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Common Mutations Impacting the Prognosis of ALS

Video

Understanding how common genetic mutations in patients with ALS plays a role in prognosis.

Jennifer Roggenbuck, MS, LGC: Different genetic mutations can sometimes be associated with a different prognosis for patients with ALS [amyotrophic lateral sclerosis]. This is a topic of ongoing study, and SOD1 was the first ALS gene discovered, in the early 1990s, so we’ve had many years to study SOD1. There’s a range in terms of the different types of genetic changes that occur in SOD1 and the correlation with the progression of symptoms and the age of onset of symptoms. Some SOD1 mutations are considered quite aggressive and tend to strike early in life and be rapidly progressive. Other types of SOD1 mutations are associated with a very slow progression of symptoms, and individuals can live for decades. It depends on the specific genetic change.

For C9orf72, there’s quite a bit of variability. But on the whole, individuals with C9 progress quicker than those with typical ALS or typical nongenetic ALS. We see quite a bit of variability in terms of ages of onset. We’re still studying C9. This gene was discovered in 2011, so we haven’t had as much time to study it. We’re doing that now because this is the most common cause of ALS.

The other gene you mentioned, FUS, can sometimes have genetic changes that are considered rapidly progressive and early onset. Other changes in FUS are associated with more variability and more typical ALS progression. It depends on the exact mutation. This is something that patients get confused about because we use all these terms—gene and mutation—but the gene is the unit of the genetic code and there can be many mutations that occur within a given gene. When we’re getting someone’s genetic testing results, we’re looking at the entire code for all these ALS genes to see if there’s a mistake. The specific mistake is the mutation. Some mutations are very rare, and we don’t have much information on them. Others are more common, and we can start to accumulate information and help understand a little better what to expect in terms of that patient’s prognosis and expected survival.

Laynie Dratch, ScM, CGC: When a genetic diagnosis is made, sometimes this can help us better understand a patient’s prognosis and anticipate the potential development of other symptoms. For example, some genetic variants are associated with more rapidly progressive disease, and some are associated with slower progressing disease. A great example of that is the SOD1 gene. There’s a variant called A4V that we know is associated with rapid progression. This also speaks to the fact that we can’t generalize based on the gene itself. The SOD1 gene isn’t as good of a predictor for a patient’s prognosis as the specific variant within that A4V genetic variant. So we have differing levels of abilities for each genetic variant to comment about prognosis.

For the ones that are more common, like that A4V variant, we can get a better understanding from the research that has been done already, and that can help us better understand prognosis. But many individuals will have variants that aren’t commonly described, and they can’t give us a good sense of prognosis beyond knowing that this is the cause of why they’ve developed ALS. We expect their ALS to progress. Some patients might have a genetic difference identified in a gene that’s associated with ALS only, like the SOD1 gene. Others might have a genetic difference identified in a gene like C9orf72 or TBK1 that can be associated with a variety of symptoms. In addition to symptoms of ALS, an individual might develop symptoms for FTD [frontotemporal dementia] or Parkinson disease. So having a genetic diagnosis can sometimes help us anticipate future medical needs by informing us of other symptoms that might develop.

Sometimes a genetic diagnosis can help us understand a prognosis in terms the expected disease duration or speed of progression. But many times it can’t tell us that much specific information. Sometimes it can also tell us if there are other symptoms we might need to keep an eye out for. For example, the gene could be associated with ALS only or with risk for not only ALS but also frontotemporal degeneration, Parkinson disease, and other related diseases. Depending on the genetic diagnosis, it could help give information about what to expect for the future in terms of progression and other symptoms to keep an eye out for.

In the future, what’s going to be most important is learning about what the gene is typically associated with, in terms of the specific variant within the gene. For example, with the SOD1 gene, there are some specific variants associated with rapid progression and slower progression. It’s hard to generalize based on the gene. In the future, as more patients get tested and we learn more about these genetic variants, we may be able to make statements based on the specific variant within the gene.

There can still be extreme variability even within the same family with the exact genetic difference. For this reason, when that patient is found to have a genetic cause of disease, it doesn’t truly inform that individual’s specific prognosis or anticipated other symptom development, except in the rare circumstances when it’s an extremely well described variant, like the SOD1 A4V variant.

Transcript edited for clarity.

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