landlines are still useful for teleconferences

Last week I had the honor of giving a teleconference interview with Dr. Brian Appleby on behalf of the CJD Foundation. CJD Foundation hosts these teleconference calls every few weeks so that people personally affected by prion disease can hear about new research in plain language and ask questions of researchers. The topic of this interview was our new study quantifying genetic prion disease risk, which came out last month.

The topics we discussed included:

  • Sonia’s and my personal story, how we re-trained as scientists, and why we got interested in doing this study. (See also this blog post).
  • Definitions of genetic terms such as variant and dominance, and what these mean in the context of the human genome.
  • The findings of the new study.
  • What this means for patients.
  • Our next steps.

Here’s the audio of the interview:

After the interview, there was a Q&A with the audience. This part is not recorded, since many people introduce themsleves by name and share personal medical information. I wanted to write this post, however, to share the answers to a few of the questions I received on the call, as well as over email and on Facebook in the past few weeks.


Is anyone looking for genetic factors in other genes, besides the prion protein gene, that might influence prion disease risk?

Yes! Simon Mead, at the MRC Prion Unit in London, is leading an effort to collect DNA from as many prion disease patients as possible in order to search for other genes that affect a person’s risk of prion disease (a genome-wide association study or GWAS for short). He presented preliminary data on Day 4 of Prion2014 and has gathered DNA from thousands more patients and is continuing to lead this effort.

Is there a centralized repository for genetic data in prion diseases?

We’re in a much better position than most diseases! For most diseases, the data are held by individual doctors at thousands of different hospitals, and aggregating all that data in one place is almost impossible. Prion diseases are reported to centralized surveillance centers in each country, such as the NPDPSC in Cleveland.

In our study we collaborated with surveillance centers in nine different countries and got a total of about 16,000 cases, over 10,000 of which had undergone genetic testing. That’s a way larger number than you could hope to gather for any comparably rare disease, or even for many more common diseases. Because it represents the last 15-25 years of data in the largest countries with the best-established surveillance programs, it may well include the majority of prion disease cases ever reported to surveillance. Those data are now made public in Supplementary Table 1 of the new paper.

There are certainly other genetic data that have been collected by these centers that aren’t public yet, but luckily, it’s a very collaborative field, and people are usually quite generous about sharing their data with one another. For instance, I know that many surveillance centers contributed data to Simon Mead’s GWAS effort mentioned above.

I’ve heard estimates that the E200K mutation has anywhere from 60 to 95% penetrance. Can you narrow down that range at all? And what is the age of onset?

There certainly exists a range of estimates out there, and unfortunately, our new study can’t do much to narrow it down. Our method isn’t precise enough, so our confidence intervals - the upper and lower bounds on what we think the true lifetime risk might be - span that whole range too. It’s frustrating, I know! Estimating penetrance, or lifetime risk, is really challenging. Part of the reason is this: it’s relatively easy to find people who have the E200K variant in their DNA and do get the disease - they get reported to surveillance centers - but it’s much harder to find the people who have that variant and don’t get the disease. For instance, when we look at E200K families, we might see a parent who already died of some other cause without developing prion disease, so we will never know whether that parent harbored the genetic variant or not. We might also see family members who are alive and at risk but have never opted for genetic testing. Because we don’t know if any of these people have the E200K mutation in their DNA, we have to exclude them from the analysis, but in reality it might be the case that some of them did have it and just didn’t get sick.

These same problems make it hard to estimate age of onset. The first large study of the E200K mutation reported an average age of onset of 53 [Hsiao 1991]. A few years later, the same group of researchers, studying the same patient population, found an average onset of 58.5 [Spudich 1995]. When I and my colleagues studied the E200K mutation recently, making every effort to include data from extended family histories and asymptomatic individuals who had undergone genetic testing, we found a median onset of 64 [Minikel 2014]. I speculate that there has been a bit of an upward trend in these estimates over time because the cases that are exceptional enough to come to the attention of researchers in the first place are the relatively earlier onset cases. After the genetic mutation is identified and the disease better understood, more elderly cases begin to be diagnosed correctly, and asymptomatic people start to undergo predictive testing, so we start getting more of the full picture. But that picture certainly still isn’t complete today, and so I’m sorry to say, we don’t have any firm answers on penetrance nor on age of onset.

Is the penetrance or age of onset different for my family’s variant depending on whether we are a cis-129M or cis-129V haplotype?

As background, a haplotype refers to one of a person’s two copies of the prion protein gene. Copies of this gene often differ in a genetic variant at codon 129: for some people, it is M, for others, it is V. For certain genetic mutations that cause prion disease, whether you have 129M or 129V on the same copy of the gene as your mutation seems to affect the age of onset, the rate of disease progression, and/or the symptoms of the disease.

Unfortunately, our new study wasn’t able to shed much light on this question. For one, due to technological limiations, for many of the genetic variants that we looked at in controls, we couldn’t tell whether it was on a 129M or a 129V haplotype. Second, because we saw only a few instances of each variant, we simply didn’t have the numbers to be able to ask whether codon 129 mattered.

While I am sorry to not have answers right now, I agree that it is important, and we are continuing to work on better understanding this issue.

My family has had several people fall sick with prion disease, and their ages of onset have been incredibly varied. Why? Is there some factor that triggers the disease to strike?

It’s a great question, and one we unfortunately have no answer to. Not only in prion disease, but in other genetic neurodegenerative diseases too, it is a mystery how people can have the genetic variant their whole lives but only get sick in middle age. And why the age of onset is so variable, even within families, we don’t know that either. A lot of the variation may simply be chance: prion diseases are caused by a protein spontaneously misfolding, and there is probably a lot of random luck in when that happens. It is possible that other genetic or environmental factors might affect age of onset too, but we have not identified any of those factors so far.

My family lost a loved one to genetic prion disease, and the doctors told us that person’s children had a 50/50 chance of getting the disease too. Our family’s genetic variant is one of the ones that, according to the new study, might not be as “high risk” as some others. Does this mean the children don’t have a 50/50 chance of inheriting it?

The loved one who died of prion disease had the genetic variant on 1 of their 2 copies of the prion protein gene, and which one they pass on to their children is random, so it is still the case that the children have a 50/50 chance of inheriting that particular genetic variant. The difference is that we now think that variant doesn’t cause a 100% risk of developing prion disease, so even on the 50% chance that someone does inherit it, they might only be at moderate risk for developing the disease.

Why did the doctors give us the wrong information about the genetic information in our family?

Genetics is really hard! It’s only the availability of new data in the last couple of years that has enabled us to re-evaluate these genetic variants and realize they aren’t all created equal. For much of the past 25 years, many of us researchers have operated in a “guilty until proven innocent” mode, where a genetic variant seen in the right gene in a patient with the right disease was simply assumed to have caused the disease. The scientific community is only now realizing how many mistakes were made as a result of this policy — see this article for some background. So the problem is by no means limited to prion disease. Similar changes are happening right now in other diseases too, where scientists are realizing that some genetic variants originally thought to guarantee that you develop a disease are actually benign or only give you a little bit of increased risk. Over the past couple of years, official sources such as the American College of Medical Genetics, and a working group of the National Human Genome Research Institute, have issued cautious guidelines [MacArthur 2014, Richards 2015], urging physicians and researchers not to assume that every variant they see is pathogenic, shifting us towards more of an “innocent until proven guilty” mode. But these recommendations are still fresh, and changing clinical practices is a slow process.

Meanwhile, it is impossible for doctors to have perfect expertise in all the different diseases they’ll see in their career, and the scientists who do have expertise in prion disease don’t always get an opportunity to convey what they know to patients. In the U.S., the surveillance center in Cleveland handles all the genetic testing, but they aren’t allowed to return results directly to patients, only to the ordering physician. The surveillance center has, over the years, modified what it writes on genetic test reports for certain genetic variants, and is continuing to do so in light of the new findings. But, particularly for genetic variants where there is some uncertainty about the interpretation, there are obstacles to getting the “right” message to the patient.

In sum, from my perspective, my feeling is that doctors have an incredibly hard job. Even where they seem to have been “wrong,” it is usually the case that they acted in good faith and did the best they could with the information available at the time.

How much crossover do you expect there will be between genetic and sporadic forms of prion disease, in terms of treatment?

Much, I hope! I am probably the most excited about therapies to reduce the amount of prion protein that the brain produces. There’s a great proof of concept for this from mouse studies, and we know that prion protein levels affect both the onset of the disease and how quickly it progresses. So you could imagine that the same therapeutic that might prevent or delay onset of genetic prion disease would also slow the progression of sporadic prion disease.

The big hitch is that right now, most sporadic prion disease patients are not diagnosed until their disease is pretty advanced. This is getting better, with advances in imaging and in spinal fluid tests, but right now it’s still the case that most patients have lost a lot of neurons and have profound dementia by the time they get a diagnosis. Once those neurons are gone, we don’t have a way to bring them back. So for sporadic patients, even if we had a therapy that could stop the disease process instantly, I don’t know how much quality of life we could give back to those patients. But I do hope we’ll see some improvement over the coming years in how early people get diagnosed, and in any case, all of this is just speculation until we actually have a therapeutic that works at all.

How have you dealt with Sonia’s genetic information emotionally? Is it hard to study prions when you’re personally affected?

Working as a scientist, I do think about prions every day, but I’ve found that’s very different from thinking about one’s own mortality every day. For me and Sonia, the hardest time was after finding out she was at risk but before getting the genetic test result. When Sonia was at 50/50 risk, all either of us could do was think about it, and turn that 50/50 over in our minds, again and again. Once we got the test result, even though it was terrible news, things almost immediately started to get better. It was almost a relief. We did spend a few weeks being really sad and grieving, but we had a new sense of knowing what we were up against, and being able to adapt to the new information. It’s amazing how adaptable people are! Many people have adapted to far worse things than Sonia and I have had to adapt to.

What can we patients do to help, short of becoming scientists?

Participate in research! Everything we did in the new study was made possible by people volunteering their own data for research — everyone from 23andMe customers spitting in a tube to prion disease patients and families donating their loved one’s brain to research. Ours is a rare disease, so we need all the numbers we can get, and your contribution really matters. Sonia has written a great blog post about this. It’s possible to participate without knowing your own genetic status, if you’d rather not know. I know it can be hard to participate in research if you don’t live near a place where there is a study enrolling, such as Cleveland or San Francisco. In the coming years I hope we can find better ways to make it easy for people to participate who want to.

Have you and Sonia changed anything in your life in order to delay onset of her disease?

In terms of preventative measures, no. Sonia doesn’t take any drugs or supplements and we haven’t changed our diet or exercise habits. There is no evidence that any of that stuff affects onset of prion disease.

That said, certainly, some things have changed about our outlook and how we live our life. Sonia was 27 when we got the genetic test results, and I think being confronted with your own mortality at that age puts things into perspective. Since then, we don’t stress as much about the little stuff, and we pay more attention to sleeping enough, eating well, and generally trying to take good care of ourselves.