2022 Global Down Syndrome Foundation Research & Medical Care Roundtable at NDSC – Q&A

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Part 1: Questions Answered Live

Q1: What is the latest research on Alzheimer’s and Down syndrome? And what could I be doing now for my young adult or older adult to help prevent them from getting Alzheimer’s?

A1 (Dr. Hartley): The good news is that the field is are now recruiting very talented scientists and clinicians to focus on this issue. In addition, there is a growing interest in building large research consortiums that involve scientists and clinicians from multiple sites and across the United States and in other counties to work together. The idea is that if we work together, we can recruit larger samples and advance science in a stronger way. I mentioned the ABC-DS consortium, which stands for Alzheimer’s Biomarker Research – Down syndrome. This study is doing a natural history study – of Alzheimer’s disease in Down syndrome. The goal is to enroll about 600 adults with Down syndrome to identify valid biomarkers of brain changes and their relation to cognitive and clinical changes across time to inform interventions. In order to prepare the field for clinical trials, we need to understand some of the differences that we see with Alzheimer’s disease in Down syndrome compared to Alzheimer’s disease in other populations. One of the things you might have noticed is that I mentioned the median age of onset of Alzheimer’s disease in Down syndrome is in the early to mid-50s – about age 53 years. That’s a lot earlier than in what we see with sporadic late onset Alzheimer’s disease. We also know that amyloid beta plaques accumulate slightly differently in Down syndrome – with early accumulation in an area called the Striatum – relative to what we see in other groups with Alzheimer’s disease. We need to understand these differences so that we can tailor interventions. The field is already preparing for clinical trials. Dr. Mike Rafii lead’s a study called TRC-DS (Trial Ready Cohort-Down syndrome) that will be one of the largest clinical trials for Alzheimer’s disease in Down syndrome. The idea is that as we learn about the natural history of Alzheimer’s disease in Down syndrome, we can also collect baseline data. We can then move more immediately into a clinical trial. These clinical trials will target different pathology and include different agents – some aimed at immune dysregulation and some that include anti-amyloid vaccinations, for example. However, the field is also preparing for clinical trials that don’t involve drugs. For example, today, I talked about sleep and its link to Alzheimer’s disease in Down syndrome. The other lifestyle factors that my lab and many others are looking at are things like physical activity, social engagement, and cognitively stimulation. We know that these things can promote healthy brain aging and are linked to the risk of Alzheimer’s disease outside of Down syndrome. Emerging evidence suggests that these things are also linked to better memory and processing speed and better brain functioning in Down syndrome. Some tips from this line of evidence would be to reduce the time that you spend sitting and increase the time you spend getting your heart rate up – in moderate to vigorous physical activity. Cognitive stimulation is the idea that if we can remain engaged in critical thinking and forcing ourselves to learn new things, this may actually help us maintain our cognitive functioning. To measure cognitive stimulation. In our studies, we’re looking at the employment activities and the leisure activities of adults with Down syndrome. Making sure you engage in these types of activities could be a good way to support healthy cognitive and brain aging.

Q2: Why is GLOBAL’s research and medical care important?

A2 (Taylor): It has helped me and everyone in small towns to have information to talk to the doctors.

Q3: I’m totally supportive of everything you’re doing but I’m also curious whether the research effort has engaged any bioethics in discussions about some of the issues that come up when you’re talking about trying to alter people’s cognition and other things that may have unexpected consequences.

A3 (Dr. Hartley): I think this is a great question. It speaks to an important shift we see in the research community – specifically, the idea that researchers need to engage with self-advocates and their families and other stakeholders to identify questions that are of importance to the Down syndrome community and to get multiple view points on how research may be perceived and what unexpected consequences could be. For this research, we spend a lot of time thinking about the consent and assent process to make sure that people with Down syndrome who participate in our studies understand the study goals, any risks, and potential benefits. We develop story books, we develop pictures, we develop videos that we send to families ahead of time, so they can see all of the procedures and make sure that they really are feeling informed about options. In terms of interventions that would stem from our work, we are focused on efforts to improve screening and treatment of sleep problems as a way to help maintain cognitive functioning and memory for longer with aging in Down syndrome. That said, it is always possible that there are negative unexpected consequences of research. That is way it is so important to have people with Down syndrome and their families on research teams and to seek out feedback from people who participate in studies.

Q4: My questions about the Tau particle. I’ve tracked the research for the amyloid B for five years now. But there’s very little I see coming out about the tau particle. Can you summarize its significance for Alzheimer’s disease and the research that may be going on?

A4 (Dr. Hartley): When we think about Alzheimer’s disease in Down syndrome, often amyloid beta plaques get attention because of the triplication of the amyloid precursor protein on chromosome 21. An increase in amyloid plaques is often the among the earliest signs of Alzheimer’s pathology. However, neurofibrillary tangles of tau also develop in the brain. And again, Tau is this protein that begins to sort of develop within those neurons. Following amyloid and tau, we talk about neurodegeneration or neurons dying and brain structural changes and that’s really the time that we think we are going to see dementia and the memory declines. In Down syndrome, most of the biomarker research that’s published right now has focused on amyloid. But cross-sectional imaging, CSF and plasma studies looking at Tau are available and longitudinal studies should be coming soon. So the field is moving to tau. We think Tau might map on to cognitive declines and be another aspect of pathology could potentially intervene on. That work is actively being done.

Q5: We’ve heard a lot about how diet and exercise can help prevent Alzheimer’s. What kind of diet or workout routine keeps you healthy?

A5 (Taylor): My parents go with me to Zumba classes three times a week. I help prepare salad and grilled chicken.

Q6: I’m a specialty pharmacist. So, I’m very interested in your autoimmune research. One of my most important roles is I’m mom to Emily. She is 33 with Down syndrome. As she ages, we’re seeing some of these autoimmune situations that are concerning. My concern is as specialty pharmacist are JAK-inhibitors and their side effects. Have you seen an increase in side effects in Down syndrome with this class of drugs?

A6 (Dr. Espinosa): Our sample size is small right now. We finished the first 10. We have recruited 13, we need to go to 40. So far, the side effects look like what you would expect. These are immune modulators that could increase your chances of getting a cold or a runny nose. We need to do probably more than 40 to see if the safety profile is different than that of the general population. A complete safety profile probably won’t be achieved with this first trial of 40, but assuming it’s safe at the sample of 40, we will go for bigger trials.

Q7: Are JAK-Inhibitors available or how would someone obtain a prescription? My son just had a quantitative MRI to evaluate the inflammation in the brain, in the various parts of it since he’s also had microglia as well as mast cell activation. So, we’re very interested in reducing those cytokines. And I didn’t know if JAK-Inhibitor is available and if so, where I would take him to get it.

A7 (Dr. Espinosa): So, this is something to be defined by the attending doctor, but I can tell you about the approved indications for the JAK inhibitors: myelofibrosis, rheumatoid arthritis, psoriatic arthritis, graft versus host disease (that’s when you get a transplant, an organ transplant, then you’re rejecting it). There is one JAK inhibitor approved now for COVID-19. Believe it or not, it helps to turn down the immune system. If you have severe COVID-19, because it’s the immune fight that is making you sick. They are also approved for ulcerative colitis and polyarticular juvenile idiopathic arthritis. So those are the approved indications. And depending on the JAK inhibitor, those are we call the on-label prescriptions. But then, doctors can look at any particular case and if the evidence supports it, do what they call an off-label prescription. And that is what the doctors, the dermatologists, in the clinical trial are doing. And, you know, they follow the same safety protocols as they would do if the person had rheumatoid arthritis say. So, the JAK inhibitors are FDA approved; they have six or seven approved indications. And then depending on the doctor and the evidence of the case, they may be comfortable doing an off-label prescription or not. Another thing is that the half-life of a JAK inhibitor is really short. That’s why you have to take it twice a day. You know, so if you stop taking it, the actual systemic activity will stop within hours. The lingering effect may be a couple days, but then within a week it is totally washed out of your body. There are other immune modulatory agents, what we call the biologicals, which are injectables. Those have a much longer half-life, things like Humira and others. So that’s why we like the JAK inhibitors because if we see an infection, we can stop, you know, bring the immune system to whatever state it was before the medicine. Something that I want to highlight that I didn’t show you the data is that because the immune system is so high in Down syndrome, the JAK inhibitor is bringing it back to a normal range. We love that result. What we talk about here is immune normalization in Down syndrome, not immune suppression.

Q8: I know the primary cause for the sleep problems is sleep apnea. What about the leptin and the cytokines and all that? Have you looked at a primary alternative explanation for those issues and is that part of it?

A8 (Dr. Hartley): Of the sleep apneas, obstructive sleep apnea is the one we most commonly see in in Down syndrome. We are trying to understand what impact sleep apnea may have on pathology that we see with age in Down syndrome. We do think that obstructive sleep apnea will lead to altered sleep-wake cycle and inflammation and it could be immune system is altered. These is work that we are doing now. I mentioned that link between getting good sleep and clearing amyloid beta so that it can’t form into those plaques. But we also see a lot of effects with like, neuroinflammation.

Q9: What’s happening in the research and trying to find the cure to Alzheimer’s from the perspective that Down syndrome is an immune system condition. What have the researchers learned from COVID-19, especially in the possibility if any, of developing an RNA vaccine, like it was developed by Pfizer and Moderna that target proteins for Alzheimer’s disease.

A9 (Dr. Espinosa): The amyloid is a protein encoded by a gene, just like the viral proteins are encoded by viral genes. So, the notion of using RNA vaccines, where RNA is an intermediate in that transference of information from gene to protein, using RNA to create a vaccine against the amyloid, in theory, is totally feasible. So, it’s early days to tell whether RNA vaccines work better, or worse in Down syndrome. We were at the T21 Research Society meeting in Long Beach last week where there were some presentations on this. The papers have not been published yet, so we don’t have solid data on that. But I can tell you that there are trials coming for vaccination against the beta amyloid. It’s not an RNA vaccine. It’s more of the traditional type of vaccine to help the immune system lower the amount of amyloid in the body. This was a small trial, a first feasibility study, and I believe there will be a follow up larger trial. So yes, RNA vaccines could be a good idea for other things, not just COVID-19. And yes, vaccines to amyloids could be a good idea as well and are being tested in Down syndrome.

Q10: Do you have any medical concerns for yourself or others with Down syndrome?

A10 (Taylor): Yes. I have a sleep issue. It was diagnosed when I was 10 years old. I use my CPAP to help my other organs work properly.

Q11: I know you were trying to check my skin when I have called you before, and I want to know if you still taking people on the skin research trial.

A11 (Dr. Espinosa): We paused the trial to look at the data from the first 10 participants, but now we are reopening in Summer 2022. We are open and back in business. If you’re not from Colorado, we have a budget for travel participants from wherever they are to travel to Denver, which is a nice place to visit. And then the doctors, the dermatologists, the skin doctors will check your skin and see if you would qualify for the trial.

Q12: I have two simple questions. One, we’re hearing about some different proteins and immune function. I’m wondering if the research is looking at medication that could affect or suppress those proteins for cognitive function and how soon that might be on the forefront of a medication that would be applicable. And my second question is, I have a nine-year-old who has sleep apnea. So that epiglottal device, how soon are we looking at? Or are, is there even like experimental studies to get the epiglottal device at earlier ages?

A12 (Dr. Espinosa):  So, ours is an active clinical trial for an immune modulator, the JAK inhibitor, and the investigations of effects on cognition are exploratory. We thought, you know, four months in persons 12 and older is not enough time to see any improvements. But we were delighted that there are some signals, but again, it’s not a placebo-controlled study. We cannot rule out that maybe the participants learn to do the task better, and then remember how to do them for four months later. So, we’re going to continue with this trial. Then we’re going to have a long term follow up as these individuals graduate from the trial and they go on the medicine perhaps off label. Now we can follow them for years to see if there is truly an improvement in cognition. I also mentioned the trial that we’re going to run with Dr. Santoro, which is focused on regression, and that could really be the path to an immune modulation to cognition more generally. If we see improvements in regression, well, perhaps that justifies a larger trial, even in cases with no regression. And then the last comment is the upcoming clinical trial from Dr. Huntington Potter. That is an immune modulating molecule. It’s a molecule that changes the balance in the immune system. That is in older adults. So, between the ongoing JAK inhibitor trial, the upcoming trial for JAK inhibition in regression and the trial with Leukine, we hope that we’re going to have a better sense of what the immune system is doing in terms of cognition across the lifespan. With regards to sleep apnea, there are several treatment options, and I do think it is important to work with the pediatrician to talk through some of these options and what you could try. There is some body positioning and things that could help you know, if CPAP or BPAP can’t be tolerated and some things to try with the hypoglossal nerve stimulator. There are active trials right now. I think it’s really exciting at this point. It’s not like globally available and so it wouldn’t fit the needs of everyone with Down syndrome, but I think these are options to be talking to your healthcare care providers about. As far as that for children though, probably the insurance company isn’t going to cover it now because they’re doing these active trials to see how effective and what considerations should be taken into account for children. But it’s a very promising, there’s a lot of excitement around that option, right.

Q13: My daughter is 20 and has juvenile rheumatoid heart arthritis. And after hearing you a little while ago, we started Xeljanz, but her physician only put her on 10 milligrams once a day. That’s too low, isn’t it?  Second, it’s very expensive. Is there a generic on the horizon, or no?

A13 (Dr. Espinosa): In our trial is twice a day, five milligrams. There’s no generic version, but in the trial it’s for free. Regarding the off-label prescriptions that I talked about, the benefits were so obvious that the medical insurance couldn’t argue against it, they had to cover it.

Q14: To enroll in the Leukine Trial –  is that through the NIH?

A14 (Dr. Espinosa): That is at the Crnic Institute, funded by NIH, led by Dr. Huntington Potter, it starts recruiting next year.

Q15: Please share information about what we know about surgery for flat feet and guidance for recovery.

A15 (Dr. Baumer): Flat feet is a very common phenomenon, certainly in children with Down syndrome, and children and people in general. I am not aware of any specific surgical interventions that have been done for flat feet. None of my patients have had surgery for that specific reason. But there are some things that can be done to help improve the flexibility of the foot. And sometimes depending on whether there are issues with the muscle strength, orthotics or physical therapy may be very helpful.

Q16: Can you please address the idea of premature aging? When does it become obvious physical changes and mental changes and you know, what could we do about it?

A16 (Dr. Bulova):  Some of the things that I see in my patients without Down syndrome that are 65-70 years old, I may see in patients with Down syndrome in their thirties and forties. One example is cataracts. We start looking for this condition around age 30. Cataracts, early arthritis, and skin changes are common at an early age. We recommend having a low index of suspicion for these conditions and recommend a healthy diet and lifelong exercise for prevention. That being said, there are other conditions such as cancer and heart disease that we associate with aging but seem to be less common in people with Down syndrome.  

Q17: Can Moyamoya symptoms be similar to regression symptoms in Down syndrome?

A17 (Dr. Santoro): Moyamoya is a tightening of the arteries that lead up to the brain. So over time, they slowly get smaller and smaller, which can cause stroke in individuals with Down syndrome. Why that’s so important is that in individuals without Down syndrome who develop Moyamoya, they often have symptoms before, kind of like a mini-stroke or a transient ischemic attack.

Sometimes it’ll be headache. Sometimes it’ll be a seizure. In individuals with Down syndrome, when they come into medical care, 70% have already had a stroke. So, this is something that we’re working on to develop a non-invasive way to identify this. Because often it’s having to do a sedated MRI, which is a logistical nightmare. A lot of the time, why that is important is that when you are showing up with a stroke, it’s usually resulting in a focal neurologic deficit, meaning you have weakness, numbness, slurring of the speech. Your face may be asymmetric– all the same things that you would see in an adult or an older person without Down syndrome, who also has a stroke. These are things that don’t go away, and they are very acute meaning that they come on rapidly over the span of typically minutes. That’s a medical and emergency and you should always seek medical care in those situations. Whereas when we start to think about regression, this is typically occurring over multiple days to weeks. And it’s a little bit slower. Often, we’re not seeing anything focal or specific, meaning that there’s not usually a weakness component or a sensory component, things like that.

Q18:  Do you follow the American Academy of Pediatrics and Adolescent Health Supervision Guidelines?

A18 (Taylor): They just came out a few weeks ago, so I’m not sure, but my family and I do follow the family friendly edition of the old version.

Q19: In looking at JASPER, what that stands for and it looks like what’s been looked at so far is for younger children, I’m wondering if there’s been thought or if it’s in place for older children and adolescents. Because I’m thinking of my daughter who has a more recent autism diagnosis as well. And I’m just interested to see if there’s research or programming that you’ve seen that’s effective for possible co-occurring disorders.

A19 (Dr. Baumer): JASPER was developed by Connie Kasari at UCLA actually, and her work has really been primarily in using the JASPER techniques in young children with autism. It has not been studied in teenagers and adolescents with autism or with Down syndrome. However, I think that some of the fundamental pieces of JASPER, which are very flexible, can be absolutely helpful and successful in older individuals. And so actually the next step within our progression of studying JASPER is to now look at it in school age children, with the primary focus on whether or not it improves behavioral regulation. And one of the phenomena that we see a lot in children with Down syndrome and also adolescents is this idea of being self-directed: wanting to do what they want to do, on their own time, in their preferred ways, but maybe being a little bit more resistant to adult led or other led type types of activities. And with JASPER this is one of the things that it targets. And so, I think that with the appropriate modification, it may be very useful in older age groups, although it has not been studied. Behavioral therapy in general, I will say is a very broad term. So, absolutely behavioral therapy is used in teenagers and adolescents using different models. I take care of people with Down syndrome and with people with autism who don’t have Down syndrome, and in my clinical experience, one of the differences and observations that I’ve seen is that in, in those, with Down syndrome, there is still more social engagement than in those with autism who don’t have Down syndrome. And so, some of the techniques (in ABA) that are a little bit more “sterile” (although it’s not a really great word) or not emotional, doesn’t tend to work as well for people with Down syndrome. So, I think for trying to find behavioral therapy that’s suitable, you want the kind of behavioral therapy that will be a little bit more socially engaging and responsive or play based, in general, can be a better fit. But it doesn’t have to be JASPER, I think just behavioral therapy in general, is great at teaching skills. And it’s also really great at reducing challenging or maladaptive behaviors.

Q20: I am from Mobile, Alabama. Have y’all noticed a regression of cognitive abilities in individuals with Down syndrome who have had COVID-19?

A20 (Dr. Bulova): I think that what we’re seeing is in people without Down syndrome, that there are long-term ramifications from the COVID-19 diagnosis in some cases. And these changes could be exaggerated in those with Down syndrome. There has not been a long-term study as of yet, in people with Down syndrome and COVID, but are researchers evaluating this. At the most recent Down Syndrome Medical Interest Group meeting, COVID was a major topic. It has had such terrible consequences for so many of our patients by eliminating so many of the social outlets that are vital for our patients. I think one of the concerns is that anytime there is a very stressful event, it can be a trigger for regression, or it can be a trigger for the beginning of an Alzheimer’s type dementia. We are concerned that this is something that may be a trigger for some of these more long-term problems. The best next steps are reintegrating our patients back into the things that were most important to them. How can we bring them back to what helped them to flourish in the beginning? Were there activities that they were very involved in? Are there people in their lives with whom they can reconnect? In some cases, our patients may need treatment for new onset depression or anxiety.

A20 (Dr. Baumer): Our team also sees individuals with Down syndrome and regression. And before COVID, we were seeing probably two to three new cases of regression per year and starting a couple of years ago with the COVID pandemic, that number rose dramatically. We have seen 16 to 18 since then. So I think that I would just add that if there really is a dramatic change in development and skills, I would have that evaluated because we know from everything that Dr. Santoro was talking about too, that it may be that there is some trigger from maybe the psychosocial aspects of the pandemic and the isolation and all of that, but also potentially for somebody who had a COVID infection, some other kind of, inflammatory or subsequent process. I think anytime that there is a decline in skills, it needs to be seriously evaluated.

Q21: A few others have also asked about sleep apnea and how to get compliant with using CPAPs. They’ve tried a lot of different things on the one hand, what is going on with the Inspire, the new device. We had promised to talk a little bit about inclusion and exclusion criteria, and there’s another question about whether very young children can participate.

A21 (Dr. Baumer): We have not been doing this in very young children. The first line treatment for obstructive sleep apnea is often having the tonsils and adenoids removed. So that is one of the first interventions. We definitely struggle with having especially young children tolerate wearing a mask. Some of the things that we’ve tried have been social stories and video modeling, and we even have had an adult with Down syndrome do video FaceTime conference calls with people before bed to show them putting on the mask and trying to use some positive reinforcement. I expect that as more data is gathered as with all sorts of things in research world and in clinical trial world, it starts with adults and then trickles down to Adolescents and then younger children and then ultimately the youngest of children. So, I think it’s going to take a little bit longer until it gets to a younger pediatric population.

A21 (Dr. Bulova): I think that sleep apnea is one of the biggest topics that we need to cover. Inspire has good data in all adults; it’s now approved for people with and without Down syndrome. The exclusion criteria that is most important is it does not work nearly as well in people that have an elevated BMI.  The most recent BMI number given is above 31 as exclusion criteria. Inspire works as a pacemaker, with one lead to the hypoglossal nerve and one to the lung. And every time you take a deep breath (inspire), it’s triggering the hypoglossal nerve to push the tongue forward allowing better airflow. It does not tend to work as well in people that have a very high BMI. There’s too much extra tissue in the way. In 2014, when the first new England journal study came out was from Pittsburgh. We have a large center here where they do the inspire procedures. Another one of the big centers is up in Boston too.

Q22: Is regression something that happens in typical people or people without Down syndrome and or any other group of people?

A22 (Dr. Santoro): We actually see regression in a variety of different genetic disorders, autism being one of them, Phelan McDermid syndrome is another one that actually exhibits kind of this neuropsychiatric regression of skills. In these populations, we’ve encountered the exact same problem that we’re seeing right now in individuals with Down syndrome. It’s called different things so that the workups have been very nebulous, or kind of heterogeneous let’s say. But we definitely see it. And I think that the question here is how linked in are these? As you saw in Dr. Espinosa’s presentation when we see all these inflammatory biomarkers, and then we see this data in individuals with Down syndrome, it makes a nice story, and it requires further research to make it concrete evidence. All of these things have been linked to changes in the immune system. And so actually, if you look at individuals, let’s say who have multiple sclerosis, not Down syndrome, you find that an environmental stress, like a marital status change or a family member moving out, things like that are present in about 30% of individuals before they actually show up with their first presentation. And again, it’s tough because I think that when we look this from this as the global picture–that’s why we really have to have that multidisciplinary approach to make that assessment.

Q23: I have a daughter with celiac disease, and I’m actually a dietician and I did not see the signs. I just thought she had lactose intolerance. She did not have diarrhea or things like that. So I just wanted to ask two things. First of all, could you go over what people should be looking for with celiac disease symptoms that they might not see? And then also is there anything you can do to help get back from when a child receives gluten on accident? A23 (Dr. Bulova): There is some information that’s on GLOBAL’s website. There is a list of common presenting signs of celiac. The most common symptoms of celiac disease include:

• Abdominal bloating and pain
• Chronic diarrhea
• Vomiting
• Constipation
• Brain fog or headaches
• Weight loss or poor weight gain
• Irritability
• Delayed growth or puberty
• Fatigue
• Anemia
• Behavioral changes

I think weight loss is probably the most important one, or in someone that’s still growing who has poor weight gain. When we’re looking at laboratory studies, the most important one would be an iron deficiency. That’s something that’s so easily missed. I check for celiac anytime there’s a behavioral change in adults. Sometimes it’s more aggression or acting out, or not being able to focus in school.  Several years ago, we had a patient who presented with regression. This individual had both sleep apnea and celiac. And when both of those were treated back to baseline, the behavioral changes resolved.

Q24: About the JASPER: How closely does it mirror ABA therapy, and have you all had anybody that in this beginning study attend both and what that difference would be?

A24 (Dr. Baumer): We have not actually have people that have received JASPER and sort of more “traditional” I’ll call it – discrete trial training type of ABA. That’s a little bit more, one to one. The main theory behind all behavioral therapy is that you reinforce the behaviors you want to see more of, and you don’t reinforce the behaviors that you don’t want to see. And that’s a sort of general principle. JASPER incorporates a lot of those principles, but all through a play mediated approach. I don’t see any reason why one couldn’t use both types of strategies. They’re not in conflict with each other in any way, but at least in, in our area, if you don’t have a diagnosis of autism, you can’t access the ABA therapy. It’s just not possible to get. We haven’t had the opportunities to see somebody having more than one. People with autism were not excluded from our JASPER study. So there are some people with autism who are getting JASPER in our Down syndrome study. But we haven’t had enough to analyze the difference in those who have autism compared to those who don’t. So it’s a future direction for us to really be able to look at that. But JASPER is not everywhere. It’s primarily right now on the west coast because an expert at UCLA is the one who has developed it and brought it into a much larger audience. And what’s really great about JASPER is that it doesn’t rely on a single provider doing all of the therapy. It can be parent-mediated. So, a parent gets trained and then beyond those sessions that are with a therapist, the parent is using those strategies all the time. And it is also being worked on in a school setting. So can we teach teachers how to use these strategies and then teachers use it and then more and more people have access. So I think it’s trickling, but more research is needed until it becomes more widely available.

Q25 (For Taylor): What do you think about the new Family Friendly GLOBAL Medical Care Guidelines for Adults with Down Syndrome?

A25 (Taylor): The toolkit is amazing. Family can check in dates through nine areas. Families continue to help our scientists.

Q26: I became familiar as a parent with IVIG when my daughter had leukemia treatment. Now, we are seeing symptoms of pain in her arms that they just can’t figure out what’s wrong. And her cytokine is way high. So is that something that I should push for? Should I ask to try for an IVIG to see if she would need that? Could it be done preventatively, or should I just keep my eyeballs on it?

A26 (Dr. Santoro): IVIG works a lot of different ways, and I think that what we see in individuals with Down syndrome, whether they’re going through a chemotherapeutic regimen or not, is that particular inflammatory components will be elevated. And it’s likely that IVIG is working on some of them. Now, the challenge, whether you have regression, or whether you have something kind of in between, is that IVIG is not going to get approved very easily. And I think that that’s where the importance of the clinical trial that we’ll be running with the University of Colorado is really important is If we can get a randomized control trial, even just for regression, it will open up a lot of doors. But as for the specifics, it’s challenging because IVIG can increase T-cell regulation and T-cells are important in this process. It can Downregulate cytokine response. And so, it has so many broad effects, but it’s also not a wonder drug for everybody. And I think that if you look even in the autism literature, there have been multiple studies looking at, IVIG and autism, some children benefited but most children did not. And I think that that kind of closed the door in that field. But similarly, we have to be very rigid with how we approach it in individuals with Down syndrome. So that way we ca hopefully access it for a variety of different reasons.

Q27: When you begin to see changes in your loved one, when you begin to notice things going on, less interested, where do you begin?

A27 (Dr. Bulova): With the presentation of a decline in skills or a major behavior change, I review medical issues first that can cause problems. Was there a change in thyroid? Was there change in B12? Is there new sleep apnea? Is there a major weight gain? Some of the dysfunction of organ systems can present differently in people with Down syndrome. GI is an important one is for a 31-year-old. I’m always thinking about reflux because it very commonly occurs in adults and often causes a behavior change of some kind. One should step back and think about what the most common medical issues are and how they might present.  Listening to our patients and seeing what type of changes they have made may lead us towards the correct diagnosis.

Q28: I’m now working with a team on my son’s nose, ears, and sleep. But he has a severe underbite. We’ve tried braces and mouth cords, but the surgical procedures absolutely scare me. So I guess I was kind of hoping that someone could recommend a direction for the underbite situation because his teeth are very important.

A28 (Dr. Bulova): The first place I would start is with the American Association for Developmental Medical and Dentistry: AADMD–this is a group of Providers that specialize in dental medicine for those with developmental disabilities. They are national.  Their website is https://www.aadmd.org/

Q29: What do you do to keep healthy?

A29 (Taylor): I visited all my doctors regularly. I use my Apple watch to close my stand goals ore and exercise me.

Q30: If you’ve had a diagnosis of Alzheimer’s and all of a sudden you see these drastic changes that of aggression and stuff that have never been before. Is that just the Alzheimer’s or do you need to be thinking about regression or, and should you even try to treat it? The person that we’re talking about is 47.

A30 (Dr. Santoro): The criteria for regression does excludes anyone that has Alzheimer’s type dementia because the treatments are probably quite different. The physiology is quite different. If there are amyloid plaques and tangles that are already present in causing symptoms. I think many of the ways that we treat it would be the same. I mean, we look at anyone with signs of mood disorder, and dementia benefit from treatments, both psychological treatments, as well as medical treatments.

Q31: There is some literature that shows that the lifespan is different in an African American with Down syndrome. What are we doing about racial diversity and looking at the growing Latino population?. Is there any good research going on there and, uh, any recommendations?

A31 (Dr. Santoro): Everybody needs to be involved in research. At our clinic in Los Angeles, 80% of my patients are of Hispanic descent. That’s not similar to a clinic in Boston or Pittsburgh or even San Francisco. I think that as we enroll patients into studies and look to do additional research, it is incredibly important because as time has gone by in the world outside of Down syndrome, we’ve seen that different ethnicities, different heritages have different risks are responsive to different medications are responsive to different medication doses.

A31 (Dr. Baumer): I think this highlights an important concept in not just research in general, but specifically research in individuals with Down syndrome–Everybody needs to be at the table.

Part 2: Unanswered Questions Submitted Online

Q32: Is there a higher prevalence of diabetes in adults with Down Syndrome?  

A32 (Dr. Bulova): In our literature review for the GLOBAL Adult Guidelines – we did find a higher incidence of diabetes in adolescents and adults with Down syndrome. This study from the UK looking at 3,808 patients found that diabetes prevalence was higher in adults with Down syndrome compared with general population–matched controls (3.5% vs 0.7%, respectively, for ages 16 to 30 years and 5.5% vs 2.7%, respectively, for 30 years or older). Because of this we recommend screening for diabetes at an earlier age than in those without Down syndrome.

Q33: Do you recommend traveling to see a doctor who specializes in adults with Down syndrome?        A33 (Dr. Baumer): If there are specific health concerns, or you are concerned that your Primary Care Physician (PCP) is not aware of best practices you should share GLOBAL Adult Guidelines with your PCP. If travel to an adult center is not feasible, can also consider use of second opinion platforms.

Q34: Are there any long-term studies following those with Tetralogy of Fallot, and please share any other information about adults with Down syndrome who have Tetralogy of Fallot.   

A34 (Dr. Santoro): There are no specific studies dedicated to following persons with TOF specifically although congenital heart disease is being followed actively. The outcomes are very broad, but it does appear that most children with Down syndrome who have TOF that is surgically repaired early do quite well. There is a link with more pronounced developmental delay (more so than other children with Down syndrome) and potentially autism spectrum disorders although the data sets are small still. More time will be needed to conclude anything specific in persons with Down syndrome and TOF.

Q35: Could you please talk about the concern around Atlantoaxial Instability, how to test for it, and what can be done to prevent issues whether it is diagnosed or not.

A35 (Dr. Bulova): Xray’s were not found to be sensitive or specific for diagnosing atlantoaxial instability.   Therefore, routine cervical spine radiographs should not be used to screen for risk of spinal cord injury in asymptomatic individuals. Instead, annual screening of adults with Down syndrome should include a review of signs and symptoms of cervical myelopathy, such as altered gait, new incontinence, brisk reflexes, or clonus, using targeted history and physical examination. This is from the GLOBAL Guideline consensus group.

Q36: Can you please speak about CBC – low white count in individuals with DS. How it is common? When to involve a hematologist? And the other factors of a CBC that may just be a part of Down syndrome?      

A36: (Dr. Espinosa): One study showed that 2/3 of people with Down syndrome had a high MCV (Mean corpuscular volume) and 1/3 had a low white count. Red cell counts are also often mildly high. We usually involve a hematologist for low white count (leukopenia) if the counts are consistently dropping, or the person has other signs of systemic or hematologic conditions such as easy bruising, petechiae (pinpoint round spots on skin), lethargy, change in feeding, or unexplained weight loss. Leukemia is much more common in children – more than 90% of cases occur before age 20.

Q37: What are they finding with COVID and the variants for those with Down syndrome? Our son was asymptomatic, and we were sick with COVID.

A37 (Dr. Espinosa): The evidence is very clear: people with Down syndrome are at higher risk from developing severe COVID-19. This is particularly true for adults. Adults with Down syndrome age 40 have a similar risk profile as typical adults 80 and older.

A38: My son has been diagnosed with rheumatoid and psoriatic arthritis. He does have a rheumatologist and is currently on gabapentin. He still has a great deal of pain on some days despite his high pain tolerance. Do you have other suggestions for treating his condition and his pain?

Q38 (Dr. Espinosa): I suggest that the possibility of using a JAK inhibitor be discussed with the attending rheumatologist. If the diagnosis is indeed rheumatoid arthritis, there are several JAK inhibitors approved for this condition, and the evidence from the study of the immune system in Down syndrome indicates that JAK inhibitors would be the preferred treatment over other approved treatments.

Q39: My daughter never seems to get full, and her doctors have asked her to lose weight. We have tried everything behavioral but have failed. Any suggestions?    

A39 (Dr. Bulova): There are weight loss medications and bariatric surgeries that have been effective in adults with Down syndrome. These are worth discussing with your doctor.

Q40: Any new developments in Moyamoya disease?    

A40 (Dr. Santoro): Better patient and doctor education has led to an increase in early diagnosis over the last few years. Our center at CHLA is looking into non-invasive ways of identifying Moyamoya disease before it happens. If you are interested in participating, please email: dsresearch@chla.usc.edu!

Q41: Any medical treatment for Moyamoya? My son 42-year-old was ruled out for vascular surgery. One of the major arteries needed for the bypass was compromised.            

A41 (Dr. Santoro): We are actively researching this as well. Right now there is no medical treatment to reverse Moyamoya disease in persons with Down syndrome. Sadly, surgery remains the only option.

Q42: We have found that multiple vitamins like MSB from NutriChem keep our daughter healthy. Do you recommend supplements?        

A42 (Dr. Baumer): We do not recommend any specific vitamins or supplements for individuals with Down syndrome. There is a lack of research demonstrating effectiveness.

Q43: Can you comment about intestinal problems from low muscle tone?          

A43: (Dr. Baumer): Constipation is very common, likely related to low tone and decreased motility in the gut.

Q44: I attribute the hand gesturing which seems to be uncontrollable to anxiety, is it? 

A44 (Dr. Santoro): Anxiety can be expressed in a number of different ways and can include unusual/altered gesturing (e.g., rubbing hands together, repeatedly playing with hair, tapping fingers). If you are noticing these behaviors during times that your son/daughter appears nervous and tense, it could be that these gestures are indeed related to anxiety. However, usual motor behaviors can also be due to other things — so this is a good question to bring up to your son/daughter’s treatment team so that they can fully assess factors that could be causing the gesturing.

Q45: My son is extremely fearful of needles, so it is impossible to give him immunizations or draw blood from him. We have tried everything from mild sedatives to bribes, and nothing works. In your experience, can you offer ways/techniques/medications to reduce his anxiety so these important medical procedures may be performed?               

A45 (Dr. Bulova): I think social stories are a great preparation tool for these situations.  Some excellent examples can be seen at these websites:

https://www.massgeneral.org/children/down-syndrome/patient-handouts

https://adscresources.advocatehealth.com/

Q46: Do people with Down syndrome have more food allergies/intolerances than those without Down syndrome?               

A46 (Dr. Baumer): Food sensitivities / intolerance are often reported; however, I am unaware of research that shows higher prevalence of food allergies.

Q47: What have we learned about COVID19 vaccination efficacy for teens with Down syndrome, particularly with the latest variants? Would you say our kids/teens are generally immune-compromised and if so, thoughts on a 2nd booster?             

A47 (Dr. Baumer): While immune differences have been described in people with Down syndrome, not all individuals with Down syndrome would be described as having “immunocompromise.” Currently available data indicates that vaccinations for COVID-19 are well tolerated and are effective in people with Down syndrome.

Q48: Does there seem to be a higher incidence of lupus in individuals (particularly females) with Down syndrome?               

A48 (Dr. Espinosa): To my knowledge, there is not strong data in this area. However, interestingly, both lupus and Down syndrome share obvious dysregulation of the interferon response, a key aspect of the immune system. Anti-interferon therapies are now approved for lupus and currently being tested at the Crnic Institute for Down syndrome.

Q49: Are their current research projects trying to unlock the mystery to why individuals with Down syndrome are less likely to develop cancer and die from it?     

A49 (Dr. Espinosa): There are. We are particularly interested in the notion that the protection may arise from a hyper-vigilant immune system.

Q50: What intellectual research is going on for the younger age?            

A50 (Dr. Baumer): Many researchers are working to understand development and cognition in young people with Down syndrome.  https://clinicaltrials.gov is the best place to look for active research studies that are recruiting participants.

Q51: My daughter was diagnosed with PANDAS several years ago, which is also a blood brain barrier disorder. We saw relief of symptoms at diagnosis with antibiotic treatment. But as she gets older, she continues to collect diagnosis (ADHD, OCD, ODD, PICA and anxiety). I’m wondering if it’s possible some of these behaviors are remnants or manifestation of the PANDAS. And like with Down syndrome regression, IVIG would help? I’m thinking the anxiety piece especially, since her doctors and I have theorized anxiety is a driving force behind the other diagnosis.               

A51 (Dr. Santoro): This is a very complex question. When unclear diagnoses are present and diagnoses are starting to be stacked, it is most prudent to seek multidisciplinary care. In your daughters case it may be best to seek the care of a center that has integrated neurology, psychiatry, and immunology. Teasing out the cause of each symptom can be very challenging, especially with regards to knowing which to treat. In general PANS/PANDAS is not reported any more or less frequency in persons with Down syndrome as opposed to other conditions.

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