Dr. Michael Kruer (00:00):
For families that might be listening, I think that this is a hot topic in the field and it's something that's worth discussing with your doctor.
Jason Benetti (00:08):
Welcome to Let's Talk CP, the new podcast series about all things cerebral palsy, presented by The Cerebral Palsy Foundation. Each episode features different clinicians, parents, people with CP, and other experts talking about ways to help you better navigate your journey with CP. I'm Jason Benetti, play by play announcer of the Chicago white Sox and ESPN. and I have CP.
Cynthia Frisina (00:35):
And I'm Cynthia Frisina, the Vice President of Partnerships for the Cerebral Palsy Foundation and a mother of a daughter with CP as well. On today's episode, back by popular demand, we have part two of our discussion with Dr. Michael Kruer. Who's here to join us today to talk more about genetics and the relationship of genetics to cerebral palsy. Dr. Kruer, thank you so much for joining us again today.
Dr. Michael Kruer (01:05):
Oh, my pleasure. Thanks again for having me.
Cynthia Frisina (01:07):
We're so excited because based on all the new research that we've been hearing about and the response to our first episode, where you started to talk about genetic causes of CP and some of the research that you are doing, we really had a lot of families reach out and want to learn more. So, for those families who didn't hear the first one, we encourage you to go to CP resource dot org under podcast, and you can hear all of our previous episodes and you can also listen to Let's Talk CP on any of your favorite podcast platforms. So, Dr. Kruer, for those who maybe didn't hear the first part, we'd love to first start out a little bit about you, and your background, and what you do. And then we're going to get more into the conversation about genetic considerations for CP and the research that you're doing.
Dr. Michael Kruer (02:05):
Yeah. So, thanks, Cynthia. I'm a physician scientist based here at Phoenix Children's Hospital and the University of Arizona, College of Medicine in Phoenix. And my specialty is in caring for children with CP and related disorders. And so, my background is as a pediatric neurologist, specializing in movement disorders and children, and as a specialist in developmental medicine as well. And for a long time now, probably about a decade, I've been very interested in trying to understand what the fundamental causes of CP are, with the hope that we would really be able to use this information to not just band-aid symptoms, but to really target what's going on in the brain in people with CP and treat the root cause of the condition. And that process has really led to my laboratory's current focus on the genetic basis of CP.
Cynthia Frisina (03:06):
That is so fascinating because, Dr. Kruer, I know that you're aware that so many families for years, decades, have been told that they, when they get received that diagnosis of CP, historically, they were not given any direction or information that this could be a genetic cause. How did that whole... How did the light shine on this area that there could possibly be some genetic causes of CP?
Dr. Michael Kruer (03:37):
Well, I think it's... There's been a couple of converging efforts that have really led us to where we are now. So, there are a number of investigators and research groups around the world that are really trying to get at the root of this question. For me though, it actually stems back to my training days when I met a single family, quite exceptional family, that really challenged my thinking and challenged what I was being taught at the time that the CP is not genetic. And it's through caring for members of that family, that my eyes were opened, I guess, to this concept that CP, in many cases, like other neurodevelopmental disorders, can be genetic in origin. And that's really been very exciting for me as a practicing physician because we're now starting to, not only see this information begin to affect diagnosis, but we're also, what I think is most exciting about all this, is that we're starting to see this actually affect treatment. And so, we're very optimistic about what this is going to mean for the future of CP care.
Cynthia Frisina (04:55):
That's so... That's really exciting and it's so gratifying. I know being a parent of a daughter with CP, we wait, we watch, for any breakthrough or something promising. And my understanding is that you do have some updates on research and National Institutes of Health, NIH, funding for your research, and would love to have you give us an update, give all of our listeners an update about what you're working on and what your current research is looking like.
Dr. Michael Kruer (05:31):
In terms of our current studies, we're focused on a number of different areas, but really the fundamental theme, I guess, is that we're trying to better understand how genetic mutations, that is how misspelling in the genetic code can actually lead to cerebral palsy in certain individuals. And this is by effecting fundamental brain development at an early stage. And we think, essentially, what's happening is that each of our bodies has thousands of genes that are responsible for telling our brains how to grow and develop, and ultimately function. Each of these genes is like a tiny recipe book within our bodies, directing these processes and taking a few cells very early in development and eventually getting them to the point where there are literally billions of interconnected brain cells in an individual's brain that are communicating and integrated into a network.
Dr. Michael Kruer (06:40):
And so, what we're starting to find, when you really think about it, it's amazing, given how complex normal human brain development actually is, that anything actually goes right when you start to really see the complexity of the process, but we're finding that, for many individuals with genetic forms of CP, there's a typo in just one out of the three billion base pairs that make up the human genome, or sometimes a small segment of the genome, the recipe book of life, if you will, that's actually missing. And these small typos can actually mean the difference between having CP or not. And we think that this is because that these typos cause brain development to turn left when they should turn right, for example.
Cynthia Frisina (07:34):
How would a family know? Are there signs to look for if they have a loved one that's been diagnosed with CP in order to think about, "well, gosh, maybe this is something genetic or there's a genetic cause I should be looking more into."? Are there clues or guidelines that you could recommend?
Dr. Michael Kruer (07:57):
Yeah, it's actually an area, a very active research, because we're trying to better define this. I think that the individuals that we're finding a genetic cause for their CP, and most frequently, are folks that don't have another apparent reason for their CP. So, people that were not born premature, that did not have a lack of oxygen, for whom there was not a stroke, or an infection, or any other of the major risk factors that are known to cause CP. We're finding this for a large proportion of those people, we're able to identify a genetic misspelling that actually seems to directly lead to their CP. So, I think that although that group represents an important subgroup, if you will, that there, we're also finding interestingly that for individuals that do have some of these traditional risk factors, we're identifying mutations as well, although to, in a smaller proportion. And so, I think that one of the reasons why I say this is an area of active research is because I think we really need to define this better to help guide practicing doctors and practitioners in terms of who should get genetic testing for their CP.
Cynthia Frisina (09:18):
Are there guidelines that families could discuss with their primary care physician or look up online that would lead them to think, "Gosh, maybe I should have my child or my family member tested."?
Dr. Michael Kruer (09:33):
Yeah. Unfortunately, at this point in time, there's not, and that's a gap that we're actively aiming to fill with our research. So, we're hoping to use the research that we're currently working on now with other, any other collaborators to answer that question scientifically, and then to turn that into two guidelines that can help guide clinical practice. Some things to think about, at this point in time, are, if a child or an individual with CP does not have an obvious environmental cause for their CP, if that individual has a normal brain MRI, that can also be very suggestive that there might be a genetic contribution. And we're also seeing that for many individuals that have genetic forms of CP, they might have other organ systems involved. So, for example, they might have birth defects that could be very small in nature or large, such as congenital heart disease. But none of these things are hard and fast rules at this point in time. And so, for families that might be listening, I think that this is a hot topic in the field and is something that's worth discussing with your doctor.
Cynthia Frisina (10:49):
It's definitely a hot topic, that is for sure. And one question I know that I keep hearing a lot is what?... Is there a suspicion on your part of what percentage of CP diagnoses might actually have a genetic cause? Is there, I know that is an evolving number, but is there a thought about what the actual percentage might be?
Dr. Michael Kruer (11:18):
Yeah, it's again, a very controversial and important question, and I think that the studies that have been done, both by my group and others, have come up with figures anywhere from 14 to more than 30% of CP might be due to genetic mutations or misspellings in the genetic code. I think that we need additional studies to really distinguish which risk factors are the major causes for CP. So, I think, again, that more research is needed to really nail that down further. But what I find fascinating is that even though, I, like many others, during my training was taught that lack of oxygen to the developing brain is the number one cause of CP. We now know that based on a number of studies that likely amounts, or accounts for, about six to 10% of CP. And so, it's looking like genetic contributions might be even more substantial than lack of oxygen.
Cynthia Frisina (12:28):
Right. [crosstalk 00:12:28].
Dr. Michael Kruer (12:28):
[crosstalk 00:12:28] Something that, if that holds up that would be quite remarkable.
Cynthia Frisina (12:32):
Right. That would be a game changer. I think there are so many common misconceptions about cerebral palsy and the cause. And one question I had, I know you mentioned prematurity, and obviously, not all babies who are born prematurely end up with a CP diagnosis, but that is a risk factor. And are there other considerations that a family who might have a baby that was born earlyish, that they should be looking at, or considering, as it relates to a possible genetic cause if their baby was also born prematurely or is it still too early to make that hypothesis?
Dr. Michael Kruer (13:16):
Well, again, not surprisingly, we don't have as much data as we would like, so it's difficult to give you a precise answer to that question, but I will tell you that we do have enough data, at this point, to know that some babies that are born premature may actually have a genetic condition that both predisposes them to the prematurity and also may predisposed to CP. And so, I think with that in mind, it's not too early to start thinking about whether genetic contributions might be at work for a particular child. And so, even though we don't have a grasp on what this means for entire population of people with CP, on an individual by individual basis, we now have the tools where we can start to ask these questions. And many times, actually, offer answers to families as to the question what is causing my child's CP.
Cynthia Frisina (14:16):
And speaking of that, is there an age limit on diagnosis in terms of having a genetic cause? I know we talk a lot about children, youth, babies, but if there's an adult who might have been diagnosed with CP years ago, but then some of these risk factors or other considerations in their family that weren't obvious maybe a long time ago, but now are, is it too late if you're an adult to be diagnosed with a genetic cause of CP?
Dr. Michael Kruer (14:52):
No, in fact, some of the best questions that I get when I do public talks and presentations on this topic come from adults with CP, who have wondered as to what the cause of their own symptoms are, or sometimes from the loved ones or family members of an adult with CP. So, no. So, our genetic makeup, by and large, doesn't change much throughout our lifetime. And so, that's something that if a person does have a genetic cause for their CP, that can be detected in childhood, but it can also be detected in adulthood. One caveat that can sometimes make things a little bit more complicated is that we're finding a lot of the genetic forms of CP arise what's called denovo, seemingly out of the blue, which means that neither the mother, nor the father carry that misspelling in the particular gene that leads to CP.
Dr. Michael Kruer (15:51):
And for those individuals, it can actually be very, very helpful to test both the mother and the father, as well as the individual with CP, to just do a comparative analysis and essentially ask the question, what's different about this person with CP, what's different about the child in their DNA and their genetic makeup that might have led to their CP. So, having parents willing to participate either in clinical testing or in research studies, like the ones that we're doing is very, very helpful. So, for example, for our current research study, there's no age limit to participate, we're accepting both children and adults, with the caveat that the parents need to be available to participate because that information can be so valuable.
Cynthia Frisina (16:43):
Well, I know the question of all of our listeners right now, now that you've said that are, how would a family get involved in your study? How would they sign up? Do they have to live in the local area? Or is there... Is it more broad than the Arizona area where you are?
Dr. Michael Kruer (17:03):
Yeah, so we we've actually partnered up with the Cerebral Palsy Research Network for our current study, which is funded by the gracious support of the National Institutes of Health. And so, through that collaboration, we're working with the CP research network, doctors, therapists, and researchers, and advocates, to gather data as people are actually seen. And so, just by receiving care at a CP research network site, the network is collecting data for the purposes of improving care for people with CP. The partnership with the CPRN is allowing us to basically match the genetic information of those individuals that are interested in participating. So, for example, if a family receives care at a participating CP research network site, then just by virtue of receiving care at that center, they're eligible to participate in our genetic research study. And that genetic research study is something that's available to folks across the country. The process itself actually involves a fully electronic self-contained consenting application. So, basically, you can pull this up on your smartphone or your home computer, enroll yourself and your family members in the study, and be able to participate free of charge.
Cynthia Frisina (18:32):
Oh, that's amazing. And we will include all of this information on our podcast show notes, as well as our websites, CP resource dot org, so that, if you're listening and interested in learning more, you'll be able to know where to go and what to do to get that information. So, Dr. Kruer, I have another question because this is really such a fascinating field of study. Of your work to date, how many different genetic causes of cerebral palsy have you found so far?
Dr. Michael Kruer (19:02):
Yeah. So, when we first were going into this, we thought that we might find more than one and, in retrospect, we were right in that regard, but I think that I am continuously humbled by how complex the human brain is. And we're finding, certainly not just one, not just dozens, but probably hundreds of different genes that are important for normal brain development may be relevant for CP. And what we think is occurring is that there are essentially hundreds of different ways that if a gene that normally help the brain to grow and develop and function picks up a mutation or a misspelling that that can affect early development and lead to CP. So, that can be a bit overwhelming to think about hundreds of different genes leading to CP, but that's actually on par with what we're seeing for other neurodevelopmental disorders, whether you're talking about learning problems, autism spectrum disorders, or even epilepsy.
Dr. Michael Kruer (20:08):
What's been heartening, I would, I'll say though, is that we're not finding so far that these genes are just randomly distributed. It's not just completely random what these genes seem to be doing. Instead, they seem to be falling into certain patterns or networks. And these gene networks are important for fundamental processes in normal human brain development.
Cynthia Frisina (20:33):
Wow, that is really helpful information. Of all of that, are there?... Have you found that there are some more common genetic causes? I mean, are there certain deficiencies or certain things that seem to cluster together that you have found so far, or not really?
Dr. Michael Kruer (20:52):
Yes. So, in fact, some of the genes that we found are important for the very process by which early brain cells will grow and sprout connections, almost like branches and leaves on a tree, if those connections and the process of forming them are disrupted. That means that brain cells might not be able to communicate effectively and form a network, talk with their neighbors to form a functional motor unit, for example. And so, we're finding that certainly some of those physical connections are disrupted. We're finding that some of the molecules that govern early brain development also seem to be affected, but what's been quite interesting is that we're finding sometimes the same genes are hit again and again. And so, even though there are looking to be hundreds of different CP genes, quote, unquote, it's seeming like certain genes are actually more common than others.
Dr. Michael Kruer (21:55):
And so, one of the implications here is that some of these genes are already known to cause certain rare disorders. And it's actually opened up a really rich dialogue between families and researchers, and physicians that are... That care for individuals with rare disorders. Because, I think from a certain point of view, one might argue that an individual who has a mutation in a gene that affects brain development and leads to learning problems, and seizures, and CP, might in fact have a rare disorder. Other people might look at that same scenario and say, "Well, that individual has CP." And so, the debate in the field is, "Well, which one is right?" And I think that, as far as my own perspective, I think they're both right. I think both perspectives are very valuable. And so, for families, I think it's valuable to have a connection, some cases to the rare disorders community, but I also think it can be very, very valuable for those families to have a connection to the cerebral palsy community. And I think through this kind of crosstalk and collaboration, we're really going to be able to help move the needle.
Cynthia Frisina (23:07):
Well, the million dollar question then, I think, probably many families would want to know is, if they are diagnosed with a genetic, any of these genetic mutations, are there any promising treatments for them that have shown up or that you know of? Is it like, are any of them a treatable situation?
Dr. Michael Kruer (23:29):
The short answer is that, so far a small proportion of them do have specific treatments outside of the usual symptomatic treatments that individuals with CP might undergo. So, for example, for some individuals with CP, we'll identify a genetic cause for their symptoms, and that can be very valuable information. It can provide a sense of closure for the family. It can give them a sense of what their risk of recurrence might be, if they have other children. It can even give their doctors the ability to potentially prevent certain complications before they arrived. But for many individuals, at this point in time, it won't fundamentally change their CP care. For probably around 10% of those individuals though, we're now starting to find that the genetic information, knowing the cause of their CP, actually can influence their treatment. And this varies based on individual cases.
Dr. Michael Kruer (24:37):
So, depending upon what we find, will determine whether or not there's anything, additionally, that can be done for treatment. And when I say treatment, sometimes this means, again, avoiding potential complications. Sometimes this means actually using dietary therapies, for example, that otherwise never would have been considered for CP. In other cases, this means that people and their families might be eligible for clinical trials that are going on, and perhaps, most excitingly, we're also starting to find that for a small, but growing subset of individuals with genetic forms of CP, we're able to reach for something off the shelf, a medication or a treatment, that might have actually been developed for a different reason or a different condition, but that can be repurposed and potentially used to treat the underlying causes of their CP.
Dr. Michael Kruer (25:35):
This is leading to a really fascinating borderline between research and clinical medicine. And this has really been the, one of the things I've been most interested in recently, because these so-called N of one trials, this space allows clinicians, and researchers, and families to work together to really try to see if, sometimes, potentially exciting new treatments might be able to be utilized appropriately for an individual with a genetic form of CP.
Cynthia Frisina (26:07):
This is such exciting and hopeful information for the field. So, I so appreciate you sharing it with our listening audience. One question I'm sure that also families are wondering is, what kind of clinician should refer a family to genetic testing? If some of this is a concern to a family, what would they do next?
Dr. Michael Kruer (26:30):
Yeah, so I think CP care is interesting because it affects so many different domains of development and function in the person with CPs life. It really does take an entire team of experts, and often specialists, in order to be able to effectively care for that individual and provide him or her with the support that they need. And so, as it turns out, people will actually identify sometimes very different providers as the primary individual that cares for their CP. What I would say is that it's more important than the precise specialty or fields of expertise of that provider is just that the family has someone that they can go to, that they trust, that knows themselves or their child, and it can serve as a sounding board.
Dr. Michael Kruer (27:23):
And so, in some cases, this means that the family might be able to approach the individual, the provider that cares for their CP principally, and that individual might be knowledgeable in this area and might be able to help guide genetic testing. In other cases, that individual can serve as the quarterback of the team and get them to someone who can. And we're finding that this varies sometimes that that individual might be a neurologist. Sometimes it might be a developmental pediatrician, a ped rehab doc, a genetic counselor, or a clinical geneticist, among others. So, I think that although the final destination can vary from case to case, just starting the conversation is the most important step.
Cynthia Frisina (28:11):
Oh, that's really helpful. And is there any other information or advice for families that you would like to share about this, in terms of things they should be keeping in mind, if it turns out that their child does have a genetic cause with CP? Or just even a family who is wondering about this? Because they don't know exactly what caused their child's CP diagnosis.
Dr. Michael Kruer (28:35):
Sure. And, I guess in some, what we're finding is that the why's do matter. And sometimes the why's might matter just to have a more complete understanding of what caused an individual's CP, but might not necessarily directly change their care at this point in time. However, I think the field is rapidly changing and as our understanding of brain biology is improving and its therapies are moving along in a, at a rapid rate. I think that over time, the number of individuals for whom we're able to target, their symptoms based upon the cause of those symptoms, is only going to increase.
Dr. Michael Kruer (29:20):
And so, research never moves as fast as we all want it to, but anything that can be done by families, and advocates, and those in the field to support this work and to really help to improve awareness and understanding is going to, I think, circle back and pay dividends for years to come. And so, I think that just increasing awareness, having conversations, and then just being aware of what might be the cause of an individual's CP, is going to prove to be increasingly important in making treatment decisions. And so, I think the future, the outlook is very hopeful.
Cynthia Frisina (30:06):
Well, thank you, Dr. Kruer, for joining us today on another great episode of Let's Talk CP. You can find all of this information on CP resource dot org, as well as your favorite podcast platforms.
Jason Benetti (30:21):
Thanks for joining us for this episode of Let's Talk CP. I'm Jason Benetti, CPF Ambassador, and sports television announcer. If you like our show and want to know more, please visit our new CP resource page at CP resource dot org, where you can listen to all of our episodes and subscribe, so you'll never miss a show. While you're at it, if you found value in Let's Talk CP, we'd appreciate a rating. And please tell a friend or another family member about the show to help others and increase cerebral palsy awareness and education. Be sure to tune in to Let's Talk CP for our next episode.
Cynthia Frisina (30:59):
This podcast represents the opinions of our guests and the content should not be taken as medical advice. Each person and situation is unique. So, please consult your healthcare professionals for any medical questions.