Leveraging Community Partnerships to Address a Rare Disease Behind a Medical Mystery in New Mexico

Cristóbal Baca and Ana Ortiz came to New Mexico in 1600. Today, they have as many as 5 million descendants. A four-year effort involving community volunteers and workers, medical professionals, researchers, and families across New Mexico unraveled what had been a long-standing medical mystery. It turns out Baca and Ortiz are the source of a founder mutation for cerebral cavernous malformation, a sometimes-hereditary illness that causes the development of abnormal blood vessels in the brain and spinal cord and is potentially fatal. Some 30,000 New Mexicans carry the mutation. We spoke to Connie Lee, president and CEO of the Alliance to Cure Cavernous Malformation, about the Baca Family Historical Project, how her organization leveraged partnerships with community leaders to identify people with the condition, and how the organization used a novel approach to engage people and improve their access to testing and care.

Daniel Levine: Connie, thanks for joining us.

Connie Lee: Thanks so much for having me today.

Daniel Levine: We’re going to talk about vascular lesions known as cerebral cavernous malformations, the efforts of the Alliance to Cure Cavernous Malformations, and how it’s used community partnerships to improve health education and outcomes for people with the condition. Let’s start with cavernous malformations. What are these?

Connie Lee: Cavernous malformations are abnormal blood vessels in the brain. They look sort of like raspberries or mulberries. They are in the smallest of the blood vessels, but they can hemorrhage and grow. You can have one so many people have one actually and don’t even know it. Or you can have many of them distributed throughout your brain and or your spinal cord.

Daniel Levine: My sense is that these can have very significant effects and be quite serious. What’s the range of problems they can cause?

Connie Lee: The lesions are leaky, and so they leak blood into the brain tissue. They’re always leaking a little bit of blood into the brain tissue, and that irritates the brain and can cause seizures. So, about half of people who are diagnosed first get their diagnosis because they’ve started having seizures more seriously. These can also hemorrhage. They can have significant hemorrhages that cause anything that you would associate with stroke, so weaknesses in limbs, problems with vision, problems with speech, problems with thinking, and that can be very serious. One of the larger issues with this disease is that it can happen to anyone at any age. So, even young children can be affected, can have major hemorrhages that can cause deficits for the rest of their lives.

Daniel Levine: What’s understood about the underlying cause of these malformations? Are they recurring events throughout a person’s life? Is there a genetic route to it?

Connie Lee: There’s both. About 75 percent of people who have the disease do not have a genetic root. In other words, it’s not passed down from parent to child. They just have one, usually lesion, one cavernous malformation in their brain or their spinal cord. And once, if it were to be removed through a brain surgery, they would not have the disease anymore. For about 25 percent of people, though, it is a genetic disease, and in fact, it’s not just a recessive genetic disease that happens every once in a while. It’s a disease where every child of a person who is affected has a 50/50 chance of inheriting it. So it’s a flip of a coin. Every kid is an independent event, but on average, if you have a family with two to four children, half of them will have the disease and it moves down the generations that way. There are three different genes that can lead to the same outcome if they’re mutated. The one that is most common is called the CCM1 gene.

Daniel Levine: How does that complicate the effort to diagnose the disease and develop therapies to treat it?

Connie Lee: It is complicated because all the three genes don’t necessarily have identical functions. One of them tends to be more severe because it works in multiple signaling pathways, molecular pathways, and the other two are still severe, but not quite as bad. And then people, who have what’s called the sporadic form have just one lesion that they developed, for some reason have yet probably a different mutation in their lesion. Some of them may have a CCM1, 2, or 3 just in the lesion itself, not anything that they can pass on. But there are a couple of other genes that have been implicated as well. So, when we’re talking about trying to develop a treatment, things do become very complicated. We don’t necessarily know that a treatment that works for one form of the disease is also going to be effective for the others and that’s part of science. That’s what we’re trying to figure out now.

Daniel Levine: You became engaged in this world when your daughter was diagnosed at four months old with a brain hemorrhage. I know she one underwent multiple surgeries, but are there any treatments today other than surgery?

Connie Lee: My daughter was four months old when she had her first brain hemorrhage, and she wound up having her first brain surgery the day that she was diagnosed. We would’ve lost her that day had she not been given the opportunity to have surgery. So, this is something that could only have gone well in the 21st century and prior times people whose infants showed up in a similar situation probably would not have made it through to the next day because of the lack of technology, the lack of diagnosis. People have only been getting diagnosed correctly since the advent of MRI. Before that, we didn’t even know really what people had until they had the surgery and then pathology could identify it. So, as much as I want to say there’s no treatments yet, the period of time that we have had to even work on treatments is incredibly short. It’s been less than 20 years. We do have drugs in clinical trials right now. One of them that’s in trials already has been developed by a drug company. Others that are in trials are repurposed. They’re already on the market for other diseases. Nothing though is approved. We don’t yet have any treatment for our families other than either wait and watch and see if something’s going to happen or go ahead and have a brain surgery and try to remove the lesion and hope for the best there.

Daniel Levine: What’s it like to live with this condition, either as a parent or a person who suffers from it? And is this an ever present time bomb that can go off?

Connie Lee: Yeah, it’s incredibly anxiety provoking. I think the time that’s the hardest is the first year after diagnosis when our patients are just beginning to understand what it means to have this in the first place. And then at the same time, they’re worried about a recurrence of a hemorrhage, especially if they had one. And in fact, their worry is not unfounded because once someone has a hemorrhage, it’s the first two years after that hemorrhage that are the highest risk for a second hemorrhage. So, really those two years, it does feel like a time bomb. It feels like any morning could be the morning that I wake up and my life entirely changes.

Daniel Levine: You’ll be participating at a panel at Global Gene’s upcoming Rare Health Equity Forum that discusses leveraging partnerships with community partners. I’d like to talk about the work you’ve done in New Mexico. Perhaps we can start with Cristobal Baca and Annmarie Ortez. Who were they and what was their connection to cerebral cavernous malformations?

Connie Lee: So, Cristobal Baca is one of the original Spanish settlers in New Mexico, when at that point it was Mexico and not New Mexico, or I believe even at that point it was New Spain. He and his family joined a number of other settlers and wound up in the Santa Fe area. This is the family that we believe, probably a couple of generations after this original Cristobal Baca were the first in New Mexico, to have what has become a founder mutation. Remember I said that every child of someone who has the disease, if they have the genetic form, has a 50/50 chance of inheriting it. And that sets us up for having multiple generations who are affected, especially with our disease. Only about half of people who have the genetic form ever wind up having symptoms. So, those folks don’t even know they have it. And they are perfectly capable of having what at that time are very large families. It was not unusual for a family to have 16 kids or more. Since that time in the 1600s, that family has grown and the disease has been passed down. We believe at this point there are probably 30 to 40,000 people in the state of New Mexico with what’s now known as the common Hispanic mutation. And it’s a mutation of the CCM1 gene. They are all related. They all genealogically can trace themselves, if they’re able to trace their genealogy back far enough, to the same ancestor. And when you look at their genetic mutation, it is identical. The CCM1 gene can break in any of hundreds of different ways. These families all have the exact same break in that CCM1 gene, which again, gives us evidence that they are indeed all related.

Daniel Levine: You mentioned the population of people with the condition, but there’s an astounding number of descendants that this couple had. Can you explain what the Baca Family Historical Project was and how large a population can be traced back to the Baca family?

Connie Lee: So, the Baca Family Historical Project came as an initiative out of the Alliance to Cure Cavernous Malformation. We had been working in New Mexico for about 10 years to try to engage patients, find new families, do genetic testing. And what we found was a lot of pushback from the families who really didn’t want to know. Many of them didn’t want to know, or if they did already know this wasn’t something they wanted to confront every day. It’s like those of us who have diabetes running in our families, if we’re not having problems with diabetes, it’s not something that most of us think about. And most of us are not huge diabetes advocates until there’s something serious that happens in the family. And this was very much the same. It’s like you just kind of live with it there. It’s a public health issue, but it’s been around for so long. So, we didn’t get traction. Around 2016, there was a patient and physician meeting that I attended, and one of the things I heard was one of the patients talking about their ancestry and how proud they were of being connected to these original families in New Mexico. And I recognized that this is something that really resonates. Having this disease actually winds up being a sign that you are related to one of the original Spanish families in New Mexico, which is something that people want to find out about. There are actual, just like in other parts of the country, the Daughters of the American Revolution, people want to know whether or not they can trace their ancestors back that far. This is the same idea. So, what we decided to do was, rather than hitting people in the face with medical stuff, is to uncover and engage folks around genealogy. Our organization was granted funds to go into New Mexico and hire a community organizing type person who did workshops in which people brought their family trees. And we tried to trace them and we called it the Baca Family Historical Project to try to indicate that the family tree that we were interested in is the Cristobal Baca family tree. So, we met in libraries and community centers and senior centers, in museums, wherever we could find folks who were interested in genealogy. And at those meetings, we would share the history of the Baca family in New Mexico. We would share the genealogy, and then we would share, finally, more about the common Hispanic mutation and CCM1 and what that meant for the Baca family through time. But also in the present day, we would have a family tree workshop where people could find out whether they were in one of the lines that we knew were more at risk. And then finally at the end of the day, if they were interested in genetic testing, we could offer them genetic counseling and testing on the spot if they wanted it. We wouldn’t have the results at that moment. We would send it off to the lab and when the lab had the results, they would go to the person’s physician who would share it with them. And then they could get attached to the University of New Mexico where we have a center of excellence.

Daniel Levine: I imagine that cavernous malformation was not a diagnosis that was made in the 1600s. How have people been able to determine when they appeared that they were related to this family line?

Connie Lee: Well, that is really the task of the genealogists that were associated with the project. We had the president of the New Mexico Genealogical Society as part of our team and then two other genealogists worked at our workshops and they were able to look at present day people and trace their family trees back to see where they intersected. And so, if you come in fresh and you can at least know who in your family, who that person was that was still alive in the year 1900.  Typically, our group could find that person in the arm of a major big family tree and trace that person back to see where the connection is to the original Baca family. We got to the point where we could, within the course of a half hour, figure out whether or not someone was at higher risk or not. Again, it’s the magic of genealogy, which is not my sphere, but I was so happy and fortunate to have folks on the team who could do that.

Daniel Levine: It’s such a fascinating solution to a problem that I think many other disease organizations face in connecting with patients. But beyond the genealogists, were there other people in the community that you had to reach out to and connect with?

Connie Lee: Yes. So, we established very strong relationships with the Department of Health in the state and also the local departments of health. One of the health provider functions that exists in New Mexico and elsewhere, but is very strong in New Mexico is a community health worker. These are lay individuals who go into the communities and talk about health related issues. And they really are the frontline workers. So, part of our work was to train every single community health worker in the state of New Mexico. I believe we trained over 800 of them over the course of four years and helped them understand who is at risk, what the disease looks like, and if you think someone is at risk and seems to be showing symptoms or maybe not showing symptoms but is at risk, what can you offer them? And so that partnership helped again to spread our reach much further than we could. We had partnerships, obviously, with the libraries and the senior centers and all of those community partners with the Hispanic Chamber of Commerce in Albuquerque, with the School of Nursing, with the University of New Mexico’s family outreach programs. Anywhere that we could get our word out, we would. We also partnered with AM radio stations in New Mexico. In the rural areas there is very little signal of any kind and folks still regularly listen to AM radio. So, we would do 90 minute talk shows on AM radio explaining what it was that we were [doing], the genealogy work and also a little bit about the disease work. Or we had little TV segments or radio segments on the NPR public radio type stations. By the time we worked most actively in the years 2017 to 2020, the pandemic tied everybody’s hands for a while. But by the time 2020 came, CCM1 was a household word in Hispanic families around the state. Folks knew about the illness and knew whether or not they might be at risk and could have the information to make good decisions about what they wanted to do about that.

Daniel Levine: One of the things you did was hold conferences about New Mexican Hispanic history, and as part of that, you’d include the family tree workshops and genetic testing to people who are at the highest risk for the illness. How did this come about as a strategy?

Connie Lee: We had planning sessions to try to understand what was most valuable. I think whenever we go into a community, I’m going to step back a moment because I think this applies not just to our New Mexican families but to anyone who’s doing work with specific populations, especially those who are underrepresented or who have had negative experiences in healthcare in the past. It’s important to find out what I can offer, what our organization can offer that’s of value. And so, in the case of New Mexico, what we could offer is a connection to history. And that’s how it came about, was knowing, hearing the voices deeply, listening to the folks in the state who were telling us about what is important to them, and then trying to figure out a way for us to be able to create something of value to offer first. I cannot imagine going into a community now knowing what I know and having my first ask of the community be, “so we got a research project and we would like you to sign up for it.” That’s not how it works. There’s trust building and there is some value added that we need to do a lot of work that needs to happen before we make the first request of a community to participate in something like that. And so, this was our strategy—let us give something back, let us build relationships and trust, and then let’s see if something good comes from that, great. If not, we tried and we are now doing the same thing with another initiative we have called Breaking Barriers in which we’re working with black patients. We do not have a higher prevalence of this disease in the black community, but we had a much, much lower number of people who are being seen at our centers of excellence or who are in our clinical databases who identify as African American. So, our goal there has again been to offer something of a value. And what we offer that community is concierge care. Basically, every new black patient who comes to our organization has a one-on-one conversation with someone who can do a needs assessment, offer free genetic testing, help them connect with a center of excellence and help them with ongoing care. And we got to that again through deep listening. First, we had an IRB-overseen study where we had qualitatively scored interviews with black patients who shared with us what their struggles were. And for the most part what we heard was that the biggest struggle was what happened after diagnosis, getting the good care, getting the right referrals. And so that’s something that we’re helping with there. And we have grown our personal clinical database threefold in the last two years as a result. And we expect that to continue for the foreseeable future.

Daniel Levine: And what’s been the effect of the Baca Family History Project?

Connie Lee: It has had a huge effect. University of New Mexico went from seeing about 30 patients a year, which is a ridiculously low number, I know, to seeing over 300 patients and to the point where they had to change their clinic schedule. They formerly had a clinic once a month for CCM, and after we started up, they wound up having clinic every week and they wound up assigning additional clinicians to the clinic because of the volume of patients that they were seeing. They were seeing almost as many CCM patients as they were stroke patients. Most recently, we have also leveraged our project into a $300,000 one-year appropriation by the State of New Mexico to hire folks to do exactly what we were doing—to do medical education and to do outreach to patients. So, our role can now transition to be more support. Our patients have formed a chapter there and they’re willing to show up for anything that is being asked of them, but the actual heavy lifting is now from inside the state rather than coming from outside of the state.

Daniel Levine: It’s interesting because you could become victims of your own success in a sense. What kind of support are you able to offer newly diagnosed patients?

Connie Lee: For people within the state of New Mexico? Often genetic testing now leads to their diagnosis, but if they haven’t yet had it and they’re not sure, then we can we offer that. We have in-person support groups in New Mexico. We have virtual support groups that meet once a month. We work with the University of New Mexico to organize an annual family conference there. We have a developed center of excellence at the University of New Mexico that we have recognized and helped to put together the different specialties. Around the rest of the country, we offer very much the same thing—support groups all the time. You almost don’t have a minute of the week where we don’t have some support group going on somewhere, as well as conferences and web expert webinars, a patient registry, a patient expert course folks can go on to teachable and spend five hours learning through multimedia about the disease to get to the point where they probably know about as much as their neurologist does when they’re done. And so, we really try to make sure that all of our patients, number one, never feel alone, and number two, are equipped with the information that they need to make good decisions for their health.

Daniel Levine: You talked about how you’ve taken your learnings from this program and applied it to a different population, but what would you say were the lessons from what you’ve done?

Connie Lee: There are two main lessons. One is invest the time. As I mentioned, we can’t go into a community expecting that we will have engagement and research participation and a very healthy, strong chapter of patients without first investing a couple of years, at least a couple of years, getting to know the community. And that holds true in our Breaking Barriers project as much as it did in our Baca Family Historical Project. And then the second point is budget. We can’t do this work without funding it. And I think that when we look at our budget, 20 percent of our budget goes to DEI efforts, and in some years it’s been more than that. Some years it’s gone up to 25 percent. If it’s not a line item in the budget, it is not a value, and that is so important, I think, to emphasize to our sister organizations out there in the world that please take the time to look at your budget. Do you have money in there to do this kind of work? And if not, why not? So, those are the two lessons.

Daniel Levine: Founder’s mutation is an unusual example. There are certainly other conditions that are analogous, but what advice would you have for other patient advocacy organizations looking to replicate what you’ve done in other diseases where there aren’t those types of fixed communities?

Connie Lee: Right. So, that’s what we’re doing with Breaking Barriers. There are no founder mutations among black patients that we’re aware of yet. And honestly, I don’t think we’re going to find one because we just don’t see enough people, enough patients to think that there might be a founder mutation among African-American patients. So, the lesson that we can share there is the deep listening lesson of “find the patients that you can find and take the time to really listen to what their experiences are and find where the shared experiences are, and especially those shared places where there are needs, and then can you do something about those needs directly?” And some of us think, well, maybe if we can get the legislator to do it, or maybe we can bring these other things to bear and prove their doctors or whatever, but the first thing I listen for always is what can I do? And for us, for the Breaking Barriers project, it was creating a Facebook group just for black patients so that they would have a space to be able to share experiences that they may not feel comfortable sharing in our larger group or may not feel would be as accepted. And so, that was where we dedicated staff, we made sure that everybody got, as I said, a one-on-one needs assessment. These were the valuable things that we could offer. And I think that that can be done in any group. There’s always, you know, if there’s always a need and there’s always a need that it’s possible to fill. It may be something having to do with childcare. It may be something having to do with care packages or school accommodations information. There is something, there’s a hook somewhere that is important to figure out in order to offer something of value.

Daniel Levine: The work has done a lot to identify people with the condition and raise awareness about it. Has this also helped to gain a new understanding of the disease or helped advance the development of potential treatments in any way?

Connie Lee: Yeah, so we’re working with industry right now, again, on our first industry sponsored clinical trial, and when it came time for them to do phase 2, which was the first time any of our patients were in a clinical trial, that was a new drug, and we were able to fill that trial early. So, our capacity to fill clinical trials is a direct function of the number of patients that we cannot just touch, but that we can engage and mobilize. And that is what this project has done. We have people who are anxious now to participate in trials who understand the importance, and so it’s done that. It’s also helped our academic researchers to recruit for whatever clinical studies they’re doing, whether they’re repurposed drug trials or surveys or quality of life studies. We’ve always, always had enough people. We’ve never had a study fail for lack of participation.

Daniel Levine: If you’d like to meet Connie or learn more about the work of the Alliance to Cure Cavernous Malformation, she’ll be on a panel at Global Gene’s Rare Health Equity Forum, discussing engagement strategies and how to leverage partnerships with community leaders. Connie Lee, president and CEO of the Alliance to Cure Cavernous Malformation. Connie, thanks as always.

Connie Lee: Thank you. It’s been a pleasure.

This transcript has been edited for clarity and readability.