Charcot-Marie-Tooth Disease

What Causes Charcot-Marie-Tooth Disease?

CMT occurs when the body cannot produce the proteins needed to build and protect nerve cells. Genes control the production of these proteins, and each type of CMT is characterized by a gene abnormality that causes abnormal production of a particular protein.

Different types of CMT affect nerve cells in different ways. Some types impair the function of axons, the parts of a nerve cell that transmit signals to other nerves. Other types of the disease affect myelin, a fatty substance that surrounds nerve cells. Without myelin, nerve cells can’t communicate effectively with each other and are vulnerable to damage.

Is Charcot-Marie-Tooth Disease Hereditary?

Most types of CMT run in families, and the genetic trigger for the disease is passed from parent to child. Sometimes, though, the genetic abnormality that causes the condition occurs spontaneously without being inherited. This makes it possible for someone who doesn’t have a family history of CMT to develop the disease.

Different types of CMT are inherited in different patterns. CMT1, the most common form of the disease, is inherited in an autosomal dominant pattern. This means that children may develop the condition if they inherit even one copy of the mutated gene from either of their parents. If a parent carries the disorder-causing mutation, they will have a 50 percent chance of having an affected child with each pregnancy.

CMT4 is inherited in an autosomal recessive pattern, meaning that a child must inherit two copies of the gene mutation, one from each parent, to develop the disorder. People who have only one copy of the mutated gene will not develop the condition but will be carriers who can pass the mutation on to their children. Two carrier parents have a 25 percent chance of having a child with the disease with each pregnancy. Half of their pregnancies will produce a carrier, and a quarter of the pregnancies will produce a child with no mutated genes.

CMTX is an X-linked inherited disorder because the gene responsible for the disease lies on the X chromosome. Women’s cells contain two X chromosomes, and men’s cells have one X and one Y chromosome.

Everyone inherits one X chromosome from their mother and either an X or Y chromosome from their father, so the CMTX genetic mutation could be inherited from either parent. But because girls have two X chromosomes, they probably have inherited at least one healthy X chromosome, making it likely that any symptoms they experience will be mild. However, boys who inherit the CMTX mutation don’t have a healthy X chromosome to counteract the mutation and are more likely to develop more severe CMT.

How Is Charcot-Marie-Tooth Disease Detected?

The first CMT symptoms often begin in adolescence. The long nerve fibers of the legs are usually first affected, and early symptoms typically affect the feet and lower legs.

Early warning signs include:

• Weakness in the feet and lower legs
• Difficulty lifting or flexing the feet
• Loss of muscle mass in the legs
• Deformities in the feet (high arches, flat feet, curled toes)
• Unusual high-stepping gait
• Frequent tripping or falling

How Is Charcot-Marie-Tooth Disease Diagnosed?

If a doctor is presented with symptoms that look like CMT, they will begin the diagnostic process by conducting physical and neurological exams and gathering a medical history. If it appears that a nerve disease is likely, several different tests can help determine which condition is the cause.

Possible diagnostic tests include:

• Nerve conduction studies. These tests use electrodes to measure nerve function.
• Electromyography. This test uses an electricity-sensing needle probe to measure muscle function. The test can detect muscle abnormalities that could be a sign of CMT.
• Nerve biopsy. This test involves removing and examining a small amount of nerve tissue. A biopsy may be able to detect nerve abnormalities caused by CMT.
• Genetic testing. These blood tests look for the specific genetic abnormalities responsible for different types of CMT.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Charcot-Marie-Tooth Disease Treated?

There is no cure for CMT, but treatments can help relieve symptoms and improve quality of life. CMT diseases usually progress slowly and typically don’t produce life-threatening complications.

Therapies

Therapy programs directed at specific problems associated with CMT may improve symptoms.

Commonly used therapies include:

• Physical therapy
• Occupational therapy
• Assistive devices (leg braces, custom shoes, etc.)

Surgery

Some people with severe foot deformities may benefit from corrective surgery. Surgical procedures can sometimes relieve foot pain and improve the ability to walk.

How Does Charcot-Marie-Tooth Disease Progress?

CMT progresses slowly, but symptoms that begin in the lower limbs often progress to affect the hands and arms.  Eventually, muscle degeneration and atrophy can lead to complications in other parts of the body.

Long-term symptoms and complications of CMT can include:

• Weakness in the hands causing difficulty with fine motor skills
• Shortening of muscles that causes stiffening of joints (contractures)
• Muscle cramping
• Nerve pain
• Loss of sensation in the extremities
• Curvature of the spine (scoliosis)
• Hip displacement

How Is Charcot-Marie-Tooth Disease Prevented?

There is no known way to prevent CMT in someone born with a genetic mutation responsible for the disease. However, people with a family history of the disease can consult a genetic counselor to assess their risk if they plan to have children.

Charcot-Marie-Tooth Disease Caregiver Tips

Many people with CMT also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with CMT:

• People with CMT are at increased risk of depression or anxiety.
• People with CMT often suffer from sleep disorders such as narcolepsy.

Charcot-Marie-Tooth Disease Brain Science

CMT is a peripheral nervous system disease, and it does not usually directly involve the brain. Brain-related symptoms such as sensory impairment are generally caused by the inability of the peripheral nerves to communicate with the brain rather than a problem in the brain itself. However, studies have identified cases in which CMT is associated with structural changes in the brain, indicating that the disorder may sometimes impact the brain and the central nervous system.

Anomalies in brain structure associated with CMT include:

• Lesions in the brain’s white matter, nerve cells deep inside the brain that are covered with a protective sheath of myelin
• Overall decreased volume of white matter
• Lower volume of cells called gray matter in the cerebellum

Charcot-Marie-Tooth Disease Research

Title: A Natural History Study of Charcot-Marie-Tooth 4J (CMT4J) (CMT4J)

Stage: Recruiting

Principal Investigator: Michael Shy, MD   

University of Iowa

Iowa City, IA

Charcot-Marie-Tooth 4J (CMT4J) is a rare inherited peripheral neuropathy often characterized by rapidly progressive, asymmetrical upper and lower extremity weakness, muscle atrophy leading to loss of ambulation, respiratory compromise, and premature death with no available treatment.

This study aims to investigate the clinical characteristics and natural clinical progression of symptoms in individuals with CMT4J. This natural history study is essential to understand disease course better to determine clinically meaningful outcome measures for use in future clinical trials.

Charcot-Marie-Tooth (CMT) diseases are the most common inherited motor and sensory neuropathies, composed of a group of pathologically and genetically distinct subtypes ranging from slowly to rapidly progressive disease.

CMT4J is a rare subtype of CMT caused by mutations in the FIG4 gene. Pediatric-onset disease can often be characterized by rapid progression of muscle weakness and atrophy, culminating in the loss of ambulation and respiratory compromise, and premature death. Adult-onset CMT4J can present with a more variable disease course.

No prospective natural history study for CMT4J has been reported. This study aims to prospectively investigate the natural history of CMT4J and concurrently identify potential outcome measures that could be used in future clinical trials. No investigational product will be provided in the study.

Title: Observational Study of Neuromuscular Function in CMT Type 1&2 and Healthy Controls (ESTABLISH)

Stage: Recruiting

Principal Investigator: William D. Arnold, MD   

Ohio State University

Columbus, OH

The primary aim of this study is to discover whether patients with CMT type 1 and 2 have neuromuscular junction transmission deficits.

The secondary aim is to collect information on different clinical and electrophysiological test procedures to perform possible future clinical trials in CMT patients.

The study is a prospective observational pilot study involving two investigational sites:

• Department of Neurology, Arhus University Hospital
• Department of Neurology, Ohio State University

A total of 20 patients with Charcot-Marie-Tooth (CMT) disease and ten healthy age-matched controls will be included with each site, including 10 CMT patients and 5 Healthy Controls. CMT patients will undergo electrophysiological (repetitive nerve stimulation and single-fiber EMG analyses) and functional (different tests of muscle strength, fatigability, dexterity, and balance) testing on four separate occasions. Healthy controls will undergo electrophysiological testing at baseline only.

To assess whether patients with CMT have deficits in NMJ transmission, results from repetitive nerve stimulation and single-fiber EMG analyses in CMT patients will be compared to those obtained in healthy controls at baseline. In addition, to inform future clinical trials, results, reliability, and tolerability estimates obtained from sequential electrophysiological and functional tests will be calculated. 

Title: Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT (INC-6603)

Stage: Recruiting

Principal Investigator: John Day, MD   

Stanford University

Palo Alto, CA

This project aims to develop a new CMT Pediatric Scale (CMTPeds) for Children with CMT. Although there is a validated score (the CMTNS) that measures disease severity for CMT, it is not always applicable to children due to their limited ability to relay information about their symptoms. The CMTPeds scale is being developed and validated to measure disease severity in children and have outcome measures available for future clinical trials. Children (defined as 21 and under) being evaluated will be asked to perform functional tasks such as using stairs, walking in a hallway, and performing hand function tests. This information will be used to validate the CMTPeds score. It is essential to have validated instruments to measure disease severity in childhood, so these can be used with clinical treatment trials are available.