Thank you. Hi everyone. Welcome to our Peds Rehab Medicine Lecture Series for today. We have a really great topic today of something that we might see less commonly but definitely comes into our practice in a great overview of it. So we have a lecture on Friedrich's ataxia by Dr. Jacqueline Omura and she is from Seattle Children's Hospital on one of the pediatric rehab docs there. So I'm gonna pass it along to her and then if folks have any questions that come up throughout the whole time, feel free to put in the Q&A in the chat and then we'll take a look at those after she's finished. Awesome. Thank you so much, Dr. Dubon and AAPMNR for having me. It's great to be here coming to you from Seattle. I just want to, if you're watching now or if you're watching us recording at the risk of sounding cheesy, take a moment to take your breath, try and put stuff out of your brain that you're thinking about. If you have your charts open or your email, try and put it to the side and let's take this hour that you have committed to and have a nice discussion and do some learning. So today we're gonna talk about Friedrich's ataxia. I have no disclosures related to this presentation. What are our objectives today? So our objectives are to describe the genetics and pathophysiology of Friedrich's ataxia, understand clinical features and prognosis of Friedrich's, recognize medical complications that are associated with this condition, and important pieces describe the rehabilitation interventions of Friedrich's ataxia. And finally, we're gonna explore some of treatment potentials and ongoing research efforts in this space. So we're gonna start with a question. So you are asked to evaluate an eight-year-old in clinic with gait disturbance. His mom tells you that he has started walking different over the past year and his foot has changed shape. On exam, you find pes cavus, scoliosis, impaired sensation in his lower extremities, and his gait you find is quite ataxic. Upon further review of his record, you discover that he has been followed by cardiology clinic since age five for cardiomyopathy. So what is the name of the affected gene product in this diagnosis? So for Taksin, this is a talk on Friedrich's ataxia, right? So kind of gave it away a little bit. Going through the other options, dystrophin is the affected gene product in Duchenne muscular dystrophy. Survival motor neuron protein is the affected gene product or protein in SMA. And peripheral myelin protein 22 is something we can see in C-charcot-marie-tooth, CMT. So Friedrich's ataxia is an autosomal protein and Friedrich's ataxia is an autosomal recessive condition. Incidence is about one in 40,000. It is the most common of the hereditary ataxias. And I always think about incidence of disease, like, well, what does that mean? How common or rare is this? And if you compare Friedrich's ataxia of an instance about one in 40,000 to something like Duchenne muscular dystrophy, it's about one in 3,500 boys or children affected. The carrier frequency, meaning how many people are walking around carrying one allele with this mutation is about one in 50 to one in 100 in Europeans and persons from North Africa. It's more rare. It's lower incidence in Asians and people of South African descent. It was first described by Nicholas Friedrich, who's German, in 1863. He first described nine different cases in three families. And he described sort of this gross microscopic changes in the heart muscle and spinal cord tissue. However, it wasn't until a bit over 100 years later that the complete clinical spectrum was described more fully. And it wasn't until even later that we discovered the genetic mutation, and that was around 1996. So these are the diagnostic criteria that were discussed in 1976 by QCSFA, stands for Quebec Cooperative Study on Friedrich's ataxia. And then Harding was an author that described Friedrich's ataxia later in 1981. Both of these groups had in common that the onset was less than 20, less than 25 as described by Harding. They both described progressive ataxia and lower limb areflexia. And then started to differ in some of the other signs and symptoms, including decreased vibration sense weakness, dysarthria, and then some EMG findings in Harding's group. The pathophysiology here is really the crux of it is it's caused by insufficient levels of frataxin, which is the gene product, the protein that is made. And frataxin is a mitochondrial protein, which plays a key role in iron homeostasis. And honestly, how exactly that happens is not well understood. When we have low frataxin, we get increased cell death. The steps that happen with this are low frataxin leads to more iron accumulation, which leads to defects in specific mitochondrial enzymes, which predispose our body to being more sensitive to oxidative stress. So then you have more free radicals. And so then that's why you have cell death. The cell, the tissues that are most susceptible are tissues that have high energy demand. So these tissues include neurons, cardiac muscle, and our pancreatic islet cells. And this becomes important as we think about clinically what we see. Other dividing cells where frataxin plays a role, but don't seem to be affected as much are liver and fat cells. So what happens with this disorder is you have basically expanded GAA triplet repeats on chromosome nine. And I put a picture down here of chromosomes and alleles because sometimes it's challenging to remember what these things look like when we haven't talked about them in a while. And so 95% of these patients have homozygous expanded GAA triplet repeats, meaning both alleles have these expansions. 5% of these patients have a heterozygous missense or nonsense mutation. So one allele has the expanded GAA triplet repeats and the second allele has this missense or nonsense mutation which results in a premature stop codon in the gene that the RNA doesn't translate the full protein. So this is a picture of what this looks like. And so on the top portion, you have sort of normal state. You have a normal RNA product. And so the GAA triplet expansion happens at intron one. And really the normal amount of, whoop, sorry. The normal amount of protein you should be seeing is ranges from about six to 65 repeats is what you'd find in a normal healthy person. Pathogenic is gonna be about the studies you read range a little bit, but 80 to 100 to 1,700 repeats. And in all studies, it doesn't seem like there's much overlap clinically between normal number of repeats and a pathologic number of repeats. Meaning we don't find too many individuals who have repeats ranging from 60 to 80, 60 to 100. This is a picture of how genotype and phenotype correlate. So this is from a study from 1996 done by Durer and that was in the New England Journal. And we'll talk a little bit more about this study in a little bit. But X-axis, you have a number of GAA repeats on the smaller allele. So the smaller half of the chromosome. And Y-axis, you have age of onset. And here we can very clearly see that there is correlation between the amount of repeats and age of onset, where the more repeats you have, the younger we're gonna see this disease process. And for us being Peds rehab providers, we are gonna be seeing kids that are presenting younger that we'll talk about how this may affect their prognosis and things. But a lot of the disease onset happens sort of in the formative years when we see patients. There was another study, a smaller study done by a group in the same year, actually 1996, which is showing the same thing where children present younger with a greater number of GAA repeats. So from a neuropathology standpoint, what does this look like? What does this, what actually happens in this disease? And I have to tell you, I spent a long time looking at a lot of studies and we know some, but I think there's still some information that's missing in terms of what is happening in the body. What we do know is there's sort of an earlier and a later stage of disease. We know that loss of primary neurons in the dorsal root ganglion is an early finding. So we have a sensory problem, a sensory neuropathy problem. We then have degeneration of our dorsal columns and spinocerebellar tracts and some degeneration of our corticospinal motor tracts as well. We see peripherally atrophy of our large sensory fibers more than motor, although motor can be slightly affected. When we look at the spinal cord, we see atrophy of Clark's column, which I'll show you what that is. I had to remind myself. Whereas the anterior horn's motor cell, motor neurons remain intact. And we'll talk about how clinically this might make some sense, but really we're seeing this sensory problem and proprioception problem more than we're seeing a motor problem initially. We also see some cranial nerve involvement, but interestingly, when they look at this and they dissect things out, what they see is that the afferent roots are atrophied, but the cell nucleus is okay. So again, sort of the sensory input problem. So this picture is showing Clark's nucleus. Basically, it's the area where sensory input from the dorsal columns is coming before it goes out to the spinocerebellar tract and goes up to the cerebellum. So it's really a nucleus for this proprioception information that's coming from our extremities. In general, these nuclei are pretty big in prominence from about C8 to L2. However, we do have two other smaller nuclei, one close to the third cranial nerve nuclei and another one that's in the sacrum. So there are some a bit higher in the cord and a bit lower as well. Later findings, we see lesions of the dentate nuclei in the cerebellum. And to remind you a little bit about the dentate nucleus, dentate means tooth-like or serrated, which is what you can see here. This is sort of the shape of what this nucleus looks like. It's the deep white matter of the cerebellum. So this is where planning, initiation and control of voluntary movements, as well as some control of your thoughts and visual spatial function can happen. We get some Purkinje cell loss later on in the disease process. And we also get some loss of Bette cells. And so what the heck are Bette cells? Bette cells are found in the lower half of layer five in the primary motor cortex. They are the largest and most numerous in motor representation of the leg. And so this can further explain what we'll talk about in a minute, some weakness that we see later on as this disease is progressing. So how does this translate? What does it look like clinically as we're talking about cells and genes and pathology and things? So what you're gonna see is an onset of an age range from about 10 to 30 years old. Some people consider that if someone is presenting with symptoms over 25 years old, they're considered late onset Friedreich's ataxia. The mean age of patients presenting, if you exclude these patients with late onset is about 10 and a half. When I was looking through some of the records of the patients that I am taking care of, and right now I think that number is in between five to seven some of the presenting signs and symptoms included, oh, my kid kind of had a clumsy gait. I thought he maybe just wasn't paying attention. Another one of the children that I take care of was diagnosed with cardiomyopathy first. And Friedreich's ataxia is on the list of differentials for cardiomyopathy clinics and testing is often done. In the child I take care of that case, the testing for the expansion units was done and it was negative because he's one of the 5% that are heterozygous. So he had a point mutation on one of his alleles. One of my patients, their children noticed foot changes first and other patients can present initially with scoliosis. This is from a review study looking at some of the clinical features. And as I've mentioned, progressive ataxia is one of the big features, but they can also have a number of different things. So common findings are things like lower limb areflexia, which was found in up to 99% of Harding's study in 1981. Extensor plantar response is super common. And we'll talk about some more of these things. This slide is just to show that you don't always have all of the signs and symptoms, but there are signs and symptoms that are very common in this disease and sort of should make you think about this diagnosis. So as I just mentioned, progressive unremitting ataxia is the main clinical feature. Initially, this may look more like a sensory ataxia and then eventually it will reflect more of a cerebellar ataxia. And we'll talk about that in a minute. When you're doing your exam, what are you looking for? You know, your cardiac and pulmonary exams may be normal. If you see a chest X-ray, they may have a big heart. The money in your exam is really in your great rehab exam, MSK, neuro, and looking at gait. So from an MSK standpoint, you may see foot deformity. They could be pes cabus, they could be pes planus, and you also want to make sure you're taking a look at their back and looking for any signs of scoliosis. From a neurology standpoint, a neurologic exam standpoint, their cranial nerve exam may be a little bit nonspecific, though you may notice that they have some dysarthric speech later on in their disease course. When you test their muscle strength, they may have lower extremity, greater than upper extremity weakness to start, although that won't be the predominant thing you find on your exam. You want to make sure you test their sensation, including their proprioception, because they will have a lot of pain and they will have a lot of pain in their bilateral lower extremities greater than upper extremities. From a reflex standpoint, they'll be areflexic, but they'll have an extensor plantar response, so they'll have a positive event speed. And then when you walk them, you'll see that their gait is ataxic. And there's one more exam maneuver that we want to make sure that we do and we're seeing these patients. And so during your clinic visit, you want to get a better understanding of the patient's ataxia. Which exam would you help to test which exam would help you decipher between if this is a sensory or cerebellar ataxia? Rapid altering movements, finger to nose, Romberg or tandem gait. It's the Romberg, right? So this is when you have them stand up, put their feet about hips distance apart, you have them balance, and then you have them close your eyes, right? And a positive Romberg is if they close their eyes and they fall over. This is, if they have a positive Romberg, it's suggestive of a sensory ataxia, sensory problem. And as I was looking at this and learning more about Romberg, this was initially studied and tried out in patients that had tertiary syphilis in which you can get lesions in the dorsal column and so you have this proprioceptive loss. The premise of Romberg is that you really need two out of three of the following things to maintain standing. You need your proprioception, you need a vestibular function, specifically knowing where your head is in space, and you need vision. And so in these patients, if you have them standing and they do fine and then they close their eyes, really we think it's positive because you take out their vision and they have that loss of proprioception. So that's why they have a positive Romberg. Later features and exam findings will include spasticity as you're including more CNS lesion, including reports of spastic bladder. You have worsening weakness. Remember, we have that loss of BET cells in later stages of this disease. Worsening dysarthria and you can have dysphagia also because you start to get some cranial nerve involvement. Further, you can have some sensory neural hearing loss and there can also be some optic atrophy that happens. Up to 50% we think of patients have spastic bladder and when it comes down to sensory neural hearing loss and things, about 1% of patients may end up being deaf and some will have more vestibular symptoms as well. Things to include on your differential diagnosis when we're thinking about this disorder and someone presenting to us with ataxia are, these are some of the, probably the most common things to look for, keeping in mind that these things are also rare, right? So ataxia telangiectasia, how would we differentiate that? Or what are some clues that it might be that instead of Friedrich's ataxia? So remember that ataxia telangiectasia is a neurodegenerative disorder that we see during infancy and some during childhood. Things that may help you make this diagnosis are, they will have telangiectasias, so reddish lesions of their skin and mucous membranes. They may also have some impaired immune function and they're predisposed to cancers like lymphoma. Ataxia with vitamin E deficiency is something else to keep in mind. Things that may differentiate this is that this onset is typically in late childhood or early teenagers. What happens here is that vitamin E is not well distributed, which helps neurons to protect neurons from free radicals. So similar mechanism to what protaxin does. The nice thing in this disorder is that you can supplement them with vitamin E to help progression of their disease and to have impairments. CoQ10 deficiency, similar idea. If you don't have enough CoQ10, you're at more risk of free radicals and oxidative damage. This has a varying presentation, but things that make it different from Friedrich's are they can have more of an encephalomyopathy, seizures. They can have hypotonia or dystonia, and then you wouldn't expect to see dystonia in Friedrich's. We should think about some metabolic disorders. Wilson's disease is one of those. Remember, Wilson's disease has to do with too much copper accumulating in tissues where we don't want it, so especially in the liver and brain. So you may see that the patient is jaundiced. They have that golden brown eye discoloration, which when you see it, you know what it is, and they're also ataxic. Finally, charcot-marie-tooth can get a little bit confusing with Friedrich's ataxia, I think, because you may see a sensory deficit in the lower extremities. They can have pes cavus. The main feature being that patients with charcot-marie-tooth really shouldn't be ataxic. Their gait may be different. They may have a steppage gait. They may have a foot slap. They really shouldn't be staggering all over the place. What do we do for diagnostics? How do we diagnose this? And back in the 1990s, 1980s, when we didn't know as much about this disease process, there was sort of that clinical picture in putting all the pieces together. And then you could also use EMG. So on your nerve conduction studies, you're gonna see an axonal sensory neuropathy with small or absent snaps. Your motor conduction velocities should be normal. They may be slightly reduced, but it should be less severe than what you see in the sensory side. And if you were to get an MRI of their spine, you might see atrophy of the spinal cord. Within early stages of disease, you should see essentially normal brainstem, cerebellum, and cerebrum. Now we're much smarter. We can do genetic testing. And so some of the patients that I have followed haven't had an EMG or many radiology imaging if we're highly suspicious for Friedreich's. What does this mean for patients? What is their prognosis? So there's been many studies looking at this as well. And I think we, as a studies, have gotten stronger over the years and we've had more patients that we can take a look at. We know a little bit more. Patients lose ambulation about 10 to 15 years after their initial diagnosis. This graph down here is, or this table down here is also from the DER study in 1996. And this helps us understand what the age of onset, how the age of onset, how the mean time until wheelchair use, and what mean duration of disease looks like based on number of GAA repeats. And so at the top of this table here, from left to right, we have an increasing number of GAA repeats. And what we see is that, as we've talked about earlier, we have a younger age of onset with more repeats. We also see that there is a quicker mean time until wheelchair use in patients with a higher number of GAA repeats. And that reached statistical significance in this study, but had a little better power than previous studies. Previous studies to this didn't necessarily show that correlation, but this one shows it fairly strongly. And then in terms of mean duration of disease, in this study, it showed the mean duration to be maybe from 15 to 17 years without a great correlates to how many GAA repeats they have. So the number of GAA repeats, I think what I take from this is that it can predict the age of onset and it can predict how fast they may end up being non-ambulatory, but it doesn't necessarily predict their mortality. And we'll talk about that in a second and why that may be the case. We know that cardiac dysfunction is the most common cause of death. At least 60% of deaths are related to cardiac cause. In one study, I looked at 60% related to cardiac cause, 10% was unknown, and then 30% was from non-cardiac causes, so aspiration pneumonias and other things. Often the cardiac causes is related to congestive heart failure, although arrhythmias can also happen. I think that, and then this study is sort of showing the correlation between GAA repeat and age of death. And again, there's not a super strong correlation. Maybe they die younger as they have shorter, sorry, they die younger if they have longer GAA repeats. We also know if they have longer GAA repeats, their age of onset is younger and the mean duration of disease is unclear. So like I mentioned a little bit earlier, I think it's hard to know how the number of repeats relates to mortality in general. Okay. So after genetic testing results are positive for Friedreich's ataxia, you bring your patient back to clinic. You notice his data is slightly worse as is his scoliosis. And after you discuss equipment concerns, mom asks about other organ systems which can be affected by this disease. What are associated medical complications seen in Friedreich's ataxia? Cardiomyopathy, scoliosis, diabetes, spastic bladder, A and B are all of the above. And I've probably already given you the answer to this. So it's all of the above, right? So we've already talked about the cardiomyopathy. We talked about the scoliosis, looking for that on your physical exam. We haven't yet talked about diabetes. We will in a minute when we talked about spastic bladder. So cardiac manifestations, as I mentioned just previously, the main clinical manifestations are arrhythmia and heart failure. 95% of these patients will have EKG abnormalities, but there's variable significance to them. Tachyarrhythmias, palpitations, and dysphia on exertion are common. When we think about arrhythmias, atrial fibrillation is what we see most commonly in these patients. We see hypertrophic cardiomyopathy in about 60% of patients. So we're seeing a concentric, we're seeing concentric left ventricular hypertrophy. Sometimes we see dilated cardiomyopathy as well. And we do know that mean allele length, mean number of repeats is significantly higher in patients with cardiomyopathy than patients who don't have cardiomyopathy. And we also know that the severity of the cardiomyopathy is not related to their neurologic function. So their ambulatory status does not correlate with their cardiomyopathy. And I think this may be some explanation for why mean disease duration doesn't matter because you can have cardiomyopathy that is presenting at a younger age that looks worse than what your neurologic function looks like. This is compared to, for example, patients with things like Duchenne's muscular dystrophy where the typical patient wants to come off of their feet, their heart failure. That's when we start to see their heart failure and things get worse. Orthopedic manifestations. So 85% of these patients will have scoliosis. It's more common to have sort of this double major curve, this S-shaped curve, rather than have a big C-shaped curve. Again, this doesn't correlate to weakness and there's different thoughts on why this is. Is there some spasticity in the spine and the paraspinals that are contributing to this happening? What is the reason why their scoliosis doesn't correlate to their neurologic function? And as you would in your typical patient population, you're thinking about monitoring these curves when they're less than 40 degrees and thinking about referral to an orthopedic surgeon or having surgery when the curve is over 40 degrees. And that's because there's concern that it will have pulmonary implications if the curve gets much bigger. 95%, upwards to 95% of patients can have pes cavus and hammer toes as seen in this picture here. Aquinovarus contractures and pes planus can also occur. When in these patients, what do you do about this? So we can consider surgical intervention for these feet. One study looking at orthopedic interventions, they had about 34 patients and nine of them were surgical candidates with more of a rigid foot deformity versus a more flexible foot deformity. And most commonly the surgery they did was released the Achilles and transferred the posterior tib to limit the amount of inversion. Some had plantar fascia release as well. The most significant improvement they found in that study was that patients had improvement in their standing transfers. However, out of those nine patients, three had complications. So two had aspiration pneumonias and one had a pulmonary embolism after surgery. So I think that risk benefit ratio really needs to be thought about in these patients because they are medically complex as well. This is just, again, showing that S-shaped curve. This is one of my patients that I follow. And so you can see, we have a little bit of a double curve happening in him. This was the initial image we got. And as I was preparing for this, I was looking to see, refresh my memory on his progression. Over the past year, he's actually stayed pretty stable, which is great. He is still ambulatory, although that might change soon. So remember, in the beaming of this talk, we talked about how Fratexin helps with oxidative stress and that cells that are at high risk and more susceptible to that include pancreatic islet cells. And so these patients can get diabetes. About 10 to 20% of these patients have diabetes. Most are insulin dependent. There's an additional 30% of patients who are just found to have an impaired glucose tolerance, but aren't labeled as diabetic. Diabetes clusters in SIM chips. So if there are siblings who are affected, the younger sibling is more at risk of getting diabetes if the older sibling also has diabetes. And we have to keep in mind that this can present acutely in children. So it can look like diabetic ketoacidosis and these children can get very, very sick. You'll see a theme here. We're always talking about the GAA repeat length and clinical features. And so we do know that in children and patients who have a higher number of GAA repeats, they are more at risk for diabetes. So X-axis here, we have our normal glycemic patients on the left and our diabetic patients on the right. And we can very clearly see that there is a correlation with a higher number of repeats and a diagnosis of diabetes. From a pulmonary standpoint, what can we see later on in the disease process as their weakness gets worse and potentially when they are non-ambulatory, they can get some obstructive sleep apnea related to neuromuscular weakness and restrictive lung disease. Later in the disease, as we talked about, they can have some dysphagia as well. And so they are more at risk for aspiration pneumonia. So we need to be thinking about those things. Okay. So what the heck do we do for these patients? What do we as rehab doctors do? And I want to just advocate that I think there's a lot that we can offer and add to these patients' treatment plans. So we're going to talk about therapy. We're going to talk about ataxia considerations, equipment considerations, and then medication intervention for asbestosity. So first, I just want you to take a pause and think about how do you think about therapy and progressive conditions? What does that look like? Is it different from patients we take care of, for example, cerebral palsy, or a patient who just had a stroke and we're trying to rehab them? I would argue that we do need to think about it differently. And I personally do think about it differently where more isn't always better in these conditions. You know, we think about cerebral palsy, we think about a patient who just had a stroke, and I think we try and get them as much physical therapy and occupational therapy and speech therapy as possible because with more therapy, they can make more gain in function. And that's beneficial for the child and their family, right? And a progressive condition, we have to remember that they're going to have loss over time because of the pathophysiology of their disease and the progressive nature of their disease. And so I think that more isn't always better. If we challenge these patients with more therapy, yes, could we improve their balance and other things, and for a short time, could we make them better? Yes, I think there is an argument for that. And I think that we should have a very goal-based approach, especially in the later stages of the disease process for these patients. For example, if their ataxia is increasing significantly in their upper extremities, we should check in about how are we doing ADLs and what are compensatory strategies to use. But having these patients and their families go to therapy three times a week and taking time away from mealtimes and other activities, I would argue maybe wouldn't be a benefit for the lifespan of your patient. It's interesting, however, as I was preparing for this presentation, I did find a protocol registered for a 30-week combined outpatient and home program for hereditary cerebellar ataxia using FIM scores and one of the standardized ataxia rating scales, and that was registered in 2020. So I think there's more to come in terms of my theory of is more therapy better or not. So what are we thinking about when we're thinking about doing therapy for these children? And so physical therapy, you're going to think about their core strength, a home stretching and exercise program so that they can do some therapies on their own at home. And like I mentioned, they may not take as much time away from the important things that matter to them. Aquatic therapy, you could consider for these patients, you remove gravity, you can help them work on their endurance a little bit better. We also need to be mindful when we're asking them to do endurance efforts of what their cardiac function looks like. You may ask your physical therapist to do some standardized evaluations to track their disease progress. And I'll talk to you a little bit about that in a second. And then think about equipment evaluations, which we'll talk about. From an occupational therapy standpoint, we can think about upper extremity strengthening exercises and strategies for upper extremity ataxia, alternative strategies for fine motor skills like buttons and zippers. And then later on in the disease process, you may have them work on functional transfers, transfers to the toilet, other transfers at home. Speech therapy will be important, especially in mid to later stages of the disease process as their dysarthria and maybe dysphagia is progressing. And so you're going to be thinking about AAC evaluation, needing to be mindful about having a really good AAC expert that can evaluate their body function and structure because their ataxia may progress when they're later in their disease process. And so they may not be able to touch a screen with something like eye gaze be helpful for them or thinking about using a different method to communicate. And then again, thinking about clinical swallow evaluation and video swallow studies for the onset of dysphagia later in their disease process. So what do we do for ataxia and the lower extremities? And so, as I mentioned earlier, early on in the disease process, you can get more of a sensory ataxia. And so you're going to get a wide-based gait. They're going to have a steppage pattern to their gait. They may not be as staggering, which you'll see more as the cerebellum starts to become more affected. You see that more in cerebellar ataxia, sort of this more staggering gait. And so really to help with ataxia in the lower extremities, we want to optimize their balance, which I'm trying to show with this picture here, which may help you just to take a breath again today. And so you're taking, to optimize their balance, you're taking into account their lower extremity range of motion. Do they have any contractures? Do they have pes cabus or pes planus or other foot deformities or craniovarous contractures that are present in their feet? You're thinking about their strength and you're thinking about their scoliosis. You really want to optimize all of those things as best as possible to help them maintain their balance when they are ataxic. When we think about how to help them, if we feel like they need a mobility device, you could consider getting them a walker, a front wheeled walker, a four wheeled walker, or a posterior walker is helpful in some patients to keep them more upright. However, if they do have sort of a lateral stepping pattern, using that as a compensatory strategy for themselves when they're walking, the walker may actually inhibit that. So you need to keep that in mind. As we're thinking of what mobility device to use as their disease is progressing and thinking about getting them some wheeled mobility, I think it's really important to, again, take into account their whole picture. And so given that this disease processing involves their upper and lower extremities being ataxic and weak, you're really gonna be looking at some power mobility. I do have one patient who used a manual wheelchair with an e-fix device, and she was able to propel her own chair at home on tile flooring, but was harder for her in the community. And when you're thinking about your power mobility, you're thinking about maybe a power scooter versus a power chair. And some things that I encourage you to keep in mind when making that consideration are, what are, how are they doing transfers? Are they still independent with their transfers? If they are, they can get in and out of a power scooter easily. Are they still doing a little bit of walking at home, maybe, and in school, maybe that's the right choice for them. If they're not able to do transfers, you may consider getting them into a power wheelchair where we can have more supportive seating and power features to tilt them back and things to keep pressure off their bum. You're thinking about scoliosis. Remember, a power scooter just has sort of that captain's chair. You can't customize that. Whereas a power wheelchair, you can customize their backrest and their seating options. And then thinking about any skin concerns you may have as a power wheelchair will serve you better in that regard. And so what do we do for ataxia and the upper extremities? The name of the game here is compensatory strategies and equipment. So studies by OTs, very smart OTs about ataxia, the goal is sort of having a task oriented approach in these therapy sessions as that's proven most effective. So some of the things you can consider are weighted tools. So weighted utensils for eating, weighted pens and pencils for writing. The other thing you might encourage in this patient population, given that it's a proprioceptive deficit, initially causing the ataxia is to look at the task they are doing. So look when you're writing, look at the spoon when you are trying to grab some food. You can also think about plate guards when eating, button hooks and zipper pulls for helping to do those fine motor tasks. Elastic shoelaces, which this picture here shows some pretty fancy ones that I hadn't seen before. And then thinking about school, what are they doing to complete their school assignments? Is typing easier than writing? Do we need to think about some other way for them to get their schoolwork done? Later stages in the disease process, this may be difficult because speech to text may be hard for them given their dysarthria as well. From an equipment standpoint, we've talked a little bit about mobility devices and what do we do for self-care and ADLs? So initially in this beautiful bathroom, you can see some grab bars. These may suffice to hold on to something in the shower. They can still maintain balance or they can still stand okay from an endurance standpoint and a safety standpoint. They just need to hold on to something for a little bit of balance and to keep their independence. Later on in the disease process, they more than likely will need some sort of bath chair or bath equipment. And ideally we'd love to get bath equipment for all of our patients, but insurance makes it a little challenging for us from time to time. And so this is a Rifton bath chair that's wonderfully supportive for their feet and their back. Although you may have families that just decide, you know what, just got a plastic chair and I put it in the bathroom. That was the easiest thing for my family to do. And I'm sure you have patients like that as well. How do we help with their dysarthria? This can get quite challenging over time. I have several patients who their family can communicate with them quite well. I have a bit of a hard time understanding. The masks we all have to wear aren't helping that recently. Really what we want to do is optimize their proximal and trunk control. So optimize their trunk stability and work on breath support with them. So how do they support their breath can help with some of this dysarthria. And one of the strategies they can also use is talking in segmented phrases. So not talking in long run-on sentences as that can be a little bit challenging to control dysarthria and controlling their rate. So not talking too fast. I know that when I talk too fast as I probably have a few times in this lecture, my words get a little bit jumbled, right? And so dysarthria can get worse if someone's trying to just spew out a lot of words at once. We've already mentioned AAC, but again, you may be looking at more of a text-to-voice software. So their problem is they have a hard time with intelligibility of their speech. And so, like I mentioned, voice-to-text isn't going to work for them. You're going to want to do something like the opposite and then considering an eye gaze device. Dysarthria, I should mention, is one of the prominent symptoms of Friedreich's ataxia and was listed on some of those lists I had earlier from the consortium groups and from the early studies. It's about 100% instance of dysarthria in Friedreich's ataxia with 10 years of diagnosis. And the last thing to consider is that communication may also be altered in these patients given some hearing loss that we can see later in their disease process. So what do we do for spasticity? And I was looking through the consensus guidelines for Friedreich's ataxia. And as I was looking through, they said there was this great algorithm for spasticity. And putting my academic hat on, I thought, oh, this is great. We can talk about this. And then looking at it, I decided, you know, it just tells us to do what we do with all of our other patients who have spasticity. So there's no magic with Friedreich's ataxia in terms of how to treat their spasticity. You're going to take a look, do your exam and look at how is this functionally affecting them? What muscle groups are involved? Is it more focal? Is it more generalized? And use your general practices to treat them. This algorithm is actually one that they took from a paper describing how to treat spasticity in multiple sclerosis. So no magic in terms of how to treat spasticity in this patient population. Similar thought for spastic bladder. So we see this in later stages of disease. I have a patient with incontinence during the day. I have a patient who has challenges at nighttime. And so again, you're going to do what your typical practice is. You may check her PBR. You may consider intermittent catheterization. Keep in mind their upper extremity function. If someone's ataxic in their upper extremities, what's that going to look like for them? And then low thresholds refer to urology to consider urodynamics and or Botox to the bladder. Lastly, in all of our patients, I would argue specifically patients with progressive disease, we need to be thinking about mood and adjustment. And I really love this quote by Gandhi, life is a continuous process of adjustment. And we need to keep in mind that for these children and young adolescents, their physical body is changing as their cognition is staying the same. So they're aware of these changes that are happening to their body. And that can obviously be very challenging for a child to digest and their family. And adjusting to different ways that they're needing to accomplish tasks and continue to engage in the activities that bring them joy to optimize their quality of life as best we can. So involving rehab psychology, if that is available in your practice is wonderful or having other resources and support for them in their community is highly encouraged. So what's going on? What's going on in the world of research for rhodioxytaxia? And so before I get into that, I just wanted to mention that there are two outcome scales that we look at when you're looking at studies in this patient population. And these are really functional outcome scales. These are scales that us as rehab doctors should know about, should think about if you're thinking about doing some research involving patients with ataxia. So the one used most in the West and the United States is called the MFARs Modified Friedreich's Ataxia Rating Scale. It's really looking at four different things, bulbar symptoms, which include how strong is their cough and what does their speech sound like, upper and lower extremities. So that's three, looking for mostly dysmetria with tests like finger to nose and heel to shin. And then the last thing that we're looking at is gait and upright stability, which they test with things like static standing with their eyes open and closed, tandem stance, so one foot in front of the other, dominant foot, so single leg stance, tandem walk, and what does their gait look like? That's mostly what we're looking at with the MFARs. The scale for the assessment of, and rating of ataxia or the SARA is something that's used more in Europe as part of the EFAX group, the European Friedreich's Ataxia Consortium for Translational Studies. And essentially it has a lot of similar components. It divides components more into eight sections where they don't clump them more into like extremities or bulbar symptoms, and they just look at finger to nose and heel to shin and what is their gait doing. So these are very similar scales. It just depends on sort of geographically where you are. So I encourage you to take a look more at those and they've both been validated for use in research. There's been a lot of effort to look at different antioxidants specifically in this disease process. Again, remember for taxon, we think plays a role in iron metabolism. And if that's thrown off, we get more oxidative stress and more cell death. So can we help this with antioxidants? And so we've looked at vitamin E and CoQ10 and this drug called Idevanone, which had some initial promising results in terms of cardiac function with inconsistent results in neurologic function. And unfortunately, there just haven't been many consistent positive outcomes until I mentioned another study. And I should mention that none of these things are FDA approved. There are no current treatments available, FDA approved treatments for Friedreich's ataxia right now. This study, safety and efficacy of Omavalexalone Friedreich ataxia or the MOXIE study. So this was published two years ago now out of some of the big names in this diagnosis are David Lynch who's on this paper and Susan Pearlman also David Lynch is out at CHOP. So what is Omavalexalone? Omavalexalone is an NRF2 activator. Well, NRF2 stands for nuclear factor erythroid two related factor. And this plays a role in mitochondrial signaling when oxidative stress is present. So by activating this, we are helping with some response to oxidative stress. They looked at 103 patients, although I believe that 80 to 90 were followed out to end of study. These patients were 18 to 40 years old and had a confirmed genetic diagnosis of Friedreich's ataxia. It was a randomized controlled trial where control group received placebo and the active study group received 150 milligrams of Omavalexalone daily for 48 weeks. The outcomes were the MFARs, the modified Friedreich's ataxia rating scale and maximal exercise testing. So this graph helps us see overall effect of this study. There's lots of details that I won't get into but on the graph on the left on the X axis, we're looking at time. So 48 weeks was the end point. And Y axis, we're looking at mean change in baseline and MFARs. And I should mention that a lower score on MFARs means higher level of functioning, higher score means more impairment. So the black line here is subjects who are on study drug and gray line is placebo. And we see this very initial first dip. So improvement in both groups out to 12 weeks. It's not really known why this happened. Was there some like hopeful thinking, wishful thinking on part of everybody? But then we see over time that there's a very clear and significant difference between folks who are on study drug and folks who are not. Where subjects who were on placebo had the expected progression of their disease worsening in their MFARs. And patients who are receiving study drug actually continued to get a little bit better, had a little more improvement and then stayed stable. This was seen the best when we were looking at the upright stability sub score. And so again, you see this is getting better over time and then stable towards the end of the study, whereas it's overall getting worse in patients who are not on study drug. And then just a quick plug that there's lots going on in this patient population and looking at research. And this is what's called the pipeline. And so lots of different pharmaceutical companies and academic centers looking at different drug products. Omovalexalone, as you can see is at the top here. And that's the study we just talked about is the closest to new drug application for FDA. And that's it. Questions? I think I see one in the chat. Oh, okay. First of all, can you guys hear me? It's Scott Paul over at NIH. Great job. It's a very interesting condition. There's another tax year rating scale that's not exclusive to Friedrich's that is worth knowing about. It's called the ICARS, an international classification of a tax year rating scale. What's nice about that is it's not disease specific, which means you can compare disease to disease. So I think that's a good one to be aware of. I haven't seen David's article, but when we partnered with him back on adebanone, we were not able to show any change in cardiopulmonary function, which is a big aspect of this. In fact, the big challenge in putting together a rehab program is that you're talking about trying to balance cardiac function, balance, sensation, and some peripheral weakness as well. But our feeling was that we would encourage them to do aerobic exercise to tolerance and wouldn't push strengthening too much because it's a mitochondrial condition. And also that we didn't publish this, my impression from our group of, I think we had about 40 patients, was that in addition to the neuromuscular issues, that there's a tendency to hypermobility, which may be a contributing factor to the scoliosis. Thank you. Those are great thoughts. I think that knowing about that skill is awesome and knowing about some of the other work that has been done and what you've seen is great additionally as well. Thank you. Welcome. Excellent talk. I mean, I thought that was a really great overview. I certainly learned a lot. I put the link in the chat for those of you who are on live, just a little information about that scale that Dr. Paul was just referring to. Looks like you got lots of praise in the chat. Lots of people are really excited about your lecture and all the great information you gave. I'll give a couple more minutes here though, if anyone does have other questions, whether you want to put it in the chat in the Q&A or raise your hand and can ask a question or make comments like Dr. Paul did as well. Always a good sign. There's no questions. I think you did such a great job that you answered everything. But I did find that really helpful and I'm sure others did as well. So thank you so much again for lecturing for us. Great job. And for those of you listening, you can claim your CME by going to the AAPMNR and just indicate that you listened to the lecture and then you'll just have to fill out the evaluation. And for those of you who are listening asynchronously, you probably figured it out already, but if your friends want to do it, they can take a look at the AAPMNR learning site and it'll be posted shortly. Thank you all again and I hope everyone has a great rest of your day. Take care. Thank you.

Friedrich's Ataxia

genetic disorder

nervous system

pathophysiology

clinical features

medical complications

rehabilitation interventions

GAA triplet repeats

oxidative stress