Shedding Light and Love on a Rare Genetic Condition with Deborah Vauclare

Episode Transcript

Dr. Correa:
From the American Academy of Neurology, I'm Dr. Daniel Correa.

Dr. Peters:
And I am Dr. Katy Peters, and this is the Brain & Life Podcast.

Dr. Correa:
Welcome back to the Brain & Life Podcast. I'm so glad you're able to join us today, and I'm looking forward to you hearing this episode. Katy, in neurology, we see and help people with many rare and uncommon conditions, how do you help people and their families understand when they are affected by a condition they've never even heard about?

Dr. Peters:
Daniel, as you know, this can be just so challenging. Patients and families, they want data, they want expectations, they want prognosis, and you know with that, they really want hope, and when it comes to a rare condition, we might not have information on what to expect, and how to prognosticate. I think it's vital to really share information about what is published in the medical literature, and moreover, if you've seen something rare, to also publish it so that it can be there for your colleagues, and for those other patients in the future, and you really want to be upfront with the rarity of those diagnoses. I don't know, do you use next-generation sequencing? We do it for our patients with brain tumors, sometimes it's their tumor tissue, sometimes we actually look at themselves, their genetic code. That testing can be really helpful to look at the genetic makeup of whatever's going on. We like to give them as much hope and support as we can.

Dr. Correa:
Yeah. When we encounter a type of epilepsy that doesn't seem to fit the typical pattern or symptoms, or in many childhood situations, sometimes we're often adding many more options of genetic and next-generation sequencing of the genome, to try to have a better understanding of what the conditions may be ongoing. Unfortunately, it is a situation, sometimes we just don't have enough of the information, and really have it becoming a partner with the people and their family. It's really sharing what we know and what we don't know, and ways that they actually then can help contribute to improving the information and knowledge for everyone. There's so much uncertainty in our world at times, and in many ways right now, and it's hard to imagine how to adapt when it affects each of us, but imagine when that impacts your child, a niece or nephew in your family, and today we will hear from a mother, Deborah, and her experience about learning her son's rare genetic diagnosis. She and the community around her took that shock into a call to action to help understand other people with this condition, and to find hope.
So please stay tuned, and listen to this interview with Deborah, and then a follow-up discussion with a medical expert to understand more about this unique condition called infantile neuroaxonal dystrophy. Make sure to check out in the show notes if you want to see more resources, to learn more about this condition, which we use the acronym INAD for, or to learn more about Deborah and her families, and their organization's efforts to help increase understanding and research for this condition. Their organization is called Bisous For Léo. Also, in the show notes, you will find the link for our listener survey. We've mentioned it a few times, but please visit brainandlife.org/survey. You can participate in our listener survey, and you get a chance to enter our drawing for one of five a $100 Amazon gift cards. It could be a nice addition to your holiday gift fund, so make sure to check it out.
Welcome back to the Brain & Life Podcast. I am overjoyed to be joined today by an interior designer, but particularly also a mother and wife, and caregiver and supporter of her son. Deborah Vauclare is based out of Paris with her husband Antoine, and are loving parents of an eight-year-old boy Leo, who loves being with his family and those around him, but is also living with a rare genetic neurodegenerative condition called I-N-A-D or infantile neuroaxonal dystrophy. This comes with a combination of symptoms, but simply it can look like a combination of Parkinson's and Alzheimer's, but it affects children. Deborah, together with the rest of Leo's family, and other people started an organization for this rare disorder with the goal of eradicating I-N-A-D, and other neurodegenerative conditions that are similarly linked genetically. Thank you so much, Deborah, for joining and sharing your story with us and the listeners.

Deborah Vauclare:
Thank you so much for having me here today. I really can't tell you how much I appreciate to have this opportunity to share our story.

Dr. Correa:
Well, I think each of our individual stories is the most important thing we have to share, and especially with many of these rare neurologic conditions that don't often get as much attention, so thank you. I wanted to start off even before Leo joined us, you and your husband Antoine have an interesting story of how you met, and your own relationship. Please share.

Deborah Vauclare:
So I'm American, from New York. I grew up there, and won a competition when I was in grad school for interior design to work for an architect in Paris, where I worked for over 10 years, and where I met my husband, Antoine. We quickly kind of got involved, and then decided to have a long-distance relationship for over a year, and then I decided to make the move to Paris permanently to be together. We got married, and two years later we had our first son, Leo, who, unfortunately, was diagnosed with INAD, he was about 14 months. He developed normally up until about 14 months, so he was crawling, and he was saying a couple of words, not very clearly, but we noticed some developmental delays and started to check what was going on. He started to walk at 14 months, but really could never fully walk. He would take a few steps and then start falling down.
We got really concerned when it continued for a while, and we thought maybe he had a vision problem, a balance problem. We checked his ears. We then went even deeper because the disease was not really showing up yet, so all the tests were coming back normal. We even went further to have MRIs, EEGs, and unfortunately, we decided that the only thing we hadn't done was genetic testing. Leo was just under two years old when we decided, or about two years old when we decided to go over genetic testing, and then was diagnosed a few months later, two months later.

Dr. Correa:
Well, I wanted to go back in the beginning, because some people might wonder how was your experience together with your pregnancy for Leo. Did you have any complications? Were there any other issues? Did any of that end up pointing towards any concerns?

Deborah Vauclare:
Actually, when we decided to go genetic testing, I had already had an amniocentesis for my daughter because I was about five months pregnant when we went in for testing. At four months pregnant, we had an amniocentesis done because she was just small, it had nothing to really do with anything. I think they decided to do that as well because they knew we were kind of searching for stuff with our son, but she was completely healthy and normal. They didn't test for INAD because we didn't know about it then, but it was a very stressful time.
I decided to stop working, and go on maternity leave early, and then when we received the results ... Yes, and I remember my husband and I, we discussed having children when we first got married. He didn't want to have any children. He was nervous because of all the things to be nervous about, and I'd never in a million years thought that anything could bad happen. I just always thought positively, I'm kind of a person who's very positive in general. So when we decided to finally give it a shot, then not even having our second child, I mean things started to go ...

Dr. Correa:
The pregnancy for Leo before he was born, did you have any challenges or problems?

Deborah Vauclare:
I had a typical miscarriage like most people, but it was my first pregnancy, but I never had any issues getting pregnant. The first or second try always was I was pregnant, and then with my son and with my daughter. I did have a miscarriage between the two, and before Leo, but even those pregnancies happened right away. So some people have a problem getting pregnant, I had a problem keeping it and having a healthy baby, I guess.

Dr. Correa:
Yeah. It's just such a stress and challenge for both of you and for the family. You highlighted several of the different symptoms and things that Leo had along the way as he was getting all of his testing, and trying to figure out a cause, but what were some of the initial symptoms that you noticed that something else was going wrong? You mentioned that he wasn't walking, but was he starting to develop any language? What other things did you notice?

Deborah Vauclare:
He wasn't really talking much, and I just thought, "Oh, he's from a bilingual family, so he's just going to take a little bit longer." I think nothing else was really like an eye-opener to me except for when he started to walk because he was crawling, and the only thing he wasn't doing was talking and walking. But he started to walk, I mean take a few steps, at least try to walk at the normal average timeframe, 12, 14 months, but he could never take more than a few steps. Then that's when we saw things slowly regress, and just in going into the different studies of, well, does he have a vision problem or a balance problem, and everything coming back normal. The only thing that wasn't normal was his vision, but it wasn't anything dramatic, he just got glasses for the first time.

Dr. Correa:
I think yours and your family's story highlights the importance of genetic testing for many children who have multiple types of developmental issues or regression that there's not really a clear cause already, and sometimes even in those cases when it's combined multiple symptoms, the importance of genetic testing. I'm glad, at least, that started to give you and your family more information. You mentioned before that it was really an active question for you and your husband when you were pregnant with your daughter Eva. As those results started to come back, how did that impact some of the discussion that you and Antoine had?

Deborah Vauclare:
I think we were both on the same page that, because the first thing that had happened when we got the results, they wanted to know what do we want to do about the pregnancy, do we want to test? Because in France, you can actually terminate a pregnancy at any stage, so I had a choice if I wanted to. I think both of us were ... Some people didn't even know, I guess, if they want to even test, maybe they're just going to have a baby and find out later, but I think we were both on the same page, we did want to test. Luckily, they had the fluid, the amnio fluid one from the amniocentesis, and were able to do the testing very quickly. I think they said they needed two weeks, and I had the results within a week or 10 days, I think, but that whole week I couldn't sleep. I really couldn't do anything. I was really just sick to my stomach, nervous, I can't imagine having two children with this horrible disease. After now, meeting other parents that did or do have multiple children, it's a traumatizing situation.

Dr. Correa:
Yeah. How is Eva now?

Deborah Vauclare:
She's a healthy, beautiful girl. I feel so fortunate for that.

Dr. Correa:
That's wonderful. How have you talked with Eva, I know that she's young now, about her experience with her brother, and what's going on?

Deborah Vauclare:
She's just the most loving sister. She just always ask questions, from a very young age asking questions. I think she's starting to become aware of the impact of Leo's disease as much as possible for a five-year-old. Does she know that he's going to die? I think so, and that's something that we all have to just be open and honest about. I don't try to hide anything from her. We just try to face the reality every day, and love Leo as much as possible, give him as much comfort as possible.

Dr. Correa:
So through this whole process you find out about Leo's diagnosis, this impairment of the PLA2G6 gene. For our listeners following our discussion with Deborah, we're going to go into more detail about this condition, and other rare genetic conditions with our medical expert, so please stay tuned after we finish our talk. But as the two of you are starting to learn more about what INAD is, what this gene does, what it all means, what were some resources that you found that were helpful? But what were some of the gaps that you felt like was there for these very few families around the world that have this, and are living with this condition?

Deborah Vauclare:
When they gave us the diagnosis in the hospital, I asked the basic questions, but they were reluctant, I think, to answer because they didn't want to give any false information. I think it's so unknown and rare, they kind of just handed over the correct website to read about it because there's not that much information on the internet, and some of the information is not really accurate, of course. When I was doing that research as well, I came across the INADCure Foundation, which is the only nonprofit organization for research and awareness in the US for the disease, and it was started by another parent, another mother, Leena Planwala, and her daughter Ariya is two years older than Leo. She was diagnosed two years before him also, two years old. I reached out to her for help because there's really not much, so thank God for them that they're so active and involved in this disease, but there's not really much more, other than what we're doing with them, happening.

Dr. Correa:
As you said, you found the INADCure Foundation, a big part of their work is both fundraising for awareness and research, and with so few families and individuals with this condition it really challenges research. I understand Leo had an opportunity to participate in research. What was your experience? What do you feel like was the importance of that, not just for Leo but for the community overall?

Deborah Vauclare:
Leo was actually the first child to be involved in the first clinical trial for a potential treatment, and then there were other children that were accepted into the trial. I don't remember the exact number of children that were enrolled, but it was because of the INADCure Foundation that pushed for this to happen. It was the first opportunity for us to try anything. I think Leo was one of the youngest children, so that was also really beneficial for them because it was before he was showing too many signs. Once the children lose the abilities it becomes harder to see results, and the potential treatment was to see if it would slow down. It wasn't a cure, but it was just supposed to slow down the progression of the disease. I want to say it did, but it really wasn't clear, and we really didn't have enough success with that trial. Now we're going even further into gene therapy, which could be the potential cure, and the only possible really treatment for INAD.

Dr. Correa:
My understanding is to support the INADCure Foundation, you also teamed up with a friend and your husband to raise money and support more research. Tell us more about Bisous For Léo.

Deborah Vauclare:
So when Leo was diagnosed, the day we got the diagnosis, my girl friend, Emily, was coming to visit me in Paris with her daughter. So she was arriving at my house the day we were coming home from the hospital with diagnosis, and I think she felt all the emotions we did. She's been my best friend since we're 15 years old, so I think her initial thought was, "How can I help?" She thought to herself, "Well, most parents want to try to kiss their child to make them feel better when they're hurt," so that's when she thought of Bisous For Léo, which means kisses for Leo in French, because Leo is French, and kind of broached the subject to Antoine and I. I didn't have the capacity to really though think that way, and she was like, "We need to do something. We need to raise awareness."
A couple of days later, I came to my senses like, "You're right," and so that's when we launched Bisous For Léo. She's really just, I can't even ... I get really emotional because she's done so much to help me. She's pushed me to do this, and without her I couldn't do this. She's done so much to raise the awareness for INAD and all these funds, and with the campaign that we have on social media with the celebrities kissing Leo and sending their bisous, it's really incredible. All of the funds we've raised, all benefit the INADCure Foundation for the research. All we want to do is help INADCure find the cure, the treatment to save these children, to save their lives.

Dr. Correa:
It's wonderful to hear about this effort, and that so much love is going into the fundraising and support for this research, and moving the science forward. As we said, it's a condition that's affecting the nerves in these childs' brains, but there are many different conditions that are degenerating and affecting the nerves of our brains, and I think the hope of the INADCure Foundation is that any future findings and improvements may also end up having impacts or improvements for other neurologic conditions. Our hope is, is that Leo helps all of us.

Deborah Vauclare:
Thank you.

Dr. Correa:
So as I understand, you said the next things that they're working on is trying to work towards gene therapy. As a mother, and also as a co-founder of an organization supporting this condition, what's your perspective on where we are with the hope of future science for future generations, and maybe even some of the children living with this condition right now?

Deborah Vauclare:
I think there is hope. I try to encourage INADCure to move forward, and the research to continue. We need to be able to have enough funds to be able to continue the research, and so that's why I continue to help raise those funds. Also, the urgency is that the faster we can find it, I don't know that we'll be able to save Leo's life, but hopefully the other children who are diagnosed with INAD, 1400 children globally are known and diagnosed, and that's way more than when Leo was diagnosed that's statistically known, and to hear constantly these new children being diagnosed, if we can find a treatment or a cure for them, then hopefully we can stop that number from growing so fast. I hope that the future children will be able to have the diagnosis sooner that they don't lose all these acquired skills that Leo has lost.

Dr. Correa:
Well, we thank you, your family, and Leo for helping push us and push science forward, and we share that hope with you. Before we transition to our discussion with the medical expert, learn more about this condition, about these types of gene therapies that are being developed for various different conditions, what do you want us to remember and learn about INAD, and how do you want us to remember Leo?

Deborah Vauclare:
I think we need to learn that INAD is extremely rare, but it's not as rare as some of its sister diseases, if you will, Parkinson's, Alzheimer's. Hopefully, if we can find a cure for INAD, we can help pave the way for a potential cure eventually for Parkinson's, and Alzheimer's, and Lewy body dementia. But I think the fact that these children are the purest form of this, they should be able to have their lives lived, and not have to lose all their abilities so young.

Dr. Correa:
We will include information about the INADCure Foundation, and Bisous For Léo in our show notes. If you want to learn more about these organizations and support them, please go there and find ways that you can support to move forward this science. But most of all, thank you Deborah for all the time, effort, and the passion, and love that you're putting into this.

Deborah Vauclare:
Thank you so much for having me. If you want to learn more, yes, please go bisousforleo.org, and inadcure.org, and thank you so much for this time.

Dr. Correa:
In the show notes you will find the link for our listener survey. We've mentioned it a few times, but please visit brainandlife.org/survey. You can participate in our listener survey, and you get a chance to enter a drawing for one of five a $100 Amazon gift cards.
So Deborah really shared with us her and her family story, and just Leo's experience with this condition called INAD. We now are joined by Dr. Darius Adams. He's a clinical geneticist, and works in New Jersey in Morristown as the medical director of the Goryeb Children's Hospital Genetics and Metabolism Division, and leads the personalized genomic medicine program at Atlantic Health System in Morristown, New Jersey. He also directs what's called the Lysosomal Storage Disease Program that helps support families and children living with Gaucher disease, Fabry's, Pompe disease, we're throwing out a few of the different terms, but today he's joining us to discuss a variety of neurodegenerative diseases in children, and specifically Leo's condition, infantile neuroaxonal dystrophy or INAD as we'll refer to it. Thank you so much, Darius, for joining us today.

Dr. Adams:
Yes, thank you for having me. It's great to be here.

Dr. Correa:
So why don't we go back and start at the beginning, Deborah shared her understanding of the condition, but help us, and see if you can explain for us what is infantile neuroaxonal dystrophy, or what we'll use is INAD, and how it affects the nervous system in young children.

Dr. Adams:
Yeah, it's a very rare genetic disorder. It's recessive. So if you think back to your Punnett square biology days, parents are typically carriers, but unaffected, but when two carriers come together they could both pass down their affected gene to a child. In this case, the gene is called PLA2G6, and if both affected copies are passed down, then the child will have INAD. There is some variability in severity, depending on the specific mutations that are inherited, or in genetics as we like to call them now, variants. We classify variants in different ways, depending on how much data we have in terms of their impact on the child. But briefly, if a child is affected, they can start to experience neurological symptoms very early in life, typically before two years of age, but can start in infancy.

Dr. Correa:
So then there are some situations when it can show up at a later stage, or they may be inherited, and not necessarily have the same kind of presentation that we hear about Leo's experience.

Dr. Adams:
That's correct. Yeah, there are some cases where the presentation could be delayed quite a bit, by several years.

Dr. Correa:
Is there a possibility with this condition and this gene inheritance that someone could have inherited and doesn't manifest or have the symptoms?

Dr. Adams:
That would be unlikely. There are situations where we find a variant or mutation in PLA2G6 that we don't have a lot of data on, we typically call that a variant of uncertain significance. So it's possible someone could have one disease-causing variant on one copy of the gene, and then one of these variants of uncertain significance on the other copy. It's possible if that variant of uncertain significance has a very minor impact on the overall function of the protein, it's possible they may not be affected in a dramatic way, but maybe in a more subtle way. It really depends on how the gene product is impacted.

Dr. Correa:
I wanted to also then go back and understand a little bit about what you do. We introduced at the beginning and said you're a clinical geneticist. You work with children with a variety of different neurologic conditions and medical conditions, but what does a clinical geneticist do if someone is referred to one? Or here, or maybe they just meet you at a cocktail party, what is your day to day? What is it that you're doing with patients, or in general, in the area?

Dr. Adams:
Well, we work very closely with the medical community, of course. We get a lot of referrals from various specialists who have questions regarding their patients. If their patients appear to have a family history, for example, of a condition, we'll get referrals to investigate that further, and determine if there is in fact a genetic component to that condition, and that can impact management a lot of times. For example, neurologists will refer a child who has a seizure disorder, because understanding the underlying genetics of that seizure disorder can impact the medication that they will prescribe in some cases.

Dr. Correa:
Okay. Are all geneticists also physicians or there's different situations in that?

Dr. Adams:
So geneticists or medical geneticists are physician-trained, but we also have genetic counselors who are fantastic in their job, and really help us a lot, they're masters trained. They are experts in, as the name would imply, conveying complex genetic or genomic information to families in an understandable way. Admittedly, sometimes physicians get a bit jargony, and so it's nice to be able to rely on the expertise of a genetic counselor to be able to really convey that information in a way the family can understand.

Dr. Correa:
At the beginning, we mentioned you work particularly also with the community impacted by lysosomal storage diseases, and threw out some jargon and names for some of those conditions, and there are many varieties and different types of neurodegenerative conditions, or genetic conditions that cause slow degeneration of the brain and nervous system in adults and children, but within children, what distinguishes some of these genetic conditions of lysosomal storage diseases and INAD?

Dr. Adams:
So the lysosomal storage disorders were in fact the first class of conditions that we developed enzyme replacement therapy for. Gaucher disease was one of those conditions that we were able to give an IV infusion, and traffic the enzyme into the lysosomes in order to break down the abnormal accumulation of substrate. It sort of created this field that I like to call interventional genetics, where we can actually go in and replace that protein that isn't working well due to a genetic abnormality. So we discovered that there are a variety of lysosomal disorders, where we can take advantage of this mechanism to get the enzyme into the lysosomes and treat the condition. Now, the challenge in all of that is we need to keep replacing the enzyme, unlike potentially fixing a gene where it could be one and done. In this case, we have to keep replenishing the enzyme, so typically once every one to two weeks, an individual is treated, and that basically corrects their disease.

Dr. Correa:
Now, with this condition, INAD in itself is not necessarily a lysosomal storage disease, what is the dysfunction that the gene is causing in the nervous system?

Dr. Adams:
There is a transferrin or iron transporter that appears to be involved, and this transporter is localized to the lysosomes, so yes, INAD also appears to have an impact on lysosomal function. Because this transporter can't be regulated properly, there is this accumulation of iron in the lysosomes, and we can see histologically enlargement of lysosomal structures. So that discovery, if you will, started to make us think a little bit more about INAD as potentially a lysosomal disorder, and really think about ways that we can address it in that manner. One of the big challenges we've had with INAD is we really don't have a great biomarker for the condition, and what I mean by that is there are a lot of conditions. For example, if you have hypercholesterolemia, we can check your cholesterol, we can see where you're doing, and make adjustments based on checking that lab. We don't really have that for INAD, so when we move forward into therapeutics, it becomes more challenging to know if the therapy we're applying is having a positive impact, because we don't have that convenient marker that we can reference to know if we're being successful.

Dr. Correa:
At this stage, we know there's excess iron accumulation in the brain, and we still need more research to understand even what to track to understand the progression of the condition, or possible directions for research and treatment. But we also mentioned a few times the word lysosomes, and so to get us all on the same page, how would you explain what is a lysosomes?

Dr. Adams:
Yes, good point. So that is an organelle we call it, or a sub-compartment in the cell, and you can think of it as the recycling center of the cell. So it tends to accumulate large molecules, sphingolipids, for example, and it's tasked with breaking them down so that they can be metabolized appropriately. Now, as you can imagine for some lysosomal disorders, if these sphingolipids can't be broken down efficiently, or if a condition is impacting the ability of the lysosomes to function in a global manner, which we think that's the situation with INAD, then you're not going to be able to efficiently recycle these large molecules. Over the years, there has been investigations to look into how maybe we can help the lysosomal function in a better manner, or potentially do more directed therapy at the underlying issue, and potentially even fix what's going wrong with the PLA2G6 gene.

Dr. Correa:
We've mentioned and talked about iron within the lysosomes, how it's involved in the recycling functions of ourselves, which includes lipids as structures, and the overall idea of these also being metabolic conditions. Most people in hearing these things would think, "Oh, is there an impact on the nutrition, and what we eat and intake, or what a child with this condition eats in the presentation or the symptoms of the condition?"

Dr. Adams:
No. I like to briefly categorize metabolic conditions into two categories. So one category, small molecule metabolic, and yeah, in those cases, diet can have a huge impact. Phenylketonuria or PKU is a classic example of that. If you look on your Diet Coke can, you'll notice a little red warning there, "Attention: Phenylketonurics: Contains phenylalanine." So that's letting people know that aspartame is in Diet Coke, and they shouldn't drink it because they can't metabolize phenylalanine. So yeah, there is dietary intervention for that small molecule condition. Now, what we have found that in large molecule conditions, and this is true of lysosomal storage disorders, dietary intake does not appear to significantly alter the course of the condition. It's really about how the body is processing cell membranes, for example, that are there and need to be repaired or replaced, for example, so the dietary involvement doesn't seem to be playing a large role.

Dr. Correa:
Specifically, so Deborah shared some of Leo's own early signs and symptoms, but with the condition INAD, what are some early signs and symptoms that parents, or other healthcare providers should be aware of or may notice that either that condition is of concern, or another neurodegenerative condition that needs more evaluation?

Dr. Adams:
Well, the main thing that we see is developmental delay. What I mean by that is ability to roll over, sit up independently, crawl, and even walk, and then later on acquisition of speech, and other milestones that we typically expect in a growing child. This is where our pediatricians do a fantastic job, and that's one of their tasks, it's one of the things that they pay close attention to, is monitoring the progression of an infant as they grow, making sure that they are hitting these milestones. So if that's not happening, then that is the first indicator that something more may be going on, and that we probably should start investigating a little bit more thoroughly.

Dr. Correa:
But we're not saying that developmental delay automatically then means that a child may have a neurodegenerative condition?

Dr. Adams:
No.

Dr. Correa:
It's just an indicator for more evaluation.

Dr. Adams:
A 100%. As the term implies, developmental delay, it implies you could catch up. So yes, there are situations where there's the delay, then the child kicks into gear, we give them a little physical therapy or whatever they need, and then they get back on track, and start heading in the right direction. But it's something that we look into, especially if we do provide the physical therapy or the occupational therapy, and we're not seeing a child bounce back or get back on track. Now you've really intervened, and if the child is still struggling, then it's something that we get a bit more concerned about.

Dr. Correa:
As you said, there's this intervention that we hope then to see that the child either catches up or progresses. But often also, we bring up the concern or the question of whether or not there's regression, and so when we're discussing that together as colleagues or with a family, what do we really mean there, that a person or the family member can help them understand?

Dr. Adams:
So regression is where a child is developing on track or close to on track, or at least is acquiring milestones, like crawling for example, or pulling to a stand, and then loses that ability, that's what we call a regression. More than just developmental delay, regression is more concerning, then alarm bells should be going off, because that's not what we would expect to see in children who just might be taking time to accomplish a certain milestone. That is something that is telling us there's potentially more going on, and in fact, something is actively impacting brain development.

Dr. Correa:
In explaining INAD, Deborah, some various different patient and community organizations will relate that there's some features of it that can be similar to Alzheimer's and Parkinson's, but occurring in a child. When we say that, what are we really referring it to in the experience of that child, and how is it different, of course, from Parkinson's and Alzheimer's that we see or think of in adults?

Dr. Adams:
Well, these are what we call neurodegeneration conditions, so there is an ongoing process that's impacting the brain at a more global scale, and that can be true of Alzheimer's certainly. Parkinson's tends to be more targeted to substantia nigra or brain stem structures, but it can have global impacts on functioning, and of course the huge difference is INAD is something that can present in infancy, whereas Parkinson's and Alzheimer's occur later in life, or maybe not that late in life. We have discovered some single gene conditions that are associated with earlier onset Parkinson's or Alzheimer's spectrum conditions, but these are all neurodegenerative disorders. There's been research, certainly with Alzheimer's disease in terms of pathogenesis involving subcellular compartments, potentially even lysosomal function. A lot of research looking at mitochondrial function, which is another subcellular compartment. I think as we learn more about these conditions, there is potential there that that knowledge can be applicable in each direction.

Dr. Correa:
Deborah and her husband, when Leo was born and where he initially had symptoms, they were living in France, is diagnosis different or even the condition is different in the United States versus other countries for INAD or some of these other genetic conditions?

Dr. Adams:
Diagnosis is generally genetic. While you can get really important and helpful information on MRI that can give you a big clue, and by doing other neurological assessments like nerve conduction studies, for example, can give you important clues, that doesn't give you a lot of specificity. Also, there's a lot of literature in the pediatric space about giving anesthesia to infants, and even the impact that that could have on the developing brain, so a lot of, not only families, but neurologists, actually will consider genetic testing first. With the development of genomic testing where we can scan through thousands of genes on a single test, this is becoming the most expeditious way to get to an answer, as opposed to traditionally where it could take quite a while before you would see, really the most profound impacts of something like INAD on an MRI.

Dr. Correa:
So in a way, the diagnosis and how it might be different is just much more dependent on the access or ability to get the different types of genetic testing. We explored this in a previous context of an episode around seizures and epilepsy in children, as a part of a series of episodes we did with families of a condition called SYNGAP-1, but what are the different types of genetic tests? Is it just you send off for one and then you'll get all the information? Which genetic tests really in this type of situation should a family be asking about?

Dr. Adams:
Well, in this case, I mean, we do have panel tests, where we can order a predetermined panel of genes to be analyzed based on indication. We do have, for example, neuromuscular condition gene panels, and PLA2G6 does appear on some of these panels, but not all of them. So one of the directions we're moving in, as opposed to doing sort of pre-configured gene panels, is toward genomic testing. That test is a little different, in the sense that we provide a detailed clinical or phenotype information on a patient to the lab, and then the lab's task is to scan through all known genes, approximately 20,000 of them, to try to find an answer.
The nice thing about genomic testing is there is more of an ability to hunt for ultra-rare conditions that may not have made the cut on the predetermined panel test. We typically do genomic analyses as a trio, meaning we include parents, because as we're hunting for potentially changes, and up to several thousand genes, the likelihood that we're going to find a variant of uncertain significance, where you're not sure what its impact is, really increases. So by being able able to use parents as a reference DNA, that can help guide us in terms of determining sometimes the potential significance of whatever we find on the genomic analysis.

Dr. Correa:
If someone is diagnosed with, let's say specifically INAD, are there treatment or symptom management options currently available for children diagnosed with INAD?

Dr. Adams:
There is symptom management support, and this would be things we've discussed a little bit already, like physical therapy, occupational therapy, feeding therapy support, and of course we could address focal issues that arise. Some kids have seizures, for example, and of course we would treat them, and address that accordingly with medication management, but we don't yet have a therapy that we can provide that directly addresses the underlying issue of INAD, unfortunately. There have been some clinical trials that have been done, but have not been successful in having a significant impact on altering the course of the condition.

Dr. Correa:
So if the doctor or the family hears that it's a possibility of there being a condition that doesn't have an available treatment or gene therapy right now, a lot of times people might wonder, "Why do the genetic testing?"

Dr. Adams:
Well, that is a good point, and that's all part of the informed consent process, and the discussion we have with the families. I think the first component of that discussion is that because the presentation, especially early on, is not that specific, when we embark on genomic testing, the hope is that we would find something that we have a directed treatment for potentially. But we are also careful to discuss with the family that it is possible we could also discover a genetic condition where we do not have a directed therapy currently.

Dr. Correa:
Is there ongoing research within INAD for either future treatments or even development, as you mentioned, of the idea of a biomarker to track the condition? Is genetic testing a requirement often into entering some of those research studies for an individual or families?

Dr. Adams:
Yes, there is a research underway. One of the things we're looking at is trying to identify a biomarker that we can use from the lysosomal storage disease literature. There's a condition called Krabbe disease, which in a lot of ways is similar to INAD. It's mechanistically different, but the onset of symptoms and the neurological degeneration follow a similar course, onset in infancy, definitely by two years of age, progression after that. What we discovered by doing research into Krabbe disease, is that a psychosine is an excellent biomarker for that condition. So that appears to be a neurological biomarker that is exquisitely sensitive to certain types of lysosomal disruption at least. We're looking right now at, we're teaming up with basic science researchers, who currently have mouse models for INAD, and we are investigating to see if those mice in fact have elevated psychosine levels, either prior to the onset of observable findings, or shortly after the onset of observable findings. If it turns out we can use psychosine as a biomarker, that will greatly help us with developing new therapeutics for this condition.

Dr. Correa:
As you've learned from other families and caregivers of children with INAD and other neurodegenerative diseases, what are some important questions for a family with a child, a new diagnosis that they should ask to help them understand, and plan for how best they can support that child?

Dr. Adams:
I think one of the big questions that is helpful is what are their local resources? So depending on where they are, where they live, the specialists they're interacting with. It can be helpful to know, for example, where do they need to go for physical and occupational therapy services? Or is there a program that allows for in-home services? That can be very helpful in terms of dealing with transportation, and potentially moving a child who has a lot of medical care needs and equipment that has to go along with them, because those services can really be helpful in maintaining some degree of function.
The other thing is just looking to be able to connect with other families to talk about the process with them. I know Facebook has kind of become a bad word, but I have to say when it comes to collaboration among families, it still is one of the leading resources for a lot of rare conditions. But then again, of course we have INADCure Foundation, which I think last but not least, I would say is certainly a wonderful resource to be able to connect with individuals from all over the world, and also to stay up to date with research, and current availability of therapeutics, and the progress that's being made.

Dr. Correa:
Thank you so much, Darius, for taking the time with us and our listeners, to help us understand this rare condition, and put a little bit more context to Deborah's experience and Leo's story.

Dr. Adams:
Sure. It was my pleasure. It was great talking with you.

Dr. Correa:
Thank you again for joining us today on the Brain & Life Podcast. Follow and subscribe to this podcast so you don't miss our weekly episodes. You can also sign up to receive the Brain & Life magazine for free at brainandlife.org. Don't forget about Brain & Life in Espanol.

Dr. Peters:
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Dr. Correa:
You can also find that information in our show notes, and you can follow Katy and me, and the Brain & Life Magazine on many of your preferred social media channels. We are your hosts, Dr. Daniel Correa, connecting with you from New York City, and online @NeuroDrCorrea.

Dr. Peters:
And Dr. Katy Peters, joining you from Durham, North Carolina, and online @KatyPetersMDPhD.

Dr. Correa:
Most importantly, thank you in all of our community members that trust us with their health, and everyone living with neurologic conditions.

Dr. Peters:
We hope together we can take steps to better brain health, and each thrive with our own abilities everyday.

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Shedding Light and Love on a Rare Genetic Condition with Deborah Vauclare

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