4 ms·

This is an important story and my critique is mundane but I wish the headline were more accurate. You don't have "genetic [disease]" unless you have "[disease]"

This is an important story and my critique is mundane but I wish the headline were more accurate. You don't have "genetic [disease]" unless you have "[disease]", and I think that STAT News should get that right. 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.

deleted 3y ago
[deleted]
beebmam 3y ago
Epigenetics might play a role, too, like it usually does.
swid 3y ago
That’s the title I shorted it to and my mistake, the STAT title actually says “They carry a gene for ALS but aren’t sick.”
A_D_E_P_T 3y ago
Truth is that we don't even know what [disease] is. 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-effectiveness-of-biogen-als-drug.html 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.
- klipt 3y ago
  > ALS could be several etiologically distinct diseases that manifest similarly. What's the common factor - are they all autoimmune diseases? Would the "inverse vaccine" approach discussed here recently help?
  - A_D_E_P_T 3y ago
    It's unclear whether or not ALS (any form) is an autoimmune disease. 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/ https://pubmed.ncbi.nlm.nih.gov/25344935/
- margalabargala 3y ago
  > in the article, you've got people without the disease in question (whatever it is) 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".
  - carbocation 3y ago
    I think you are nicely describing the field of preventive medicine. You picked a particularly good example (CAD) because we know that preventive efforts work. Hopefully that will expand to all diseases in time. In the circumstances where we really understand the disease process, is seems much better to prevent symptom onset than to wait to treat after things are so bad that the patient notices them.
oidar 3y ago
I really want to like stat news, but it seems like much of their journalism style has been informed by celebrity rags. It makes it less trustworthy to me.
ferfumarma 3y ago
You are simply wrong. 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.
- carbocation 3y ago
  I guess you disagree with my point that having a disease is different from having the risk allele for it, but I stand by that distinction. I specifically addressed timing of onset being important in my original comment, because that matters to the person living with the problem.
  - ferfumarma 3y ago
    I agree: the word "disease" necessarily implies signs or symptoms of some kind. But what does that add? The entire point of the article is that the carriers are not symptomatic yet, so where's the confusion?
    - carbocation 3y ago
      > 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.
      - carbocation 3y ago
        A coda that I would add is that as our ability to detect abnormalities expands thanks to improved diagnostics, what we consider to be a sign of disease will evolve. 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.
btilly 3y ago
The article is about those with the genetic risk struggling to get classified and treated as having the 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".
- carbocation 3y ago
  I guess what I would say is that if this is how patients refer to it themselves, I'm onboard.
armadsen 3y ago
I disagree with you. If the risk is 100% as it is with some ALS-causing gene mutations, as well as one that runs in my (in-law) family, it's does indeed alone explain risk. At least for the disease in my family, timing of onset is relatively consistent too (+/- 5 years or something). And maybe more importantly, the pathology is such that internal damage is happening for years, probably decades, before the first outward symptoms appear. If "family member noticed a tiny little problem that maybe was nothing, maybe the first symptom of the disease, but was concerned enough to go to the doctor" is the criteria for diagnosing the disease, and starting treatment, that's way, way more subjective and silly than looking for a specific gene mutation that causes the underlying pathology.
- carbocation 3y ago
  In the liability threshold model for disease, complex traits can certainly have monogenic variants that essentially guarantee that disease will occur. For example, homozygous FH (LDLR) will cause clinical disease onset in infancy or early childhood. But most people with FH don’t have homozygous FH. 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.

deleted 3y ago

[deleted]

beebmam 3y ago

Epigenetics might play a role, too, like it usually does.

swid 3y ago

That’s the title I shorted it to and my mistake, the STAT title actually says “They carry a gene for ALS but aren’t sick.”

A_D_E_P_T 3y ago

Truth is that we don't even know what [disease] is. 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-effectiveness-of-biogen-als-drug.html 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.

klipt 3y ago
> ALS could be several etiologically distinct diseases that manifest similarly. What's the common factor - are they all autoimmune diseases? Would the "inverse vaccine" approach discussed here recently help?
- A_D_E_P_T 3y ago
  It's unclear whether or not ALS (any form) is an autoimmune disease. 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/ https://pubmed.ncbi.nlm.nih.gov/25344935/
margalabargala 3y ago
> in the article, you've got people without the disease in question (whatever it is) 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".
- carbocation 3y ago
  I think you are nicely describing the field of preventive medicine. You picked a particularly good example (CAD) because we know that preventive efforts work. Hopefully that will expand to all diseases in time. In the circumstances where we really understand the disease process, is seems much better to prevent symptom onset than to wait to treat after things are so bad that the patient notices them.

oidar 3y ago

I really want to like stat news, but it seems like much of their journalism style has been informed by celebrity rags. It makes it less trustworthy to me.

ferfumarma 3y ago

You are simply wrong. 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.

carbocation 3y ago
I guess you disagree with my point that having a disease is different from having the risk allele for it, but I stand by that distinction. I specifically addressed timing of onset being important in my original comment, because that matters to the person living with the problem.
- ferfumarma 3y ago
  I agree: the word "disease" necessarily implies signs or symptoms of some kind. But what does that add? The entire point of the article is that the carriers are not symptomatic yet, so where's the confusion?
  - carbocation 3y ago
    > 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.
    - carbocation 3y ago
      A coda that I would add is that as our ability to detect abnormalities expands thanks to improved diagnostics, what we consider to be a sign of disease will evolve. 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.

btilly 3y ago

The article is about those with the genetic risk struggling to get classified and treated as having the 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".

carbocation 3y ago
I guess what I would say is that if this is how patients refer to it themselves, I'm onboard.

armadsen 3y ago

I disagree with you. If the risk is 100% as it is with some ALS-causing gene mutations, as well as one that runs in my (in-law) family, it's does indeed alone explain risk. At least for the disease in my family, timing of onset is relatively consistent too (+/- 5 years or something). And maybe more importantly, the pathology is such that internal damage is happening for years, probably decades, before the first outward symptoms appear. If "family member noticed a tiny little problem that maybe was nothing, maybe the first symptom of the disease, but was concerned enough to go to the doctor" is the criteria for diagnosing the disease, and starting treatment, that's way, way more subjective and silly than looking for a specific gene mutation that causes the underlying pathology.

carbocation 3y ago
In the liability threshold model for disease, complex traits can certainly have monogenic variants that essentially guarantee that disease will occur. For example, homozygous FH (LDLR) will cause clinical disease onset in infancy or early childhood. But most people with FH don’t have homozygous FH. 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.