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C9orf72 - a major cause of MND?

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    #46
    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.
    Mum died with MND in 1979 – My sister and I have a wonky gene, probably inherited from mum. Reckon my MND started sometime in 2018.

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      #47
      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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        #48
        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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          #49
          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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            #50
            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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              #51
              I think the mutation is just unstable and can either worsen or improve from one generation to the next. The data suggests it is caused by a combination of a gene with a higher number of stable repeats (quite common) mixed with an instability variant on the preceding DNA. It's usually not a problem unless you have both, and even then it doesn't cause problems for everyone.
              I think most don't know they have it. People with the instability variant are twice as likely to be diagnosed with speech disturbances, but they do not otherwise have noticeable motor neuron problems that would make them suspect C9orf72 might be the cause. Others with it have mild movement difficulties or osteoporosis or memory loss that they just put down to old age.
              The more we realise it is a wider issue than we thought, the more effort might be put into research. That's what I'm hoping.

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                #52
                Well at the end of the day this needs solid scientific research and of course that’s the bit that is missing the most.

                Comment


                  #53
                  Originally posted by Marc from London View Post
                  Well at the end of the day this needs solid scientific research and of course that’s the bit that is missing the most.
                  The good news is there's a lot of research in the pipeline! Most details are "confidential", but it seems to focus mainly on complex cutting-edge treatments.

                  I'm slightly concerned it looks a little uncoordinated - lots of groups in small funded projects independently chasing their own golden nuggets. My feeling is they need to stand back a bit and focus more on the basics, note that MND encompasses a number of different diseases, work together and recognise each other's results a bit more.

                  I can't see much attention being given to some of the most important C9orf72 discoveries:
                  1. The identification of its instability variant (Reus 2021)
                  2. Correction of bioenergetic deficits reversing some C9orf72-related motor neuron damage (Mehta 2021), and bioenergetic stimulation by Acetyl-L Carnitine preserving function and doubling survival time (Beghi 2019).

                  Acetyl-L Carnitine is a relatively cheap and simple nutrient. Not sure why it doesn't seem to have been picked up on or tested further.

                  Comment


                    #54
                    Hi Paulaf

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

                    Doug
                    Diagnosed April 2017

                    Comment


                      #55
                      Originally posted by Doug Carpenter View Post
                      Hi Paulaf

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

                      Doug
                      Yes, although nothing to do with this field.

                      Comment


                        #56
                        Ditto

                        Doug
                        Diagnosed April 2017

                        Comment


                          #57
                          Originally posted by Doug Carpenter View Post
                          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?


                          Comment


                            #58
                            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,
                            Diagnosed April 2017

                            Comment


                              #59
                              Originally posted by Doug Carpenter View Post
                              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.



                              Comment


                                #60
                                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.

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