These individuals have what we think is the genetic risk factor for ALS. ALS is probably a complex disease, in which case a single monogenic variant will not, alone, be enough to explain risk, timing of onset, etc.
ALS could be several etiologically distinct diseases that manifest similarly. And there are indications of this in the fact that certain drugs -- like the recently approved Tofersen -- have some effect on a subset of ALS cases but have no effect on others.
On that note, even Tofersen is of very questionable efficacy: https://www.cnbc.com/2023/03/22/fda-advisors-vote-against-ef...
I'm usually hugely sympathetic to "Right to Try" cases. But, in the article, you've got people without the disease in question (whatever it is) seeking the right to try drugs that are of very questionable efficacy to begin with. I say let them have it, for whatever good (or harm) it'll do. People can decide for themselves whether the side effects they might experience are worth the amelioration of fear and glimmer of hope they receive.
Honestly my takeaway from the article, and from a lot of the comments here, is that we should be (but aren't) updating our definition of "disease" for some diseases as our understanding grows.
If you have partially blocked arteries, you're not actively suffering from heart disease, but it's normal to give that person drugs and advise lifestyle changes as soon as that's detected. You don't wait for them to have a heart attack.
Of course, the cause and effect is much better understood with heart attacks and isn't at all clear with ALS. But the fact that ALS doctors were bewildered that someone might want to take prophylactic measures says to me that they have some blinders on.
Imagine getting some tests done, learning your coronary arteries are 60% blocked and your LDL levels are at the 98th percentile, and having a cardiologist tell you "Don't think about it for now, come back once your heart stops beating".
What's the common factor - are they all autoimmune diseases?
Would the "inverse vaccine" approach discussed here recently help?
Autoimmune diseases are typically associated with autoantibody production. These are in evidence in (-- at least some forms of --) ALS, but in an unusual way that makes their role highly uncertain. They are potentially beneficial. See: https://pubmed.ncbi.nlm.nih.gov/25344935/
"Right to try" might be worthless in the last case. (Unless there's reason to believe that it's reversible with some as-of-yet uninvented treatment.)
In fact, we know that ALS is a complex disease because we know that common genetic variants influence ALS risk, but that doesn’t mean that every monogenic ALS variant is going to have its penetrance and onset modified to the same degree. So by saying that ALS is a complex disease I don't mean to take away from the fact that for some families, their causal variant may have a consistent effect with only minimal variation from the genetic background.
I’m fully supportive of preventive therapy. I think that is the actual future of medicine. And so I am a big fan of the idea of using genetics to identify a population at risk, doing individual biochemistry (or whatever endophenotype people use - perhaps imaging or other measurements) to see if the pathophysiologic process is occurring, and treating to prevent disease.
Calling it "genetic ALS" seems like a fair compromise. They didn't say "with ALS". They said "with genetic ALS". Which seems like a reasonable shorthand for, "with the genetics that evidence shows will lead to ALS".
The mutations described in this article are a sufficient condition to develop ALS, period.
That means that if you live long enough, you will get ALS.
The fact that there are other, yet-to-be-discovered genes that could also cause ALS is irrelevant for the individuals that are already positive for the SOD1, for example.
I specifically addressed timing of onset being important in my original comment, because that matters to the person living with the problem.
The entire point of the article is that the carriers are not symptomatic yet, so where's the confusion?
I don't think there is any confusion. In medicine, the disease begins when the symptoms start. Indeed, it's useful to be able to distinguish being a carrier from having a disease.
We can’t translate from DNA to biochemistry for almost any trait except for Lp(a), so I don’t count DNA as being a sign right now. But eventually it could be. That will moot this conversation, because at that point we will all be in agreement.
Before cholesterol testing, the sign for FH was a thick layer of lipid particles visible when blood was drawn. As our diagnostics improved, the sign of hypercholesterolemia has been refined to a quantitative value. And each field is trying to accomplish the same.
We don't simply don't know that. There is an incredibly wide spectrum of phenotypes, even for SOD1 mutations (~2 of cases) the life span could be as short as 6 months and as large as 25 years.
There are ~120 gene mutations that are incriminated in what scientists call ALS. Each of them has dozens alleles on average.
In addition there are associations between ALS and dozens of occupations, and exposure to thousands of substances. The scientists tell of multi-step diseases.
You are only right in the sense that we will all die at the end.