C9orf72 - a major cause of MND?

[PaulaF]

10% are familial, but the number of genes involved has grown substantially in the last 12 years.

Yes, thèy are finding more and more that genetic factors are a major cause.

I think the 10% familial figure can be a little misleading, as this only counts the people where the genetic weakness has been firmly evidenced by MND in another family member. There are probably other people with genetic weaknesses that just haven't been triggered as MND. Familial is not the same as hereditable.

[Drumond30]

Does this mean there is no hope for those of us who have a family member with MND and that is most likely genetic they just haven't found the gene yet? We are waiting on results coming back from my Dad, whilst there is no family history of MND or FTD before my Dad's generation, my Aunt has FTD. Nothing else so far on that line but I'm not hopeful this won't come back as genetic.

[PaulaF]

Does this mean there is no hope for those of us who have a family member with MND and that is most likely genetic they just haven't found the gene yet? We are waiting on results coming back from my Dad, whilst there is no family history of MND or FTD before my Dad's generation, my Aunt has FTD. Nothing else so far on that line but I'm not hopeful this won't come back as genetic.

No, there is hope. They are finding only in the last couple of years that many of these genes link to each other, and you might need a combination of them plus an environmental trigger to actually get the disease. Not everyone in families gets the same problem.
For example, a mutation in the CTAGE12p gene has been linked to C9orf72 gene expansions, which have in turn been linked with reduced expression from the SOD1 gene.
Understanding this better will help them come up with treatments that could block the actions of some of the harmful mutations and/or boost the actions of the good genes.

[PaulaF]

Does this mean there is no hope for those of us who have a family member with MND and that is most likely genetic they just haven't found the gene yet? We are waiting on results coming back from my Dad, whilst there is no family history of MND or FTD before my Dad's generation, my Aunt has FTD. Nothing else so far on that line but I'm not hopeful this won't come back as genetic.

When did your Dad take the test?
in my case, the NHS consultant wanted to discuss this first (3 month wait to next appointment), so paid for one privately - they said it will take up to 2 months for the results.

[Drumond30]

Last week. We've been told 5-8 weeks to get the results.

[Drumond30]

For a number of complicated reasons we were able to bypass the NHS Consultant and get the test via the genetics lab in Edinburgh. From our experience the NHS Consultant my Dad is under and the specialist nurse know very little about the genetics side of things.

[PaulaF]

For a number of complicated reasons we were able to bypass the NHS Consultant and get the test via the genetics lab in Edinburgh. From our experience the NHS Consultant my Dad is under and the specialist nurse know very little about the genetics side of things.

Well done!
The lack of knowledge is not surprising, as some of the main discoveries have only taken place in the last two years, and even the researchers are unclear and disagree on them.
C9orf72, a common factor in MND and FTD, has differences to the others. It has an inflammatory element and seems associated with strenuous exercise, so the treatment when it comes might be different.
Thankfully, they are putting a lot of effort into researching it.

[PaulaF]

Fascinating report from BBC today of a Bjornevik study indicating that the main trigger for Multiple Sclerosis is the glandular fever virus (Epstein-Barr).

As C9orf72 MND shares many features with MS (including biomarkers such as increased neurofilament light chains, TNF alpha and CRP), it would not be surprising if they found a similar viral trigger for this too, opening up more avenues for therapies.

[Olivia H]

There was some research publicised in 2015 about the likelihood of MND/ALS being linked to a possible re-activation of 'junk dna' ancient virus materials carried in our bodies.
Given the random and sporadic nature of mnd for most, the commonality of a virus seems a highly possible trigger. I hope, given today's MS 'breakthrough' that this line is still being considered for mnd too.
It is way past the time there should be both effective treatments and reversal therapies for this illness! I feel we can't be left to do our own detective work indefinitely... I certainly don't accept the 'there is nothing we can do' line.

[PaulaF]

There was some research publicised in 2015 about the likelihood of MND/ALS being linked to a possible re-activation of 'junk dna' ancient virus materials carried in our bodies.
Given the random and sporadic nature of mnd for most, the commonality of a virus seems a highly possible trigger. I hope, given today's MS 'breakthrough' that this line is still being considered for mnd too.
It is way past the time there should be both effective treatments and reversal therapies for this illness! I feel we can't be left to do our own detective work indefinitely... I certainly don't accept the 'there is nothing we can do' line.

Thanks, Olivia.
*
Research from Reus published just a few months ago pretty much proved that a genomic mutation flanking a pseudogene (understood to be non-functional 'junk DNA') is strongly linked to C9orf72 expansions. This mutation (chr9:27,607,975-C) is associated with around 12 times the risk of expansions, but it doesn't noticeably cause MND in everyone who has it. This seems to require some kind of catalyst that sparks a chain reaction leading to neuron damage in later life, and a viral or bacterial infection could easily be such a catalyst.

The more we find out about viruses and bacteria, the bigger culprits they become - H Pylori is known to be a major trigger of stomach cancer, HPV a major trigger of cervical cancer and now the Epstein-Barr virus a major trigger of Multiple Sclerosis. This possibility of a viral trigger might be good news, as it provides another potential treatment avenue in the form of anti-viral medication.

Much of the preliminary detective work has been done. If it could all be pieced together and we could target the disease at several stages of the chain, I think we might get somewhere. I don't want to upset anyone talking about this, but I suspect there is something we can do. I will post more about this later.

[PaulaF]

To recap why I think this is important:
c9orf72 expansions make up 40% of familial ALS, but Al Chalabi estimated that as much as 61% of ALS is hereditable - much higher than is recognised as familial (I understand you have to have 2 other close family members diagnosed in order for it to be categorised as familial). This suggests that c9orf72 might be responsible for anything up to a quarter of all ALS.
Around 20% of the population have the chr9:27,543,283-T variant that makes them susceptible to expansion, with 4% inheriting this from both parents.
Although repeats are only considered an expansion when they reach 30 in number, this does not mean that 29 repeats are risk-free. Iacoangeli estimated that risks increase 5 or 6 fold when there are 20-23 repeats (15 fold in North Europeans). Kaviola estimated that having more than 6 repeats can predispose to expansion, especially when excessive repeats are inherited from both sides. About 3-4% of the population have 10 or more repeats. Repeats can be unstable, varying within tissues and especially between tissues, and are more unstable the more repeats there are.
Even in people whose ALS has another cause, this is likely to be exacerbated by a tendency to toxicity from having more than the usual number of repeats.
In other words, c9orf72 repeats could be affecting more people than just those who have been officially diagnosed as having c9orf72 ALS.

Research into c9orf72 ALS has identified a number of intriguing features that distinguishes it from other kinds, and is perhaps suggestive of it resulting from a chain of processes involving immune reaction, inflammation, abnormal protein production, cell replication and oxidation. I'm trying to understand it better, as there might be some ways of helping disrupt this chain and fight back. I'll try to post more over Easter.

[PaulaF]

There are 2 routes for c9orf72 ALS.
1. CCGGGG expansion - Having more than 30 CCGGGG repeats is linked to ALS. Reus (2021) showed expansion is linked to mutations rs3849942-T, rs117204439-C and rs-147211831-A.
2. 11 other mutations - Jones and Woollacott (2013) showed these are linked to ALS when there are more than 2 repeats, but no expansion.

It seems very likely that c9orf72 ALS has a common cause, so what is there in common between these 2 routes? Only that there are (i) more than 2 repeats and (ii) mutations around the c9orf72 gene (different mutations in each route). While repeats are a common feature, individual mutations are not and full expansion is not, indicating that neither specific mutations nor expansion are the common cause. It has been noticed for some time that the number of repeats in an expansion appears to have no effect on ALS progression. Perhaps the failure of the Biogen trial shows that toxins linked to expansion are a bit of a red herring, and that ALS is instead the result of a general weakness of the c9orf72 gene in carrying out its function?

Most people with a small number of excess repeats do not get neuron damage, but some do when they have other weaknesses/mutations around their c9orf72 gene. This suggests 3 ways in which we might be able to disrupt the cycle that leads to neuron damage:
1. Reducing factors in the environment that might be damaging and overwhelming weak c9orf72 genes.
2. Trying therapies that benefit other health conditions linked to the same or adjacent mutations.
3. Boosting things that might have a similar function to the c9orf72 gene.

I would welcome any thoughts or suggestions before I go further on this.

[PaulaF]

My estimate is perhaps a quarter of people with ALS may have some degree of c9orf72-related disease, which looks to me like an auto-immune condition.

Both c9orf72 expansion and related ALS link to a mutation at 9:27,607,975 between c9orf72 and a T-cell antigen gene (CTAGE12p) connected to the activation of the immune system. The nearest mutation to this with known effect is involved with the PCA3 antigen that fights prostate cancer and is sometimes generated without evidence of any cancer (it is interesting to see another recent BBC report on a study now linking prostate cancer with infection). C9orf72 is the only type of ALS associated with substantially-elevated inflammatory markers typical of auto-immune disease. Many other auto-immune diseases are highly predictive of subsequent ALS (including asthma, coeliac disease, type 1 diabetes, multiple sclerosis, myasthenia gravis, myxoedema, polymyositis, Sjogren syndrome and lupus), and the same mutations are associated with c9orf72 disease and auto-immune diseases. Microbe exposure increases c9orf72 expression and interferon stimulation (the interferon gene IFNK is adjacent to c9orf72), which can trigger auto-immune encephalomyelitis, a condition only found in the c9orf72 variety of ALS. Viruses can disrupt c9orf72 expression.

Strenuous exercise (increasing oxygen intake) is linked specifically to the c9orf72 variety of ALS. C9orf72 mutations in neuron cells reduce secretion of antioxidants (including SOD1 known to be linked to ALS), increasing oxidative stress that can cause cell death – but when mutated cells are placed in a control medium with normal antioxidant levels, they do not exhibit pathological features.

This looks to me like a chain process – infection/toxin triggers an immune reaction that does not properly switch off due to mutations in the genes, the resulting inflammation damages the gene further causing it to produce insufficient and poor quality antioxidant proteins, making it susceptible to oxidative stress, bringing cell death and failure of normal bodily processes.

There are many links in this proposed chain that could theoretically be tested for treatment in this disease. Many (e.g. rituximab and anti-TNF alpha medication) are restricted under the prescription system. There is also a range of anti-oxidant and anti-inflammatory supplements which could be trialled – some are likely to be effective to some degree. There is already some limited evidence in favour of curcumin/turmeric, melatonin, alpha-linolenic acid, alpha-lipoic acid, l-serine, paracetamol and NSAIDs, and there will probably be others that I haven’t seen any information about. I feel there is more that could be done now if the medical profession were to adopt a more proactive and less resistant approach. But that’s just my opinion.

Are there any other similar treatments that anyone has heard about?

[PaulaF]

Just heard on BBC that none of the £50 million pledged for MND research last year has yet been awarded and that it is not specifically ring-fenced for MND in any case. It's no good waiting for these people, especially as we've already had plenty of useful research, much of which does not seem to have been followed up.

For what it's worth (you may think not a lot), my belief is that research has pointed towards at least c9orf72 MND developing as follows. In some people, genetic mutations weaken the ability of neuron proteins to pull in sufficient fats to service their high energy demands. As we age and the neurons come under stresses from energetic activity, injury, infection, auto-immune disorders etc,, damage to some of these neurons increases stress on the remaining neurons, which can trigger a vicious circle of neuron collapse.

They have already identified ways in which such damage can be minimised, but seem reluctant to bother recommending them or researching them further - perhaps because they are mostly simple treatments from which little money can be made by the pharmaceutical industry.

The keys seem to be keeping the neurons energised and reducing the stresses on them - (i) using supplements or medication to promote their uptake of fats, (ii) providing more of the types of fats that do not oxidise easily or promote inflammation, (iii) minimising high energy-expending activities, (iv) targeting infection, (v) dampening any inflammatory or auto-immune responses, (vi) using supplements or medication to minimise oxidation damage and (vii) promoting energy-restorative sleep. These are not panaceas, but they seem to be relatively simple, safe and accessible treatments, and we don't really need to wait for the arrival of cutting-edge pharmaceuticals before doing anything.

[Arcadian]

Particularly interested in the genetic aspect as I also have Crohn's Disease, which has interesting overlaps with risk.
Hope to contribute to some research deending upon consultantband resources.