Genetic testing in
clinical practice

I believe we need to consider detecting and defining the genetic status of all ALS patients. The proportion of patients with the sporadic form of the disease is smaller than we thought at first, and the number of patients with familial or inherited forms of ALS is growing all the time.^2,3

Our colleagues from The Sheffield Institute for Translational Neuroscience in the UK confirmed the importance of a systematic genetic screening which enabled them to highlight pathogenic mutations in around 20% of the overall ALS population.⁴ In my department, we screen all our patients for genetic mutations; in C9orf72, SOD1, and TARDBP, for example. In my opinion, genetic analysis should be part of the first exhaustive physical examination of someone with ALS. I think we need to better understand this disease while considering all the parameters—including genetics, age, family history, site of onset, medical history, and other potentially contributing factors.

In my experience, many patients picture genetic testing as being like a test for cholesterol or glucose levels. They think it is a blood analysis that will provide us with a rapid, accurate conclusion: ‘you have a mutation and because of that, your disease will progress in a certain way.’ It is important for us to help patients understand why it takes so long to receive a result, and why, even when you have that result, it does not necessarily tell us everything we need to know. For example, if we discover they have a mutation, that alone will not tell us which form of the disease they may develop or when certain symptoms will begin—or, most importantly to them, if their children will get the disease.¹

I’ve also seen that not all patients have—or should be expected to have—a clear understanding of what it means to have a genetic mutation, whether it is in SOD1, C9orf72, or another gene. I have found a face-to-face interview always helps when explaining all of this. That gives me time to really talk to patients about the relationship between ALS and genetics. But in genetics, you have causative genes, which are responsible for the disease, and susceptibility genes, which increase one’s risk of eventually developing the disease. Susceptibility genes alone are not sufficient for the onset of disease symptoms. So I explain to my patients that, even if they have a genetic mutation, that is not sufficient to confirm whether or when their children will develop ALS.^1,2 Many points remain unresolved. This is why I give the patient all the explanations they need to help them understand the limits of these results in our ability to predict the risk of developing the disease.

We know how genetics may help us understand the nature of a patient’s ALS.⁵ That is one reason genetic testing may be worthwhile. I have also noticed that, when a patient is diagnosed with ALS, one of their worst fears is transmitting the disease to their children. If a mutation is identified in a patient, subsequent presymptomatic testing of relatives may help us determine or rule out their risk.^1,6

More importantly, many of my patients want to undergo genetic testing because they simply want to contribute to ALS research. They want to help a researcher or medical group better understand, better diagnose, and, hopefully someday, better manage the disease. Maybe not at the time of the diagnosis, but after some time with the disease, my patients are often willing and eager to get involved in research—not for them, but for the future, because the future is for their children.

There are many cases of ALS that are linked with genetics, so it makes sense to know their genetic status.^1,7 Yes, it can be helpful to order a brain MRI or a spinal MRI to rule out other conditions,⁸ but for me, genetic analysis is part of the first level of examination that I like to do because it can have a lot of impact for the patient, for their family, and for us as physicians.⁹ The first question patients ask after the diagnosis is often, "What is the risk for my children?" If you do not perform a genetic test, it can be difficult to provide an answer.¹

My position is to say to relatives of patients, "If you want a genetic test, that can help us determine whether or not you have a mutation, but not whether or not you will get ALS." Identifying a genetic mutation can confirm that a patient may be at risk, but it cannot inform if, or when, the disease will start.¹

But genetics alone cannot confirm who will get ALS.⁷ So, even if your children have the same mutation that you have, they also have to be in contact with similar environmental factors as you to develop the disease.^7,10,11

Yes, we can communicate that risk may be higher as a result of some genetic mutations. But this is not sufficient to predict if they will be affected by ALS in the future.^1,7,11 All we know is you do not have the disease now, but you may be at higher risk for it than an individual who has no ALS in their family.^1,6 I find it helpful to remind patients and their families that, if I can’t answer one of their questions, it is not because I do not want to; it is because I can’t be certain of the correct response and none of us can predict the future.