C9orf72 - a major cause of MND?

[PaulaF]

Thanks PaulaF I think I might begin taking Lysine again - although another supplement I have heard about is Lions Mane

https://pubmed.ncbi.nlm.nih.gov/24266378/

I'm not sure there's enough evidence on Lions Mane? But studies suggest that L-Serine and curcumin subdue interferon-generated inflammation, and L-Acetyl Carnitine circumvents interferons by stimulating delivery of nutrients that they block.

Did you end up getting a genetic test? In my case, the NHS one was requested in January, eventually taken in May and results haven't arrived yet. Took a private one which was a bit quicker. It was what the NHS calls 'negative' for C9orf72 expansion, but sufficiently abnormal to approximately double the risk (positive for all the MND risk variants + 15 repeats in total). It showed two rare C9orf72 mutations at the end of the gene on which there is no published data. All other MND risk genes were normal.

I still contend that C9orf72 problems are likely more prevalent than they claim. Roggenbuck's study in 2020 concluded that (i) it accounted for 79% of the mutations classified as likely pathogenic in familial MND and 36% of all variants of uncertain significance in patients classified as C9orf72 negative, and (ii) when C9orf72 testing is limited to familial patients, half of all C9orf72 cases are missed.

[Cinderella]

Thanks PaulaF I think I might begin taking Lysine again - although another supplement I have heard about is Lions Mane

https://pubmed.ncbi.nlm.nih.gov/24266378/

[PaulaF]

Hi PaulaF you might be onto something - I used to suffer terribly from cold sores and had shingles when I was 17 - I used to take Lysine supplement daily for many years to help but then wondered if I should be, so stopped somewhere around/before the year my symptoms later started...
Two years before my first mnd symptoms I had cause to visit the doctor as my back felt on fire - he said it was nerve damage from the shingles even though well over 30 years had passed - it lasted weeks but eventually subsided. Coincidence?

There is also the news this week about herpes being used to cure cancer - maybe these researchers might be worth contacting?

According to studies, shingles has been estimated as giving 4 times the risk of multiple sclerosis and Epstein-Barr 32 times the risk. Both are herpes viruses.

I'm not aware of studies on Lysine and MND, but it appears to subdue Interferons and other inflammatory responses, so I suspect it might be protective against MND in C9orf72-compromised people.

One of the more promising trials currently is an anti-inflammatory immune-modulating drug being tested by Alector on FTD (known to link to C9orf72). But there are also over-the-counter supplements that seem to play a similar role. No one is bothering to test them further though.

[Cinderella]

Hi PaulaF you might be onto something - I used to suffer terribly from cold sores and had shingles when I was 17 - I used to take Lysine supplement daily for many years to help but then wondered if I should be, so stopped somewhere around/before the year my symptoms later started...
Two years before my first mnd symptoms I had cause to visit the doctor as my back felt on fire - he said it was nerve damage from the shingles even though well over 30 years had passed - it lasted weeks but eventually subsided. Coincidence?

There is also the news this week about herpes being used to cure cancer - maybe these researchers might be worth contacting?

[PaulaF]

One thought.

There are many viruses, especially in the herpes family, that are known to continue residing dormant indefinitely in the neurons. Our bodies would react by generating a continuing interferon response to keep them subdued. However a repeat-expanded overactive C9orf72 gene in the neuron cells would be constantly blocking that interferon response, so you have the body endlessly trying to react in opposite ways at the same time.

An overactive c9orf72 appears endemic to neuron cells that have repeat expansion. Perhaps a continuing interferon response to the virus can only proceed through an inactivation of the neuron cell itself - hence motor neurone disease.

If this is the case, a key to controlling the disease would seem to be by finding other ways to block or circumvent the interferon response?

[PaulaF]

Does anyone else have a view on a major paradox in C9orf72 MND? The experts don't seem to have a clear handle on it, but sometimes you can't see the wood for the trees.

The C9orf72 mutations associated with a high risk of MND are also associated with substantially higher levels of C9orf72 protein production, yet people with C9orf72 MND have a deficiency of C9orf72 protein. So how could one abnormality cause the opposite abnormality?

To explain the background to how it works as I understand it, C9orf72 is intimately connected to an adjacent interferon gene IFNK that inflames and attacks unwanted intruders and damaged cells. As C9orf72 proteins increase, interferon levels decrease and vice versa, depending on what the body needs.

C9orf72 repeats sit at the start of the gene and direct it towards producing a truncated version of the gene (variant 1) that stops at exon 5 and allows the body to switch off the full version of the protein. When the repeats expand, the ability of the body to switch off appears to be reduced, production of the full protein can overheat and inflammatory interferon should be inhibited.

In which case, why can this sometimes cause an inflammatory C9orf72 MND in which deficiency of C9orf72 protein occurs? Any thoughts?

[PaulaF]

A technical update for anyone who might be interested.

Using tools available on the internet, I've identified that both of the MND high risk genetic mutations in the Netherlands (presumably the same as UK) are strongly associated with a series of the same five variants that all sit just in front of the C9orf72 repeat zone - rs13302855, rs34460171, rs36062268, rs34555425 and rs1354271694. At least two of these variants also associate with a massive increase in expression of C9orf72 protein (typical of an auto-immune disorder) at the base of the brain. Strangely, I can't find that any researchers have made any reference to this. And it is impossible to obtain verification of whether this is the factor behind repeat expansion or MND, as the databases are kept private/confidential.

These same variants are also linked to other diseases, which could provide keys to identifying effective treatments. It is sometimes quite frustrating to sit here powerless waiting in the hope that someone might eventually look into it and do something about it.

[PaulaF]

PaulaF I read an article on "tremor in motor neuron disease " is presenting in up to about 10% and said it expands the idea that mnd is a multisystem neurodegenerative disease. I havent had any genetic testing for mnd, only hsp genetic tests to rule that out initially.

My opinion is that MND covers a range of diseases that are lumped together because they have similar symptoms. C9orf72 disease seems to be the most common type of MND, and it looks like an inflammatory auto-immune condition. Sometimes it can cause frontotemporal dementia instead of MND, so I don't see why it couldn't also sometimes cause tremor, which the Kobo study seems to bear out.

Much standard genetic testing for MND is pretty useless, as it rules out C9orf72 as a cause unless there is a huge repeat expansion, when plenty of studies suggest that the risk of different neurological symptoms can begin with much lower numbers of repeats.

[Zante]

PaulaF I read an article on "tremor in motor neuron disease " is presenting in up to about 10% and said it expands the idea that mnd is a multisystem neurodegenerative disease. I havent had any genetic testing for mnd, only hsp genetic tests to rule that out initially.

[PaulaF]

PaulaF as always thanks for the info. To be honest I don't understand a lot of it. I received my clinical letter after having the 2nd opinion and it states I have a left sided tremor. Is this common for mnd? I am aware of it. But clearly she noted it also.

According to the nurse, it isn't very common. But the data in Kobo's study suggests it is three or four times more common when people have mildly-expanded C9orf72 repeats.

[Zante]

PaulaF as always thanks for the info. To be honest I don't understand a lot of it. I received my clinical letter after having the 2nd opinion and it states I have a left sided tremor. Is this common for mnd? I am aware of it. But clearly she noted it also.

[PaulaF]

I've found reference to the tremors.

Kobo's 2021 paper"C9orf72-G ₄ C ₂ Intermediate Repeats and Parkinson's Disease" links such symptoms specifically to intermediate levels of C9orf72 repeats (more than 11 repeats, but less than a full expansion). More evidence, I suppose, that C9orf72-related neurological damage can occur even when tests for full C9orf72 expansion come back negative.

[denise]

PaulaF thing is as everyone's mnd is different how does anyone define normal?

[PaulaF]

It's like Moderna suing Pfizer over the Covid vaccine. Most research seems to be about the lure of financial gain and few researchers seem to want to take any notice of each other's research.

Targeting excess interferon in C9ORF72 disease is unconnected to gene therapy, which tackles the problem from a different angle. Curcumin and L-Serine both subdue interferon, which would I think function as a second line of defence if the gene therapy proved effective. At least with these, I suppose you know you are not getting the placebo! The trouble is they are cheap, so there is little money to be made from them, and therefore no one wants to fund further research after the promising initial research on them several years ago.

In my case, there has been no real progression over the past year, apart from developing a tremor. Asked the MND nurse if this was normal, and she said no, so don't know if this signifies anything.

[EvelynMW]

Another comment, the trial i was considered for last year was the biogen. This new trial is based on a slightly different treatment, which, i believe caused a bit of patent fighting between Biogen and Wave! Last year my progress was too slow! Different rules for the Wave trial. i don't know if i got the real thing, or the placebo.