What is CMT?
A Brief Overview
Charcot-Marie-Tooth disease is an inheritable neuromuscular disease, and it is the world’s most commonly inherited neuromuscular disease. Known simply as CMT, the chances of inheriting the disease and how the disease is inherited are both determined by the specific genetic mutation. Currently, there are CMT-causing mutations discovered in 120 different genes. Mutations in these 120 genes account for 155 CMT subtypes. Regardless of subtype, CMT can affect everybody differently, and even within the same family.
CMT gets its name from the three physicians who first described it, Jean-Martin Charcot (1825-1893), Pierre Marie (1853-1940), and Howard Henry Tooth (1856-1925), CMT, in its simplest of terms, is a hereditary peripheral neuropathy. A peripheral neuropathy is a disease of the peripheral nervous system. The peripheral nervous system is made up of the nerves that lie outside of the brain and spinal cord, with the exception of the optic nerves, which are part of the central nervous system. CMT affects all peripheral nerves, making CMT a polyneuropathy. Polyneuropathy means a disease affecting more than one peripheral nerve. The extent of these affects on the parts of the body the peripheral nerves control becomes the question.
CMT, today, as a disease name, has evolved to refer to many different sensory and/or motor neuropathies. These many different neuropathies are each a type of CMT, and each type has many subtypes. In short, these many different neuropathies, each with their own name and acronym, are each a different name for CMT. These include, but are not limited to, HMSN, HSAN, and dHMN. These are in addition to the six types that bear the CMT acronym.
Experts in CMT's
Most Common Inherited Neuropathy
More Than 100 Different Genetic Causes
Affects 1 in 2,500 People
More Than 3 Million CMTers World Wide
Affects All Ethnicities and Age Groups
Affects the Nerves that Control the Muscles, but the Muscles are not Directly Diseased
Progressive Over One's Lifetime
Is Not an Autoimmune Disease
Is Not Acquired and Is Not Contagious
Currently No Cure nor Direct Treatment
What are the Symptoms of Charcot-Marie-Tooth Disease?
The first signs of CMT may include toe-walking, frequent tripping, ankle sprains, clumsiness, and “burning” or pins-and-needles sensations in the feet or hands. Structural foot deformities such as high arches (pes cavus) and hammertoes are common, but some people have flat feet (pes planus). Foot drop, poor balance, and problems walking as muscle wasting in the lower legs and feet progresses, can also be early signs of CMT.
Difficulty with tasks involving manual dexterity, such as writing, and manipulating zippers and buttons, often accompanies muscle wasting in the hands. Abnormal sensation, loss of ability to feel light touch, inability to differentiate between hot/cold, and the loss of proprioception are also common. Many people experience neuropathic pain, muscle pain, and joint pain. Poor tolerance to cool, cold, and/or hot temperatures is typical. Many people with CMT have chronically cold hands and feet.
Additional symptoms may include flexed fingers, contractures, tremor, knee and/or hip problems, cramps, thenar muscle atrophy causing weakness of the muscles between the thumb and forefinger, loss of hand strength, chronic fatigue, sleep apnea, respiratory impairment, vocal/speech difficulties, swallowing difficulties, absent or reduced reflexes, poor circulation, scoliosis, kyphosis, hearing loss and vestibular disturbances, optic nerve atrophy, cognitive impairment, bladder involvement, and gastric involvement. This is not a full list of symptoms but is just a general overview.
Not every person who has CMT will experience all the CMT symptoms and nor will everybody experience the same degree of severity nor rate of progression. This holds true regardless of subtype, this variability occurs within the same family, and this variability can occur even amongst siblings. The reasons for this variability are not yet understood.
What Causes Charcot-Marie-Tooth Disease?
CMT, regardless of type or subtype, is caused by mutations in any one of 120 different genes. Each individual mutation that causes CMT disrupts a molecular process within the peripheral nerves. This disruption, whatever it might be, causes an impairment in the ability of the peripheral nerves to do their job—to carry out their function. Some peripheral nerves control skeletal muscle movement—walking, writing, breathing, etc. Some peripheral nerves send sensory information back to the brain—touch, temperature, pain, etc. Some are responsible for controlling the organs—bladder, stomach, intestines, etc. Because the mutations that cause CMT impair the peripheral nerves’ ability to do their job, whatever their job might be, everything the peripheral nerves control—innervate, can suffer as a consequence of this peripheral nerve impairment.
The list of genes scientists have discovered to have CMT-causing genes is forever growing. The first cause of CMT was discovered by scientists in 1991. Scientists have discovered CMT-causing mutations in new genes every year since. These genes are known as CMT-associated genes. A CMT-associated gene is simply any gene that has a CMT-causing mutation. While there are 120 CMT-associated genes today, there are another five chromosomal locations suspected of having a CMT-causing mutation, but the exact gene is not yet known. Scientists also believe we might only be about halfway to discovering all genes harboring a CMT-causing mutation.
What are the Types of Charcot-Marie-Tooth Disease?
CMT as a disease name has emerged to encompass many different sensory and/or motor neuropathies. Currently, there are 14 categories into which CMT subtypes are sorted. 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. These 14 categories are each referred to as a Type, and they are CMT1, CMT2, CMT4, CMTX, Dominant Intermediate CMT (CMT-DI), Recessive Intermediate CMT (CMT-RI), dHMN, dSMA, GAN, HMSN, HSAN, HSN, SMA-LEP, and [Gene-Name]-CMT. Please visit our Basics of CMT Subtypes page for an overview of each of these categories.
How is Charcot-Marie-Tooth Disease Diagnosed?
CMT can be difficult for a doctor to diagnose, especially when there is no established family history of CMT. Doctors who specialize in CMT advise that to diagnose CMT, one must meet the correct clinical picture: high arches, reduced sensation especially in the lower limbs, reduced or absent reflexes, frequent tripping, difficulty writing, abnormal nerve conduction study 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 those that can be easily treatable, such as Vitamin B12 deficiency.
CMT as a Clinical Diagnosis: CMT1 or CMT2, What's the Difference?
A CMT clinical diagnosis is a definitive CMT diagnosis. A clinical CMT diagnosis is a diagnosis that infers no genetic cause—the responsible genetic mutation is not yet known. There are three types of neuropathies associated with CMT: demyelinating, axonal, and intermediate. Each are determined by their respective nerve conduction characteristics, and these determine whether the clinical diagnosis is CMT1 or CMT2.
When symptoms are consistent with CMT and nerve conduction study abnormalities are consistent with demyelinating CMT—velocities less than 38meters/sec (the speed at which the nerve transmits a signal), slightly reduced amplitudes, prolonged latencies, fairly uniform in all nerves tested, doctors use CMT1 as a 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 9 subtypes that are each demyelinating as determined by their nerve conduction characteristics. However, there are currently 27 demyelinating subtypes. Therefore, a clinical CMT1 diagnosis might not remain a CMT1 subtype diagnosis after genetic testing.
When symptoms are consistent with CMT and nerve conduction study abnormalities are consistent with axonal CMT—velocities faster than 38 meters/sec, significantly reduced amplitudes, prolonged latencies, and there can be significant variability between the nerves tested, doctors use CMT2 as a 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 34 CMT subtypes that are each axonal as determined by their nerve conduction characteristics. However, there are currently 112 axonal subtypes. Therefore, a clinical CMT2 diagnosis might not remain a CMT2 subtype diagnosis after genetic testing.
Intermediate CMT is CMT in which the nerve conduction characteristics don’t comport with the rules-of-thumb for either demyelinating or axonal CMT. They are somewhere in between. They are intermediate. Because they are somewhere in between, intermediate CMT can be exceedingly difficult to differentiate from demyelinating or axonal CMT. For these reasons, doctors don’t use intermediate CMT as a clinical diagnosis, instead favoring either CMT1 or CMT2, using the greater-than or less-than 38 meters/sec dividing line. An important note is that intermediate CMT refers only to nerve conduction characteristics and not to disease severity or disease progression.
Is CMT Genetic Testing Needed and is it Definitive?
CMT genetic testing being an absolute definitive diagnostic tool is a misconception. On one hand, genetic testing has the potential to definitively confirm a CMT clinical diagnosis. In this regard, CMT genetic testing is definitive. However, CMT genetic testing has limitations. These limitations cause test results that don’t confirm a clinical diagnosis to be fairly common. When symptoms and nerve conduction study results are consistent with CMT, and a genetic test fails to identify a known genetic cause, the result means only that the gene with the responsible mutation was not analyzed, and the result means only this. Because of these limitations, CMT specialists rely on clinical findings as a definitive CMT diagnosis when genetic testing fails to identify a known CMT-causing mutation. Where genetic testing is needed to pinpoint the subtype, it’s not needed to definitively diagnose CMT.
Since CMT is Hereditary, Can You Have CMT Without Inheriting It?
The short answer is yes, but the answer is a little more involved. CMT is hereditary. CMT is hereditary because each of the many CMT-causing mutations are in genes that are inherited from one’s parents. While CMT is hereditary—inheritable, one does not have to have inherited CMT from a parent in order to have it. When somebody has CMT and did not inherit it, the CMT is referred to as a de novo case. A de novo CMT case is caused by a genetic mutation that occurred randomly spontaneously at or shortly after conception. A de novo genetic mutation is a mutation that was not inherited from a parent.
When CMT is a de novo case, the chances of passing it onto each of the person’s children is the same as though the CMT had been inherited, and these chances are determined by the genetic mutation itself. How CMT is passed on, that is how it’s inherited, is called an inheritance pattern. CMT has five different inheritance patterns, and these are autosomal dominant, autosomal recessive, X-Linked dominant, X-Linked recessive, and one subtype can be inherited via mitochondrial inheritance. The chances of passing on CMT are different for each of these five inheritance patterns.
How is Charcot-Marie-Tooth Disease Treated?
Currently, there is no known treatment or cure for CMT. Treatment centers around supportive care and symptom management in a multidisciplinary approach. Physical therapy, occupational therapy, AFOs, other orthopedic devices 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 and their severity.
What Research is Being Conducted for Charcot-Marie-Tooth-Disease?
Research into all things related to Charcot-Marie-Tooth disease is occurring in all corners of the globe. From natural history studies, to identifying new gene mutations, to developing effective drug therapies for treating CMT, researchers are leaving nothing unturned as they work to unravel the mysteries of CMT. Follow the links below to learn what the prominent organizations are currently working on.