Charcot Marie Tooth Disease (CMT)

Everything to know about CMT, from the experts.

Podcast

Author and Contributing Experts to this Guide include:

Jessica Bucher Genetic Counselor, MSGC LinkedIn
Michael Shy Professor of Neurology at the University of Iowa
Shawna Feely Genetic Counselor
Elizabeth Ouellette Board Member & Volunteer Community Relations Specialist at CMTA LinkedIn

What is Charcot Marie Tooth Disease (CMT)?

Charcot-Marie-Tooth disease (CMT) is one of a group of disorders that cause damage to peripheral nerves in the body 1. Essentially, these are the nerves that transmit messages from the brain and spinal cord to the peripheral regions such as legs, feet, arms, hands, and fingers.

It is named after the three physicians who first described it in 1886. They were Jean-Martin Charcot and Pierre Marie of France, and Howard Henry Tooth of the United Kingdom 2.

CMT can affect the transmission of sensory information but can also cause muscle weakness as well. Onset of CMT can happen at any age, but in most cases, progressive muscle weakness is typically noticeable in adolescence or early adulthood 3.

“CMT is a genetic disease that affects the long nerves that start from the spinal cord and go out to the feet and hands,” said Shauna Feely, a genetic counselor focused on working with people who have neuro genetic diseases. She is also a member of the medical advisory board for the Charcot Marie Tooth Association.

“Because those nerves are in the periphery of the body, we call those the peripheral nerves. It causes peripheral neuropathy, starting out in those long nerves in the feet and hands, and damages those nerves in a way that moves upwards towards the body.

“Those nerves help to maintain the muscle strength and the sensation that goes from our feet and hands to our brain, so when people lose muscle strength in those areas of the body, they can also lose sensation. It affects people's mobility, balance, can cause fatigue, and some chronic pain issues over a person's lifetime,” added Feely.

Longer nerves are usually affected first, meaning that symptoms generally begin in the feet and lower legs before moving to parts of the upper body.

Most all cases of CMT are an inherited neurological disorder, and those with this disease usually have some kind of physical disability, although some people may never know they have the disease. Different types of CMT are caused by mutation in different genes in the body.

Currently, more 80 genes have been associated with the disease 4, 5, 6

Multiple genes can be linked to one type of CMT. More than half of all cases of CMT are caused by a duplication of the PMP22 gene on chromosome 17 7.

It’s estimated that more than 125,000 people in the United States and more than 2.5 million people worldwide are affected by CMT 8.

Charcot Marie Tooth disease is also known by other names, including: hereditary motor and sensory neuropathy (HMSN) hereditary neuropathy Charcot-Marie-Tooth hereditary neuropathy Charcot-Marie-Tooth syndrome

Types of Charcot-Marie-Tooth (CMT)

Charcot-Marie-Tooth is a group of conditions and includes many types of Charcot-Marie-Tooth. Some of these share the same symptoms but will vary in other ways such as the age of onset, pattern of inheritance and whether the axon or myelin sheath is involved.

CMT is caused by gene mutations, also known as damaging variants, that support or generate proteins involved in the structure and function of either the peripheral nerve axon or the myelin sheath.

The most common types of CMT include:

CMT1

CMT1 is caused by abnormalities in the myelin sheath. The autosomal dominant disorder has several main subtypes.

CMT1A typically results from a duplication of the gene on chromosome 17 that carries the instructions for producing the peripheral myelin protein-22 (PMP22) 9. The PMP22 protein is a critical component of the myelin sheath. CMT1A is usually slowly progressive.

Individuals may experience weakness and atrophy of the muscles of the distal limbs, with the lower more affected than the upper limbs 10. Foot deformity with hammertoe is common 11.

CMT1B is caused by mutations, or damaging variants, in the gene that carries the instructions for manufacturing the myelin protein zero (MPZ, also known as P0) 12. It is another critical component of the myelin sheath. CMT1B produces symptoms similar to those in CMT1A 13.

Other less common causes of CMT1 result from mutations in other genes, including 14:

  • LITAF
  • EGR2
  • PMP22
  • NEFL

CMT2

CMT2 results from abnormalities in the axon of the peripheral nerve cell, instead of the myelin sheath 15. Less common than CMT1, this form has many subtypes with each subtype being associated with mutations in a specific gene.

Symptoms are similar to cases of CMT1, but there is often less disability and sensory loss than with CMT1 16. CMT2 usually develops in childhood or adolescence in general, may be less disabled and have less sensory loss 17.

There are many different types of CMT as classified by the newer naming system suggested by Magy et al 18.

What Causes Charcot Marie Tooth?

CMT is caused by mutations in genes that support or produce proteins in the structure and function of either the peripheral nerve axon or the myelin sheath.

CMT gene mutations are inherited in autosomal dominant, autosomal recessive, and X-linked patterns.

Autosomal dominant means only one copy of the CMT gene mutation, or spelling error, is needed to get the disease. This can come from either parent, or may be a de novo mutation (a new spelling error seen for the first time in the child).

A child of a parent with an autosomal dominant form of CMT has a 50 percent chance of inheriting the disorder.

Autosomal recessive disorders happen when a child receives two gene mutations (spelling errors), one from each parent. Typically, neither parent would have the disease and are “carriers” of the condition. In this cases, a child has a 25 percent chance of inheriting the disease.

Autosomal dominant and recessive disorders affect males and females equally.

Some types of CMT are inherited in an X-linked pattern. This means they are dependent on the chromosomes that determine an individual’s sex.

Women have two X chromosomes, one from each parent. Men have an X and a Y chromosome.

The Y chromosome is inherited from the father. The son of a mother who carries a CMT gene mutation on one of her X chromosomes has a 50% chance of inheriting the disease.

The vast majority of people with CMT 1A have inherited the condition from a parent who passed it on to them 19. When a parent has CMT, each child has a 50% chance of it being passed on to them.

But there are also instances when a new mutation occurs de novo, or spontaneously, during conception. The new mutation can be passed to the child’s future generations.

“Before 1991, all people, knew was that there were types of CMT that affected the myelin insulation around nerves, or that affected the axons inside the myelin. And so they called patients type one or type two.

But beginning in 1992, when the first gene was identified, we've now moved to over 100 different genes, all with different mutations. And then they can cause CMT or inherited neuropathies.

This means some patients don't present in a classic way,” said Dr. Shy.

Because of this, some types can start in childhood, while others won’t see symptoms until later in life. It depends on which specific gene is causing the problem long with other factors.

“As a genetic counselor, I help to narrow that down by helping patients through the process of genetic testing,” explained Feely.

One of the most common types is CMT type 1A which is typically caused by a duplication or an extra copy of the gene PMP 22. So the majority of people with CMT have an extra copy or a third copy. That leads to damage to the outside part of the nerve, called the myelin.

“It depends on the specific gene mutation that is causing damage to that part of the nerve. That’s why not everyone presents the same. We have to look at the symptoms that a person has and narrow down what the specific gene mutation might be.,” said Feely.

“Even if someone has no family history, they still could have CMT. A lot of the time when we're working with someone, it starts with examining their symptoms, when things started, how they progressed, and looking at what damage is being done to the nerves. From there, we talk about what genetic testing might be appropriate,” added Feely.

Signs and Symptoms of Charcot-Marie-Tooth Disease

Various forms of CMT will present signs and symptoms differently in each person, even among family members. Some people may have the disease and never realize it because the symptoms are so mild.

However, the earliest symptoms of CMT generally start with muscle atrophy in the feet. People with CMT may also have high arches, flat feet or curled toes (hammer toes).

“The overall presentation for most patients is slowly progressive weakness and what we call a length dependent fashion. That means it's worse at the feet and hands as it is than it is higher up the legs.

And then most patients also have decreased ability to feel things,” said Dr. Mike Shy.

Dr. Shy is a professor of neurology at the University of Iowa who works in inherited peripheral neuropathies related to Charcot Marie Tooth disease and is the principal investigator of the Inherited Neuropathy Consortium (INC), a multidisciplinary clinic at the University of Iowa that is one of 20 INC sites worldwide.

This creates difficulty flexing a foot or walking on the heel of a foot. That can result in increased ankle injuries and tripping. As the disease progresses, legs usually get weaker.

“Because sensory nerves also provide information to the brain about where your body is in space. Balance is a big problem for many patients,” added Dr. Shy.

CMT also creates difficulty lifting a foot at the ankle (footdrop) or an awkward or higher than normal step (gait).

Curvature of the spine may also be present (scoliosis).

People with CMT may also develop a weakness in their hands, leading to increased difficulty with daily living activities such as buttoning, writing, turning doorknobs or tasks requiring other fine motor skills.

In addition, people also experience a decreased sensitivity to heat and cold in the lower legs. This may also produce aches or a burning sensation.

In rare cases, people suffering from CMT may lose their vision or undergo a gradual hearing loss until deafness occurs.

In severe cases of CMT, breathing difficulties may lead to a shortened life. However, CMT is slowly progressive and people with this condition can remain active for years, enjoying a normal life span.

Age of Onset of CMT

The age of onset can vary, although there is a common presentation that most patients have. But there are exceptions to this as well.

“There are some mutations and some genes that really affect children in infancy. As a result, the children may be in wheelchairs by the time they're 10 or 12.

“And then there are other types that adults are presenting much later on. There are also some types that affect the nerves that go to muscles more than the nerves for sensation. Also, there are types where the nerves for sensation are primarily affected as opposed to the nerves that go to muscles. Basically, there are many different presentations,” said Dr. Shy.

Some patients may not show symptoms until they’re in their 20s.

“But looking back, many times there have been problems and actually started in childhood. For example, the person may have been the slowest runner in their group of friends or may have had particular problems with balance for activities like walking or performing various athletic activities in a gym class while in school,” added Dr. Shy.

Many patients also find they may have had trouble finding shoes that fit before being diagnosed because one of the common symptoms is an abnormal foot structure.

Prevalence and Risk Factors for Charcot Marie Tooth

Charcot Marie Tooth or CMT affects about one in 2,500 people worldwide.

“It's actually one of the most common neurogenetic diseases that there is. When I say it's one of the most common conditions no one's ever heard of, there are over three million people affected in the world. About one in 2,500 people are affected with one form and other.” As stated by Feely.

Diagnosis of Charcot Marie Tooth

Deciding when to seek treatment or be tested for the presence of CMT is not an exact science. If someone is not having trouble keeping up with their friends, or if they're not really developing symptoms, there's no data that suggests that diagnosing somebody early has a better outcome, at least at this point. That may change in the near future.

“Over the long-term if a child is asymptomatic, there's no medication that can make the problem go away.

“There are potential psychological issues about knowing that you have a disorder, even if it's not affecting you, creating unnecessary worry for some people.

It’s the patient’s and the family’s choice. Our overall philosophy is that it is important to do natural history studies. We have a number of clinical outcome assessments that investigate infants and children who may or may not have CMT. So, it's important for us to evaluate infants and kids in those studies, just to understand the natural history, but we set this up in such a way that patients aren't forced to make a genetic diagnosis if it's not clinically apparent,” said Dr. Shy.

Over time, natural history studies will hopefully make it possible to better identify the progression of the condition at all stages. That way, when a treatment becomes available, clinical trials are easier to measure.

According to Dr. Shy in terms of clinical care and treatment, there may not be a reason for a patient or a child to come and be evaluated at a clinic if they don't have any problems or risks to have CMT.

For those who do have signs and symptoms, examinations, family history, and clinical findings can often narrow things down from the start.

“If someone has signs of classic CMT 1A, we can usually pick up a lot of the clinical findings and narrow that down 90 percent of the time.” said Feely.

“In cases like that, we might just test to see if someone has an extra copy of that PMP 22 gene, because it helps to cut down the costs. It’s cheaper for people who can just cut it down to the test for that one gene,” she added.

However, as the genetic science for CMT advances, costs have come down for genetic testing as well. That means it’s easier for patients to have genetic testing for large panels. At other times, patients may have access to sponsored testing as a way to also offset costs.

“The type of testing we recommend depends on what we're looking at in terms of the type of symptoms a person has,” said Feely.

Aside from genetic testing, there are other studies that can help with a diagnosis. One of these is an electrophysiology (EMG) or nerve conduction study.

An EMG involves putting connections on a patient’s arm and leg and sending an electric signal to those regions. Those signals are measured for how quickly and how strong they are when they travel in the body.

This is a clinical way to measure how well a peripheral nerve is functioning.

“An EMG would pick up a change if someone had CMT, but it would also pick up a change if someone had a condition that was acquired, not genetic, that was affecting that nerve,” said Feely.

“If CMT is present, when we do a nerve conduction test, the speeds of the signal are very slow. So instead of 50 meters per second, we will see speeds about half of what they should be, or about 20 to 25 meters per second.

That's a very clear sign that someone has a problem with those peripheral nerves and that they might have the most common type of CMT, like CMT 1A,” added Feely.

Treatment & Care Options for Charcot Marie Tooth

There is no cure for CMT, but various symptoms can be managed.

Finding an effective treatment is complicated by the fact that that researchers must deal with the fact that there are many different genetic causes of CMT. That demands different approaches and possible treatments for each form.

“For CMT 1B, one of the four common types of CMT, it is caused by mutations in a gene called myelin protein zero. For these patients, there are medications that affect or have processed in cells called the unfolded protein response. There are also candidate medications that have been published in journals in which this has been able to be modified,” said Dr. Shy.

“But for CMT X and for the recessive forms, it's thought that the disease process involves a loss of function of the normal protein. So, there are gene replacements and gene therapy studies that are fairly advanced in animal models to use a gene placement,” added Dr. Shy.

Although there are no medications to cure CMT, scientists believe they are getting close on a number of them. Several solid candidates are close to entering clinical trials according to Dr. Shy.

“There are several candidate therapies which are out there. But to me, one of the most exciting potential treatments has been the development of antisense oligonucleotides (ASOs) developed by a company that has successfully treated other neurological diseases with ASOs. They've successfully treated a rat model and a mouse model of CMT-1A.”

For now, treatment and care must take a different route.

“In our multidisciplinary clinic, genetic counseling is at the heart of it, just to give true knowledge about who's at risk in the family, what's disease causing, and what's not, and how to interpret variants,” said Dr. Shy.

That multidisciplinary approach extends to other forms of treatment.

“We also have a physical therapist and occupational therapist in the clinic, as well as an orthotist who comes to the clinic on a weekly basis to look at bracing, with or without any needs. In addition, we have access to orthopedic surgery audiology, pulmonary functions, and services that are needed for patients on an as needed basis,” said Dr. Shy.

Physical therapy is also an important treatment component and part of a modified regimen of treatment for many people who have CMT.

“Right now, our treatment strategies focused on management of symptoms. We work a lot with physical therapists, and occupational therapists for hand development issues such as being able to use tools and other ways to manage day to day living tasks. We try to work also closely with orthotists to help with braces and help with mobility issues,” explained Feely.

Dr. Shy, echoed those sentiments, noting, “There are ongoing research studies looking at exercise, looking at the bracing, looking at activities. Much of it is loose in terms of rigorously being evaluated. One thing to note is that many patients develop pain in their ankles and joints over time and they have foot structure problems.”

“We want people to exercise so we usually encourage low impact exercise that's good for the cardiovascular system. And this would include things like swimming or riding bicycles, either real bikes or stationary bikes. We encourage stretching and maintaining flexibility. People also do well with things like yoga and Tai Chi. We tend discourage and avoid high impacted exercises, like jogging, or other similar activities that are hard on the joints,” he said.

As more and more of the mysteries of genetics are unraveled, researchers are slowing working toward introducing gene therapy trials in the hopes of stopping the progression or curing different forms of CMT.

“There's a lot of cautious optimism about a real ability to cure these conditions,” says Feely.

Potential Complications from Charcot Marie Tooth

Because CMT is generally a slow progressing disease, many people who properly manage the condition remain active and live to a normal age. However, there are still certain complications to be aware of so that you take steps to lessen their impact when possible.

These include:

Injuries or infections of the feet that go unnoticed because of lack of pain and temperature sensation.

When CMT affects breathing muscles, you need to be aware of this, especially at night, and you may require an assistive breathing device.

Injuries due to falls created by less sensitivity in limbs.

Increased susceptibility to skin breakdowns, burns, nonhealing foot ulcers.

Bony, bilateral foot deformities.

For women, CMT increases the risk for complications during delivery. This often requires emergency interventions during birth.

Other causes of neuropathies, such as diabetes, may cause CMT symptoms to worsen.

Certain medications can make CMT much worse. These can include the chemotherapy drugs vincristine (Marqibo), paclitaxel (Abraxane, Taxol) and others.

Commonly used medications that pose moderate to significant risk include the following:

Amiodarone (Cordarone) Bortezomib (Velcade) Cisplatin and Oxaliplatin Colchicine (extended use) Metronidazole (extended use) Nitrofurantoin Pyridoxine (mega dose of Vitamin B-6) A complete list of potentially neurotoxic drugs can be found at the Charcot-Marie-Tooth Association.

One of the complications of CMT is a lack of providers who fully understand what CMT is. Providers may have limited time and resources to fully diagnose a CMT case or are slow to refer people to neurologists or even physical therapists for treatment.

“We see people from all over the world because we specialize in this. We see more people in one week than others may see in a lifetime. Because of this, we're able to guide local care so patients and providers feel like they're doing the right thing at home. The biggest thing we try to do is do training programs for future physicians some that more people will have access to good treatment,” said Feely.

Prognosis of Charcot Marie Tooth

Because CMT presents in so many different forms and levels of severity, prognosis of the disease will vary from person to person. In most cases, there will be physical challenges, but for many people these are not life threatening.

“People with most forms of CMT will enjoy a normal life expectancy. However, the problem is that that for many people with the CMT, their ability to get around is really diminished, even with walking aids. Fine movements in the hands can get impaired for daily activities like buttoning a shirt or blouse.

“Also, having impairment in the workplace for many people is a big issue. It limits their ability to do many of the jobs that they would like. But for most types of CMT, it does not shorten a person's lifetime. For some of the severe types that's not always the case,” commented Dr. Shy.

To improve your prognosis if you’re diagnosed with CMT, you should work closely with a neurologist. Genetic counseling is also important, especially for family planning.

In addition, other ways to manage CMT include:

  • Performing regular low-impact aerobic exercise to keep your muscles strong, helping to increase balance and coordination
  • Stretch regularly to improve range of motion, flexibility, and to prevent or reduce joint deformities
  • Don’t drink alcohol except in moderation
  • Eating a healthy diet
  • Staying at a healthy weight
  • Checking your feet regularly for injury or infection to prevent calluses, ulcers, wounds
  • Cut your nails regularly in a way that avoids ingrown toenails.
  • Wear the right shoes that fit properly and protect your feet. Boots or high top shoes may provide additional ankle support. If you have foot deformities, such as a hammertoe, consider having your shoes custom made.
  • Also check with your healthcare provider before you take any new medications. Some will make your CMT symptoms worse.

What to do Next: Living with Charcot Marie Tooth

To contact clinics involved in CMT research and treatment near you, interested parties should go on the NIH website for the Rare Disease Clinical Research Network, RDCRN. Another option are patient groups, which include the Charcot Marie Tooth Association (CMTA), and the Hereditary Neuropathy Foundation (HNF) and the Muscular Dystrophy Association (MDA).

Some researchers are administering clinical trial ready studies to document the natural history data for the various subtypes. However, a few are launching clinical trials or there are clinical trials that have recently started.

Contact these organizations for more CMT information:

National Institute of Neurological Disorders and Stroke Brain Resources and Information Network (BRAIN) BRAIN P.O. Box 5801 Bethesda, MD 20824 301-496-5751

CMT Research Foundation 4062 Peacetree Street, Suite A209 Atlanta, GA 30319 info@cmtrf.org

Charcot-Marie-Tooth Association (CMTA) P.O. Box 105 Glenolden, PA 19036 800-606-CMTA (2682) 610-499-9264 info@cmtausa.org

Hereditary Neuropathy Foundation, Inc. 432 Park Avenue South, 4th Floor New York, NY 10016 212-722-8396 855-HELPCMT (435-7268) info@hnf-cure.org

Muscular Dystrophy Association 3300 East Sunrise Drive Tucson, AZ 85718-3208 800-572-1717 520-529-2000 mda@mdausa.org

Referenced Sources

  1. Charcot-Marie-Tooth Disease Fact Sheet | National Institute of Neurological Disorders and Stroke. (n.d.). Retrieved October 7, 2020.
  2. Diseases—Charcot-Marie-Tooth Disease (CMT) | Muscular Dystrophy Association. (n.d.). Retrieved October 7, 2020.
  3. Charcot-Marie-Tooth Disease Fact Sheet | National Institute of Neurological Disorders and Stroke. (n.d.). Retrieved October 7, 2020.
  4. Bird, T. D. (1993). Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews®. University of Washington, Seattle.
  5. OMIM Entry Search—Charcot Marie tooth. (n.d.). Retrieved October 7, 2020.
  6. Stojkovic, T. (2016). Hereditary neuropathies: An update. Revue Neurologique, 172(12), 775–778.
  7. Charcot-Marie-Tooth Disease Fact Sheet | National Institute of Neurological Disorders and Stroke. (n.d.). Retrieved October 7, 2020.
  8. Charcot-Marie-Tooth Disease Fact Sheet | National Institute of Neurological Disorders and Stroke. (n.d.). Retrieved October 7, 2020.
  9. Matsunami, N., Smith, B., Ballard, L., Lensch, M. W., Robertson, M., Albertsen, H., Hanemann, C. O., Müller, H. W., Bird, T. D., & White, R. (1992). Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth 1A. Nature Genetics, 1(3), 176–179.
  10. Thomas, P. K., Marques, W., Davis, M. B., Sweeney, M. G., King, R. H., Bradley, J. L., Muddle, J. R., Tyson, J., Malcolm, S., & Harding, A. E. (1997). The phenotypic manifestations of chromosome 17p11.2 duplication. Brain, 120(3), 465–478.
  11. Bienfait, H. M. E., Verhamme, C., van Schaik, I. N., Koelman, J. H. T. M., de Visser, B. W. O., de Haan, R. J., Baas, F., van Engelen, B. G. M., & de Visser, M. (2006). Comparison of CMT1A and CMT2: Similarities and differences. Journal of Neurology, 253(12), 1572–1580.
  12. Hayasaka, K., Himoro, M., Sato, W., Takada, G., Uyemura, K., Shimizu, N., Bird, T. D., Conneally, P. M., & Chance, P. F. (1993). Charcot–Marie–Tooth neuropathy type 1B is associated with mutations of the myelin P0 gene. Nature Genetics, 5(1), 31–34.
  13. Diseases—Charcot-Marie-Tooth Disease (CMT) | Muscular Dystrophy Association. (n.d.). Retrieved October 7, 2020.
  14. OMIM Entry Search—CMT1. (n.d.). Retrieved October 8, 2020.
  15. Bird, T. D. (1993). Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews®. University of Washington, Seattle.
  16. Bird, T. D. (1993). Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews®. University of Washington, Seattle.
  17. Bird, T. D. (1993). Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews®. University of Washington, Seattle.
  18. Magy, L., Mathis, S., Le Masson, G., Goizet, C., Tazir, M., & Vallat, J.-M. (2018). Updating the classification of inherited neuropathies: Results of an international survey. Neurology, 90(10), e870–e876.
  19. Bird, T. D. (1993). Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. In M. P. Adam, H. H. Ardinger, R. A. Pagon, S. E. Wallace, L. J. Bean, K. Stephens, & A. Amemiya (Eds.), GeneReviews®. University of Washington, Seattle.

Transcript

Jessica: You're listening to the Rare Disease Connection, a production of aspect, health and raredisease.com. There are roughly 7,000 rare diseases and estimates are that a rare disease affects nearly one in 10 Americans and hundreds of millions of people worldwide. The genetic disorder we cover in this episode is actually relatively common. Charcot Marie Tooth or CMT affects about one in 2,500 people worldwide. When you hear numbers like that, it's clear that rare diseases aren't so rare and it's impossible to know how many rare diseases go undiagnosed. Jessica: If you or someone you love is affected by a rare disease, you likely have more questions than answers. That's why we're here. Rare Disease Connection, and our additional resources on raredisease.com and yourdna.com, brings together the people whose expertise can explain what you're facing, from diagnosis to prognosis, to treatment options, all the way to questions like, "Who do I talk to? And where are the people who've been through this before?" You'll find those answers here. From doctors, geneticists, academics, genetic counselors, patient organizations, other patients, and their families all within your reach, we're here to connect you. This is Rare Disease Connection. Jessica: Hi everyone. This is Jessica, genetic counselor and cohost a Rare Disease Connection. I'm excited to bring you some recent conversations we've had with experts from around the world about a very specific, rare genetic disorder, Charcot Marie tooth syndrome. Before you listen, we know that hearing from these experts is only the beginning for you. That's why we've taken the information here and added additional resources, explanations, links, and references for you and a downloadable guide on CMT. You can get your free copy of that guide by going to raredisease.com/cmt. Again, that's raredisease.com/cmt. Head there for so much more to help you on your journey and understanding this disorder. It will certainly help support you and your ongoing plan of action. The experts are here. So let's talk about CMT. Our first conversation is with Dr. Mike Shy. So would you mind just introducing yourself, Dr. Shy? Mike Shy: It'd be my pleasure. And thank you for asking me to be part of this. I'm a professor of neurology at the University of Iowa and I work in inherited peripheral neuropathies that are loosely called Charcot Marie tooth disease. I'm the principal investigator of what's called the inherited neuropathy consortium. This is funded by the NIH as part of their rare disease clinical research network. And we're now in our 11th year of operation. I see a number of patients come through our clinic at the University of Iowa and within our consortium we follow over 6,000 patients worldwide. And also I run a laboratory where we do experimental work with disease models. Jessica: Wow. And what is your current role in treating Charcot Marie to do have a multidisciplinary clinic there? Mike Shy: Yes. We have a multidisciplinary clinic at Iowa and to be a member of the inherited neuropathy consortium, there's 20 sites worldwide, the requirements are willing to have a multidisciplinary approach. Jessica: Great. Mike Shy: Currently there aren't any medications to make any type of CMT go away. Although we're very close on a number of them. We do actually have solid candidates to enter clinical trials. But in our multidisciplinary clinic, we have first of all, genetic counsel, which I don't get to tell you, but the heart of our whole program is developed and it's why people come from all over the world to our clinic, even though we don't have medicines to make the CMT go away. So genetic counseling is at the heart of it just to give true knowledge about who's at risk in the family, what's disease causing, and what's not, and how to interpret variants? That really are a major part of what our clinic offers to our excellent genetic counselors. Mike Shy: We also have a physical therapist and occupational therapist in the clinic, and we have an orthotist who comes to the clinic on a weekly basis to look at bracing, with or without any needs. And then we have access to orthopedic surgery audiology, pulmonary functions, and things that are needed for patients on as needed basis. Jessica: And for people that are just learning about CMT, what are some of the common neurologic features that you see with CMT? Mike Shy: So the overall presentation for most patients is slowly progressive weakness and what we call a length dependent fashion. So that means it's worse at the feet and hands as it is than it is higher up the legs. And then most patients also have decreased ability to feel things. Again, in a length dependent fashion, that's worse at the feet and the fingers than it is as you move up the limbs. Because sensory nerves also provide information to the brain about where your body is in space. Balance are big problems from many patients. And yeah, so falling down and just, again, being able to maintain balances is a big issue for patients. Mike Shy: Now that's just the standard presentation and I'm just going to backtrack for just a second. Before 1991, all people, knew was that there were types of CMT that affected the myelin insulation around nerves, or that affected the axons inside the myelin. And so they called patients type one or type two. But beginning in 1992, when the first gene was identified, we've now moved to over 100 different genes, all with different mutations. And then they can cause a CMT or inherited neuropathies. And the reason I'm mentioning this is that some of them don't present in that class of way. Mike Shy: So there are some mutations and some genes that really affect children in infancy. And as a result, the children may be in wheelchairs by the time they're 10 or 12. And then there are other types adults are presenting. So adulthood. And there are also some types that affect the nerves that go to muscles more than the nerves for sensation. And there are types where the nerves for sensation are primarily affected as opposed to the nerves that go to muscles. So there's different presentations, but what I told you is sort of classic form. Jessica: And what is the average age that you would say you would see neurologic symptoms? I know you said, of course there's different types, but is there an average age of onset? Mike Shy: Well, I would say is that there's a common phenotype or a common presentation that most patients have, but not everybody. And in those, they may not present to see a physician or a caregiver until they're like in their 20s or something. But when you look back, there's been problems and actually started in childhood. For example, the person may have been the slowest runner amongst their friends, and may have had particular problems with balance for activities like walking on a balance, being in gym or walk over a screen when they're out with their friends. And they may have had trouble finding shoes that fit because hierarchy is an abnormal foot structure is a common feature as well. Jessica: And you were saying that there is not currently a medication, but that's something that you're getting close to or that there might be a candidate. Would you be able to talk a little bit more about that? Mike Shy: I can, but it involves recognizing that there are different genetic causes. So the most common form of CMT is called CMT-1A. And that actually affects about half of all people who have CMT. And I should say that the current prevalence is thought to be about one in 2,500 people for CMT. So about 50% of people of that group will have CMT-1A. And that's caused by a duplication on chromosome 17 and with an extra copy of a gene called peripheral myelin protein 22 or PMP 22. And there are several candidate therapies which are out there. But to me, one of the most exciting potential treatments has been the development of antisense oligonucleotides developed by a company which has successfully treated other neurological diseases with ASOs. And they've successfully treated a rat model and a mouse model of CMT-1A. Mike Shy: And so again, part of what we do at our inherited neuropathy consortium is really work on getting the natural history data to be clinical trial ready for diseases like CMT-1A. Now for CMT 1B, which is one of the four common types of CMT, this is caused by mutations in a gene called myelin protein zero. And for these patients, there are medications which affect or have processed in cells called the unfolded protein response. And there are a candidate medications which have been published in journals, including science, in which this has been able to be modified. And so there are candidate treatments for CMT 1A on the horizon. For CMT X and for recessive forms of CMT, so about 10% in North America of CMT cases are all somehow recessive. CMT X is obviously X linked. Mike Shy: But for CMT X and for the recessive forms, it's thought that the disease process involves a loss of function of the normal protein. And so there are gene replacements and gene therapy studies that are fairly advanced in animal models to use a gene placement with approaches and also [inaudible 00:11:11] viruses to treat these forms. And again for all of these reasons, we're really focusing on natural history studies and biomarkers to be clinical trial ready. Jessica: And are the clinical trials, the research that you're currently doing, is that something that you are recruiting patients for? And if so, how can patients connect with you and your clinic? Mike Shy: So the best way to connect with our clinics is to go on the NIH website for the Rare Disease Clinical Research Network, RDCRN. Or the patient groups, which include the Charcot Marie Tooth Association CMTA, and the Hereditary Neuropathy Foundation, HNF. And of course the Muscular Dystrophy Association, the MDA, and they will put people in contact with the sites that are doing these studies. So for most of them, these are clinical trial ready studies. So really to nail down the natural history data for the various subtypes, but for a few of them, actually there are clinical trials and there have been clinical trials that have been started. Jessica: And thinking about patients who know that they are genetically predisposed to CMT, so say they may be diagnosed very early in life, but not have any symptoms yet. Is that someone that should still come to clinic or what age would you recommend that they begin being seen in a multidisciplinary clinic? Mike Shy: Okay. So first of all, I want to be upfront to that. There's two purposes for clinics like ours. So one is to provide good patient care. And then the other is to investigate research, to try to get the appropriate natural history studies, including when diseases start. So our policy in terms of this clinical care is that there's not a reason for a patient or a child from sample to come and be evaluated at the clinics, if they don't have any problems. I wouldn't say if they're not having any problems, I mean if they're not having any problem keeping up with their friends, if they're not really developing symptoms. And the reason we feel that way is if there's no data that suggests that diagnosing somebody early has a better outcome, long term, at least in terms of whether their kids are asymptomatic. And there's no medication that can make the problem go away at present. Mike Shy: So there's potential psychological issues about knowing that you have a disorder, even if it's not affecting them that we worry some of them. And this is all the patients and the families choice. So that's sort of our overall philosophy. Having said that when we're doing the natural history step studies, and we have a number of clinical outcome assessments that investigate infants and children who may or may not have CMT. And it's important for us to evaluate that infants and kids in those studies, just to understand the natural history, but we set this up in such a way that patients aren't forced to make a genetic diagnosis if it's not clinically apparent. Jessica: And from your perspective, how can families best support someone facing a new diagnosis with CMT? Mike Shy: Well, I think it's a family disease rather than an individual a disease. And I think having awareness of what the disorder is and what the natural history of that type is, and who's at risk in the family, are important issues. And this is one of the reasons why personally, I think that genetic council is so important in the care of this disease because the counselors really develop a relationship with the family as a whole, and sort of address a lot of these concerns with them on a very personal level. Jessica: We will have a chance to talk to your genetic counselor later, which is great. And I wanted to also ask you what the journey typically looks like for a patient who finally gets to your clinic or finally gets that right diagnosis? How long do you think they've been searching for a diagnosis or are there other common diagnoses that people have been diagnosed with instead of CMT? And maybe it wasn't the right diagnosis to begin with? Mike Shy: So first of all, with the journey, it depends upon the family situation. So if there are other people in the family who have CMT and knowing, and then when somebody develops symptoms, that can be relatively quick. Many types of CMT, even with [inaudible 00:16:16] dominant inheritance, present the Nova without a family history of course. That's true for the recessive forms as well. So for those patients, that can be a long journey. So they may have seen multiple other caregivers along the way, and this path can take years. I think the issue is often that the physician or the caregiver doesn't have experience with a genetic diseases or with CMT and may say, "Well, it could be a genetic condition. It could be CMT, but genetic testing is expensive. There's no treatment. So there's no reason to get to testing." Mike Shy: And so a lot of patients get that type of approach before they come to us. And again, this just acquiring knowledge, I think, is a reason that many people travel with their money expense from all over the country to see our clinic. Jessica: I definitely think that's the truth. Getting to a clinic like yours must be a huge part of their treatment. And what are some of the activities that you would say people with CMT should avoid, or is there something that makes their condition worse? Mike Shy: So there are ongoing research studies looking at exercise, looking at the bracing, looking at activities. And so a lot of it is still sort of loose in terms of rigorously being evaluated, but many patients develop pain in their ankles and joints over time and they have foot structure problems, and we want people to exercise. So we usually encourage low impact exercise that's good for the cardiovascular system. And this would include things like that, not treadmills, but- Jessica: Elliptical. Mike Shy: Yeah. Elliptical thank you. And to them it will include things like swimming. And of course I'm talking about pricier ones here, but just riding bicycles, either real bikes or stationary bikes, that type of approach is something we encourage. And then stretching and maintaining the flexibility is a big deal. And it's not really, it's not a literature that I'm aware of things like yoga and Tai Chi and things like that, people who really seem to do well with. But again, in terms of like to avoid high impacted exercises, like jogging, things which are hard on the joints, we tend to discourage. Jessica: What is the life expectancy of someone with CMT? Mike Shy: For most forms it's normal. So the problem is that that for many people with the CMT, their ability to get around is really diminished. Even with walking AIDS and find movements with the hands can get impaired even for daily activities like buttoning, a shirt or blouse. And so I think just having impairment in the workplace for many people is a big issue. So it just limits their ability to do many of the jobs that they would like. But for most types of CMT, it does not shorten a person's lifetime. For some of the severe types that's not always the case. Jessica: And is there anything else that you would like to share about CMT that we haven't discussed yet? Mike Shy: Well, there are a number of caregivers like myself who are really working to try to understand the different types of CMT and develop rational treatments. And none of this would happen without the partnership with patients and their families. So that I just wanted to answer that as how much we appreciate that and how much we've appreciated over the years. And I think we're getting into an era where there's really going to be rational treatments that will slow progression and improve CMT for many of the genetic causes and none of this would happen without the patient participation. Jessica: Thanks to Dr. Shy. Our next conversation was Shauna Feely. She's an experienced genetic counselor with a specific expertise in CMT. Let's hear from Shauna. Okay. Shawna, thanks so much for joining us. Would you mind introducing yourself? Shauna Feely: Sure. My name is Shauna Feely. I am a genetic counselor and I am originally from Washington state sort of bounced around the country due to my profession. And my work has allowed me to focus and work with people who have neuro genetic diseases. So those are genetic diseases that affect the nervous system. And I have had a lot of experience working in the population of people who have Charcot Marie Tooth disease. And I sit on the medical advisory board for the Charcot Marie Tooth Association. Jessica: How did you originally become involved with CMT? Shauna Feely: I originally became involved because I was interested in neuro genetics and specifically wanted a position in that field. And when I graduated as a genetic counselor those were hard to come by. So I made a jump or a move from LA to Detroit at the time, for a position in a neuro genetic position. And that's how I came to work with Dr. Michael shy. And so it was an unusual jump, not just geographically, but also jumping into the world of CMT because lots of folks, it's a very common condition, but lots of folks have never heard of it. And that's how I first got my start and was able to meet all the lovely people I've been able to meet in that community. Jessica: And can you explain to people who maybe have never heard of CMT before people who are just starting to research CMT? What is CMT? Shauna Feely: So CMT is, it's a genetic disease that affects the long nerves that start out from the spinal cord and go out to the feet and hands. So because those nerves are in the periphery of the body, we call those the peripheral nerves. So CMT affects, what we call a peripheral neuropathy. So it starts out in those long nerves, in the feet and hands and damages those nerves in a way that moves upwards towards the body, sort of in a stocking glove pattern and people develop. Because those nerves help to maintain the muscle strength and the sensation that goes from our feet and hands to our brain, people lose muscle strength in those areas of the body, and they can also lose sensation. And so it affects people's mobility balance can cause fatigue and sort of chronic pain issues and things like that over a person's lifetime. Jessica: And how common is CMT? Shauna Feely: It's actually one of the most common neuro genetic diseases that there is. When I say it's one of the most common conditions no one's ever heard of, it's actually there was over three million people affected in the world. About one in 2,500 people are affected with one form and other. And it's important to remember that CMT is actually not one disease, there's over 100 different genetic causes that we now know of that cause different forms of CMT. So it's actually sort of a lot of different conditions, all grouped under one umbrella. And so there's a lot of different types out there. Jessica: And what is the underlying cause of CMT? I know that you said there are several different types, but could you give us some information on what the general underlying causes and perhaps the underlying cause for some of the more common forms? Shauna Feely: Sure. All CMT by definition is genetics. So it's a gene mutation that leads to damage of those peripheral nerves, but because there's so many different types that can sometimes start from childhood or adulthood, it just depends on which specific gene is causing the problem. So we, as a genetic counselor, I helped to sort of narrow that down by helping patients through the process of genetic testing. One of the most common types is CMT type 1A. And that's caused by a duplication or an extra copy of a gene called PMP 22. So that's the majority of people with CMT have an extra copy or a third copy. So instead of two copies, they have an extra copy of this PMP 22 gene that leads to damage to the outside part of the nerve, what we call the myelin, but there's again, many, many different types of CMT. Shauna Feely: So it depends on the specific gene mutation, which is causing damage to that part of the nerve. So not everyone presents the same and we help to look at the symptoms that a person has and narrow down what the specific gene mutation might be. But even if someone has no family history, they still could have CMT. So a lot of the time when we're working with someone, it starts with examining their symptoms, when things started, how they progressed and looking at what damage is being done to the nerves by doing examinations, it's like the neurological examination. And then talking about what genetic testing might be appropriate. Jessica: Are you often ordering panels of genetic tests? Shauna Feely: It depends on what we're looking at in terms of the type of symptoms a person has. If someone has sort of classic CMT 1A, which is the most common cause that I mentioned, we can usually pick up a lot of the clinical findings and narrow that down 90% of the time, we were pretty certain that we know when someone has CMT 1A. So we might just test to see if someone has an extra copy of that PMP 22 gene, because it helps to cut down the cost conservative, so the cost is cheaper for people who can just cut it down to the test for that one gene. But costs have come down a lot for genetic testing and you can do large panels and there may be access to sponsored testing that we have for patients and things like that. Shauna Feely: So there's different ways to get testing for people in a reasonable way in terms of costs. And a lot of times testing for CMT is done in panels, but genetic counselors on our team help patients and guide them to what tests might be appropriate for them. What lab would be appropriate, things like that. Jessica: And the symptoms that you were talking about that narrow down the type of genetic test that you send, are the studies that patients have done before they have genetic testing. Are they specific to CMT or are there other conditions that people are frequently diagnosed with? Shauna Feely: They are more general studies that help, for example, an EMG, which is electrophysiology or nerve conduction study, where you put stickers on the arm and on the leg and send a signal and you can measure how quickly the speed is being sent and how strong that signal instant. And you're measuring that peripheral nerve. So you're measuring how the peripheral nerve is functioning in terms of the strength and the speed of the signal. And that would pick up a change if someone had CMT, but it would also pick up a change if someone had a condition that was acquired, not genetic, that was affecting that nerve. Shauna Feely: And so these are more general types of tests that people have when they start to have problems with nerve function that's leading to some of the symptoms. I already mentioned like weakness or balance issues, pain, numbness, all of those things can result from damage to those peripheral nerves. And so an EMG is a really basic test that a neurologist might start with to determine if there's a problem with those peripheral nerves. And if there is what that looks like with, for example, CMT 1A, when we do a nerve conduction like that, the speeds of the signal are very slow. So instead of 50, 5-0, meters per second, right away, we will see speeds about half of what they should be, 20 to 25 meters per second. And that's a very clear sign that someone has a problem with those peripheral nerves and that they might have the most common type of CMT, like CMT 1A. And then that combined with evidence from their neurological exam and when they started walking and those types of clues might lead us into a direction of a certain type of CMT. Jessica: And what proportion of people who have CMT have an inherited form versus people who have a new or Denovo form of CMT? Shauna Feely: That's also dependent on the type of CMT. So we see that for CMT 1A, most of the time, people are going to have a parent that had passed it on to them. So probably 85, 90% of the time, they had a parent that had a 50% chance or a one in two chance of passing it onto them. But for the most common type of CMT type two, which is an axonal form of CMT, not demyelinating form, in CMT type 2A, which is that the most common type of CMT type two, 50% of those are Denovo or brand new. And it also tends to be a more severe form of CMT in terms of the progression and level of weakness and physical impairment that people want to sometimes develop. So it depends, there's differences depending on the type. And there's also recessive forms of CMT. And so it's also different depending on how it's inherited in the family. Jessica: And what are the current treatments available for people with CMT? Shauna Feely: Right now, our treatment strategies focused on management of symptoms. So we work a lot with physical therapists, occupational therapists for hand development issues and things like that. So being able to use tools and other ways to manage day to day living tasks and things like that. We try to work also closely with orthotists to help with braces and help with mobility issues. People use other devices to help with mobility. So a lot of the focus is more on managing symptoms as they progress through disease. We are working towards now that we've identified many of these genes, it allows us to work towards introducing gene therapy trials in order to be able to potentially stop the progression of disease or cure different forms of CMT. Jessica: How many different centers are involved in a clinical trial like that right now? Shauna Feely: Well, I think the clinical trials are just about ready to start, in terms of, in the human population, there's been a lot of things going on in animal models now. But one important thing to have when you're starting out in human trials is to have a network in order to be able to evaluate people who have CMT all in the same way and how outcome measures to be able to assess change over time. And so what we've been trying to do in order to be ready for these clinical trials is to develop this networks or part of the inherited neuropathy consortium with Dr. Michael Shy and together we've helped to develop about, there's about 20 sites in our consortium that are all interacting with patients and seeing them every six months or a year and evaluating folks in a similar way. And everyone's cross trained so that we can be ready for clinical trials, particularly gene therapy trials, as they become available. Jessica: Great. That's an exciting time it sounds like. Shauna Feely: Yes, it's exciting as a genetic counselor, because the way you counsel patients, especially folks who are getting a new diagnosis changes is because you're not talking necessarily just about the disease and the fact that there is no cure for this disease. You're actually talking to the patients and talking about how this is the condition. This is how it's passed on in the family. And this is what the future holds. And this is what we're doing right now. This is what will be explored in the next few years. And so there's a lot of cautious optimism about a real ability to cure these conditions. Jessica: Absolutely. What do you think is the greatest barrier you see for patients with CMT right now? Shauna Feely: The biggest thing I hear being in clinic is that people do not have access to providers who know what CMT is. So they're in their communities. They feel like they're the ones educating their providers or that they say they have CMT and the providers just looking it up and trying to figure out online what it is. And they're seeing neurologists even, or physical therapists, people that they need to be able to have someone monitor or treat their condition. And they don't feel like they're getting good guidance. So a lot of our clinicals that we have are to guide that local cares. So people come from all over the world really because we specialize in this and we see more people in one week than others may see in a lifetime and we're able to sort of guide that local care so they feel like they're doing the right thing at home. And so that's the biggest thing we try to do is do training programs for future physicians and things like that, to be able to allow people access to good treatment. Jessica: Are there tools that you recommend for your patients to take back to their doctors? Shauna Feely: There are a lot of tools and that we provide in the clinical setting for patients to take back to their providers. For example, there is a physical therapy and occupational therapy packet, or booklet that has recommendations for folks with CMT. And every patients is given that so that they can take it back to their local OT or PT folks that may not have worked with someone with CMT before. And those resources are publicly available through organizations like the CMTA. So there's things out there for people so that they can try to educate their providers. And there's also information for teachers in schools and things like that. So there's a lot of resources online and we try to help patients connect with those resources. Jessica: Great. What are your hopes for the future of CMT? Shauna Feely: My hopes for the future are that we do find a treatment for CMT that actually helps to hear the condition or stop the condition in a real way that significantly impacts patient care. And I think that we are ready through all these trials that I've been working with Dr. Shy for the last 15 years to run these clinical trials because we have developed outcome measures, not only for adults, but children and infants in order to treat as early as possible. It may be that treating in childhood is important because then you don't have as much of the damage already accrued. We've seen that for other genetic diseases. So I think that's the goal that we all have. Shauna Feely: And I know that's the reason why a lot of us have gotten into genetics is because in the genetic world, you can actually identify what the problem is because you can specifically define that and you can understand that mechanism, then there's a real way to approach how to treat that. And that's different than some of the other diseases that may be more common, but what we don't know what causes Alzheimer's or things like that, for example. And so that goal is that being able to develop these outcome measures and being able to define genetically the cause of all these, that it's eventually going to lead to a real treatment, secure CMT. Jessica: How can family members best support their loved ones with CMT? Shauna Feely: I think family members can support their loved ones by trying to understand what CMT is and how it impacts them. It's a disease that's hard to see. And there's a lot of the underlying things that are hard to measure: pain, fatigue, some of the things that go along with living with a chronic disease, those are all sometimes hard to understand. So being open and allowing people to share their experience and learn from them is important. It takes a lot of energy for a person with CMT to do simple tasks on a day to day basis. Like even walking from point A to point B because they have to focus a lot more in things due to issues with balance and stuff like that. So kind of considering that in people's day to day life, and for kids with CMT or kids in a family with CMT, it's helpful for the family to kind of sit down and discuss what CMT is at an age appropriate level. Shauna Feely: And for kids who might have to wear braces or things that are more visible, helping them come up with a way to describe what CMT is to their friends. So that is quick and easy and that they understand so that if someone is asking them in class, why they're wearing braces, that they know what to say. And that's something that then they feel more comfortable with and they don't feel pressured or bullied. So there's ways to come together as a family that sort of deal with these issues in an open way that destigmatizes the disease. Jessica: Thanks to Shauna. Elizabeth Ouellette is a parent advocate of CMT. Let's hear from Elizabeth. All right. Would you mind just introducing yourself? Elizabeth Ouellette: Sure. My name is Elizabeth Ouellette, and I live in California and I'm very involved with the Charcot Marie Tooth Association. I started working with the Charcot Marie Tooth Association as a volunteer about 20 years ago, well 18 now, and I've been a patient advocate and I have a son with CMT so that's why I'm involved. But I live in California. I have a master's in counseling psychology and I grew up in Vermont, moved to France, met my husband there. We had our son Johann in France in here. And when we learned he had CMT, I have been very involved. So I'm on the board of directors and I'm also more importantly, a volunteer and patient advocate for people to CMT. Jessica: So you told us a little bit about how you became involved with CMT. Would you mind sharing a bit about how your son was diagnosed? Elizabeth Ouellette: Sure. So I had never heard of Charcot Marie Tooth ever. And I have this seven year old, who's tired all the time, whose feet are starting to get really high arches, hammer toes. And she started to fall behind in school, not with the materials at school, the fall behind his classmates with exercise. He couldn't do the monkey bars. That was his nemesis at school, and he would come home very upset about it. And really the biggest thing is fatigue and not really wanting to go and play any competitive sports. And so we had a physical therapist who said, "You now, I just tried to get his reflexes and I'm not getting anything. I think he needs to see a neurologist." And we were pretty much stunned. And we said, "Okay." And thankfully at that time, this was 17 years ago. Elizabeth Ouellette: We have found a neurologist who knew about CMT and he said, "It's either cerebral palsy." And I retained that name cerebral palsy because I knew what cerebral palsy was or something with a tooth. So we did the tests. He did not have cerebral palsy. And what happened is he came back, he tested the Johann for CMT 1A and that was at the beginning of genetic testing. And he did have one a and he said, "Johann has Charcot Marie Tooth 1A, CMT 1A." And we didn't even know what that meant. And I started doing a little bit of research and we were totally freaked out and there were so many questions. And at that time there weren't a lot of resources. So I started to get online and look up things and try to figure it out. And there wasn't a big patient community at that time or a lot of resources. So it was tough at the beginning and we really struggled with this diagnosis. And I almost wished in retrospect, I thought, "Cerebral palsy at least is not progressive." And then you go, "Oh, well it is a progressive disorder. So what does that mean for Johann's future?" Jessica: And when you were on this journey, what were some of the tools that had helped you become successful? Elizabeth Ouellette: So my way of dealing with it and our family's way of dealing with Charcot Marie Tooth is to get involved and to be open, to talk about it and to embrace it. And we didn't get there overnight. It was a journey, but I called the Charcot Marie Tooth Association and I saw one online whose daughter also had CMT 1A. And at that point there weren't branch meetings or meetings or anything. And I got involved with the CMTA. We were very small at the time, we had two employees. We did not have a research program at that time. And I just got involved. It was a very small organization and there was intentionally to do so much with this organization. And so I jumped in and it was just when I had finished my degree in counseling psychology. So I had that background. Elizabeth Ouellette: And the first thing I did was I did a school program for Johann and Johann wanted me to come in into school and talk about CMT. And I created this teaching kids about CMT and it was an hour long program where I went into the school and it was fun. It was game-like and it was interactive and it did not put Johann on the spot, but it was to show the other kids what CMT was all about and how it felt like to have CMT. So to imitate the burning nerve pain that you might get on the bottom of your feet, I had them rub their hands together for 30 seconds and feel that, and then I had them put socks on their hands and I said, "The bus is coming, you've got to get this shirt buttoned up all the way to the top," and they were struggling. Elizabeth Ouellette: And so then we'd talk about it. People with CMT have fine motor skill problems and they can't do things as fast and they can't run as fast. So I developed this whole program and the kids is... He was young, was getting bullied at school because a lot of times CMT isn't something that you can see you. "He looks fine." So the kids were able to embrace this program and to embrace Johann, but not feel like you know, "Oh, poor Johann you can't do this, or how to do this or this," but just to empathize with them to get it, why he was slower, why he couldn't do the monkey bars and it changed Johann's life. It literally changed his right because his friends [inaudible 00:46:07] or bat him. So that was the first thing I did. And then as I got more involved, I have a lot of ideas. Elizabeth Ouellette: So I started the national branch system for the Charcot Marie Tooth Association. He had a couple of branches here and there scattered, but it became a network of branches across the country so that people with CMT had a place to go. And so that was a lot of fun, man. I had my own branch here in the Bay area. And from there I've just been very, very involved in just starting the awareness month initiative that we have and continuing with the branches. And now I did the advisory board. So I guess the supports that we have on the way is the fishing community. We've done a lot of the CMT also for social media, Facebook groups that I moderate those. And we have patient family congresses and Dr. Shy actually started those patient failing conferences in Detroit. Elizabeth Ouellette: And I took the idea and he's like, "No, you have to do this for the CMTA." So we've had a lot of conferences all over the country is centers of excellence. So those supports is really openness and family have a lot of family support and I've done this school program with my family. And so they understand. So it's been very, very hard at times with the supportive people, family, community, and a great medical system, like with Dr. Shy and Shauna, and the centers of excellence it's been very, very helpful. Jessica: That's incredible. And if you don't mind, I'd love to ask you a question about how you talk to Johann about the medical information? Because something that we do know with rare disease and especially children who have been affected by a rare disease is that when you talk to them about their condition in an age appropriate way and involve them in their care, they become much more empowered and able to transition and take independence of that as they become an adult, when you can't go to all their appointments. So I'm wondering if you have any tips for that? Elizabeth Ouellette: Yes, absolutely. So what helped is I wrote a lot of articles about CMT and even for the local papers and everything. And well, I would tell Johann, and I don't quite remember. I remember there was this big controversy, "Do you tell him, do you not tell him? Do you tell him, do you not tell him?" And I was of the mind that she has this, we're going to live life to the fullest. And I don't know where CMT will bring him or us in the future. So let's live in the moment. And I would tell Johann that, "CMT does get worse over time, but that's the reason you have this tremor. And that's the reason your handwriting's not that great. And that's the reason this and this and this, but let's go to physical therapy and get stronger." And I think a big thing with kids if you have them stretching exercise, if you can do that with your children, it's empowering because they... I remember saying, "Johann you have to stretch in front of the TV with this block and your Achilles tendon." Elizabeth Ouellette: And he felt like it was a punishment. So I would do it with him or my husband would do it with him. So we were doing it together as a family. And I think the biggest thing is I told Johann, that we were all involved. My husband was involved, I was involved. We were going to find something to stop the progression of this disease. And so to live in the moment and we would deal with the symptoms and as they came along and the fatigue, we would get them checked out, it would be okay for sure as a family to support you. And your legs might feel tired, but you can still do the things that you want to do. And we really focused on activities that he wanted to do, that were competitive. So my husband taught him to scuba diving and brought him to Mexico to learn to scuba dive. And then we got him horseback riding lessons, which helped his confidence so much. And then he loved archery. Elizabeth Ouellette: So finding the things that he liked to do, he got a lot of comfort out of knowing that we were behind them 100%. We would talk about the disease is nothing to be scared of and that we were in it for the longterm. And we would keep fighting to find a way to stop the progression or treatment for this disease. Jessica: What have been some of the biggest challenges? Elizabeth Ouellette: Well, the bullying at school has been very difficult and Johann's always been pretty positive, but I also firmly believe in counseling and psychology. And we found him a great counselor who was male, and they would just discuss some of those fears and things that he was worried about. And I felt like that helped us a lot along the way. The whole bracing thing and Johann has had surgery on both of his feet, on one of his feet, but it had to be done twice. And that was very, very difficult because he had to take a year off between college and graduate school. He did it, the first surgery didn't work. We had a [inaudible 00:51:44] done, he never wanted to wear braces, the tripping, the falling. Elizabeth Ouellette: So those things were very, very difficult and explaining it to people, explaining CMT to people where they would understand it and not be judgmental. And growing up was really getting the other kids to get on board and learn what he had. But we all have something. So we really focus on, we all have something and this is what Johann has. Sometimes the ignorance of some of the medical professionals, people that didn't know CMT, I think honestly the best thing we did was go to a center of excellence. And thankfully I knew Dr. Mike Shy and Shauna, and we had posters [inaudible 00:52:29], and doc for the CMT for awareness month. And when he walked in, he felt like he met his family. This was his family, and everybody knew him and understood him. So I think outside of that world of the center of excellence, it's not this protected universe and people didn't understand him. Elizabeth Ouellette: And now I'm jumping ahead. We have camp footprint at the CMTA and it's just been such a great thing for kids because kids are getting together with other kids. So one of the big challenges is he didn't know anyone else with CMT. And that was tough. At his age, especially his age, he knew people that were 80 through the branches. He didn't know anyone his age. So that was really comforting. Jessica: So what other types of supports can a family find through the CMTA? Elizabeth Ouellette: Yeah, so we have a big presence on social media. We have a CMT discussion group. We have our own page that gives announcements. We have a CMT active that we just started to help people with CMT remained active because people who stay active do much better in the long run than people who are sedentary. And I think that's just true among the general public. We have conferences, we have a large expensive branch system. So we have maybe 75 branches across the US where people can call the branch leaders, get involved, meet other people with CMT. That's been just wonderful. We have a pretty robust awareness month program where people get together and talk about CMT and try to educate the public. We also have camp footprint for Kansas CMT, and Johann was a counselor there when he was growing up. Elizabeth Ouellette: He didn't really want to go to other camps for chance with no differences or disabilities, but he went as a counselor to camp footprint in what I didn't know, where I didn't realize what he would come back with is he came back with friends with CMT his own age that he still keeps in contact with. And it's something that really made a big impact in his life. And that was just last summer. So he was a counselor, he was a mentor. And he also came back with friends with CMT. We also have an advisory board who gives webinars and answers questions, and we have patient conferences and I know this is time of COVID, but we usually have to a year big patient family conferences all over the country. And so we have a helpline, we have asked the expert. So we have a lot of resources. We did an OTPT guide to CMT. Elizabeth Ouellette: We're working on an orthopedic guide to CMT. We done a bracing guide to CMT. So we're always coming out with more and more resources. We're here to talk to people and offer support and even Johann he's working part time for the CMT. And now he loves to talk to younger people and to people who want to know more about CMT because I think it helps him and he loves that role of helping other people. Jessica: That's fantastic. And I was going to ask you for some of those people who don't have access to the physicians that are maybe at a center of excellence, or maybe it's a financial issue where they maybe can't come to some of those conferences, it sounds like there are some resources online that you were mentioning that they could bring to their local providers and help advocate for themselves there? Elizabeth Ouellette: Absolutely. And if you call the CMT, we'll send you out a packet of information about we have a guide is what a CMT. And we have a lot of online resources. And when I started with the Santee, we only had a couple of small centers of excellence, like not Dr. Shy and Dr. [inaudible 00:56:28] in Pennsylvania, but now they're all over the country. So we have over 25 centers of excellence around the country. So that's huge yet we do have through the branch system, there are other ways of finding physicians that know about CMT, that aren't big centers of excellence. So there is a big network of people telling you where you can go to find the best care. And if people with financial difficulties, if they're not in network and you can't get that care then now we're doing, through the branches, because of COVID we're doing more and more zoom meetings. Elizabeth Ouellette: And so people from all over the world who get online and meet others and talk to people. And so in a way, COVID's helped us expand that virtual online program which has been really helpful for people who can't get out of the house or who can't drive to a meeting, or can't go to a big conference. And our library at the CMTA is so extensive. We have so much information. I think if you spent a day going through all the things that we have on our website for past conferences and recordings, and there's so much information there. Jessica: What do you think is something that families and friends can do to someone facing CMT? Elizabeth Ouellette: That's a great question. Thanks for asking that. I think learning about CMT, figuring it out, because again, a lot of people... And Johann's mutation is a new mutation. We do not have CMT in our family. So that was kind of like out of the blue, a new mutation. A lot of people and usually it's passed along through generations. So a parent will have CMT or pass it along to the child or children. And there's a lot of guilt in that. People feel very guilty and don't like to talk about CMT because they've passed it on to their kids. And I think we all pass things along to our kids. It's genetics. It could be mental illness, it could be anxiety, it could be heart disease. Elizabeth Ouellette: And so I think the biggest thing is really acceptance of the disease and talking about it. And if the person is comfortable with CMT and having CMT that person's going to be able to talk to other people. So as a friend, we want to know as much about CMT as possible. And I have a very good friend Bethany [inaudible 00:59:10], and I remember she was pretty fascinated with CMT. She has a hard time walking and I'm this patient advocate. And I know a lot about CMT and we're watching, I had just met her and she's like, "Geez Elizabeth we're crossing the road. The least you could do was give me your arm." Elizabeth Ouellette: And like having her struggle across the street, but it was awkward because I didn't know what to do. I didn't know if I was doing too much. And so Bethany was very good at saying, "Geez, I thought you're good with people with disabilities," and I didn't know what it was about. So I give her my arm and we walked across the street, but it kind of broke that tension. Like, "What can I do to help you?" And the other way in the biggest way. And we have really, a lot of family support is fundraising. And we have a very robust research initiative called STAR, and we're doing gene therapies and a lot of research with CMT and we're making a lot of progress. And so get involved, get involved and you can say, "Have a birthday for a cause or do one of our walks across the country." Elizabeth Ouellette: My brother started a cycle for CMT in Vermont, which has become very, very big and we're doing it virtually this year. And so get involved and raise money for research or make a donation in honor of their friends this is going to make them feel better and it's going to a great cause because our research program is expanding. And it's doing very, very well actually. So even though I'm very involved in resources and patient advocacy, I do believe in our research program. And that's the one thing that I continue to support every single year, because I want Johann to know. And I want our patients to know in our community that I will not stop until we do find a treatment for CMT and we're getting there. Jessica: What is your advice to those who are really struggling with a diagnosis? Elizabeth Ouellette: There are a lot of people working for you and there's more research than ever before and more interests in CMT than ever before. And I've been around for 17 to 20 years now. And so I see the difference. It's palpable. You can tell, and if you are just diagnosed with CMT, now, you may feel like, "Oh, there are no resources." But the number of people who do know about CMT is huge. The resources that we have now there are many resources and there are a lot of people to talk to if people are writing blogs and I've actually written my own blog about our whole journey with CMT, and especially orthopedic surgery. And we know much more now about orthopedic surgeries. So there's a lot of information that you can hold tight and know that more and more people are working for you. Elizabeth Ouellette: And more and more for our super local companies see a future of working with CMT because of the gene therapies that are coming out now. So there's a lot of promise and a lot of hope for the future. And there's actually promise and hope for today. So hang in there and get involved. It helps to get involved. Knowledge is power. That's how I feel. Knowledge is power, and there are a lot of people working for you. And just to know, we're CMT family. So my husband is chairman of the board of the CMTA and he works extensively with our researchers on the research. And not just on 1A but all types of CMT and I'm on the paid patient advocacy side. And Johann also is working for the sand chain because it's his community. So also for Kansas CMT, there's a lot of support with camp footprint, it has been so successful. Elizabeth Ouellette: And this year we're doing it virtually. So that's what I was saying. This promise. Staying positive, there's promise and talk to others, call us, we want to hear from you. Jessica: How can people get in touch with you? I know you said that there's the website and we'll make sure to link that as well, but calls emails, what's the best way to do that? Elizabeth Ouellette: If you go to the CMT website, it's cmtausa.org, there's a forum where you can say info@cmtausa.org. It's info@ and then there's ask the expert, or you call, we don't have somebody answering the phone, but we give the call back within 24 hours. My number's on there. Gina Sweeney, who is our development director, Laurel Richardson, who's a community person. And John Berger who runs our camp footprint also is available. So there are a lot of people and if the right people don't answer the phone, we'll put you in touch with the right people and we will help you find the right resources and the necessary resources that you need. Elizabeth Ouellette: And the last thing I wanted to say in regard to our resources and I just remembered is we do have an emotional support group on our website. It's not on Facebook. It's close. It's run by one of our advisory board members [inaudible 01:04:27] Tanenbaum. And a lot of people do need emotional support, especially during this time of COVID and we're staying inside and wearing masks. And this group is wonderful as it's raw, it's authentic, and you can be real in this group. And it's very small, and it's not out there on Facebook and people aren't sharing your comments all over it's also can be found on websites. So emotional support is also very, very important. Jessica: What are your hopes for the future of CMT? Elizabeth Ouellette: That more people know about it that they figure out it's not a tooth disease, because as soon as you say shake over a tooth, somebody things you have [inaudible 01:05:11] disease. Jessica: Sure. Elizabeth Ouellette: I've kind of make a joke about it. I'm like to get people to remember seeing CMT, I'm like, "Okay, it's not Country Music TV, it's not musical theater," you know? Jessica: Uh-huh (affirmative). Elizabeth Ouellette: And it's not Certified Massage Therapy. And so just joking, people will maintain, "Oh, it's not bad thing. Is that medical thing, let me look it up." And so that's my way of telling people about CMT, but my hope is that pharmaceutical companies continue to be a big resource and have an interest in CMT. And really we need a treatment. We need to treat it to stop the progression at least. I use the word cure carefully. With some of the gene therapies coming out, you probably will be able to cure CMT, but there's a lot of folk and I want people to be informed, I want people to be hopeful, but we do need a treatment. And so my hope is that we find something that will lead to other therapies in the very near future for Johann and for all my friends with CMT in the community. Jessica: Can I ask what Johann is doing now? Elizabeth Ouellette: Yes. Last year he graduated with organizational psychology master's degree from Claremont University, and he was doing his big job search. And then COVID hit. He called the CMTA said, "I have a lot of information and resources and I have a lot to offer people with CMT." So now he's working part time with the CMTA answering phone calls, working on camp grant. And so he's very, very busy doing that. And he also is applying for jobs and getting his resume together. And he's a very bright kid and he'll find something and he's living at home, which is not his you know. [inaudible 01:07:10] could be doing it 27. We love each other. And we get along and it's a CMT household. Elizabeth Ouellette: A lot of commonalities to discuss, but it's exciting. It's fun. And we've done webinars together. And it's something we have in common. We make the best of it. We try to help others. So he's doing very well, but I think he's getting a little antsy. He liked living on his own and doing his own thing, but he'll get there. Jessica: You must be a very proud family to have him doing such great things and your presence is just contagious. So thank you for all the work that you've been doing. And hopefully we can get this message out there. And I really appreciate your time. We would like to give a big thanks to our guests once more for their time and commitment to CMT. We all find ourselves with a small bit of information that only leaves us wondering, "Okay, what now?" So what now? We know that hearing from these experts is only the beginning for you. That's why we've taken the information here and added additional resources, explanations, links, and references for you in a downloadable guide on CMT, you can get your free copy of that guide by going to raredisease.com/cmt. Jessica: There, you can download a recap of this episode that lists the key points, as well as several links and resources for you to further explore. Finally, if you need to speak with someone directly about CMT or your personal situation, we're here to help. It's at raredisease.com/health to get in touch. We are standing by, this is Rare Disease Connection, a production of aspect, health and raredisease.com.

Clinical Trials

Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease

Memorial Medical Center

Learn More on ClinicalTrails.gov

A Registered Cohort Study on Charcot-Marie-Tooth Disease

First Affiliated Hospital of Fujian Medical University

Learn More on ClinicalTrails.gov

Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others

University of Iowa

Learn More on ClinicalTrails.gov

Rare Disease Guides

CHARGE Syndrome (CHD7)

Everything to know about CHD7, from the experts.

Listen Now

Neurofibromatosis Type 2 (NF2)

Everything to know about NF2, from the experts.

Listen Now

Prader-Willi Syndrome (PWS): Symptoms, Treatment + Podcast

Everything to know about PWS, from the experts.

Listen Now