Amyotrophic Lateral Sclerosis (ALS) is commonly organized into one of two broad categories: sporadic ALS and familial ALS. Roughly 10% of ALS is familial – meaning that there is a family history of the disease. In this situation, ALS is often linked to a specific inherited genetic mutation in genes such as SOD1, TDP43, and C9orf72. The other 90% of ALS is sporadic, meaning that there is no family history of the disease. However, it is currently estimated that about 15% of sporadic ALS is also caused by the same genes found in familial ALS. While the true cause in many people with sporadic ALS remains unknown, researchers believe that in most it will involve a mixture of genetic and environmental factors.

These terms have been in use for decades – however, Among these researchers is Dr. Ammar Al-Chalabi, a Professor of Neurology and Complex Disease Genetics at the Maurice Wohl Clinical Neuroscience Institute at King's College, London who has written about the need for better terminology. Dr. Al-Chalabi spoke with the ALS Therapy Development Institute (ALS TDI) about why sporadic and familial ALS can be problematic distinctions – and how we can better describe the different forms of the disease.

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Why do you believe “familial” and “sporadic” ALS are inaccurate terms for describing ALS?

I think the main problem is that people use them as a proxy for "genetic" and “not-genetic," but that’s not really what they mean. Familial just means someone else in your family has had ALS. There are lots of problems just with that. What counts as your family? Does a second cousin count as your family? What about an uncle or a first cousin? Your siblings and your parents and your children clearly would, but should we care about whether uncles are affected or cousins or second cousins? And when do you stop? What about a fifth cousin?

The other problem is actually with the word “history.” What about frontotemporal dementia in the family, but no ALS? Should that count as a positive family history? Actually, we now know it should, because frontotemporal dementia overlaps with ALS risk genetically. There are probably other conditions that we don't know about, yet, that we should count as a positive family history.

So, just using whether someone has a family history of ALS or not isn't a good way of determining how strong the genetic risk is. We also know that sporadic ALS can have a genetic component. We know that in some people, that genetic component is just lots of small risk factors that have nudged that person towards getting ALS, and because they've just got a lot of them, they've had a big push towards ALS.

In other people, it's a gene that you'd normally find associated with a family history in that person. But, because carrying a disease gene isn't enough to get the disease, other people in the family haven't been affected. It's just occurred out of the blue. That person has “sporadic ALS,” but they've still got a genetic risk factor that has implications for them and their relatives. So, dividing into sporadic and familial isn't the same as dividing into non-genetic and genetic. We really need to be clear about why we say familial.

So what kind of problems do you think categorizing ALS as either “familial” or “sporadic” creates?

I don't think we should get rid of the terms, I just think we should be clear about what we mean by them. If someone has a family history of ALS, you might look for a disease gene in that family differently from how you would in somebody who doesn't have a family history. So, should you do a genetic test on everybody? Or should you only do it for people with a family history? We've got gene therapies coming online. If you only test people with a family history, that means 90% to 95% of people aren't going to have a genetic test. But in those people, we know, about 15% will carry a disease gene that would otherwise be labeled familial ALS. So, you're missing out on 15% of people. That's actually more than the proportion of people with a family history.

Of course, you shouldn't force genetic testing on anybody because it has to be with the person's consent, and it requires full genetic counseling and takes a long time to do that. Everybody should be offered genetic counseling regardless of whether they have a family history or not.

How common are these genetic factors in people with sporadic ALS?

It's not uncommon and depends really on what you mean by “genetic factor”. A high-risk gene variant, one that would often be associated with familial ALS like a genetic change in SOD1 or TDP43 or C9orf72, those kinds of variations may occur in between 10%, 15%, or 20% percent of the population with ALS without a family history, depending on the population you’re studying.

The real problem is what you count as a pathological variation. And this is something we're having to learn as well. When we do a genetic test, it's not just "yes, you carry a gene mutation or no, you don't." There's a third category in the middle, which is when you carry some genetic variation, but we don't know enough about whether this is responsible for your ALS or if it's just a coincidence that you carry this genetic change. That's called a “variant of uncertain significance.” Those are relatively frequently seen.

When we get those results, giving that information to a person is very complex because, how can that person know whether those genetic changes are relevant to their ALS? There's no computer-based test or cell-based test or anything you can say you can use to say this genetic change is causing ALS. Unless that genetic change has been seen already in lots of people who developed ALS and has never been seen in people who didn't, who are of the right age, then you can't be absolutely sure.

It also leads to the other problem of what counts as an ALS gene. If someone's found a change in somebody with ALS in the past, it might have actually been one of these variants of uncertain significance, but because it happened in somebody with ALS, it was published as, “hey, look, this is an ALS gene.”

If you look at the ALS Online Database (ALSoD), there are about 160 genes that have been associated in some publication somewhere with ALS. But we know, really, there's probably about 25 to 30 of those that are proper ALS genes, and the rest probably aren't. There's an initiative called ClinGen, a panel that meets twice a month and looks at a certain gene. We go through all of the evidence for whether that gene is an ALS gene or not – the genetic evidence, the functional evidence, how many people are affected, the statistical evidence, all of those things. Unless that gene goes over a certain threshold, we conclude it’s not a definite ALS gene, but we rank them between good evidence and poor evidence.

Given all this, what would be the best terms to describe these different kinds of ALS? Perhaps “genetic” and “non-genetic”?

Probably. There are even some people who would say that all ALS has a genetic contribution. It might not be the major bit, but it's nudged you towards getting the disease. If you've got something that increases your risk by two percent, is that an ALS gene? It's increased your risk of getting it. If you've got five of those, then you've got a 10% increase. What if you've got some other thing that you do that raises your risk by another 20%, then you've got a 30 percent chance. It depends on what you count as genetic. But yes, probably genetic versus non-genetic is the best distinction. If we're talking about high-risk genes, where if you carry them, you're very likely to get ALS.

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The ALS Therapy Development Institute (ALS TDI) is 100% focused on research to find treatments for ALS. Through our Precision Medicine Program (PMP) we partner with people with ALS around the world to learn more about this disease – including potential genetic risk factors.

What to do next:

  • Learn more about our Precision Medicine Program
  • Read our previous interview with Dr. Al Chalabi on the Multi-Step Hypothesis of ALS
  • Learn more about ALS TDI’s research to end ALS