Maria Ramos-Arroyo has been part of HD research from the beginning of her career. A member of the team that originally discovered the location of the gene from samples from Venezuelan people, she would later be the Spanish representative on the steering committee for REGISTRY, the study that preceded Enroll-HD in Europe. She is now head of the medical genetics department at the Complejo Hospitalario de Navarra in Pamplona, Spain.
How did you begin studying HD?
I started working on HD a long, long time ago, as a postdoctoral fellow. I finished my medical degree in 1979 and then wanted to do genetics. Spain did not have that specialty. So I went to the United States, and I happened to go to Indianapolis where the big Venezuelan-United States study was starting. I was really delighted.
From 1984 until, I think, 2003 I went to Venezuela every year. We used to go as a team, between 11 and 15 people: geneticists, psychiatrists, neurologists. We collected data from the families and we lived with them for 13 to 15 days a year.
It was a fantastic experience. I got to know people there who we visited every year. And I also got to know fantastic people who were part of my team. We lived day and night together in the same hotel and worked for hours and hours and hours, from early morning until late at night.
I got to know people and see all the kids growing, but also becoming ill and dying from the disease. The living conditions of the families there in Venezuela were so different from how we were living at that time. It was a lesson for life. It was a big experience for me from the scientific point of view, but also the human.
What is the significance of what the team discovered in Venezuela?
The HD gene was the first dominant gene discovered by linkage. That was a really big issue at that time.
The thing is, when we found the gene we thought we’d have the knowledge to find the cure for HD and other diseases. We expected that if we knew what the gene was we’d be able to find a treatment, something to give back to patients and alleviate symptoms. Unfortunately, with HD and other genetic diseases, treatments have not been as easy as we initially expected.
Why has that been so difficult?
We know what the gene is. We know what the protein is. But that protein is in all tissues in our body. We don’t know why that protein is doing something wrong in tissues like the brain, and not in other tissues like muscle, for instance.
Concerning treatment, how do we get the normal protein to only those tissues where the protein is doing damage? [That] is very difficult for HD and many other genetic diseases.
How have things changed since then?
When I first came back to Spain nobody knew much about HD. I remember trying to find a job, going to hospitals, saying: I know something about HD, would they be interested in research on it? They said ‘What? What is that?’ The disease was not really known.
Finally I got a position here in Pamplona to set up a genetic clinic. I started my own HD clinic here and started to collaborate with neurologists, collecting the families in my region.
There are 45 families in my area. Not all maintain frequent contact with me but they know we’re here. That’s the most important thing—that there’s someone in the clinic who cares for them, and is willing to treat them.
What research questions were you asking then?
We were trying to correlate the number of repeats of the mutation that causes HD with the age of onset of the disease or the symptoms. Because sometimes people show motor symptoms but also have psychiatric symptoms, or behavioral problems.
We also tried to see if we could find another gene that could modulate the age of onset. Also some epidemiological studies, trying to see how frequent the disease is in Spain. The prevalence is 0.5 per 10,000 people, which is relatively low. But although it’s a rare disease, it’s not as rare as we thought it was.
How did you get involved in REGISTRY, the European observational study that came before Enroll-HD?
In the beginning I didn’t join. I didn’t find it very interesting in terms of research. I’ve told Bernhard [Landwehrmeyer, the principal investigator of REGISTRY and also Enroll-HD] this before!
A few years later I started to see the aim of REGISTRY: That they tried to follow patients along their lives, in a prospective study.
[It seemed like] a possibility for patients to get more care, and for us to be closer to them. At that point patients didn’t come to the clinic very often, because we didn’t have much to offer. REGISTRY was like a joint effort to get something together. In 2006 I joined and started collecting participants for the study. I also was asked to be the member of the steering committee, representing Spain.
From the scientific point of view, REGISTRY is a very important and interesting study. But there’s another side of the study that is very important for patients.
One of the things REGISTRY really did for Spain was get other neurologists interested in HD. It’s now a well-known disease among my colleagues. Families are more willing to accept the disease and be informed about diagnosis or possible treatment. Mostly they ask for help to give the best care to family members. That is something REGISTRY did.
What kinds of things can we learn from these studies?
We are now investigating the possible clinical manifestations in carriers with 27 to 35 CAG repeats, known as intermediate alleles. At present, these alleles are not considered to be associated with symptoms of the disease. However, in the last five to six years, there have been individual reports as well as data from large studies, like COHORT and PHAROS, which suggest that a person with an intermediate allele might develop some neurological symptoms similar to those we see in HD patients, but at an older age.
“HD has been one of the most important things that happened to me, from the personal and professional aspect. It gave me good friends, and the possibility of helping my community.” —Maria Ramos-Arroyo
Recently, we have also analyzed data from REGISTRY with similar, but not absolutely conclusive, results. We need additional large prospective population-based studies to confirm or rule out these preliminary findings, as it may have important implications for genetic counseling.
With REGISTRY and Enroll-HD we can gather data from a large number of patients followed for many years, which is crucial for picking up subtle clinical manifestations caused by the HD gene.
I ́m sure that these studies will give us the possibility to conduct robust investigations with enough power to reach a definitive answer.
What do you expect will be different with Enroll-HD?
REGISTRY was kind of a family study. All the researchers knew each other, we had an annual meeting. It was very familiar, very cozy. We also shared our research with family members, because they would go to the meetings with us.
Enroll-HD enlarges the study. It may be that because it’s bigger it might be impersonal. But it needs to be done. It will be more powerful. And numbers in HD really count: We need numbers, we need data. We need to collaborate, to go all at once, with the same goals and tools and purposes. I think that’s the way to do it.
You’ve been involved in HD research for so long— what insights do you have about it?
HD has been one of the most important things that happened to me, from both the personal and professional aspect. It has been not only the main part of my research, but part of my personal life. It gave me good friends, and the possibility of helping my community. That is the summary.
This story was originally published in the Autumn 2016 issue of Enroll!