My son Yohan was diagnosed with CMT at 7 years old. We have no prior history of CMT in our families. Yohan has CMT due to a new spontaneous genetic mutation. He’s the first in our family to have CMT. Though Yohan’s CMT has thrown roadblocks and presented challenges in his life, it’s also made Yohan resilient, empathic, loving and kind.
A huge thank you to all our friends and family who have supported Yohan throughout the years. My husband, Gilles has always been so good at finding ways to spend quality time with Yohan, engaging him in so many activities: camping, horse riding, kayaking, and now, mountain biking. Yohan’s Uncle Chris has also had a profound influence on Yohan throughout his lifetime. Here is a chapter in their story.
Chris flew in to Claremont, CA to attend my Grad School Graduation. It was a total surprise!!!
Yohan’s CMT Story – Uncle Chris
By Yohan Bouchard
VT summers: me and Uncle Chris
Since I was 4 months old, every summer (and a few below-zero Christmas holidays) were spent visiting my mother’s side of the family on the east coast. Vacations in Vermont were a blast – often the highlight of my year. I have such fond childhood memories of our adventures, which included spending time with my grandparents, aunts, uncles, cousins and longtime friends.
Yohan, cousin Warren, my mom, Kevin, James, my grandmother, Uncle Chris, Aunt Mia and cousin Lila.
In particular, I spent a lot of time with my Uncle Chris; we’d go fishing, hiking, and swimming. In winter, he’d also take me skiing and snowboarding. But, as my CMT progressed, it was more and more difficult for me to keep up. I realized I was participating less and less in those outdoors activities, which we both enjoyed so much.
Snowboarding in VT with my dad and Uncle Chris.
Throughout the years, Chris and I had grown very close; he was always there for me regardless of my limitations. He knew my muscles were getting progressively weaker and noticed I was becoming more limited in my physical capacities. It was hard for both of us to embrace the effects of CMT, but we always managed to find alternative activities, like fishing, swimming and just some plain ol’ goofing around.
Goofin’ around with Uncle Chris and Warren
When Chris first brought up the idea of organizing a CMT fundraising event centered on cycling, I was impressed by his drive to actively raise money for a CMT cure. Witnessing his passion first hand, I too got excited by his vision which was to launch both an in-person and virtual Cycle event to fund treatment-driven research. I was convinced it would be a phenomenal successful, and I was not wrong. .
Over the last eight years, the Cycle 4 CMT has shown me just how far my uncle, and all my family and friends everywhere are willing to go to support me and so many others struggling with my CMT.
A surprise visit to the 1st Annual Cycle 4 CMT event
After the second or third annual event, I decided to face my fears and try to ride a bike again. My childhood adventures of being scared and unbalanced came back to haunt me, but I persevered. I wanted to show my Uncle Chris how much his effort, time and love meant to me. I biked around my college campus a bit, but that was the extent of my efforts.
Last year, with my dad’s encouragement and help, I gained confidence while I peddled on streets and swerved around people; I got back in the saddle. I was determined to actually ride alongside Chris and my friends on one of the Cycle 4 CMT routes. Of course, COVID had other plans, but it did not stop me. I did cycle in the Virtual Cycle (and Walk!) 4 CMT event with my dad and a group of friends over the Golden Gate Bridge in San Francisco. It was extremely fulfilling to do the actual ride with my dad and peers instead of sitting on the sidelines. My new electric bike was a game-changer!
Me and my dad, Gilles. We don’t go around obstacles, we face them straight on!!
I’m so pumped to go to Vermont this year and finally ride with my Uncle Chris in the 8th Annual Cycle 4 CMT. I will realize this dream as I want to show Uncle Chris how all his work has inspired me to face my fears and overcome them. I am extremely fortunate to have a supportive, loving family and an Uncle who is willing to go the extra mile.
Registration opens March 15, 2021. We are having both an in-person event in Charlotte, VT, on Sunday, August 29 and a virtual even from March 15-August 31, 2021, an anyone, anytime, anywhere can participate!!
Q: I have gained a lot of weight since March after the start of the shelter in place, and continued to gain throughout the year due to COVID restrictions, stress, etc. Is CMT making this worse? What can I do about it?
A: First of all, you’re not alone! This is one of the most common things I’ve heard from patients and clients in recent months. Weight gain during the last 9 months or so is very common. For most people it has been a combination of stress, uncertainty, depression, lack of routine, inability to fit in traditional physical activity, and lots of free time to eat.
If it took you 9 months (March to December) to gain the weight, you can count on it taking at least 9 months to lose again. That said, it is most likely going to take even longer because weight loss is inherently more difficult than weight gain. The bottom line is to adjust your expectations and try to exercise patience during the process. The most important thing is to just keep going, stay consistent, and try not to let the slow progress derail you. If you have a tough day, making small progress and steps forward is always better than staying off track.
CMT itself is likely not slowing your weight loss, although you may be limited in physical activity which can make weight loss more difficult. When we discuss losing weight what we’re really talking about is creating a calorie deficit. Calories in must be less than calories out in order to lose weight. Exercise alone is unlikely to be enough to promote weight loss without dietary adjustments. Exercise helps create a larger calorie deficit and has more benefits including muscle health, cardiovascular health, mental health, etc. so it is important to exercise regularly on this path to weight loss. Diet, however, is going to have the highest impact on weight loss. Eating less, but still above the basal metabolic rate, is the target to hit. For most women BMR is 1200-1500 calories per day; men are 1500-1800 calories per day. Eating significantly less than your BMR may actually stunt your weight loss efforts.
It may help to really examine your eating habits during the shelter in place and identify the parts that significantly changed from what you were doing before. Those are the parts of the diet to target and try to work on. There is not one general recommendation for everyone to help lose weight, it’s a matter of looking at your individual habits and making adjustments for the most success.
Don’t give up! Working on your diet and exercise on a daily basis will yield results over time, but it will likely take longer than you hoped.
*Sara Kevern, RD, CNSC Clinical Dietitian III
Sara Kevern is a Registered Dietitian and Nutrition Support Specialist at Stanford Health Care and Stanford Children’s Health. She joined the Neuromuscular team in 2019 to inaugurate and build nutrition services. She works as part of the multi-disciplinary clinic where she provides Medical Nutrition Therapy to those patients diagnosed with neuromuscular disorders. Sara completed her training at Ohio University and has been practicing as a clinical Registered Dietitian for 8 years.
Dr. Glenn Pfeffer: Orthopedic Surgeon at Cedars-Sinai
The CMTA hosted a very informative talk on Zoom in September, 2020 to the CMT community featuring well-known orthopedic surgeon, Dr. Glenn Pfeffer. I’ve transcribed this talk for you! Enjoy!
Elizabeth Ouellette: Welcome Dr. Glenn Pfeffer. Dr. Pfeffer is the Director of the Foot and Ankle Surgical Program at Cedars-Sinai in Los Angeles.
I can’t tell you how much I appreciate and admire Dr. Pfeffer. He spends all his time with people with CMT. He wants to better their lives. He wants to see people walk. He has devoted so much time and energy to the CMT community. I am just so honored to have him here as a doctor, my son’s surgeon, as a friend and as a colleague. So welcome, Dr. Pfeffer, and thank you for coming on.
Dr. Pfeffer: Well, thanks for having me, and I’m surprised so many people came on a Saturday!
Elizabeth: First, I’d like to get to know Dr. Pfeffer a little bit more. And when I was doing some research on him, I saw that he did magic. I’m like, what surgeon does magic?
Dr. Pfeffer: Actually, magic is important to me. I did this through high school, college and medical school. I actually performed in nightclubs. I spent the summer in Nantucket at the Rose and Crown as their magician. And whatever it is that attracted me and still attracts me to magic, is the exact same feeling I get two weeks after surgery when a CMT patient is sitting in the office. Your foot’s going to be a little bloody. You’re going to have some sutures to take out, and we open up the cast, and you’ll see some pictures of this, and I hold their foot and I say, “Take a look here, your foot.” And it’s a new foot. It’s a foot they haven’t seen, perhaps ever, and the look on their face is identical to the look on people’s faces when you do a magic trick for them.
So whatever that is that attracts me is why I continue with magic. Magic is very simple you know. You can do things like this where you can take something and have it disappear. You can make it a little more complicated, which I do in the office for kids. You just take the same little piece of foam or whatever, and you just put it into this hand and you can just show people that it’s empty. So that’s sleight of hand, which of course is great for the magician. I still do this at orthopedic parties. But not to belabor it, if I were going to do this I wanted this to have the same absolutely startling response that people have with CMT when they see their new foot.
Elizabeth: Your father was a surgeon?
Dr. Pfeffer: He was a general surgeon.
Elizabeth: Oh and so is that what inspired you to be a surgeon?
Dr. Pfeffer: Yes, absolutely – I don’t think I’d ever have even gone into medicine if not from my dad’s influence. You know like all of us, I’m a mix of my dad’s DNA and my mom’s and they were very different people. But dad really inspired me with his surgery, and he was hard-working and I think it was my destiny. I probably have very little free choice in life. He didn’t make me but in terms of who I was, it was sort of my destiny, like the Jedi.
Elizabeth:You horseback ride or you did in the past. You scuba dive, you dance, you create bonsai, and I read somewhere you made a correlation between bonsai trees and surgery. Could you tell us a little bit more about that?
Dr. Pfeffer: I’ve always been interested in bonsai which are, you know, plants; they’re trees, and you keep them miniature by trimming their leaves, by trimming their roots, and you keep them in small pots. Everyone knows what they are, and what you do to shape them is you wire the branches and you hold them down so they look like a tree. And I realized only a year ago that what I’m doing with bonsai is identical to what I’m doing with CMT feet. I was sitting there in surgery and we were wiring a foot down and putting screw into it, and somebody who knew about bonsai said, “You know, Glenn, that’s exactly what you’re doing with bonsai.” And it was startling to me. You would think it would be obvious but it wasn’t.
As you may know I’ve got my own foot problem.
Elizabeth: I was just about to ask you; when you told me you had foot issues, I’m like, “He gets it.He knows what it is like to have a foot problem, and I think that’s a bonus for your patients.”
Dr. Pfeffer: Well I was just going to say, though, that’s how I got into horseback riding. Because I’m athletic by nature, but I couldn’t run. You know, I didn’t know what I had. It’s very poignant for me, the CMT world, because patient after patient, everyone who’s listening knows this, everyone, unless you had a mother or father who had CMT, you grew up not quite knowing what was wrong with you, right? And I didn’t either. I didn’t know I had a problem with my foot for 40 years. It sounds dumb, right? But if someone’s out there with CMT and no one told them they had CMT for 40 years, and they just thought they walked funny and they couldn’t keep up, and they were a little unbalanced, nobody would know. So I took up horseback riding because I could do what I wanted to do. I could fly through the air and jump, and I’m sure all the people listening have modified their lives in way so that they can function with their CMT.
Elizabeth:I think you can really relate to people with CMT and understand foot issues and the inability to do certain things.
Dr. Pfeffer: Well there’s no question, you know I don’t like to talk about it too much because you don’t want to get a little corny on a Zoom chat with all these people, but yes, I 100 percent relate to what people are going through. I’m not in a wheelchair. I don’t have problems breathing. My hands are strong. But for the isolation that somebody feels, the difference that somebody feels growing up with CMT, that is exactly what I felt for sure, and I don’t know that you can teach somebody that. I’m not sure you can really learn it, but it’s just in my soul. I’m not as bad off as most of the people with CMT at all but that’s why I get it, you know, that’s why I think it’s probably why I was attracted to all this.
Elizabeth: So why don’t we start your presentation, I think you are a fascinating person, and I know you’re an expert surgeon and the best of the best. And you’re also a great presenter, so I’m sure people want to hear what you do every single day.
Dr. Pfeffer: I want to just show you my world of CMT, and I have a certain kind of person that comes to me, right? Somebody who was unfortunately paralyzed in a wheelchair would not be getting to my office, so I do understand that I’m seeing a segment of the CMT population. But this is my world and what I go through every single day. At this point I’m confident that we at Cedars are operating on more CMT patients than anywhere else in the United States and we have a plethora of experience with it.
We’re lucky enough to have a large CMT program at Cedars with some of the most famous CMT neurologists on the face of the planet, such as Rich Lewis and Bob Baloh, and with amazing geneticists. If you have an issue, you can come to see the program. You’ll see a lot of people. Instagram is as alien to me as, you know, speaking Russian or French and yet it’s been a tremendous success for me and the people who follow it. I mean, my gosh, I didn’t even understand that at one point I had two people following it. Now we have close to 1400 people across the world, and I communicate with them all. It’s sad when someone from Ethiopia says “How can I come and have surgery?”, and of course the chance of them having surgery is almost zero for financial and travel reasons.
I encourage you to follow me on Instagram: #CharcotMarieToothSurgery
The foot has 20 muscles.
The foot’s complicated, right? It’s got a lot of muscles in it. There are 20 muscles in the foot, more than there is in the entire leg.
The tibialis anterior lifts the foot.
The tibialis anterior muscle is the strongest dorsiflexor (muscle lifting foot up toward the shin) and helps to lift the foot from the ground. The Tibialis Anterior Muscle also facilitates flexion of the foot upwards and extension of the toes. The Tibialis Anterior Muscle originates from the outer surface of the tibia and inserts into the first metatarsal bone in the foot which is located behind the big toe.
Toe extensors
Above are the toe extensors. These are what lift up your toes, and interestingly with CMT, if the tibialis anterior that lifts your ankle gets weak, these toe extensors will start working harder, which is why so many of you will have a toe deformity. As the Tibialis Anterior muscle gradually weakens and the foot drops down, a contracture of the Achilles will occur because the tendon is no longer being stretched out during gait. The worse the contracture, the harder it is for the weakened Tibialis Anterior to lift (dorsiflex) the ankle.
The Achilles tendon tightens with CMTPeroneus Brevis
Above is an image of the Peroneus Brevis, one of the key muscles that weakens in CMT. Why it happens exactly is still unknown, but this muscle, when it weakens, destabilizes the ankle and the foot starts to turn in, because this muscle is weak. And the other reason the foot starts to turn in so commonly is because this muscle in the right foot, looking from behind, stays strong.
So one weak muscle, and one strong muscle causes the foot to start to deform.
So let’s talk about that what causes the CMT deformity. I’m talking about this common cavovarus (very high-arch) foot. This is what happens every millisecond in our body. Muscles are pulling back and forth but keeping us balanced, right? With CMT, because of the paralysis that’s uneven, involving some muscles but no other muscles, they become weak. There is CMT. Some muscles are powerfully strong, and others are weak and that causes a deformity. It’s called a cavovarus, and you can really see it on this right foot.
cavovarus foot
If you took your hand, put it in your pocket and left it there for a year. Not only will you not be able to move it, you’ll probably never be able to open it up again because all of the soft tissue contracts. And that’s what you don’t want to have happen. If there’s one message I can give you, don’t let that happen.
The minority of patients I think benefit from surgery with CMT: Most patients do not need surgery.
The person below is wearing ground reaction force braces. This type of brace, made from carbon fiber or plastic actually bends and stores energy.
So when you have no function in the leg and the Achilles tendon isn’t working, these braces are just terrific. This person could walk a hundred miles if they had to because their foot’s flat on the ground and they’re doing great. Now, here are all the types of braces there are. Some are off the shelf. Some are custom made. Which is better than the other? I don’t know.
I absolutely think chocolate ice cream is the best. Does anyone disagree? Some people like strawberry or maybe vanilla, and the problem with the braces is you can’t try them all on unless you go to a spectacular brace shop, which I’m lucky enough to work with at our Center of Excellence. Would anybody say that a size six dress of a certain brand is perfect for you? Of course not. You’d want to at least get it in the mail, try it on and send it back. That’s what you have to be able to do with braces. Unfortunately, we can’t try all these braces and some of them cost thousands of dollars, so try to go to a brace shop that has a wide selection to let you try some of them off the shelf.
Now that is not the right brace for a for this crooked foot. Some of you have it. I see this situation every day of the week. Would anyone put a foot like this into a brace? It’s like putting a square peg into a round hole. This is from Friday.
This brace does not work for a crooked foot.
I was a little delayed today getting my talk all set because this gal just came in. She lives on a ranch. That’s the shape of her foot. That’s the shape of her brace. Shame on everyone taking care of her. Shame on her brace maker. She has pain walking on the side of her foot in a brace that looks like it’s something to a caged up an animal. That foot should never be allowed to walk the face of the Earth. That can be made flat, and even if this woman can’t get out of her brace, she can get into a brace with her foot balanced and her body weight plumb lined with no pressure walking on the side of the foot.
I can’t see you all, but how many of you have had or have a callus on the side of your foot? Right. That’s what happens. So these people should all have surgery, that’s how I feel. Now some people don’t want to wear a brace.
This is Katie’s Story
“Hi, my name is Katie. I live in Florida and I have CMT. Katie didn’t want to wear a brace. It was in sixth grade when I first started getting made fun of for the way that I walked and noticed that running and keeping up with my friends was becoming more difficult for me, and my parents started taking me to some doctors to try to find out what I could do to help me with my CMT. With each doctor that I met with, I felt like they didn’t understand my specific case of CMT. And they gave me some options, like braces and orthotics, and some of them would help me temporarily but nothing ever really helped me. So when I was in high school, I started falling almost regularly, and I missed out on my homecoming and my prom and just gave up on trying to find shoes that fit and started to become really discouraged.”
So Katie was a young woman, and she didn’t want to wear braces. She could have actually been in a brace. So she came from Florida. She said, “I don’t want to wear braces the rest of my life.” So I said okay and she had some muscles that were working. We operated on one foot, and she was incredibly brave and so we operated on the other. Katie could hardly walk without a brace without holding onto a wall.
Many of you know that kind of person. So the CMT type foot deformity is a tricky surgery. That’s the problem, right? People have had a lot of issues with it. There’s so many components to CMT surgery. The surgeries will take at least three to four and a half hours. There’s no way to get through it quickly. Basically, the failure of CMT surgery is when we don’t do enough.
So this is what we put on the operative board at Cedars-Sinai. We put all the procedures someone’s going to have. “Hi, we’re going to fuse a part of your toe joint,” you’d say to a patient, “Okay, let’s schedule you for surgery. Hi, we’re going to do a tendon transfer on you. Okay let’s schedule you for surgery.” But the tendon transfers are some of the most complicated and extensive surgeries that there is in all of orthopedics except for some spine surgery or hip surgeries with dislocations and acetabular malformations.
Many surgeries in one – CMT foot surgery
Now how do we know what to do? Well, the problem is there is no good consensus on what to do. At least there hasn’t been, but we’ve done a lot of studies on this at Cedars and much thanks to the CMTA for their help.
This was a study we did. It was published in 2018. It was sponsored by the Charcot- Marie-Tooth Association (CMTA) and this was really incredible for us because we won a prize for this operation telling us how to correct the heel varus. And we won a prize for this as one of three research studies of the year most likely to change orthopedics. I just happened to have it here.
We took a print of one of my patient’s foot – Sarah. And we printed out 18 “Sarah’s”, 18 of these and then we studied them with different operations in the lab, but very exactly, and we showed which was actually the best operations for correcting heel deformities in CMT patients with her type of problem. Since then we’ve done other research more on heal osteotomies. We’ve looked at extensor transfers The most difficult, competitive organization in the world and the most academic is the orthopedic research society. And Max, who’s going to be joining us, he’s the second author, won a prize here just this past spring for a young investigator’s prize. I mean this is like winning a Nobel Prize in orthopedics and I was actually stunned by it. But part of the reason is because the whole area of CMT surgery is so poorly investigated, it’s not that hard to do some landmark work if you do the research.
Now there’s a big hole on how you should do CMT surgery and how it ends up in people and how do people do it. We’re just starting now. Some of you I’ve operated on. I always say I’m a pretty accessible guy and I don’t hear about too many people doing poorly. I know the ones I’ve had to re-operate on. I just spoke to a woman this morning where a young girl in New York is not having the motor strength that she needs. So I think I have a sense of it, but we’re going to study it and hopefully publish that by the end of the year.
So this was a remarkable thing – years in the planning. There were seven past presidents of the American Orthopedic Foot National Society and some of the most famous foot and ankle surgeons on the face of the planet, and with the sponsor of the CMTA sponsorship and Elizabeth’s fire in her belly. we brought these people together. And it almost killed me, literally, but we finally published a paper on our results, which just came out, and this is a consensus. We didn’t get everyone to agree, but I think just to sum it up here, this is accessible. You can get it through the CMTA and other places and if you’re going to have surgery locally in your area if you can’t come to Los Angeles for some reason, give this to your surgeon and say, listen I’m sure you know all about this but would you mind taking a look at this paper. And if they haven’t seen it they’ll be grateful to have it. https://www.cmtausa.org/news/breakthrough-guide-to-orthopedic-surgery-for-cmt/
The goal of surgery is to give you a flat foot, and to balance your foot. My goal is to keep you out of a brace if I can, and I usually can if I’m willing to operate on you. It doesn’t always work that way, and if we can’t get you out of a brace, at least we’ll get you into a smaller brace. Much better to wear just a small piece of plastic than some of these bigger, bulky braces. So what do we do? We transfer tendons, which is moving muscle. We move strong muscles that are deforming the foot to weaker muscles which are letting the foot become deformed. We cut through the bone. Here you can see a bone. This is a right heel we’re looking at.
We take a wedge out of the bone. We twist the heel around. Here you can see it. So this is the heel from behind on the right side. You can see what we do. We take a wedge out and then we just simply shift the heel.
Okay, now who can you trust to do surgery? I hear there’s a lot of talk about me in chat rooms and stuff. I said, is there anything I ask my patients they don’t like. One person said, well you kept them waiting a lot, and another person apparently said, well, I just didn’t like him, but I guess he’s a good surgeon. But look out there. I don’t hear anybody saying about me, anyway, oh he sold me a bill of goods. He said I’d be good but I’m not. I just do not hear it. And if you do, tell Elizabeth and she’ll tell me because I want to hear about the failures I’ve had. I know the failures. I know why they’ve occurred but most of them have just been in the hands of God. Find someone who does at least one CMT surgery a month.
Find someone you trust
That’s a fair number of CMT surgeries to do. Most very experienced, busy surgeons will be doing three CMT surgeries, maybe two a year. But if you can find people around the country. that’s a good thing.
When should you do your surgery? Do it as soon as you know that you or your child can’t live with their foot the rest of your life. The sooner the better. Dr. K, my partner, because I don’t operate on people really under the age of nine, he just operated on a four-year-old yesterday from Utah, both feet. All these people are the perfect age for me to be doing surgery. You know, 10, 11, 15, 16, but you can do it anytime. It just gets harder because things get stiffer the older you are. So every day, because of Instagram, I chat with people. Some people are from Eastern Europe. Some people are from United States, and I have met most of them. I guarantee you I will make you better. I don’t know how much better. I’m not 100% sure I’ll keep you out of a brace, but I tell people you’re about a C-. I’ll at least get him to a B +. All right. So all I need is one strong muscle.
All I need is that muscle to move. That’s it. I just need any muscle. Is there risk? Of course.
CMT Foot
The biggest reason surgery fails are that not enough was done. To do 18 surgeries at one time is a lot. T
Sarah was one of the most amazing. You may have seen her. She was 16. She couldn’t walk. We operated on one foot. All she said she wanted to do was walk down the high school aisle without having to hold on to her father. I called her years later. I said, “How are you doing? What’s going on with you?” And she said, Dr. Pfeffer, you don’t understand.” She said, “I just walked 10 kilometers around London with my boyfriend in cute shoes.” So that’s a magic trick all right. This gal, she said, “I don’t want to wear braces. I’ve had surgery. I’m going to be the first woman President of the United States. I’m going off to college.”
There she is. I mean, I can’t do that. Could she? She texted me a while ago. She goes, “After five or six hours of walking around campus, I need a little co-op brace. You know, ones that go into your laces because I get tired at the end of the day and sometimes need a little bit of help.” That’s better than I ever thought.
Q & A
I’m wondering how you deal with toes. Yeah it’s a great question. Very succinctly, toes are among the most difficult, actually, of surgery to do and the the longer people wait, the worse off they are. I can still fix the rest of the foot, but the toes become more and more problematic and there’s no easy answer for that. Sometimes as simple as just transferring the tendons. Sometimes we just cut the flexor tendons but I don’t like to do that in someone who has a motor disease. And what I’ve been doing lately with severe problems is we actually have been fusing these joints. It’s okay because the joints are useless. It’s not doing anything for anyone except getting in the way. So we fuse the joints and leave the tendons alone and and we can have some beautiful results with that. The problem is it’s a lot of surgery. That, in and of itself, that operation could take an hour, hour and a half. To add that onto a four hour operation … someone like the boy I’m operating on on Monday who has all that may have to come back, he may for the toe operation.
I had foot surgery, now my knee and hips are not aligned with my feet and I am having gait problems as well as some knee and hip issues. I’m wondering if that is because she waited too long and the CMT foot made her walk differently or do you do gait analysis beforehand? Have you heard of these problems? Someone has foot surgery. They get deconditioned and the hip muscles which are vulnerable to begin with, and the knee muscles get weaker, right? So they just get deconditioned. I know of one person in my career from Santa Barbara, and she had foot surgery. She was, you know, recovering and then she had that problem. You know, and all of a sudden her hips started to have a problem. It’s really really rare if the foot’s have been bad … feet have been balanced properly. My first thought is that the surgery didn’t work on the feet and that they’re imbalanced. The key is to remain conditioned, even if confined to a bed. Get some five pound weights on your ankle and lift up the leg.
Do you ever do both feet at the same time?
Never. You could do double surgery, like in a four-year-old like yesterday where Dr. K did that. Where you can just carry them around easily, but no, an adult is going to be completely impaired because they can’t put any weight on their foot for six weeks. Yeah. They would have to be tiny. Carry them around to the toilet. Carry them to the chair. What weight would that be? I don’t even know. You know, 50 pounds if dad’s strong.
Is there a particular age you recommend surgery?
There’s not a specific age, but how do you know to bring your child to trust you with his feet or her feet? When do you do it? Well, it’s absolutely the most important question anybody can ask, and I don’t have an answer. To operate on the crooked foot at any age, operate certainly on the young adolescent at 12 or 13, as soon as you know that person’s not going to live with that foot ideally for the rest of their life. If you look at your child, your friend, and you say I don’t want them to have that foot the rest of their life, that’s the time to have surgery.
Since CMT is a progressive disease do you do surgery and then 20 years later you have to do it again because the foot deforms or what is your experience with that?
There’s no literature on that whatsoever. The study that we started in 2017 will be coming to fruition soon. I said I told you, anyone I’ve operated out there please answer us when we write to you, and we’ll follow these patients along forever, and the only way anyone will have an answer for that is in 2037 when those patients are still around. Most … many of them … many of them were young and we’re going to find out how they’re doing but I can tell you this. If anyone’s considering surgery and they’re not doing well, don’t delay because someone says, tells you, you’re just going to be paralyzed in 10 years anyway. That’s not my experience. I’ve been operating for 30 years in California and no one has ever come back to me and said the operation hasn’t worked because I’ve gotten weaker, ever. And I’m around, you know, so I’ve never had that. So I don’t think these things progress. and I personally think that when you do this on a young person … this is really critical … what do you think happens? And we’re doing a study on this.
Is it true you should not operate on children until their bones are finished developing? Is that sort of an old school philosophy?
No, it’s an old school philosophy. Just throw it out the window.
How can you find a foot and ankle surgeon, one who really knows what they’re doing on the CMT foot,
I want people to come here if they can. I’m amazed but I admire that COVID is not stopping anyone. Tomorrow there’s a girl from Texas and she’s driven up. There’s a boy next week from New York, and he’s flying in, you know. So it doesn’t seem to stop anybody much for the CMT and they think it’s a good time, right, because schools are virtual. So all of a sudden someone’s saying, well, this is not worth it to be freshman in college for seventy thousand dollars a year. I’m gonna get my feet taken care of. People come, I want them to stay. A lot of surgeons wouldn’t want that, but I want the person to stay here for two weeks.
Now it’s a big city and a lot of people have relatives and I would say what I tell everyone. You can get a hotel out of town for $59 somewhere a week and you can get a hotel in town for $5,900 a night, and I’ve had both types of patients. Normally the former than the latter but you stay and then the sutures will come out in two weeks and then you go home. Insurance will … we’ve never been denied insurance because most … if you’re in North Dakota … in your town the insurance knows that there’s nobody who’s going to want to do this, and if they do want to do it, the patient will say doctor how many have you done? Have uoi done hundreds of patients, the way they have at Cedars? It’s too difficult a surgery to take on you know so the the surgeons don’t want it. Even the HMOs will allow people that … one of those people I showed you is from an HMO, which is very restrictive healthcare, right, in Hawaii but the HMO doctor doesn’t want to do it. Medicaid and the medical patients aren’t allowed to come but almost all insurances will allow this.
I’m an employee. I don’t get a penny from doing the surgery, just not a penny. I’m an employee of Cedars and Cedars is part of almost all plans. And the last thing I would just say is if somebody doesn’t allow you to come at first, they will because all you have to do is say this is where I want to go. Are you willing to take the responsibility, doctor, insurance plan, but I’m not going to do well. And the answer for that 99% of the time would be, why don’t you go to Los Angeles? Now there are certainly people who do what I do in the United States, but they’re large areas where they’re not. Okay, that’s a really helpful answer. Great to know. I just said the cash price is just insurmountable. I just … it’s tens and tens of thousands of dollars. So you really need to to go through insurance and get that.
So in that regard we’ve never had anyone turned down. Sal Rosette, my surgery scheduler … I was working late night in the office, he was leaving late and I asked Sal about this. And he said to me is exactly what he said. I don’t know if it’s true or not. He said, Doc, he goes, we have no one ever turned down by insurance for you. Each doctor has something called an NPI number that designates them. He said he’s at the insurance company I’m talking to them on the phone and they say well what’s his NPI number and it’s CMT and the insurance just immediately says, oh yeah, you can go there. I don’t know if … I don’t know if he’s just reading into that or not. I said, so they’re tracking us with CMT and my doctor number? He goes. ” they must.” Blue Cross, he said … I don’t know if it’s true … but according to him he said Blue Cross knows about you and CMT. Anyway that’s a long answer. That’s okay, very helpful. Back to the age a little bit, and I know you spoke to the crooked foot being, you know, of surgical possibility at any age.
What are your thoughts on ankle fusion?
There was a consortium in Europe which you know about. Dr. Shy was there and others looking at this, the surgical issue, and we met and I was amazed that one of the surgeons there does a lot of CMT surgery said we do fusions in everyone. We do tendon transfers and fusions.
So I was born with a fusion You can do okay with the fusion of the joints that are usually involved with CMT, but you’re not perfect. And I had … if my foot moved perfectly, I would not have dislocated my ankle when I fell in the pool recently. You don’t want to do a fusion in a young person. If you have to, it’s not the end of the world. Let me tell you, if anyone’s telling you who has CMT that you need an ankle a fusion, you need another opinion from out of town.
But never fuse an ankle in a CMT patient as a general rule. Why? Because you’ll do much better with those braces. When you fuse the ankle, you take all the spring out of the ankle and you negate the ability of using those wonderful braces, those ground reaction force braces that are made now, and those braces are anything from over the counter or basically online to ten twelve thousand dollars a pair, so there’s a lot of options. But you have options unless you get your ankle fused.
Who should do my surgery?
There are orthopedic foot and ankle specialists. That’s who you want to see. An orthopedic MD foot and ankle specialist … M-D, someone who went to medical school. You know, that’s the first thing. Not a podiatrist. If there’s a podiatrist out there who’s done 100 CMT surgeries, then fine, I have no problem with that. You know, podiatrists are not medical doctors. There’s some natural competition between orthopedic surgeons and podiatrists.
I’ve operated on always over 40 000 people with CMT. Wow. In this one you need somebody with gray hair. I am so much better at this than I was 15 years ago. Go see somebody. Contact me if you want. Set up a telemedicine visit, and I’ll tell you whether I agree with your opinion or not.
And I know everybody, and I’ll secretly tell you if I think it’s a good person to go with.
The Consensus Paper – Take that paper, put it in your pocket bring it to your surgeon … learn it. CMT patients are pretty smart people. And learn what’s in that paper. Ask a few questions and see what the answers are. What we wrote in that consensus patient paper will change and it’s not the final answer, but it’s a very good start to knowing who the right surgeon is for you, right?
Elizabeth: I can’t thank you for being so passionate about our cause, and you’re very approachable, and even in the world of orthopedic surgeons. And it’s you guys are very very busy, and very task oriented, but you care. You have heart. You have soul. You follow up with your patients. I mean, the quality of care that you give is amazing. So not only are you a very competent surgeon, but also you’re somebody that’s approachable and you can talk to and you’re interesting. And so A+. Thank you so much. Thank you so much for this wonderful presentation and caring about our community.
As someone living with CMT, I’ve found that living in a city — in my case, Toronto — has made living a healthy and active lifestyle easy.
Of course, urban living might not work for you. But I’d like to share with you how I owe much of my health, mobility, and happiness to living in a walkable and cycleable community.
To start, let me introduce myself. My name’s Mike. I’m a 39-year-old male living in Toronto with my wife, and I have CMTX. While I haven’t begun using AFOs yet, my CMT has progressed to the point that I do regularly walk with a cane for stability — like many of you, I’m a wobbly guy who’s prone to falling down.
I live just outside of Toronto’s downtown core in a 25-storey apartment building. I originally moved in because it had both a swimming pool and a gym, which has made daily exercise, especially in our harsh Canadian winter, so much easier — all I have to do is go downstairs! Even at the end of a long day, having the pool and gym only a few floors away makes it hard to be lazy. On average, I swim about two km (1.2 miles) each week. And now, after 12 years of living with these amenities, I can’t imagine living without them.
Mike at the pool!
Toronto is a dense metropolis with many walkable neighborhoods. Most of central Toronto has a high walk score, which means most amenities — such as grocery stores, pharmacies, community centers, restaurants, and bars — are within walking distance to residential areas. So, I walk a lot. I walk for groceries with a wheeled “drag bag.” I walk to run errands, go out to restaurants, and to meet up with friends and family.
Using a “drag bag” in town.
For distances a little farther away, I walk to public transit stops, take a bus, subway, or streetcar, and then walk the rest of the trip. As I already mentioned, I walk with a cane most of the time, but occasionally switch to walking poles in the winter.
When I’m not walking, I’m biking. I bicycle to work most of the year, except during the iciest and snowiest months of winter. During those months I drive my car — yes, I have a car, but only drive about 6,500 km (4,000 miles) a year.
My office is about 8 km (or 5 miles) from home, so it’s a reasonable bike ride both ways. I’m also lucky that my employer values active transportation and has shower facilities for employees. This seems to be something that more and more urban-based employers are providing, and it’s definitely appreciated.
So I’ve managed to set myself up with an active lifestyle where I can swim, walk, and bike regularly: urban living has allowed me to stay physically active on a regular basis. In fact, many urban centres like Toronto actually make it harder and more expensive to drive than to walk, cycle, or take public transit. By default, I’m active and getting physical exercise just going about my daily life. Whether heading to work, shopping for groceries, running errands, visiting friends, or heading out on the town, I’m using my own body to get there. Plus, having a gym and pool in my building means I don’t have any excuses, even when I’m home.
Luckily for me, my wife loves being active and exercising too, and maybe even more than I do — she often pushes me to keep going. We often joke that our hobby is exercise.
As someone with CMT, I find that this works really well to ensure I’m fit and staying active. Not only do my daily routines and life keep me mobile, but I actually enjoy swimming, cycling, and going on long walks in my spare time. Urban living has made all of this easy.
I’ve found that the best path for physical health is about making exercise as easy and as part of your daily routine as you can. Look, even if big-city living won’t work for you, maybe it would benefit someone you know. If you’re young and still trying to figure out where you want to live for school or work, at least consider the simple health benefits of living in a more accessible and walkable city or town. As a person with CMT, you don’t need to “find time” to be active — it’ll just happen.
Mike Driedger is the Co-Leader of the CMTA Toronto, Canada Branch. He’s also on the CMTActive Facebook team, moderating the group and encouraging members to be active in their daily lives. Mike himself is passionate about keeping active and a proponent of active transportation. He cycles to get to work and walks, swims and cycles in his free time. He’s a Program Director focused on work engaging people and businesses on issues related to health and the environment. Mike has a BA in environmental studies with a sociology stream and a graduate certificate in environmental management and assessment. Mike lives in Toronto with his wife, Adrienne, and their mischievous cat, Diego. He loves to explore the sights, sounds and tastes within his own city, as well as in destinations around the world.
Mike participated in the VIRTUAL Cycle 4 CMT, riding 1,000 km throughout the month of August, raising an amazing $3,800 for CMTA research – STAR or Strategy to Accelerate Research. If you’d like to donate to Mike’s efforts, go to: https://cmta.akaraisin.com/ui/cycle/participant/6048747
The training wheels came off my own bike so long ago; I’d forgotten the emotions, challenges and vulnerable feelings of trying to balance on two wheels for a few pedal strokes without crashing to the ground. In fact, I had always taken riding a bike for granted until my 5 year-old son, Yohan, attempted to ride his bike without stabilizers. The experience was stressful, defeating and frustrating.
“This is not fun. Not fun at all. I’m done.” he said as he walked slowly back in the house, head down. “I keep tipping over. I can’t get my feet on the pedals. I’m going to die out there. Biking’s dangerous and stupid!!” When Yohan sets his mind to something, there is no going back. He gave up biking on the spot – forever?
Fast forward 15 years to the excitement of leaving home for University. Yohan was thrilled to have been accepted to Pitzer, a small college in southern California, expanding over 35 acres of relatively flat land. At 20 years old, Yohan’s arches had become extremely high, his toes curled and his ankles, unstable. Chronic burning pain and fatigue were also issues to taken into consideration. Pitzer did not offer transportation between classes, so we discussed alternative solutions.
How about trying a moped, a scooter, a golf cart, or a Segway (I was half joking about the Segway)? Every single idea was shot down in a blink of an eye, until Yohan’s dad mentioned a bike. There was a pause before Yohan said, “Lemme think about it.”
Segway? No Way!
The following week, we were looking for a bike with a low crossbar. “Oh, you are looking for a girl’s bike?” joked the salesperson. No one laughed. “Idiotic comment.” I muttered under my breath. “No, we are looking for a low top tube for people who have a hard time swinging their leg over that bar.”
At about the same time we purchased Yohan’s bike, my brother, Anthony, happened to be in town. He spent an hour with Yohan in our long driveway, providing the guidance, confidence and tips Yohan needed to succeed. With a little practice, Yohan overcame a lot of his fears, stayed upright and felt comfortable enough to bring the bike to campus, where he used it a handful of times to get back and forth to class.
Look Mom! No training wheels!
Riding a bike on campus comes with its own challenges, including other student bikers doing wheelies, skateboarders weaving in and out of people, inattentive students tuned into their cellphones, etc. At graduation, we packed up all his belongings, minus the bike, which was in a state of complete disrepair, still attached to a bike rack, with a kryptonite lock whose combination had been long forgotten.
Just when we thought biking would never be in Yohan’s future, we rented a Scott e-bike during a trip to Tahoe….and overnight, a cyclist was born. He was able to go farther, faster, and for the first time in his life, could accompany his friends and his dad on some longer rides. It has a low step-through design (aka a girl’s bike), and in pedal-assist mode, you still get a great work out and have backup power when needed.
Photo Credit: Yohan’s friend – the one and only, Vincent Billard
So, this year, for the VIRTUAL 7th Annual Cycle (and Walk!) 4 CMT, Yohan rode his e-bike across the Golden Gate Bridge, up the Marin Headlands, and back for a 20 mile ride with 2200 feet of climbing. Never would we have thought that the child who could not ride a bike due to lack of balance, sensation, and confidence would one day ride over the Golden Gate Bridge, maneuvering around pedestrians, cyclists, kids, dogs, etc… There were setbacks, spills, road rash, fatigue, but with the support of friends, family and our CMT community, he conquered. The smile says it all….and more! Thanks to all our supporters and cheerleaders – You are CMT Champions!
To learn more about the Cycle (and Walk!) 4 CMT, click here: www.cycle4cmt.com
How much do you know about CMT? Take the quiz to find out and let us know how you did! Answers at the end. Good luck! For more information on CMT, CMTA or CMTA STAR research, please visit: http://www.cmtausa.org
*Denotes explanation at the bottom of page.
1) CMT is a genetically heterogeneous disorder. What does heterogeneous mean?
a. Like the process of breaking down fat molecules in milk, CMT can be broken down into smaller particles through a high-pressure procedure.
b. Mutations in different genes can produce the same clinical symptoms.
c. A term used to explain the genius-level IQ of most people with CMT.
d. Belonging to the same family,
2) When researchers study the natural history of CMT, what exactly are they doing?
a. They are trying to figure out which components of CMT are artificial.
b. It’s all old news.
c. They are studying the progression of CMT over time.
d. They are trying to determine the origins of CMT and when it all began.
3) People with CMT often use AFOs. What does AFO stand for?
a. Ankle Foot Orthosis
b. About-Face-Onward
c. Air Force One
d. Area Financing Officer
*4) What is HNPP?
a. HNPP stands for Hereditary Neuropathy with Liability to Pressure Palsies
b. HNPP is a sub-type of CMT.
c. HNPP is most often caused by a deletion of the PMP22 gene.
d. All of the above.
5) What is Foot Drop?
a. An abrupt 1-foot fall or slope
b. Inability to lift the foot at the ankle due to weakness or paralysis of the anterior (front) muscles of the lower leg.
c. A secret play in football when the quarterback drops the ball 1 foot from the goal line.
d. The name of a used shoe company.
6) To date, how many genes have been found to cause CMT?
a. 10
b. Over 100
c. 212
d. We cannot count that high.
7) If a child inherits CMT from a parent, will it be the same type of CMT?
a. Yes. The type of CMT does not change between generations.
b. No. CMT is variable and changes sub-types from one generation to the next.
c. Children do not inherit CMT from parents.
d. I do not know, but the child will love Country Music Television!
*8) Is CMT like Muscular Dystrophy (MD) or Multiple Sclerosis (MS)?
a. Yes, because CMT is under the Muscular Dystrophy umbrella.
b. No. They are completely different and separate diseases.
c. No one really knows.
d. Yes, because MD, MS and CMT are just different acronyms for the same disease.
9) Anyone in the world can be born with CMT because everyone is susceptible to random or de novo gene mutations.
a. Only people in the US are susceptible to new, random mutations.
b. This statement is false.
c. I have no idea if this is true or false.
d. True
*10) If two people who have an autosomal dominant (“Autosomal” means that the gene in question is located on one of the numbered, or non-sex, chromosomes. “Dominant” means that a single copy of the disease-associated mutation is enough to cause the disease) form of CMT (like CMT 1A) have children, what is the chance that their children will inherit CMT?
a. 0%
b. 25%
c. 75%
d. 100%
*11) What isDominant Intermediate Charcot-Marie-Tooth Disease (DI-CMT)
a. A rare, dominantly inherited type of CMT
b. Just an expression used to liken the inheritance of CMT to a roll of the dice.
c. Does not exist. Just a made up name to throw you off the right answer.
d. A type of CMT that affects people with Type A personalities.
12) Your CMT genetic test comes back negative. What does this mean?
a. No one really knows.
b. You still may have CMT. There isn’t any one lab testing for all known mutations in any one test. Moreover, not all genetic mutations underlying CMT have been found or can be detected with a DNA test.
c. A negative result rules out CMT since all sub-types of CMT are easily recognizable.
d. Retake the test 5-6 more times to be sure of the results.
13) What does the CMTA’s research initiative, STAR, stand for?
a. Strategy to Accelerate Research
b. Strategy to Advance Rats
c. Situation, Task, Action Result
d. Sewage Telecommunication Access By Robot
14) Although there is no medicinal cure for CMT, we can treat the symptoms of CMT with:
a. Exercise, physical and occupational therapy, healthy diet
b. Braces and other orthopedic devices
c. Surgery can help prevent or reverse foot and joint deformities
d. All the above
15) Since the launch of STAR in 2008, how much money has the CMTA spent on treatment-driven CMT research?
The ankle dorsiflexors, the muscles that lift up the foot and ankle, are frequently involved in foot drop. When the Tibialis Anterior muscle weakens, the foot begins to drop down. This is usually a gradual process, occurring over months or years.
b
a
b
Charcot-Marie-Tooth (CMT), Multiple Sclerosis (MS) and Muscular Dystrophy (MD) are three completely separate and distinct diseases. Remember that our neuromuscular system really starts at the brain, which is the master computer, and sends signals to the motor (muscles) via the spinal cord (an intermediate connecting cable), which hooks up to the peripheral nerves (the connecting lines between brain and muscle).
Muscular Dystrophy is a disease of the muscle itself, which causes weakness of varying degrees. There are many forms of MD. Sometimes the heart is involved because it is a muscle too. The lungs can also be affected because the breathing muscles are weak (similar to CMT, although in CMT it is because the phrenic nerves are affected, which in turn weakens the diaphragm, the main breathing muscle).
CMT is primarily a disease of the peripheral nerves (the connecting lines between brain and muscle). CMT causes weakness and impaired sensory perception because the signal can’t get to and from the brain to muscle and skin, among other things. The muscles shrink because they aren’t getting the proper signals, but the muscles themselves are not directly diseased per se.
Multiple Sclerosis is a disease of the brain and spinal cord. It can affect both movement and sensory perception and sometimes thinking processes.
d
There is a 75% chance that they will have a child that is affected. Broken down, there is a 50% chance that the child will get the duplication from one or the other parent, a 25% chance they will get it from both parents (i.e. for CMT1A they will then have 4 copies of the PMP22 gene), and a 25% chance they will not inherit CMT and have the normal copy number of PMP22. We have seen a few cases of kids that have inherited 4 copies of the PMP22 gene and they seem to be more significantly affected than their parents, but we have not looked at this longitudinally because it is rare. (Answered by Shawna Feely, CGC)
c
a
CMT-DI takes its name from the nerve conduction velocity (NCV), which is considered intermediate. The nerve biopsies from patients with DI-CMT have shown both axonal degeneration as well as demyelination. Dominant mutations in the genes DNM2, MPZ, and YARS are associated with DI-CMT types B, D, and C, respectively.
Over the past 20 years, I’ve gotten to know many people from all all over the world who are interlinked by one common denominator – CMT or Charcot-Marie-Tooth Disease. Despite cultural, social and economic differences, they share a common story, one which includes nerve degeneration, weakened leg/arm muscles, drop foot, claw toes, hand contractures, tremor, leg braces, foot surgeries, chronic pain and disability, just to name a few.
Some experience life-altering fatigue, easily broken bones, lack of proprioception due to loss of feeling, while others no longer have control of their hands or fingers and gasp for breath due to diaphramatic weakness. Some have even died due to complications from CMT.
Last week, I was speaking to a longtime friend, whose now 55-year-old son is bed-bound, unable to move, practically paralyzed from head to toe. His CMT, type unknown, has progressed rapidly, leaving this fiercely independent man completely reliant on the help of others.
His mom has been an extremely generous CMTA supporter for the past 30 years, and a supporter of the Cycle (and Walk!) 4 CMT event. When I heard just how much her son’s CMT had advanced, I felt angry. “I’m so done with CMT and its ravaging effects on my friends…SO OVER IT! I hate this stupid disease. It’s not only maddening, it’s depressing.”
I felt as though I had failed this family……and my own.
If only I could have done more to help her son….and so many others. I told her as much: “I wish I could have done more for him, for your family. It’s heartbreaking to think of him today, lying in that bed, unable to move. It’s disheartening to think of all my friends whose nerves are slowly degenerating as we speak. ”
Action empowers. Inaction disempowers.
If there is one action I can take, it’s to continue to support CMT treatment-driven research by fundraising, donating and ask others to do the same.
This chart shows the depth and breadth of CMTA research projects. 11 years ago, this was a blank page. Now we have 50 projects and over 30 partners, all funded 100% by individuals who believe in the power of our scientific endeavors.
Charity Navigator, America’s largest & most-utilized charity evaluator, also awarded the CMTA its highest rating last year (4-star), which fewer than 1% of charities receive. Now, that gives every one of us bragging rights!
My friend reminded me, “The CMTA is doing miraculous life-changing work and if it does not help my son, I know it will help others. Together, with our CMT supporters, we will make an indelible mark in this world. We already have!”
She’s right. With her words spurring me on, and with renewed energy, I decided to transform my anger into passion and drive.
So, yes, I’m asking again this year for your help because I want my son to have the best life possible. I want my friends to remain healthy and able-bodied. I want our future generations to be free of CMT.
So, instead of cancelling the Cycle (and Walk!) 4 CMT, we’ve decided to host a VIRTUAL event. Anybody, anywhere can participate. www.cycle4cmt.com
If you don’t want to get your walking shoes on or your bike out, you can sponsor a participant or a team…….like Team Yohan! Will you sponsor Team Yohan and help us advance CMTA research? If so, click here: https://cmta.akaraisin.com/ui/cycle/team/300635
And for the first time ever, Yohan is actually biking, thanks to a lot of practice, commitment to our cause and his e-bike! The plan? They are doing a classic ride across the Golden Gate Bridge and around the Marin Headlands on Saturday, August 29. Meanwhile, I’ll be in Crissy fields wearing a Shark Costume (Shark-O-Marie-Tooth) spreading CMT awareness and scaring little kids (kidding).
HEREDITARY NEUROPATHY WITH LIABILITY TO PRESSURE PALSIES
CMT Researcher Dr, Jun Li is the leading expert in HNPP
Jun Li, MD, PhD
Professor and Chairman of Neurology
Wayne State University School of Medicine
Detroit Michigan
Nerve tissues that reside in the skull and spinal canal make up the Central Nervous System (CNS). The CNS extends numerous nerve fibers out of the space of the skull and spinal canal that make contact with muscles, skin, tendons, the gut, and other organs. These nerve fibers outside of the CNS space are collectively called Peripheral Nerves. When the peripheral nerves are damaged by a cause, it is called peripheral neuropathy. If the cause is a genetic mutation in a specific gene, it is called Charcot-Marie-Tooth disease (CMT). There have been over 100 genes identified where a variety of mutations lead to different types of CMT. Hereditary neuropathy with liability to pressure palsies (HNPP) is one type of CMT.
CNS vs PNS
HNPP is caused by missing a DNA segment on chromosome 17. The segment is called c17p12, which contains the Peripheral Myelin Protein-22 (PMP22) gene, as well as others. Scientific evidence supports that loss of one of the two copies of the PMP22 gene (one from mother and one from father) is responsible for HNPP. Genetically, it is called “heterozygous deletion of PMP22”. The remaining genes in the c17p12 segment play a negligible role in the disease. Therefore, HNPP has a 50% chance of being passed to offspring. A small fraction of patients with HNPP may develop this mutation on their own, which is called de nova mutation, and thus would not have any family history of the disease.
Clinical Manifestation: While exceptions do occur, the majority of patients with HNPP develop initial symptoms around the first or second decade of their life. Patients typically present with focal numbness, tingling (pins/needles) and muscular weakness in limbs. These episodes are often brought on by mild physical activities that do not cause symptoms in healthy people. The activities include compression, by sitting with legs crossed, putting pressure on the peroneal nerve, or leaning on elbows against the ulnar nerve, repetitively doing the same movements (stereotypic movements) for a prolonged period, and over-stretching of the arms or legs. It can take anywhere from hours to months to recover from an episode. While most episodes are transient, some patients with HNPP may experience permanent weakness. Some episodes may not have any identifiable triggers.
Peripheral nerves that go to muscles and sensory organs in the head are called cranial nerves and can also be afflicted by HNPP. For instance, partial hearing loss and facial numbness have been reported by patients with HNPP. Many patients with HNPP may also develop generalized symptoms, such as intolerable fatigue and pain. There is a wide range in the severity of these symptoms. Life expectancy for people with HNPP is usually not affected by the disease.
Some patients may be asymptomatic. HNPP may lead to severe limb paralysis when asymptomatic patients are challenged by strenuous physical activities such as running 10 miles a day with a 50lb backpack. An asymptomatic woman developed leg paralysis after prolonged labor of 9 hours to deliver a baby while sitting in birthing position. These possible outcomes could impose a catastrophic risk in the fraction of patients with undiagnosed asymptomatic HNPP.
Upon physical examination, physicians may find sensation loss and muscle weakness in the hands and feet. Unlike other types of CMT, high arching feet or hammer toes are not common in patients with HNPP.
Diagnosis: The diagnosis of HNPP can be quite challenging. This is often due to many physicians’ unfamiliarity with the disease. An HNPP patient may be misdiagnosed with a lacunar stroke, multiple sclerosis, spinal muscular atrophy, chronic inflammatory demyelinating polyneuropathy (CIDP) or idiopathic axonal polyneuropathy, etc. Therefore, a high index of suspicion is often needed to reach the diagnosis in patients with episodes of focal sensory loss or weakness.
Electromyogram/Nerve Conduction Study (EMG/NCS) is an important diagnostic tool for HNPP. It shows changes in areas where peripheral nerves are exposed to mechanical pressure, such as the ulnar nerve at the elbow or median nerve at the wrist. This finding should prompt physicians to seek the diagnosis and perform DNA testing.
DNA testing allows physicians to reach a definitive diagnosis if the loss of one copy of PMP22 is found. There are several issues relating to testing that should be emphasized here: a). Unlike the majority of lab tests, which use blood samples from a red-top tube, blood samples for DNA testing should be collected in a purple-top tube that contains a chemical to prevent the blood from clotting. This is necessary for DNA extraction. If a red-top tube is mistakenly used, clotted samples will be rejected by the lab. The patient may have to return to the clinic for another blood draw. b). The HNPP mutation is usually tested using a technique called multiplex PCR. In rare cases, this technique may not detect the mutation. If the clinical suspicion is strong, alternative techniques would have to be used to clarify the diagnosis. c). There have been a few reported cases that were not caused by a missing copy of PMP22. Instead, their HNPP was caused by an altered DNA sequence in the PMP22 gene that multiplex PCR cannot detect, but DNA sequencing can.
Clinical Management: There is no cure for HNPP at this point. Therefore, clinical management mainly aims to alleviate symptoms and optimize quality of life.
1. Avoid physical triggers: We advise that HNPP patients avoid the physical activities (compression, prolonged stereotypic movements and over-stretch) that may bring on symptoms. However, we do not advocate for a sedentary lifestyle either since this may lead to obesity and metabolic problems. Thus, activities should be tailored for individuals to have adequate exercise without triggering nerve symptoms.
2.Pain control: Many patients with HNPP complain of pain, regardless if focal symptoms are present or not. Those with true neuropathic pain (sharp, burning, tingling, highly sensitive to touch) tend to be responsive to treatments. Others may not show features of neuropathic pain, and the pain may be difficult to control. Physicians may have to carefully seek additional factors contributing to the pain, such as inadequate ankle braces causing overuse of leg muscles, etc.
3. Medication side-effect: Severe side-effects have been reported in patients with CMT1A who took Vincristine and developed limb paralysis. This is a difficult subject to study in patients with HNPP due to ethical issues. However, an HNPP animal model shows slower recovery from nerve damage. We believe that patients with HNPP should be carefully monitored for side-effects when they receive any new medications.
4. Diet:Many patients with HNPP question if they should avoid any foods. We are not aware of any specific dietary restrictions for HNPP patients. A high dose of vitamin C has been shown to reduce PMP22 levels. We recommend that HNPP patients avoid consuming high doses of vitamin C. However, we do not see any problems with a regular dose (75-90mg daily) of vitamin C. This issue needs to be further investigated in carefully designed studies.
Contact Information:
Professor and Chairman,
Department of Neurology,
Wayne State University School of Medicine and Detroit Medical Center,
I’m confused about the difference between electromyograms (EMG) and nerve conduction studies (NCS)—can you please explain?
Dr. Richard A. Lewis* answers:
EMG, which stands for electromyogram (“myo”= muscle), is the term used for electrodiagnostic tests (EDX) for neuromuscular disorders. The total EDX includes both nerve conduction studies (NCS) and needle EMG. Depending on the clinical question, one or both parts of the test may be conducted.
For CMTers, the most important component is the NCS, which determines whether one has a neuropathy and whether it involves sensory nerves, motor nerves or both. If the disorder just involves motor nerves, it’s Hereditary Motor Neuropathy (HMN); if sensory, Hereditary Sensory Neuropathy (HSN) and if both Hereditary Motor/Sensory Neuropathy (HMSN). HMSN is the primary disorder that comprises CMT.
Machine for Nerve Conduction Velocity
Sensory nerves usually only require one stimulation point—the wrist (sometimes the finger) or ankle. The motor nerve conduction study requires stimulation of the nerve: and recording electrodes are put on the surface of the skin overlying the belly of the muscles being studied.
To determine motor nerve conduction velocity, it is necessary to stimulate the nerve at two locations: In the arm, the two stimulation sites are the wrist and the elbow. In the leg, they are the ankle and knee. The motor nerve velocity in the arm is determined by taking the time it takes (latency) for the signal to go from the wrist to the muscle and subtracting that from the latency from the elbow to the muscle. Dividing that nerve latency (subtracting out the time it takes for the signal to get from the nerve to the muscle) into the distance from wrist to elbow determines the motor nerve conduction velocity (see below).
The amplitude of the response indicates whether the nerve fibers are functioning: A low amplitude suggests that many have stopped. The velocity determines whether the disorder primarily affects the myelin and Schwann cells or the axon. The disorders that comprise CMT1 are characterized by very slow velocities and are due to mutations of genes that form myelin. CMT2 has more normal velocities but very low amplitudes and are disorders of the axon. Normal nerves conduct at ~ 50 meters/second. CMT1A usually has nerve velocities around 20 meters/second. There is a somewhat arbitrary cut-off of 38 meters/second (m/sec) in the median or ulnar nerve of the forearm that determines CMT1 or CMT2. CMTX is considered intermediate with velocities between 30 and 40 meters/second.
The EMG portion of the test, which involves the insertion of fine needles in the muscle, can determine if there is nerve damage to the muscle not identified by the nerve conduction tests. This can be particularly helpful in HMN and can determine if there is any muscle involvement in HSN. EMG can evaluate muscles that are more proximal—above the knees and elbows—which are not easily tested with NCS. This can be helpful, but rarely allows a diagnosis of CMT. Because it is not always necessary for the EMG portion of the EDX to be done, the decision should be discussed with the doctor and electromyographer.
Electrodiagnostic studies are not risky or dangerous and do not cause problems afterward, but they can be uncomfortable. The NCS requires electrical stimulation, which is very brief but can be painful. Some CMTers have nerves that are difficult to stimulate, which can require higher amounts of stimulation. This may be painful, but the pain lasts a fraction of a second. It’s best if the patient can allow testing of at least one motor and one sensory nerve even if it’s uncomfortable. Sensory nerves need less stimulation than motor nerves and are less painful. For CMTers, studies of the arms may provide more information than the legs, but each case is different. Relaxation techniques can help reduce anxiety and pain.
The needles used in EMG are very thin and sharp. They are disposable, so there is virtually no risk of infection. They are thinner than the needles used for drawing blood and there is minimal risk of bleeding even if one is on aspirin. Anyone on a blood thinner should bring it to the electromyographer’s attention, but most muscles can be tested even if the patient is taking Coumadin or other major blood thinners. For most patients, the needle examination is only mildly uncomfortable, but for some, particularly patients with aversion to any needles, the needle examination can be painful. The good news is that if needle studies are done, there shouldn’t be the need to study many muscles.
NCS and EMG can be performed at any age, including infancy, but with children, the examination has to be modified to account for their size and inability to fully cooperate during the study. The 38 m/sec velocity that distinguishes CMT 1 and 2 cannot be used under the age of 2. The examination in young children is usually brief and sedation is not normally necessary. If a child is from a family with known CMT that has been diagnosed genetically, then EDX may not be needed. If the child is symptomatic, there may not be a need for any testing.
*Dr. Lewis is the co-director of the Inherited Neuropathy Clinic and the director of the EMG Laboratory and of the Clinical Specialty Clinic at Cedars-Sinai Medical Center in Los Angeles. He moved to Los Angeles in November 2012 after 19 years at Wayne State University in Detroit, Michigan, where he helped develop the CMT clinic. He was the principal investigator of the Vitamin C trial for CMT1A. He has served on the Board of Directors of the Peripheral Nerve Society and is currently on the Steering Committee of the Inflammatory Neuropathy Consortium.
Vicki Pollyea – October 27, 1956 – September 15, 2019
When I first met Vicki over 12 years ago, she was the leader for the Tampa CMTA/MDA branch, the largest CMT group in the country. We hit it off immediately, and I knew she’d be a forever friend, and I was right. Over the years, Vicki has played a variety of different roles at the CMTA, all in which she’s poured her heart and soul. When I wrote this article, Vicki was recuperating from radiation therapy for recurrent lung cancer, and from her hospital bed, she continued to moderate the CMTA’s Facebook Group, giving fact-based answers and helping other find resources, comfort and support.
With Bethany Meloche in California
Born into a family with CMT1A, Vicki grew up in Tampa Bay, Florida. Her CMT prevented her from riding a bike and running, but she could swim and catch needlefish to sell for bait to tarpon fishermen.
After undergoing a lot of physical therapy in her youth, Vicki decided to get a degree in occupational therapy from the University of Florida. She worked as a pediatric occupational therapist until her CMT forced her to change her life path. Undeterred by this setback, and soon on full disability, Vicki became a CMTA branch leader and neighborhood activist. She was part of a former Mayor’s Neighborhood Task Force and helped draft Tampa Bay’s tree-protection code. Vicki was also president and one of the founders of Bayshore Gardens Neighborhood Association, where she and her husband, Archie Giannella, live in a 1921 bungalow they restored. Her hobby was fishing, a passion she and Archie shared.
Archie and Vicki
Since 1985, Vicki had more than two dozen orthopedic operations. Over time she became more homebound, but turned to the phone and the computer on CMT chat rooms. Soon thereafter, she stepped up as a CMTA Branch Leader. Her mantra? Vicki often said, “I cannot control the things that happen in life, but I can control my attitude about the things that happen.”
True to her word, Vicki valiantly battled lung cancer, and the most recent occurrence was found to be inoperable. After 6 weeks of intensive radiation therapy, pneumonia set in, delaying her progress. Yet, whenever she had a chance or a little extra energy, she continued to spread CMT awareness and moderate the CMTA Facebook group, sharing her lifelong experience and knowledge of CMT.
In addition to her sister, Vicki has two cousins who live in New Zealand and also have CMT. She knows that all the research currently underway will make a difference in their lives. Vicki reflected, “I don’t know how much longer I’ll live, but Archie will be by my side. It teaches you to live in the moment, to tell the people around you that you love them. You never know what will happen tomorrow.”
As a person dealing with Charcot-Marie-Tooth condition, she was always 100% committed to the community, supporting the newly diagnosed, helping find resources for those coping with CMT as well as increasing awareness of this condition. These have been her most meaningful life goals. Vicki believes that increasing Awareness + Raise Research Funds = Treatment/Cure. And I could not agree more.
CMTA Branch Leader Meeting
Vicki Pollyea, your selfless volunteerism has made a tremendous difference in the world of CMT and beyond. You’ve touched more people than ever you could imagine and we are eternally grateful for your relentless drive and motivation to make positive change in the here and now.
On behalf of the CMTA board, staff and community, I want you to know that you are deeply appreciated and truly missed. Your spirit lives on and there is not a day that passes that I do not think of you!
True to form, here is one of Vicki’s favorite quotes from Cornel West: “I’m a militant for tenderness. Justice is what love looks like in public, just like tenderness is what it looks like in private. Love is a steadfast commitment to the well-being of others.”
As a post script, Jeana Sweeney and I were invited to speak at Vicki’s Cerebration of Life. The room was overfilled with people who wanted to honor Vicki. Vicki was so loved and admired by family, friends, local community advocates and CMTA supporters. It was a beautiful ceremony, filled with tears, laughter, and reminiscence.
We’ve lost a CMT warrior extraordinaire, but in her name we will fight on to cure CMT, which was a big part of her life’s work. She will always be remembered as a CMTA advocate, fighter and visionary and her spirit and energy will live on.
This is a transcript of the CMTA’s recent STAR gene therapy webinar. CMTA Board Chairman Gilles Bouchard begins by giving an overview of CMTA’s research initiative – STAR (Strategy to Accelerate Research), followed by an in-depth review of our gene therapy program by Drs. John Svaren and Kleopas Kleopa, members of our Scientific Advisory Board. These world-renowned researchers will explain what gene therapy is, how it can be used to advance treatments for CMT, and cover the latest advances from the STAR program. This webinar will also explain how we are preparing for clinical trials for many types of CMT.
STAR stands for “Strategy to Accelerate Research,” and it’s really core to the CMTA’s mission: our role is to accelerate treatments for CMT. In this work, we are driven by you and powered by you, the CMT community. You provide more than 80 percent of our resources, so, in essence, STAR is really your program. STAR is for you, and by you.
When we started STAR over 10 years ago, we really wanted to take a business approach. We wanted to bring the rigor, the focus, the accountability that you have in a business.
When you run a business, the first thing you do is try to figure out your strengths and your weaknesses, and the best strategy to be successful.
Taking drugs to market is a tough business, and it takes well over 10 years on average to develop a drug. Most new drugs fail in clinical trials. And it costs hundreds of millions of dollars. So how do we make this attractive to partners? How do we accelerate research?
One of the most attractive things about CMT is that for most types we have very well-defined genetic causes. CMT is what the scientists call a monogenic disease, which means we can replicate and test this disease in the laboratory.
There are also a lot of new therapies and technologies to address genetic issues. And those play right into what CMT is as a disease.
Biotech companies once looked at CMT as a slowly evolving disease, which would therefore require very long and very expensive clinical trials. If anything, this has been the biggest inhibitor for pharmaceutical companies to get involved in developing drugs for CMT. So more than 10 years ago, in partnership with the Inherited Neuropathies Consortium (INC), we embarked on a major effort to develop what are called biomarkers, and also to develop an important clinical infrastructure so it would become much easier, faster and cheaper to run clinical trials on CMT. We have made tremendous progress there. And this barrier is really starting to crumble.
Finally, from a business point of view you may think being a rare disease is a disadvantage, but because of the laws in the US and in Europe, it is actually attractive for companies to work on rare diseases. There are some advantages for businesses on the tax side and the protection of intellectual property.
So, if attracting partners is the core of our strategy, how do we make CMT attractive to partners? We need them because even though we’ve raised a lot of money from this community, we don’t have the billions of dollars it takes to develop drugs. In working with partners, we found that there are five key things they look for.
The first one is what they call KOLs (Key Opinion Leaders) or experts. In general, companies are experts in drug development, but they don’t know CMT very well. So they want to engage with CMT experts. That’s why we built our incredibly strong Scientific Advisory Board with over 30 great scientists.
The next thing they want is the ability to test in the lab, what we call preclinical tests. This is how drugs are developed, and we spent a lot of effort building a very broad, very powerful preclinical testing infrastructure. When they contact us and see what we’ve developed thanks to your support, they tell us that they feel like kids in a toy store!
The third one is clinical trial readiness. This was a major inhibitor for CMT research and for companies. But again, we’ve made tremendous progress, and we feel that we can run much shorter clinical trials.
That’s great on the medical side, but companies also want a strong, reliable and trustworthy business partner. What we found is not all companies are the same; they want different things. So we have to be flexible and adapt how we work with them on the business side based on what they need. Some companies, for example, are early stage companies that need money so we do co-funding with them. But others are loaded with money and they are looking more at licensing or buying technologies that we’ve developed with our partners. Other companies are looking at raising money, so we help them and engage with their potential investors. We have a lot of people with business experience on our board, and we really try to leverage this to help companies be successful on the business side as well.
Last but not least, what’s really interesting is that companies are very interested in engaging the CMT community, especially as they get closer to the clinical treatment of patients, because ultimately the CMT community is their market. So they want to know the impact the disease has on the patient community. Moreover, engaging patients is becoming very important as part of the approval process of drugs. In Europe right now you have to partner with a patient advocacy group to get a drug approved. And in the US the FDA is doing more and more of the same thing. So the fact that we can reach tens of thousands of CMT patients and that we have this really vibrant CMT community is a great asset for us and really attractive to our partners.
Now may ask, how is this working? We just put a few numbers together, and thanks to your support, we’ve made tremendous progress. We also realize that we have a lot of work left to do, but we feel like we’re in a really strong position right now.
We have a expert Scientific Advisory Board.
We have about 50 active projects, by the end of the year, we’ll have invested $15 million in CMT research.
We have developed really helpful testing tools for all major types of CMTs that our companies are using.
As a result, we now have 25 industry partners. That’s a really important metric—the one thing that makes us the most hopeful about the future. A few years ago we just had a handful of partners and it was hard to bring them in. Now people approach us all the time because they want to work on CMT with us. They want to use our tools and infrastructure. And you can look at these numbers, these 22 joint preclinical studies. Those are 22 actual studies that people are running this year using our infrastructure. Now, last year, this was only a handful. So in business terms I think we are seeing a bit of an inflection point: you invest and you work hard for a few years, and all of a sudden your business starts taking off. That’s what we’re seeing right now in CMT research. A lot of things are starting to accelerate!
And then we have this really wonderful, vibrant community—all the CMTA branches around the country and the CMTA Centers of Excellence. This has created a very powerful and helpful infrastructure, not just for us as a community, but also for our partners as well.
When we look at where to invest in STAR, we try to look at leverage points. So there are a lot of areas where we invest that cut across all CMT types or many CMT types.
We already talked about the testing infrastructure that we’ve developed that cuts across most types of CMT.
We will cover and go in depth today into gene therapy.
We’ll cover biomarkers as well.
Another area that’s quite interesting but we’re not going to cover as much is Axon Degeneration. It turns out that a lot of companies are working on ways to prevent nerves from degenerating for a broad set of neuropathies. And they want to use CMT as one of the rare disease indications for this. These companies are working with us now to try to find ways that to slow down or even stop the damage to nerves with some of their drugs.
Finally, you’ll hear about all the great progress on gene therapy. Obviously to apply gene therapy you need to know which genes to fix. So we’ve really doubled down on trying to find more CMT genes.
This is an overview of what we do across all types of CMT. Dr. Kleopa and Dr. Svaren are going to focus on a couple of them today, but keep in mind that while we won’t cover everything we do today, we have very thorough plans for each major CMT type and, in general, three or four key projects which are specific to each type.
Gene therapy is the use of genes or gene editing as a treatment. This process involves the introduction of genetic material, for example DNA or RNA, into cells and tissues of an individual instead of other treatments such as drugs or surgery.
There are different types of gene therapy, including replacing a faulty gene that would be a missing or mutated gene that can be replaced by a healthy copy of the same gene, or inactivating or silencing a mutated gene that has taken a toxic gain of function—a harmful effect on the body that occurs because the gene is functioning improperly.
And finally, editing a part of a mutated toxic gene that has a harmful effect—essentially a cut and paste approach where you selectively cut out part of the gene and replace it with a healthy part of the gene. This is a technically more challenging approach than replacing or silencing a gene.
How does gene therapy actually work?
In most cases we use viral vectors (tools commonly used to introduce genetic material into cells) to deliver the therapeutic gene. These viruses are used as vehicles to package and deliver our therapeutic genetic material. They have been modified so that they’re not infectious or contagious. They have the ability to enter the cell.
Once inside the cell they will release the genetic material and that will start the production of the protein, and this will correct the defect in the cell and be a treatment for the disease.
And here it’s important to note that this will be a once-in-a-lifetime treatment, so once the virus is inside the cell and releases the genetic material, it will stay and keep producing the protein that the cell needs to function.
Now let’s look at the types of CMT so that we can understand how we can apply gene therapy to CMT neuropathies.
First of all, nerves are bundles of many nerve fibers, and most of them are wrapped in myelin. They are similar to electrical cables, as you can see in the picture on the lower left, that are made of many wires and these wires have a plastic coating.
And in nerves this coating is called myelin. It’s an insulating and protective coating that is formed by specialized cells known as Schwann cells. Myelin is very important because it speeds up the conduction along the nerves by a hundred times, like going from 3G to 4G, but also supports and maintains the nerve fibers.
So depending on whether the damage is in the Schwann cells in the myelin or in the axons, we will have demyelinating types of CMT or axonal types of CMT.
In the diagram of a healthy nerve that would for example be a motor neuron, you notice that it starts with the cell body which is located in the spinal cord, and that sends a long extension all the way to our muscles in the arms or legs. This is the peripheral nerve. All along this nerve you need to have myelin and this is formed by Schwann cells.
There are over a hundred different genes that can cause CMT neuropathies. They have various functions in the cell, and this results in many different mechanisms. If the mutated genes are mostly expressed in Schwann cells, then you have a demyelinating type of CMT because myelin suffers first. But this will eventually also destroy the axon. And if the mutations are found in neurons then we will have an axonal type of CMT.
In addition, we classify CMT neuropathies by the type of mutation and whether this is a toxic gain of function mechanism or a loss of function. And that will also determine the gene therapy approach.
So what are the potential gene therapies we can use for CMT neuropathies?
We have to address the disease mechanism described in the previous slide. For CMT neuropathies that are caused by a loss of function of the gene (this is the case with most CMT4 neuropathies and CMT1X), we have to introduce a healthy copy of the gene, so that’s a gene replacement.
For CMT neuropathies with a toxic effect of the mutation (as is usually the case with CMT1 and CMT2 types), we have to either silence the toxic gene, repair it, or modify it so that we can prevent the toxic effect.
In addition, we have to deliver this treatment to the particular cell type that needs the treatment. So for the myelinating CMTs we have to target the Schwann cells and for the axonal CMTs we have to target the neurons, so that means a different approach because the cells are located in different parts of the body.
Now that you’re all experts on CMT genetics and gene therapy, let’s outline the efforts that the CMTA has spearheaded to try to bring new treatments to the clinic!
The science of gene therapy has actually been around for a couple decades. But there were a number of safety issues that had to be addressed. What has generated a lot of excitement in the last couple of years are treatments that are FDA approved for different diseases. The specific example we want to discuss is a disease known as Spinal Muscular Atrophy (SMA). This is actually a motor neuron disease, and it actually affects the same neurons that are affected in CMT. But SMA is a devastating disease that affects infants, and until recently there was really no treatment. But there are now two new genetic therapies that have been recently approved for Spinal Muscular Atrophy.
This includes AAV gene replacement therapy using viral vectors, just as we just outlined, by a company called Avexis. The diagram above summarizes how this therapy works, again by delivering the correct gene to the motor neurons. And there’s another genetic therapy involving antisense oligonucleotides (small pieces of DNA or RNA that can bind to specific molecules of RNA and block the ability of the RNA to make a protein or work in other ways) which we’ll cover a little bit later. The good news for SMA is that there were dramatic effects with both therapies, as long as they’re administered early enough in the disease.
We’re not only grateful for these advances for SMA, but they also provide us with an avenue we can pursue with CMT because it affects many of the same cell types affected by CMT.
To take advantage of this, we convened a gene therapy workshop for CMT in the summer of 2018 to get our plans together and take advantage of a number of different advances. We invited scientists and clinicians that were involved in SMA, Muscular Dystrophy, and different types of CMTs like CMT2D and CMT4J. There are also trials going on for Giant Axonal Neuropathy, or GAN.
We have number of assets that we outlined earlier. First of all, we had previously funded efforts of Dr. Kleopa to apply gene therapy and we’ll cover these specific examples in a minute. We have also partnered with other companies using ASOs. The animal models that we have developed are very important testing systems for development of gene therapy for CMT.
Another aspect that’s not to be neglected is the fact that we need to have good biomarkers (measurable indicators of the severity or presence of some disease state) and clinical trial planning expertise, which is critical for labs that want to invest in CMT.
And then ultimately we realized that we needed to recruit some leading gene therapy experts to our Scientific Advisory Board to lend their expertise and their advice as we move forward.
These experts include, Dr. Kleopa, from whom you just heard, who’s really pioneered a lot of the development of gene therapy for demyelinating CMTs. And then we have two additional experts: Steven Gray at University of Texas Southwestern, and Scott Harper at Nationwide Children’s Hospital. They are really leaders in the field, Dr. Gray for example is already engaged in efforts for CMT4J and another type of CMT (GAN). Recruiting these experts has been instrumental in us being able to plan how we can best use CMTA investments to accelerate the development of new gene therapy treatments.
With their advice we have formed a plan essentially to:
Develop a CMTA sponsored effort to target CMT2 using AAV9-based gene therapy. AAV9 has been used in other FDA approved treatments, and we decided initially to focus on the most common form of CMT2 which effects roughly 10 percent of people with CMT. This is caused by mutations in the Mitofusin-2 gene and is classified as CMT2A.
Our second objective is to develop gene therapy for CMT types 1 and 4, the demyelinating forms of CMT. Dr. Kleopa’s work in this area will be covered in the next several slides. Basically we need to optimize our approaches to improve delivery of the genes to Schwann cells. And we also definitely want to target the most common form of CMT which is CMT1A using another kind of technology called RNA interference.
And finally, we want to develop company partnerships that can help us actually bring these therapies to market.
On that last point, just one year after this workshop, we were pleased that our efforts met with some success particularly in our initiative to develop a new gene therapy for CMT2A. Based on studies by one of our board members, Dr. Robert Baloh, we found that there is a way to overcome the mutation in CMT2A.
We formed a partnership with one of the leading companies in the gene therapy space, Passage Bio. You may be aware of the announcement that came out a while back where we formed an alliance that will develop and test gene therapy using some of the rat models of CMT2A that were originally sponsored through the CMTA. This will be a broad collaboration, including the Inherited Neuropathy Consortium (INC), to sponsor preparations for clinical trials in CMT2A.
We should mention that we have other efforts on other types of CMT in discussion with not only Passage Bio, but with other companies as well.
We wanted to have a comprehensive approach for different types of CMT. The pie chart represents the different types of CMT ranging from the most common—CMT1A—to some that are much rarer. And the arrow around the pie chart shows the number of types of CMT that are covered under existing plans or projects, or ones that are under discussion.
We are well on our way to covering almost 75 percent of people affected by CMT with our ongoing projects, and we’re hoping that we can expand that in the future. This includes AAV delivery and many different technologies, and we’ll mention more about gene silencing and Antisense Oligonucleotides in a minute. We are trying to leverage success in one type of CMT to achieve success in other types as well.
Let’s look at two examples of gene replacement that we have developed for two representative types of demyelinating CMT neuropathies. The first one is the X-linked CMT which is one of the most common types. It’s about 10 percent of all patients, and this results from a loss of function of a gene that is important for Schwann cells.
Our strategy was to design a viral vector to deliver the healthy copy of the Connexin gene to Schwann cells. With several years of work we have shown that we can achieve a replacement of this gene in Schwann cells and, in the picture above, there are examples of an untreated and a treated nerve and you can see that the myelin structure has improved in the treated nerve. This translates also into improved function with better muscle power and improvement of the nerve conduction velocity.
This is an initial proof of principle that we can actually achieve a treatment for this type of CMT with gene replacement.
The second example is about CMT4C. It’s a rarer type of CMT but very important because it’s representative for all the recessive CMT4 demyelinating neuropathies. Like for CMT1X, we designed a vector to replace the mutated gene in Schwann cells. We showed that we can achieve the expression of the gene using this viral vector. The slide shows pictures of an untreated nerve on the left and a treated nerve on the right, and you can appreciate the improvement of the myelin structure and better preservation of the nerve fibers. This translates into improved motor performance. The muscle power is improved and the nerve conduction velocities are faster, again providing proof of principle for this technology.
Still we have a long way to go before we can reach the stage of clinical testing. We have now several lines of activities trying to optimize the tools in order to reach that stage.
Four major issues that we are trying to address include first of all the finding of the optimal viral vector. We’re focusing on vectors that have been already used in clinical trials, and selecting the best one to target Schwann cells. We also evaluate the best way of injecting these vectors that will be safe and easy to apply to patients. We want to make sure that these vectors have no toxicity—that they’re safe—and we also want to make sure they can get to the whole nerves around the body because this is what we need to correct in the demyelinating CMTs.
These issues are really crucial not only for the two types that we described before but for all demyelinating CMT neuropathies. So results from this work will be relevant for moving ahead with other types of demyelinating CMT.
We’re also focusing on optimizing the treatment for CMT1X using new and safer vectors, and we want to show that the treatment can benefit various CMT1X mutations both before and after the beginning of the neuropathy, which is a very relevant question for patients.
And for CMT4C we also developed a new vector that is safer to deliver the mutated gene and demonstrate that we can benefit the model. So we hope that this work will get us closer to clinical testing with the proof of principle that these treatments can work.
And we are very excited also to mention that this work has attracted interest from several biotechnology and pharmaceutical companies.
Although there are remaining challenges, we have confidence we can overcome them. The success achieved in CMT1X and 4C by Dr. Kleopa is actually encouraging for CMT1A, so we’re focusing our efforts to apply this technology to CMT1A, which is the most common form of CMT.
One of the reasons we have confidence in that success is due to another company collaboration with Ionis Pharmaceuticals, which uses antisense oligonucleotides (ASOs). CMT1A is a little bit different than the other types of CMT since there’s not actually a mutation of a single base but rather a duplication of the gene, so that you have excessive levels of PMP22.The work published with Ionis showed that if you use antisense oligonucleotides to suppress PMP22, you see in two different models of CMT1A a fairly dramatic improvement in the myelination. We are continuing to work with Ionis to try to perfect and refine and make more potent antisense oligonucleotides.
This success also made us realize that you can use a related technology known as RNA interference, or RNAi, to accomplish the same goal, that is, to reduce PMP22. In collaboration with Drs. Kleopa and Svaren and with Dr. Gray at UT Southwestern, we’ve just initiated a project that’s targeting the same technology used for CMT1X and 4C but that’s now targeting a model of CMT1A.
This is a three-part project where we continue to try to address the challenges that Dr. Kleopa mentioned, which is to optimize the delivery to Schwann cells, while developing and optimizing the RNA interference for PMP22, and then also trying to make this system as safe as possible by targeting this suppression to Schwann cells rather than other cell types.
Our efforts also include an exciting extension to the relatively new technology that many people have read about, which is sometimes referred to as genome editing, or CRISPR- Cas9. Many people have read articles about this and it has generated a lot of excitement in the field because this is actually a way to take mutations and actually fix them, so you really can fix the source of the disease.
This new technology is being applied and has entered clinical trials for some types of diseases, particularly for those in the blood stream where you can replace blood-generating cells relatively easily.
The extension of CRISPR-Cas9 to diseases affecting the nervous system will probably take some more time to do all the safety studies and refine the system. But we are really pleased to announce that we are partnering with one of the leading genome editing groups that has focused on axonal forms of CMT, 2A, 2E, and 2F. And we are also collaborating with a company called Toolgen which has developed an approach for CMT1A and has published some positive results.
While this technology may be a few years behind gene replacement therapy, there is a lot of excitement in this area and ultimately this will become a technology that will really spur development of novel therapies for CMT.
All these approaches depend on having good measures that can be used in clinical trials. When we talk to companies, they want to know how they can plan a clinical trial in a way that they’ll get a definitive answer relatively soon. And this has been a challenge for a slowly progressive disease like CMT. But we took this challenge seriously and we supported a number of initiatives.
Some of them have developed within the context of Inherited Neuropathy Consortium, which is partially supported by the CMTA. And there’s also been direct funding of CMTA of some of these efforts as well.
Looking at muscle MRI has turned out to be one of the most sensitive measures of progression in CMT. We are also looking at proteins in blood samples that can be used to measure neuropathy. We’ve used skin biopsies to develop other methods. There’s been a lot of work in CMT evaluation score development. And we’re also investing in wearable devices that can be used in the clinic or even at home to assess balance and movement.
The coordinated use of all of these biomarkers and outcome measures is such that we can hopefully provide companies and investors with relatively quick assessments of whether a clinical trial will be effective. And this is really crucial for those entities to be able to actually provide investment in these new technologies. Progress in this area is just as important as development of the gene therapy itself.
We covered a lot of ground in a few minutes here so let’s just take a minute to share with you how all the pieces of this puzzle fit together.
First, we learned there are two major types of gene defect: what we call “loss of function” where the gene stops working, or what is called a “toxic gain of function” where the gene starts doing something toxic to the body.
And there are three major technologies in gene therapy. Gene replacement, where you take a virus (AAV) and send a replacement gene; gene silencing, where you use technologies like RNA interference (RNAi) to interfere with the protein production; and gene editing, also known as CRISPR-Cas9.
What you see on this chart is how all the CMTA-funded projects and CMTA partners we discussed today map onto this matrix, and how the strategy we launched last year has already brought in great partners and projects across this spectrum, with more to come in the near future.
It’s also very important to be able to deliver the therapy to the right cell. For neurons (CMT type 2s), there is general optimism there because it’s been done before in SMA, for example.
But for Schwann cells (CMT types 1, X and 4), it’s a whole different challenge because you have to deliver therapy to the millions of Schwann cells which are along your nerves. So that’s why we launched this very important collaboration with Drs. Kleopa, Gray and Svaren to optimize delivery to the Schwann cells.
And finally, you have to deliver this to humans and run efficient clinical trials. This is why biomarkers are so important, and thanks to recent advances the scientists think that we can run clinical trials with fewer than a hundred patients in less than a year.
We’ve covered a lot of ground but this is not random, we are very strategic and thoughtful about where we invest and where we spend your investment.
We’re not done—there is a lot of work to left to do. And that’s why it’s important to continue support the STAR program. There are five key reasons that we ourselves support STAR.
The first one is that it is an incredibly strong program. It is recognized as the leading CMT research program. Top researchers and top companies are now calling us to work with us, and nothing could be more exciting.
We take very good care of our financials. We keep our overhead very low; 15 percent or less is our goal, and we’ve achieved that in the past two years. Most nonprofits tend to spend twice as much in overhead. Part of the reason for that, by the way, is thanks to you: because most of our resources come from the community, we don’t spend time chasing government money, big foundation grants, or running fancy fundraising events. That keeps us very efficient and very focused.
And we are recognized for this. If you look at all the independent evaluation agencies like Charity Navigator, we get very high ratings.
The other point, which is very unique to the CMTA, is that the board members—the people who actually make decisions—are also very invested themselves Over 20 percent of our resources and funding comes directly from board members, which means that the people in charge are voting with their own dollars. They put their money where their mouth is.
Finally, our strategy is based on partnerships, and our partners spend at least 10 times more money than we do. So, when you support STAR, your money gets multiplied by a big factor through the involvement of our partners.
We have all come into this for our own reasons and our involvement is very personal, but at the end we all have a role to play. Please get involved and be part of this incredible movement. At the end, this is your program, for you, and by you.
We have wonderful branch events and patient/family conferences around the country.
It’s really important to be part of the CMTA Center of Excellence network and to register with the INC. It will help our research and it will help you.
Because we have more partners, we have launched the Patients as Partners initiative, so you can be involved with companies.
There’s a lot going on, so please sign up for eNews and stay informed!
And remember the three Ws: you can help with work, with wealth and or with wisdom.
A big thank you to everybody. Remember: STAR is all because of you and everybody in the whole CMT community. We’re very proud of where we’re at today, but there’s a lot left to do and we need your involvement and support now more than ever before.
Tremors are fairly common in people with CMT, and can intensify when the person is nervous, cold or tired. CMT expert neurologist, Dr Richard Lewis writes, “Clinically, when someone has CMT and a tremor, they sometimes call this Roussy-Levy Syndrome. Tremors are thought to occur because of decreased sensory input to the brain about where fingers are in space (pseudoathetosis) so that fingers (and sometimes legs or trunks) have tremor. Please consult your neurologist to understand if your tremors are CMT-related. “
Genetic counselor Shawna Feely adds, ” It is possible for only one person to have a tremor, despite everyone having the same type of CMT, because of CMT’s variability of symptoms. If CMT is the cause of your tremor, it can still be treated with medications that help with other forms of tremor (Parkinson medications for tremor).
The severity of symptoms of people in the same family with the same type of CMT can vary greatly from one person to the next. The Inherited Neuropathies Consortium (INC), which is part of the National Institutes of Health’s Rare Diseases Clinical Research Network (RDCRN) is trying to understand why this is by doing a genetic modifier study. They collect samples of DNA from people with CMT. They can screen the DNA through a process called GWAS to look for other genes that may contribute to more or less severe symptoms. This may lead to a better understanding and treatment of CMT in all its forms. If you are interested in participating, you should contact a CMTA Center of Excellence, participating in the INC. https://www.cmtausa.org/living-with-cmt/find-help/cmta-centers-of-excellence/ “
If you have not yet registered online with the Inherited Neuropathies Consortium (INC) Patient Registry, where CMT expertneurologist and researcher, Dr. Shy and colleagues continue working to research the many unknowns in CMT, here is the link: https://www.rarediseasesnetwork.org/cms/inc
It is easy to join, and free, and there are studies that come up periodically where they need feedback from the patient community.
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