FUNNY NAME
SERIOUS DISEASE

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WHAT IS CMT?

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A BRIEF OVERVIEW

 

Simply stated, Charcot-Marie-Tooth disease is a rare inheritable peripheral neuropathy affecting an estimated three million people worldwide. More broadly, Charcot-Marie-Tooth disease is a vast heterogeneous group of inheritable sensory and/or motor peripheral neuropathies, axonopathies, myelinopathies, and neuronopathies. Clinically, Charcot-Marie-Tooth disease is a multisystem neuromuscular disease. Medically, Charcot-Marie-Tooth disease is arguably one of the most complex diseases to understand. For those who have Charcot-Marie-Tooth disease, the disease is intrusive, unrelenting, often debilitating, unforgiving, and can sometimes be fatal.

 

Known by its acronym, CMT, the disease gets its name from the three doctors who first described it in 1886: Jean-Martin Charcot (1825-1893), Pierre Marie (1853-1940), both from France, and Howard Henry Tooth (1856-1925) from England. In its infancy, CMT described a disease that causes lower leg muscle weakness and atrophy, or what is aptly called peroneal muscle atrophy. Over time, CMT has revealed itself to be profoundly more diverse with reaches far beyond the lower legs.

 

Although first described and named in 1886, the cause of CMT remained elusive for more than 100 years. Scientists knew CMT was inheritable, they could see it clearly ran in families, but they didn’t have a cause. Finally, in 1990, and published on January 1, 1991, scientists had discovered a cause: a duplication of a tiny segment of chromosome 17 (17p11.2). Scientists quickly learned not all who had CMT had this genetic mutation—there was another cause. At the time, knowing there was more than one genetic cause for CMT, scientists believed there might be three or four different causes, and perhaps five at most. Enter the age of CMT genetic discovery.

 

What was once just one cause of CMT in January 1991, quickly became several. The original chromosome segment duplication quickly became a pinpointed PMP22 gene duplication in 1992. By the end of the decade, scientists had discovered CMT-causing mutations in six different genes causing ten different CMT subtypes. By the end of 2001, marking the first ten years of CMT genetic discovery, another seven genes were discovered to have CMT-causing mutations, adding another ten subtypes to the list, although four of these subtypes (and their related genes) weren’t classified as CMT until many years later.

 

Today, scientists have discovered CMT-causing mutations in 124 different genes and have identified four chromosomal locations they suspect to have a gene with a CMT-causing mutation, but they have not been able to identify the specific gene. These combine to account for a staggering 158 individual subtypes. These are classified into fourteen type categories that are a combination of the CMT acronym and other acronyms that describe the type, such as, but not limited to, HSAN (Hereditary Sensory and Autonomic Neuropathy), dHMN (Distal Hereditary Motor Neuropathy), and GAN (Giant Axonal Neuropathy).

 

Despite such a diverse composition of CMT subtypes, there isn’t necessarily any one thing that is necessarily unique to any one subtype. Anybody who has CMT can experience any symptom associated with any subtype, regardless of the subtype they have. The age at symptom onset, disease progression, symptom severity, overall disease severity, etc. are quite variable. CMT as a whole can affect everybody differently, and even within the same family, resulting in an inability to reasonably predict what anybody’s disease course will look like. One thing is for certain: CMT is progressive over one’s lifetime. The progression, however, can look different for everybody who has CMT.

EXPERTS IN CMT'S
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CMT QUICK FACTS

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  1.  Most Common Inherited Neuropathy

  2.  More Than 120 Different Genetic Causes

  3.  Affects 1 in 2,500 People

  4.  More Than 3 Million CMTers World Wide

  5.  Affects All Ethnicities and Age Groups

  6.  Affects the Nerves that Control the  Muscles, but the Muscles are not Directly  Diseased

  7.  Progressive Over One's Lifetime

  8.  Is Not an Autoimmune Disease

  9.  Is Not Acquired and Is Not Contagious

  10.  Currently No Cure nor Direct Treatment

What are the Signs and Symptoms of CMT?


The signs and symptoms of CMT are typically described as high arches, numbness and/or tingling in the feet and hands, frequent trips, frequent ankle sprains, walking/standing on the sides of the feet, a slow response to temperature (hot and cold water), poor balance, muscle cramps in the lower legs/feet, muscle cramps in the hands, and fine motor skill issues. These are just a small example of some of the things CMT can cause. It would take volumes to cover all the symptoms of CMT, but we’ll go over some basics here.


Some early signs and symptoms of CMT might include but are not limited to toe-walking (especially in children), frequent tripping caused by catching the toes due to a weakening of the muscles that pick up the front of the foot, frequent ankle rolls/sprains caused by ankle instability due to a weakening of the muscles used for controlling the ankle, frequent muscle cramps in the hands and problems with using pens/pencils/crayons and eating utensils, and issues with other tasks involving fine motor skills—zippers, buttons, keys, etc.


CMT often causes numbness, especially in the points farthest away from the spinal cord, such as the hands and feet. Hand numbness can be random and episodic. It’s not uncommon for somebody who has CMT to wake up in the morning with painfully numb hands. Sometimes, this numbness clears up within a couple of hours. Other times, it can last for weeks.


CMT often causes severe chronic pain. The pain can be debilitating. Sometimes, the pain is neuropathic pain. Other times, it’s muscle and joint pain. For many who have CMT, it can be both. CMT often causes a great deal of fatigue. It’s well known that somebody who has CMT typically expels three times more energy performing even the most remedial of tasks than somebody who does not have CMT. Chronic pain only adds to the fatigue.


CMT often causes high arches as part of what’s called cavovarus foot deformity. A cavovarus foot has a high arch and is twisted downward towards the front and outward onto the lateral (outside) edge of the foot. This deformity is caused by an unbalanced weakening of the muscles that control the foot.


For reasons unknown, some of the muscles that control the foot remain relatively strong in CMT while their opposing muscles become relatively weak. The unbalanced muscle forces exerted on the foot are strong enough to cause bones in the foot to change shape. The result is a painful, twisted, and crooked foot that poorly distributes weight, makes mobility difficult; and over time, can lead to premature ankle, knee, hip, and lower back wear/degenerative changes.


As common as cavovarus foot deformity is in CMT, the opposite deformity can also occur: pes planus, or what is a flat foot. A pes planus deformity in CMT is also caused by an unbalanced weakening of the muscles that control the foot. The unbalanced weakening occurs in muscles opposite to those that cause cavovarus deformity. A pes planus deformity causes the foot to turn inward rather than outward, again, because opposite to cavovarus. Pes planus deformity is as painful and problematic as cavovarus foot deformity.


Kneecap dislocations can commonly occur in CMT, especially in children. A condition called patella alta, or what is a kneecap (patella) that is located higher up the leg than it should be, can be seen in many who have CMT. This is likely caused by a weakening of the leg muscles and likely contributes to the dislocations.


CMT often causes finger contractures (clawed hands), toe contractures, tremor, absent or reduced reflexes, poor circulation (neuromuscular-induced venous insufficiency), scoliosis, kyphosis (kyphoscoliosis when scoliosis and kyphosis occur together), and the list goes on. Less common, but still quite troublesome, CMT can cause neurogenic bladder issues, neurogenic bowel issues, vision problems (due to optic atrophy and/or slowly reactive pupils), vestibular issues, speech/vocal issues, and swallowing/choking issues, just to name a few more.


The above represents just a small snapshot of the signs and symptoms of CMT/what CMT can cause. Additional selected symptoms are briefly discussed below. This page is not intended to be an all-inclusive CMT symptom list. Rather, the purpose here is to provide only a brief overview of what CMT can look like for many. Not every person who has CMT will experience every symptom CMT has to offer, and each person will experience their own symptom mix, individual symptom severity, and overall disease severity. The reasons for this variability are poorly understood.


The signs and symptoms of CMT are typically described as high arches, numbness and/or tingling in the feet and hands, frequent trips, frequent ankle sprains, walking/standing on the sides of the feet, a slow response to temperature (hot and cold water), poor balance, muscle cramps in the lower legs/feet, muscle cramps in the hands, and fine motor skill issues. These are just a small example of some of the things CMT can cause. It would take volumes to cover all the symptoms of CMT, but we’ll go over some basics here.


Some early signs and symptoms of CMT might include but are not limited to toe-walking (especially in children), frequent tripping caused by catching the toes due to a weakening of the muscles that pick up the front of the foot, frequent ankle rolls/sprains caused by ankle instability due to a weakening of the muscles used for controlling the ankle, frequent muscle cramps in the hands and problems with using pens/pencils/crayons and eating utensils, and issues with other tasks involving fine motor skills—zippers...

What Causes CMT?


CMT is a disease of the peripheral nerves. The peripheral nerves are every nerve that lie outside the brain and spinal cord with the exception of the optic nerves, and CMT affects every one of these. CMT is caused by a mutation in any one of 124 different genes, and the number of genes continues to grow. A gene mutation that causes CMT disrupts a molecular process within the peripheral nerves. The mutation alters the gene’s function—how it works, causing the gene to behave abnormally. It’s akin to substituting powdered sugar in place of brown sugar in your favorite cookie recipe. Sure, you’ll still get a cookie, but the cookie just won’t be the same. Extend this to the peripheral nerves and sure, you still get peripheral nerves, but they just aren’t the same.


A gene that’s been discovered to have CMT-causing mutations is called a CMT-associated gene. Some CMT associated genes have just one lonely mutation that’s known to cause CMT. Most, however, have many individual mutations that each cause CMT, while some have hundreds of individual mutations that each cause CMT, such as the GJB1 gene which has over 400 discovered mutations that each cause CMTX1 (formerly CMT1X).


Most CMT subtypes are caused by a single mutation within their associated gene. Others are caused by having two mutations within their associated gene. When the subtype is caused by having just one mutation within the gene, and the gene lives on a numbered chromosome (1-22—the autosomes), the subtype is considered autosomal dominant. When the subtype is caused by having two mutations within the gene, and the gene lives on a numbered chromosome, the subtype is considered autosomal recessive. Likewise, one mutation in a gene that lives on an X-chromosome is considered X-Linked dominant, and two mutations is X-Linked recessive. Each of these are also an inheritance pattern. An inheritance pattern is how the CMT-causing mutation is passed on/inherited, and each have their own rules governing the chances of passing on/inheriting the mutation.


CMT is a disease of the peripheral nerves. The peripheral nerves are every nerve that lie outside the brain and spinal cord with the exception of the optic nerves, and CMT affects every one of these. CMT is caused by a mutation in any one of 124 different genes, and the number of genes continues to grow. A gene mutation that causes CMT disrupts a molecular process within the peripheral nerves. The mutation alters the gene’s function—how it works, causing the gene to behave abnormally. It’s akin to substituting powdered sugar in place of brown sugar in your favorite cookie recipe. Sure, you’ll still get a cookie, but the cookie just won’t be the same. Extend this to the peripheral nerves and sure, you still get peripheral nerves, but they just aren’t the same.


A gene that’s been discovered to have CMT-causing mutations is called a CMT-associated gene. Some CMT associated genes have just one lonely mutation that’s known to cause CMT. Most, however, have many individual mutations that each cause CMT, while some have hundreds of individual mutations that...

How Many Types of CMT are There?


Prior to scientists discovering the first genetic cause of CMT, there were three basic types: CMT1, CMT2, and CMT3. The advent of CMT genetic discovery coupled with a growing understanding of what CMT is has resulted in an ever-evolving manner in which CMT types are classified, categorized, organized, and newly discovered subtypes named. CMT as a disease name has emerged to encompass many different sensory and/motor neuropathies and neuronopathies.


What was three different CMT types thirty years ago has grown into fourteen types that are each a classification/category into which subtypes are organized. Six bear the CMT acronym, seven are represented by non-CMT acronyms, and one group of subtypes are known simply by their gene name, as in DST-associated CMT, where DST is the name of the gene.


The fourteen categories that are each currently referred to as a CMT Type are CMT1, CMT2, CMT4, CMTX, Dominant Intermediate CMT (CMT-DI or DI-CMT), Recessive Intermediate CMT (CMT-RI or RI-CMT), dHMN, dSMA, GAN, HMSN, HSAN, HSN, SMA-LEP, and [Gene-Name]-CMT. Each of these Types have several subtypes, totaling 158 subtypes in all. Please visit our Basics of CMT Subtypes page for an overview of each of these Types.


Prior to scientists discovering the first genetic cause of CMT, there were three basic types: CMT1, CMT2, and CMT3. The advent of CMT genetic discovery coupled with a growing understanding of what CMT is has resulted in an ever-evolving manner in which CMT types are classified, categorized, organized, and newly discovered subtypes named. CMT as a disease name has emerged to encompass many different sensory and/motor neuropathies and neuronopathies.


What was three different CMT types thirty years ago has grown into fourteen types that are each a classification/category into which subtypes are organized. Six bear the CMT acronym, seven are represented by...

How is CMT Diagnosed?


CMT can be difficult for a doctor to diagnose, especially when there is no established family history of the disease. Doctors who specialize in CMT advise that to diagnose CMT, one must meet the appropriate clinical picture: high arches, reduced sensation especially in the lower limbs, reduced or absent reflexes, frequent tripping, difficulty writing, abnormal nerve conduction study (NCS) results, and any number of other CMT symptoms. CMT shares symptoms with other conditions, such as Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Vitamin B12 deficiency, G6PD-deficiency associated blood disorders, etc. Part of diagnosing CMT is ruling out conditions that are potentially treatable, and especially those that can be easily treatable, such as Vitamin B12 deficiency.


There is a misconception that in order to diagnose CMT, genetic testing is needed, or that genetic testing is all that is needed. In actuality, due to many factors and variables that contribute to inherent limitations in CMT genetic testing, genetic testing is only one piece of the diagnostic puzzle doctors have for diagnosing CMT. For everything CMT genetic testing can potentially identify and/or confirm, due to its limitations, CMT symptoms and NCS results are the standard for clinically diagnosing CMT. True, genetic testing is needed to pinpoint the exact CMT subtype, but when signs and symptoms are consistent with CMT (the appropriate clinical picture is met) doctors can definitively clinically diagnose CMT as CMT1 or CMT2 based on NCS results.


CMT can be difficult for a doctor to diagnose, especially when there is no established family history of the disease. Doctors who specialize in CMT advise that to diagnose CMT, one must meet the appropriate clinical picture: high arches, reduced sensation especially in the lower limbs, reduced or absent reflexes, frequent tripping, difficulty writing, abnormal nerve conduction study (NCS) results, and any number of other CMT symptoms. CMT shares symptoms with other conditions, such as Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Vitamin B12 deficiency, G6PD-deficiency associated blood disorders, etc. Part of diagnosing CMT is ruling out conditions that are potentially treatable, and especially those that can be easily treatable, such as Vitamin B12 deficiency.


There is a misconception that in order to diagnose CMT, genetic testing is needed, or that genetic testing is all that is needed. In actuality, due to many factors and variables that contribute to...

What’s the Difference Between CMT1 and CMT2?


CMT1 and CMT2 are the two basic CMT Types that doctors are able to clinically diagnose. CMT is divided into three types of neuropathy: demyelinating, axonal, and intermediate. Each of these three are determined by their related nerve conduction characteristics—how the nerves conduct (transmit) a signal. Clinically, demyelinating CMT, as determined by nerve conduction, is CMT1. Axonal CMT, as determined by nerve conduction, is CMT2. Intermediate CMT exhibits nerve conduction characteristics that don’t comport with either demyelinating or axonal CMT—the nerve conduction profile is somewhere in between, it’s intermediate. Intermediate does not refer to disease severity or progression.


Doctors trained in recognizing the electrodiagnostic abnormalities of CMT and the nuanced differences between demyelinating CMT and axonal CMT can use NCS data to tell whether CMT is either demyelinating (CMT1) or axonal (CMT2), but intermediate CMT is exceedingly difficult to elecctrodiagnostically differentiate (NCS is a type of electrodiagnostic test). Because of this difficulty, doctors typically will not clinically diagnose somebody as having intermediate CMT, instead favoring either a CMT1 or a CMT2 clinical diagnosis.


How can I tell if I have CMT1? Doctors can tell the difference between demyelinating CMT and axonal CMT by NCS results. Demyelinating CMT nerve conduction exhibits velocities less than 38meters/sec (the speed at which the nerve transmits a signal), slightly reduced amplitudes (signal strength), prolonged latencies (how quickly the nerve responds to an input signal), fairly uniform findings in all nerves tested, and there might be absent sensory nerve responses. When NCS results meet these criteria, and the person meets the appropriate diagnostic picture, CMT1 is the clinical diagnosis.


Once the underlying responsible gene mutation is identified, the diagnosis is transitioned to the related subtype—CMT1H, for example. CMT1 is a group of ten subtypes that are each demyelinating as determined by their nerve conduction characteristics. However, there are currently twenty-nine demyelinating subtypes. Therefore, a clinical CMT1 diagnosis might not remain a CMT1 subtype diagnosis should CMT genetic testing identify the genetic cause.


How can I tell if I have CMT2? Axonal CMT nerve conduction exhibits velocities faster than 38 meters/sec (the speed at which the nerve transmits a signal), significantly reduced amplitudes (signal strength), prolonged latencies (how quickly the nerve responds to an input signal), there can be significant variability between the nerves tested, there can be evidence of conduction block (different conduction results at different segments of a nerve), and there can be absent sensory nerve responses. When NCS results meet these criteria, and the person meets the appropriate diagnostic picture, CMT2 is the clinical diagnosis.


Once the underlying responsible gene mutation is identified, the diagnosis is transitioned to the related subtype—CMT2C, for example. CMT2 is a group of thirty-six CMT subtypes that are each axonal as determined by their nerve conduction characteristics. However, there are currently 114 axonal subtypes. Therefore, a clinical CMT2 diagnosis might not remain a CMT2 subtype diagnosis should CMT genetic testing identify the genetic cause.


CMT1 and CMT2 are the two basic CMT Types that doctors are able to clinically diagnose. CMT is divided into three types of neuropathy: demyelinating, axonal, and intermediate. Each of these three are determined by their related nerve conduction characteristics—how the nerves conduct (transmit) a signal. Clinically, demyelinating CMT, as determined by nerve conduction, is CMT1. Axonal CMT, as determined by nerve conduction, is CMT2. Intermediate CMT exhibits nerve conduction characteristics that don’t comport with either demyelinating or axonal CMT—the nerve conduction profile is somewhere in between, it’s intermediate. Intermediate does not refer to disease severity or progression.


Doctors trained in recognizing the electrodiagnostic abnormalities of CMT and the nuanced differences between demyelinating CMT and axonal CMT can use NCS data to tell whether CMT is either demyelinating (CMT1) or axonal (CMT2), but intermediate CMT is exceedingly difficult...

Can I have Normal EMG/NCS Results and Still have CMT?


EMG and NCS are both types of electrodiagnostic tests. NCS stands for nerve conduction study and uses electrodes placed on the surface of the skin that record how well the nerve conducts (transmits) a signal when the person administering the tests “triggers” the nerve. EMG stands for electromyography and uses needles inserted into a muscle. The needles are used to measure how well the muscle responds to its nerve signal when the person flexes/moves the muscle. These two are often confused with one another with NCS often being referred to as an EMG. While EMG is often performed in conjunction with NCS in CMT, the two are not the same test, and NCS is the standard electrodiagnostic test for CMT.


In CMT, when symptomatic, there will be detectable abnormalities on NCS, and sometimes on EMG. Demyelinating CMT (CMT1) typically has fairly uniform nerve conduction—each nerve tested will show nearly the same result. Some subtypes, such as CMT1A, for example, will have detectable abnormalities even when not symptomatic and from an incredibly young age. Axonal CMT (CMT2), however, can have significant variability between the nerves tested. For example, the peroneal nerve in the lower left leg might show conduction results that are clearly consistent with axonal CMT, yet the medial nerve in the right forearm might show fairly normal conduction, especially if it’s early in the disease course. For these reasons, it’s imperative to test nerves in both arms and both legs.


What constitutes a normal NCS result is unfortunately subjective to the person who is interpreting the data. For example, somebody who specializes in dementia might look at a report and see that everything is normal. Yet, somebody who specializes in CMT might look at the same report and see a clear CMT case. Another variable to consider is the nerves that were tested.


If the nerves in only one arm or one leg were tested and the results fall within normal ranges, but no other nerves were tested, despite clear CMT symptoms, the test was too limited to yield an overall comprehensive result potentially indicative of CMT.


In CMT, when symptomatic, and the nerves in both legs and both arms were tested and the results are within normal ranges, it might not be CMT. The keywords are “when symptomatic” and “when both legs and arms are tested.” A condition called Small Fiber Neuropathy (SFN) has symptoms remarkably similar to CMT. A significant difference between the two is that SFN causes no detectable abnormalities on NCS when symptomatic.


Can EMG/NCS results be normal, and still have CMT? For the reasons discussed, and the reasons stated with distinction, yes, this is possible. When this happens, it lends itself to the difficulties doctors can have with diagnosing CMT.


EMG and NCS are both types of electrodiagnostic tests. NCS stands for nerve conduction study and uses electrodes placed on the surface of the skin that record how well the nerve conducts (transmits) a signal when the person administering the tests “triggers” the nerve. EMG stands for electromyography and uses needles inserted into a muscle. The needles are used to measure how well the muscle responds to its nerve signal when the person flexes/moves the muscle. These two are often confused with one another with NCS often being referred to as an EMG. While EMG is often performed in conjunction with NCS in CMT, the two are not the same test, and NCS is the standard electrodiagnostic test for CMT.


In CMT, when symptomatic, there will be detectable abnormalities on NCS, and sometimes on EMG. Demyelinating CMT (CMT1) typically has fairly uniform nerve conduction—each nerve tested will show nearly the same result. Some subtypes, such as CMT1A, for example, will have detectable abnormalities even when not symptomatic and from an incredibly young age. Axonal CMT (CMT2), however...

Do I need a Genetic Test to Know if I have CMT?


Do you need a genetic test to know if you have CMT? The short answer is no. The long answer is also no. You do not need genetic testing to know if you have CMT. It’s a misconception that genetic testing is needed to diagnose CMT (see How is CMT Diagnosed?), or that genetic testing will tell you for sure if you have CMT or not. The reality of CMT genetic testing is much different.


Yes, CMT genetic testing can confirm the clinical diagnosis. Yes, CMT genetic testing is needed to know the specific subtype, but it’s not needed to diagnose CMT—to know if you have CMT. CMT genetic test results that do not find a clearcut overt genetic cause for the CMT are more common than results that do find a cause. The first genetic cause for CMT was found just over thirty years ago. In the time since, scientists have discovered another 123 genes to have CMT-causing mutations, and they believe they are only about halfway to discovering all genes that have CMT-causing mutations.


Today, an estimated 95% of people who have a demyelinating CMT (CMT1) are able to obtain genetic confirmation of their CMT. In sharp contrast, an estimated mere 50% of people who have an axonal CMT (CMT2) are able to obtain genetic confirmation of their CMT, and some estimate this to be as low as only 30%. Adding to the limitations of CMT genetic testing, there isn’t any one commercial diagnostic laboratory that includes in their testing every gene known today to have CMT-causing mutations. These data combine to perfectly illustrate the limitations of CMT genetic testing.


When clinically diagnosed with CMT, whether CMT1 or CMT2, or when symptoms match the appropriate clinical picture and nerve conduction study results are consistent with CMT, and CMT genetic testing fails to reveal an underlying genetic cause, the results mean only that the gene with the underlying responsible mutation has not yet been analyzed. The results mean nothing more, and they certainly do not rule out CMT.


Do you need a genetic test to know if you have CMT? The short answer is no. The long answer is also no. You do not need genetic testing to know if you have CMT. It’s a misconception that genetic testing is needed to diagnose CMT (see How is CMT Diagnosed?), or that genetic testing will tell you for sure if you have CMT or not. The reality of CMT genetic testing is much different.


Yes, CMT genetic testing can confirm the clinical diagnosis. Yes, CMT genetic testing is needed to know the specific subtype, but it’s not needed to diagnose CMT—to know if you have CMT. CMT genetic test results that do not find a...

How is CMT Inherited?


CMT is inheritable because the genetic mutations that cause CMT, whatever those mutations might be, are inheritable. The chances of passing on CMT to your children/your children inheriting CMT from you are solely dependent on the specific underlying responsible genetic mutation. How CMT is passed on/inherited is referred to as an inheritance pattern, and CMT has five of these patterns. To describe these, we’ll first cover the basic terminology.


In genetics and inheritance, autosomal refers to any gene that lives on a numbered chromosome (1-22)—the autosomes. Dominant refers to a gene needing/having one mutation. Recessive refers to a gene needing/having two mutations. X-Linked refers to any gene that lives on an X-chromosome. Mitochondrial refers to a mutation in a gene that is found only in mitochondrial DNA. Y-Linked refers to a gene that lives on the Y-chromosome (there are no Y-Linked CMT subtypes at present time).


What is autosomal dominant inheritance? In autosomal dominant inheritance, the gene lives on an autosome, and the gene has just one CMT-causing mutation. The majority of CMT subtypes (84 subtypes) are inherited in an autosomal dominant pattern. Somebody who has an autosomal dominant CMT subtype has a 50/50 chance of passing on their CMT to each of their children, regardless of gender and regardless of their children’s gender.


What is autosomal recessive inheritance? In autosomal recessive inheritance, the gene lives on an autosome and the gene has two CMT-causing mutations. There are 67 CMT subtypes that are inherited in an autosomal recessive pattern. Because these subtypes are caused by having two mutations within the gene and having only one of the needed mutations does not cause CMT, these subtypes are more rare than autosomal dominant subtypes, as a whole.


We normally have two copies of every gene, with only a few exceptions. When somebody has an autosomal recessive CMT subtype, they have a CMT-causing mutation in both copies of the associated gene. When somebody has an autosomal recessive CMT subtype, they likely inherited one of their two CMT-causing mutations from one parent, and the other mutation from the other parent. Each parent likely had only one mutation each, having only one mutation in this context does not cause CMT (this is different than autosomal dominant CMT), and each likely were not aware they even had this one mutation until after their child was diagnosed. In this situation, there was a 25% chance of inheriting both CMT-causing mutations.


Somebody who has an autosomal recessive CMT subtype will pass on one of their two CMT-causing mutations to each of their children, regardless of gender and regardless of their children’s gender. They cannot pass on both of their CMT-causing mutations. Their children, however, will not have CMT. They won’t have CMT because they will have inherited only one of the needed two CMT-causing mutations.


What is X-Linked inheritance? In X-Linked dominant inheritance, the gene lives on the X-chromosome and has one CMT-causing mutation. In X-Linked recessive inheritance, the gene has two CMT-causing mutations. Chromosomal females (X-X) who have X-Linked CMT, whether X-Linked dominant or X-Linked recessive, have the same chances of passing on their CMT-causing genetic mutation as though the subtype was autosomal dominant or autosomal recessive. Chromosomal males (X-Y), however, will not and cannot pass on their X-Linked CMT-causing mutation to any of their sons but they will pass it onto every daughter. This difference between chromosomal females and chromosomal males who have X-Linked CMT owes itself to chromosomal females having two X-chromosomes, chromosomal males having only one X-chromosome, and chromosomal males passing on their Y-chromosome only to their sons while passing on only their X-chromosome to their daughters.


Because chromosomal males have only one X-chromosome and therefore only one copy of the genes that live on the X-chromosomes, X-Linked dominant and X-Linked recessive inheritance terminology isn’t used. Instead, in the context of chromosomal males, the patterns combine into a single X-Linked inheritance description.


What is mitochondrial inheritance? In mitochondrial inheritance, the genes found in mitochondrial DNA are passed only from a chromosomal female to her children. There is only one CMT subtype caused by a mutation in a gene found only in mitochondrial DNA (ATP6-associated CMT). If a chromosomal male has this CMT subtype, his children will not inherit it from him. But, if a chromosomal female has this subtype, each of her children will inherit it from her. There is some research that suggests chromosomal males do pass on mitochondrial DNA to their children, but the research, at this time, is not conclusive.


The inheritance patterns of CMT are complex, have many variables, and are difficult to fully explain. This description is intended only as a brief overview. For a more detailed discussion, see “Where’d it Come From, Where’s it Going?: Exploring the Inheritance Patterns of Charcot-Marie-Tooth Disease.”


CMT is inheritable because the genetic mutations that cause CMT, whatever those mutations might be, are inheritable. The chances of passing on CMT to your children/your children inheriting CMT from you are solely dependent on the specific underlying responsible genetic mutation. How CMT is passed on/inherited is referred to as an inheritance pattern, and CMT has five of these patterns. To describe these, we’ll first cover the basic terminology.


In genetics and inheritance, autosomal refers to any gene that lives on a numbered chromosome (1-22)—the autosomes. Dominant refers to a gene needing/having one mutation. Recessive refers to a gene needing/having two mutations. X-Linked refers to...

Can I Have CMT Without Inheriting It?


Yes, you can have CMT without having inherited it from a parent. CMT is inheritable/hereditary because the genetic mutations that cause CMT are inheritable/hereditary. These same mutations, however, can occur on their own without having inherited them. When somebody has CMT without having inherited it from a parent, their CMT is referred to as a de novo case.


A de novo CMT case is CMT that was caused by a genetic mutation that occurred at or near conception. Rather than a parent passing down the genetic mutation, the mutation occurred spontaneously and randomly on its own. When somebody has a de novo CMT case, the chances for them to pass it onto their children are the same as though they had inherited it, and the chances are governed by the inheritance pattern of the underlying CMT-causing mutation. The only difference between a de novo case of CMT and CMT that is inherited is that a de novo case is caused by a genetic mutation that was not inherited.

Can CMT Cause Breathing Problems?


Yes, CMT can cause breathing problems. When it does, it’s an extremely specific kind of respiratory impairment called CMT-induced neuromuscular respiratory muscle weakness. This type of impairment, which is not a disease of lung tissue because CMT does not cause lung disease, is caused by a weakening of the muscles used for breathing.


The muscles used for breathing, therefore, can become weakened as a consequence of CMT much in the same way as do the muscles of the lower legs. The question becomes focused on to what extent are these affects.


When CMT causes breathing problems, the cause is from the muscles used for breathing becoming weakened and impairing the ability to fully expand the chest with each breath, leading to a reduction in the ability to fully inflate the lungs. This is called hypoinflation. Because lung tissue is unaffected, oxygen levels will typically remain normal. CO2 levels, however, can become elevated, leading to a condition called hypercapnia.


CMT-induced neuromuscular respiratory muscle weakness is treated with non-invasive ventilation, or NiV for short. While this is a scary term, NiV is a small tabletop device that resembles a CPAP. CPAP (Continuous Positive Airway Pressure) and BiPap (Bi-Level Positive Airway Pressure) are common devices most have heard of. There’s a newer one called VPAP (Variable Positive Airway Pressure). These three devices are intended only to keep the airway open and nothing else. Somebody who has CMT-induced neuromuscular respiratory muscle weakness, however, needs assistance with more fully inflating the lungs. Conventional treatment, therefore, is insufficient. Instead, AVAPS is the therapy CMT experts prefer.


What is AVAPS? The conventional CPAP, BiPap, and VPAP therapies do not provide the type of therapy needed by somebody who has CMT-related respiratory impairment. Instead, what is needed, is a type of NiV device and technology called AVAPS. AVAPS stands for Average Volume Assured Pressure Support. AVAPS provides pressure support for keeping the airway open like CPAP, BiPap, and VPAP do, but then adds what’s called volume support. Volume support provides a volume of air with each breath that’s equal to the person’s tidal volume. Providing this measured volume of air with each breath helps the lungs to more fully inflate, thereby assisting the muscles used for breathing with doing their job.


This is not intended to be an inclusive description of CMT-related breathing problems. Rather, it’s intended to provide a very brief overview. For a much more detailed discussion, see “CMT Respiratory Involvement: What It Is and What It Is Not,” coauthored by Experts in CMT founder, Kenneth Raymond, and neuromuscular pulmonologist & CMT-related respiratory impairment expert, Ashraf Elsayegh , MD, FCCP, FAASM.


Yes, CMT can cause breathing problems. When it does, it’s an extremely specific kind of respiratory impairment called CMT-induced neuromuscular respiratory muscle weakness. This type of impairment, which is not a disease of lung tissue because CMT does not cause lung disease, is caused by a weakening of the muscles used for breathing.


The muscles used for breathing, therefore, can become weakened as a consequence of CMT much in the same way as do the muscles of the lower legs. The question becomes focused on to what extent are these affects.


When CMT causes breathing problems, the cause is from the muscles used for breathing becoming weakened and impairing the ability to fully expand the chest with each breath, leading to a reduction in...

Does CMT Cause Atrophy?


Yes, CMT causes atrophy. There are three types of atrophy: physiologic, pathologic, and neurogenic. Atrophy is defined as tissue wasting caused by something happening outside of and separate from the tissue that is wasting. Whereas dystrophy, on the other hand, is defined as tissue wasting caused by something happening within the tissue that is wasting.


First and foremost, CMT is not a disease of muscle tissue. Yes, CMT causes muscle tissue to waste. However, muscle tissue wastes in CMT as a consequence of the disease within the nerves that control the muscles. Because the muscle tissue wastes as a result of diseased nerves, the wasting is medically defined as atrophy (the nerves are separate from the muscles that are wasting). By comparison, muscular dystrophy gets its name from muscles wasting as a direct result of the muscles themselves being diseased—the very definition of dystrophy. For these reasons, CMT is not a type of muscular dystrophy, despite the MDA including CMT within its wheelhouse, as it does ALS and many other non-MD diseases.


What is physiologic atrophy? Physiologic muscle atrophy is atrophy caused by not using the muscle enough. CMT can often lead to a sedentary lifestyle. In turn, this often leads to physiologic muscle atrophy. Physiologic muscle atrophy is also quite common with surgery. Muscle tissue lost from physiologic atrophy can be recovered through proper exercise, physical therapy, post-op surgery recovery, etc.


What is pathologic atrophy? Pathologic muscle atrophy is usually seen with aging and malnutrition/starvation. Muscle tissue lost from pathologic atrophy is typically recoverable with proper diet and nutrition, proper exercise, and becoming more physically active.


What is neurogenic atrophy? Neurogenic muscle atrophy is muscle atrophy that occurs with injury to, or disease of, the nerve that controls the atrophied muscle. This is the type of atrophy caused by CMT, and unfortunately, is not recoverable. People who have CMT can have muscle atrophy for many varied reasons, and not all muscle atrophy is necessarily neurogenic atrophy just because the person has CMT.


Somebody who has CMT can experience physiologic atrophy and pathologic atrophy. In CMT, any muscle loss not caused by neurogenic atrophy is still recoverable. For this reason, proper exercise and remaining as active as can be is essential. Should a muscle experiencing physiologic atrophy be overtaken by neurogenic atrophy, the lost muscle tissue will not be recoverable. It’s critically important in CMT to give the muscles as much of an advantage as possible. Proper exercise and remaining as active as can be together provide this needed advantage.


Yes, CMT causes atrophy. There are three types of atrophy: physiologic, pathologic, and neurogenic. Atrophy is defined as tissue wasting caused by something happening outside of and separate from the tissue that is wasting. Whereas dystrophy, on the other hand, is defined as tissue wasting caused by something happening within the tissue that is wasting.


First and foremost, CMT is not a disease of muscle tissue. Yes, CMT causes muscle tissue to waste. However, muscle tissue wastes in CMT as a consequence of the disease within the nerves that control the muscles. Because the muscle tissue wastes as a result of diseased nerves, the wasting is medically defined as...

Can CMT Cause Bladder Issues?


Yes, CMT can cause bladder problems. When it does, it’s a type of impairment called neurogenic bladder. This type of bladder dysfunction is a result of the consequence of the effects of CMT on the nerves that control the bladder and urinary tract. For some who have CMT and experience neurogenic bladder issues, urine retention is an issue. For others, incontinence is an issue. For some, it can be a combination of both.

How is CMT Treated?


Currently, there is no known treatment or cure for CMT. However, many of the things CMT causes can be well-managed. Treatment centers around supportive care and symptom management in a multidisciplinary approach. Physical therapy, occupational therapy, AFOs, other orthopedic devices and mobility aids as needed, respiratory therapy when needed, and even surgery can help manage many of the things CMT causes. Disease management is highly individualized to the symptoms, their severity, and individual needs.