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Is non-familial ALS a genetic disease?
I have read that familial ALS can be traced to a specific gene mutation. I have not read that a known genetic mutation is the cause of non-familial ALS, yet they both cause a very similar result. Is it fair to say that non-familial ALS is a genetic disease, and if so, what genes are involved, and is anyone doing research where Crisper gene editing is being used?
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3 Replies
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Michael, difficult to answer with a clear yes or no. In familiar ALS we have the genes e.g C9orf72, FUS and SOD1 with clear causalities in ALS cause by damaging motor neurons (MN) mostly triggering the mislocation of the hallmark ALS protein TDP-43 from the nucleus to cytosol and generating TDP-43 deposits. Since TDP is regulating its gene expression in MN itself, these deposits lead to further diss-regulation and more deposits, a vicious cycle starts with the end result in MN dying.
In non familiar ALS TDP-43 is also thought to be the root cause but why is deposits in the cytosol of MN and what triggers this is unknown. There are many angles looked at from mitochondrial dysfunction, stress causes inflammation causes and many more. Most recently there had been a publication claiming over 140 different genes being linked to ALS in non familiar ALS. So which one to go after?? If we know which one(s) are good reasons to target to have meaningful disease alterations Crispr or Antisense or RNA interference can all be deployed to “fix” it. It’s complicated. At this point only further research can help untangle these relationships. So funding this research and education about ALS is the best we can do to speed up the hunt for further medicines. Long answer and not satisfying I know. But I guess it sums up the reality where we are in research right now. If you are interested I can share literature references for you to read up more.-
Thank you for thorough response. I learned a great deal. Please send more info.
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Thank you Kluas68, a good reply for a me as a non-science, non-medical pALS. However, I am very concerned for my children and grandchildren —even though I am a “sporadic, non-familial” ALS person. DID have generic panel for all the known generic, familial ALS & have NONE. Short lived peace of mind—Then, I too read that there are genetic mutations at play in sporadic ALS. This news is horrible as the disease itself. I would be interested in having links to share/leave with kids items…or sharing with ALS Clinc dr’s. I want clinic dr’s to share this kind of info—instead of just marking progression, taking samples, and never sharing what results tell them about me & my situation (such as why my system rejects totally the use of Riluzole, Radicava, etc. so I am left with NOTHING to slow progression) —except working at keeping my BMI above 25 (which is neuro protective I have read on my own).
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@Micheal,
You pose a great topic and one of interest to many of us on the forums. Over a decade ago when I first started volunteering for ALS medical research due to a large number of family members having ALS, they only knew of one mutated gene, SOD1. Since then, I believe they have identified more than 25 genes with mutations associated with ALS. Just within the SOD1 gene there are over 100 different variants. Each variant, and gene mutation, from what I understand manifest a little differently. I still go to the ALS clinic where I volunteered for research, and what I believe researchers (from me asking way to many questions) suspect is that there are likely more genes to be identified. This is good and bad.Obviously the bad is that there is still much to learn about ALS. I always explain ALS to friends as a “cluster disease” and that it may be more like a group of diseases that result in the same outcome, loss of muscle, paralysis, and life. The journey or exactly how it causes the damage may vary. For example just within the SOD1 mutations, some are associated with rapid progression and some very slow progression but all have to do with the SOD1 gene producing SOD1 proteins that unfold improperly causing damage.
The one good thing to come out of this type of research is that gene therapy is being pursued as a possible treatment. Tofersen, which is in clinical trials now, targets the specific mutation impacting the SOD1 gene. The research looks promising, and the technology can be applied to other mutations and diseases.
Clearly I’m not in the medical field, nor am I an expert. I’m a pALS with a long family history of ALS and a passion for advocating for our community and doing whatever I can to help find a cure or treatment. I try to read up on the research but I may not be up on the latest on all mutations. I tend to focus on what impacts my family.
As more is learned, and as more genetic mutations are discovered, the more we can prepare. If you are the only person in your family with ALS, perhaps there is a environmental factor or something specific to your case.
I can share some websites if you are interested.
Amanda
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I found out through genetic testing that I have a repeat gen expansion on the ATXN2 gen. This gene mutation was found to be a risk for ALS. I was able to enter a trial, BIIB105, this fall at UMC in Utrecht, Holland, which is testing an antisense drug in phase 1. Sponsor is BIOGEN and more details can be found at: https://clinicaltrials.gov/ct2/show/NCT04494256. Even though this ATXN2 mutation only occurs in 3.9% of ALS patients, I think it is great that I may experience an effect by participating in the study. I recommend a whole gen screening to all ALS patients.
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Here is an article th twas in ALS News Today last year finding 22 genetic mutations linked to sporadic ALS https://alsnewstoday.com/news/mutations-22-genes-linked-sporadic-als-large-patient-group-study/
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