF]

C9 genes may be a cause, trigger point, or the repeats may be caused by ALS. C9 is has a large body of research behind it which may be why we are much more aware of it than other genes. They got excited at the discovery and it triggered a rush of exploration.

At this point, science does not know how to detect ALS at its earliest onset. The best guess would have to think that onset may be innocuous while it sets up the conditions for it to do actual damage and be noticed. The thing is they do not know enough about ALS to rule that out because there are no known biomarkers. Of the many genes we acknowledge at this time, onset may be caused by any or all of them, or none. We may not have yet identified the actual genetic path ALS takes. There is a lot of guesswork at this time.

Dr. Snyder from Stanford University in the Everything ALS Zoom from 11 May this month explained the new DNA sequencing program they use and that there may be more than 600 genes involved with ALS. Cause and effect though is still a mystery.

I'm pretty sure it's the C9 genes that cause the ALS. The Reus study showed that 29% of people with C9 variant rs147211831-A and 18% of those with C9 variant rs117204439-C had pathological repeat expansions; and the Murphy study showed that by the age of 83 over 99% of people with such expansions had developed symptoms. Both variants are present from conception, so cannot be caused by the ALS.
In the Reus study, 64% of people with expansions had one of these variants and they are fairly cheap to test for, so I think they make pretty good biomarkers that can identify from birth nearly two thirds of people who are at risk.

Seems to me that variant C9 genes most likely do their damage by altering immune reactions in such a way that blocks the delivery of nutrients to neurons in order to prevent nourishing a pathogen/virus (real or imagined) present in those neurons. In the absence of genetic engineering, the keys would seem to be in calming down the immune reactions and stimulating the delivery of the nutrients that the immune system is restricting. One way of calming down the immune reaction would of course be to eliminate any virus causing the reaction.

[PaulaF]

PaulaF There are as yet no specific therapy for HSV1, but research is proceeding. A problem is that any viable therapy may eradicate the virus yet not remedy the damage to the genes which cause the disease; on the othe hand, maybe it would halt progression of the disease.
It seems to me important to establish how many sufferers of MND have the HSV1.

I agree. And even just halting progression of the disease would be a very fine thing. Think I might look at this further.

[PaulaF]

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).

[Johnny5]

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.

[PaulaF]

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.

[Michael Nicholas]

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?

[PaulaF]

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?

[Johnny5]

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.

[Johnny5]

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.

[PaulaF]

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.

[PaulaF]

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?

[Johnny5]

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.