C9orf72 - a major cause of MND?

[EvelynMW]

I have no idea about any other possible active cause. i am now on a gene therapy trial for us with the C9 orf gene. One is running at Kings College Hospital, and i recently heard that Addenbrookes is about to start the same trial. i go to London, shame Addenbrookes didn't start earlier!

[PaulaF]

A study by Olesen in 2020 showed that interferon was higher specifically in the C9 variety of ALS.

A study by Poutiainen in 1996 showed that interferon treatment caused cognitive decline in ALS patients that reversed when treatment ceased.

A study by Liu in 2015 showed elevated interferon in ALS patients, and that the higher the interferon level, the faster the disease progressed.

A US trial of the interferon-inhibitor baricitinib for C9 ALS was supposed to begin in February 2022, finishing in late 2023, but seems delayed.
Such interferon-inhibitors (JAK inhibitors) are prescription only, and currently expensive. Milder natural JAK-inhibitors (turmeric, berries, alpha-linolenic acid, omega 3 oils and some Chinese herbal remedies) are not so expensive.

[PaulaF]

My mother started her MND at the age of 52. Mine started at the age of 63. Mum died within 3 years, i have fairly minor issues and have been showing symptoms for 4 years, so far. My sister has the c9Orf gene too, but has no symptoms and she is 5 years older than me.
There must be other factors to produce such a variety of MND statuses, but i'm leaving the research to people way more capable than me.

There has been a lot of capable research, but I can't see much sign of it being acted upon. In my case, there has been no clinical advice whatsoever, apart from 'we don't know what causes it' and 'do not waste your money on any therapies, as they don't work', which both seem to be in direct contradiction with the results of many academic research papers available over the internet.

Having an expanded C9orf72 can result in other disease instead or no disease at all, and I agree that C9 MND looks to be based on a number of factors, not just C9orf72 itself. This is a cause for optimism, as blocking any one of these factors could potentially prevent, delay, subdue or arrest development of the disease.

I don't suppose you know whether you also have a rs10967965 mutation on the MOB3B gene and an elevated interferon count, do you? I suspect that nearly all people with C9 MND do.

[EvelynMW]

My mother started her MND at the age of 52. Mine started at the age of 63. Mum died within 3 years, i have fairly minor issues and have been showing symptoms for 4 years, so far. My sister has the c9Orf gene too, but has no symptoms and she is 5 years older than me.
There must be other factors to produce such a variety of MND statuses, but i'm leaving the research to people way more capable than me.

[PaulaF]

I've checked quite a few brother and cousin mutations to rs10967965 and can see no reports linking any of them to MND. I've checked the rs10967965 mutation itself and several of its linked and descendant mutations, and all are reported to be associated with a higher risk of MND or other neurological disorders.

My suggestion is that this mutation is likely a co-factor with C9orf72 expansion in the development of C9 MND.

The mutation is reported to be associated with lots of other medical conditions, especially type 1 diabetes which itself is known to be associated with MND.

In type 1 diabetes, raised levels of interferons destroy pancreatic cells. We know that interferons are raised in C9 MND, so it seems reasonable to hypothesise that these raised interferons can also damage neuronal cells, particularly when an interferon-producing gene sits right between the rs10967965 mutation and C9orf72.

By subduing interferons, I wonder whether the development of C9 MND can itself be subdued?

[Ellie]

Doug Carpenter It isn't really a National Register unfortunately - it is an 'opt-in' register run by several MND Centres and Clinics, so is incomplete. xx

[PaulaF]

Cinderella

That database/register exists.

Doug

Thanks, Doug. It would be interesting to know what is on this database, and how much data it includes on genetics. I'm not sure what proportion of patients have been genetically tested. In my case, it had to be pushed for.

Marrying up the various national C9 databases might also prove useful, as there seems to be some striking differences between Dutch, Finnish and British databases (to the extent their data is available and comparable), even though their cases seem to emerge from the same basic mutation.

[PaulaF]

Acetyl-l carnitine works in a different way to edaravone, I believe. It is likely that auto-immune varieties of MND would restrict the supply of nutrients to neurons, which acetyl-l carnitine appears to counteract by stimulating nutrient transport and supply. The other differences to edaravone are that acetyl-l carnitine is freely available over the counter and relatively cheap.

The trial only included people aged under 71 who'd had symptoms for less than 2 years. Not sure if this is significant, as it might just be their way of maximising the number of people able to complete the trial.

I've just noticed something else very curious about the C9 version of MND, which seems to me to be much more widespread than they have so far realised or let on. The genetic mutation rs10967965 is only one individual twig emerging from the massive tree that is the so-called MND risk allele rs38449942. However, (i) all three MND high risk mutations sit on this same twig, and (ii) I have just looked at 30 random sub-groups on the rs38449942 tree, and the only ones identified as showing any increased MND risk at all are all also on the same rs10967965 twig.

If this is the case, then surely we have to consider whether the rs10967965 mutation is the cause of C9 MND, which might give some big clues as to the mechanism by which it works and therefore how to treat it. I have looked on the internet and cannot find any identification of the possible significance of this mutation nor any specific focus on it, which again seems very odd.

I will investigate as far as I can, although this might not be very far, as much of the data is not publicly accessible.

[Doug Carpenter]

Cinderella

That database/register exists.

Doug

[Cinderella]

PaulaF

This is really interesting - I found the same evidence via ALSUntangled - carnitine supplements dated 11 Feb 2020. I don't understand why, when they have so little to offer us that this is not considered worth trying as it appears you can take it in conjunction with riluzole?

On my first (and only) visit to see the neurologist after diagnosis early this year, I asked about edaravone which I have since understood to be the 'active' part of acetyl L carnitine? (But I may be mistaken as I have researched so much online). I cannot remember what the answer was as to why I would not be offered this.

It may be that it takes so long to diagnose (in my case 6 years) as it appears with edaravone there is strict inclusion criteria and you have to be in the early stage of the disease. But what determines 'early' as in my case it has progressed relatively slowly, and the rate of receiving early diagnosis is considered poor for most people.

I have not had any genetic test although I understand we should all be offered this and will be contacting my mnd nurse this week to ask about this being carried out.

I wholeheartedly agree with your sentiments regarding paragraphs 1 and 5 of post #59. I asked one researcher whether they could be involved in a particular trial as that would open it up to people in the UK, but was told that they hadn't been invited, but if they were they would be happy to work with them. Surely it is not down to 'manners' and waiting to be asked, this is a global disease that can only benefit from professionals working together? Time to be proactive and drop all this archaic protocol in order to get results? I realise big pharma have a part to play in this though. Also, the egos of the players.

Anyway, the chances of one of us being accepted onto these drug trials also seems to be slim - why? They should be clamouring at our doors if there are so few of us? And as for double blind - that is just plain cruel, heartless and unnecessary.

I keep being told I am the expert, as I am the one living with mnd, but it appears even though we are all so different in our presentation of the disease, there is no-one out there interested enough in collecting our individual data to produce statistics to better understand the causes, let alone any form of cure. They can't even be bothered to create a national database of those registered as having the disease in the UK and for me, that just about sums it up.

[PaulaF]

Fingers failed, this post is being dictated.
.
Hi PaulaF


I'm sorry, I don't know enough about C9 genetics and subsequent protein synthesis to comment meaningfully. But such correlations are always interesting.


Could I suggest that you collate all the valuable information in your posts into an email to MND Connect and ask them to passit to their research team for comment. You could even suggest that the team may want to seek advice from experts in the field, e.g. Profs Talbot, Turner and al Chalabi. They should certainly be familiar with such material.


Doug,

Thanks for this suggestion, Doug, but I don't see many signs of the experts learning from each other, let alone from a layman, and especially when the information is to be passed through intermediaries.

C9 ALS understanding at the highest levels is still permeated with mythology. Its supposed 'risk allele' rs3849942 is said to be Finnish and linked to the Vikings, but this is almost as far out as you can get. SNP analysis shows that rs3849942 is almost certainly of ancient African origin and probably extends back further than the last glacial maximum.

The 3 high risk alleles so far identified (rs117204439, rs147211831 and rs139185008) are all closely linked to the same relatively recent parent allele rs10967965, but no one seems to have pieced this together and investigated further.

People are said to be negative for C9 ALS if they have less than 45 repeats, when:
1. Iacoangeli has shown that >23 repeats is pathogenic.
2. Kaivola's data from Finland shows ALS correlating with repeats > 23, and also correlating with repeats > 6 when both alleles are > 6.
3. Data from the British/ADNI dataset shows ALS correlating with repeats > 3 (with correlation gradually strengthening as the number rises), and the size of the allele with the smaller number of repeats correlating even more strongly with ALS risk than the size of the larger one.
4. After adjusting for homozygosity, Kaivola's data shows a 30% higher ALS risk for 10 repeats than for 11-17 repeats, and Xi's data from USA, Italy, Spain and UK compiled 10 years ago showed 10 repeats were linked to a 93% increase in neurological disorders in general. However, I can't see since then that anyone has looked into the significance of 10 repeats or whether it links to any specific genetic mutations, despite about 5% of the population having this number of repeats.

Sorry to sound negative, but I don't see signs that anyone is doing anything much about the information that has come out. I would do the further analysis myself if the data were not withheld from public access.

In the absence of this analysis, all we can do is look at published evidence appearing to support therapeutic strategies, like Beghi's Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for ALS in which survival time was doubled and lung function in particular was substantially preserved. This promising trial reported 10 years ago, but I can't see that anything further has been done to follow up on it, and I'm not aware of anyone with ALS being recommended to try the apparently successful therapy.

[Doug Carpenter]

Fingers failed, this post is being dictated.
.
Hi PaulaF


I'm sorry, I don't know enough about C9 genetics and subsequent protein synthesis to comment meaningfully. But such correlations are always interesting.


Could I suggest that you collate all the valuable information in your posts into an email to MND Connect and ask them to passit to their research team for comment. You could even suggest that the team may want to seek advice from experts in the field, e.g. Profs Talbot, Turner and al Chalabi. They should certainly be familiar with such material.


Doug,

[PaulaF]

Ditto

Doug

Just noticed something striking about C9orf72 stats, and would appreciate your take on it.

I've run some correlations on Kaivola's repeat expansions dataset which show (counter-intuitively) that for intermediate repeats ALS risk correlates far more strongly with the number of repeats on the shorter healthier allele than the expanded one! I then checked this to the smaller British dataset and found the same thing.

For large expansions, the expanded allele itself seems to be the problem, regardless of the other allele. For intermediate expansions, the risk appears to depend more on how well your other allele is functioning.

Perhaps this ties up with other strange differences noticed between large and intermediate expansions. In large expansions less C9orf72 proteins are produced and toxins accumulate around the neurons, whereas in intermediate expansions more C9orf72 is produced and there are usually no signs of toxins, yet both are associated with a higher risk of ALS.

This suggests to me that large and intermediate expansions function in different ways, and therefore perhaps could benefit from different potential treatments?

[Doug Carpenter]

Ditto

Doug

[PaulaF]

Hi Paulaf

thank you for your detailed posts..Were you a scientist yourself?

Doug

Yes, although nothing to do with this field.