Sorting Out CMT

As recently as the early 1990s, many experts hoped that understanding just a few genes that influenced the development or maintenance of myelin or axons would explain all of Charcot-Marie-Tooth disease.

It didn’t turn out to be that simple, however. Today, there are dozens of genes recognized that, when flawed, can cause CMT.

Many CMT-related genetic mutations cause defects or abnormal levels of proteins in the myelin sheath. Other CMT mutations directly affect proteins in the axon. Still other flaws have complex, indirect effects on myelin, axons or the interactions between the two.

The currently used classification system for CMT is based on two criteria:

• whether it’s primarily the myelin or the axon that’s affected; and
• how the disease is inherited.

In broad strokes, CMT is divided into types 1, 2 and 4. (For complex reasons, type 3 no longer exists as a type of CMT.) Types 1, 2 and 4 are further divided into subtypes based on specific genetic mutations.

Severe forms of the diseases are sometimes called Dejerine-Sottas disease.

CMT types 1 and 2

Michael Shy performs a nerve conduction velocity test, which measures the speed at which a signal travels along a nerve.

“Type 1 are the problems where there’s abnormal myelin; in type 2, the myelin is normal,” says Michael Shy, a neurologist and professor of molecular medicine and genetics at Wayne State University in Detroit. Shy is a longtime MDA research grantee, a member of MDA’s Medical Advisory Committee, and co-director of the MDA clinic at Wayne State.

If the myelin is damaged, nerve conduction velocity (conduction speed) slows down.

“You use nerve conduction velocities in the arm to see if they’re slow or not,” Shy says. “The cutoff, historically, has been 38 meters [about 125 feet] per second. If they’re less than that, we say it’s type 1. If they’re more than 38 meters per second, we say it’s type 2. For type 2, you usually see that the strength of the signal is reduced, but the main diagnostic criterion is speed of conduction.”

Both CMT1 and CMT2 are inherited in an autosomal dominant manner, meaning it only takes one parent with one genetic defect to pass on the disease to a child. New mutations can occur spontaneously in a family with no previous history of the disease, after which the genetic mutation can be passed on to future generations.

“Type 1” and “type 2” still work as broad diagnostic headings, says Shy, but further subdivisions — types 1A, 1B, 1C, 2A, 2B, 2C and so forth — now indicate the specific genetic causes within each type.

The classification system gets a bit unwieldy, Shy explains, because it reflects a combination of causation (myelin versus axonal damage) and inheritance pattern.

CMT type 4 and CMTX

CMT disorders transmitted in an autosomal recessive pattern, meaning mutations must be inherited from both parents, are generally called type 4, whether they originate in the axon or the myelin, Shy says.

He notes, however, that this system of classifying recessive CMTs is not universal. Some systems use CMT4 to describe only myelin-related recessive CMTs.

CMT that’s inherited in an X-linked pattern, meaning the gene flaw is on the X chromosome, usually manifest more severely in males than in females.

These originally were called “CMTX.” Now, the most common form of X-linked CMT is called CMT1X, and there are at least four additional X-linked types.

For a full list of CMT subtypes, see Hereditary Motor-Sensory Neuropathies at the Washington University Neuromuscular Disease Center.

Flow charts help narrow down CMT types

Today, the classification system, while still imperfect and unwieldy, provides physicians with a guideline for assigning the CMT type to a broad category, based on the results of nerve conduction velocity testing, physical examination, and patient and family history.

From there, if the family desires it, physicians can proceed to specific genetic testing, which is much more expensive, sometimes running into thousands of dollars.

With MDA support, Shy and his colleagues at Wayne State have developed a series of flow charts for physicians to follow that can drastically reduce the cost of CMT genetic testing by reducing the number of genes that need to be analyzed.

A paper on the subject was published online Jan. 28, 2011, in Annals of Neurology. (See Flow charts will aid CMT diagnosis in Research Updates in the April-June 2011 Quest.)

The investigators found that the most common types of CMT, in order, were CMT1A, CMT1X, CMT1B and CMT2A.

Athena Diagnostics, a commercial testing laboratory in Worcester, Mass., offers DNA analysis of some 15 CMT-related genes. Other laboratories that offer various types of CMT genetic testing can be found through Gene Tests, a listing overseen by the National Institutes of Health and sponsored by the University of Washington, Seattle.

Physicians and genetic counselors associated with MDA clinics can help locate and interpret genetic tests for CMT, as well as offer advice on how to focus testing to reduce costs.

Why do genetic testing for CMT?

When asked about genetic testing in CMT, Shy says, “This is the patient’s decision, not the doctor’s. There are pros and cons; it depends on the person.”

That said, he thinks there are some benefits to genetic testing beyond intellectual curiosity or research applications.

“Once you find the gene, you can get a handle on what the natural history of the disease might be and also the inheritance pattern,” Shy says.

For example, family histories may look the same for people with CMT due to a new, dominant mutation and for those with CMT caused by inheriting two recessive mutations, “but there’s a big difference,” says Shy.

“In both cases, the patients may look the same, and nobody else in the family may have ever heard of CMT. But the person with a new, dominant mutation will have a 50 percent chance of passing it on, and the person who has inherited a recessive mutation from each parent will be very unlikely to pass it on.”

Also, Shy notes, there are now opportunities for those with a family history of CMT to avoid passing along the mutation to future children through the use of preimplantation or prenatal genetic diagnosis. These tests require knowledge of the specific gene involved.

Available in some laboratories for some forms of CMT, these tests can predict whether a child will develop CMT based on genetic testing of the fetus during pregnancy (prenatal testing) or testing of an embryo before it’s implanted into the uterus (preimplantation testing). (For more on this type of testing, see The Pain and Promise of Prenatal and Newborn Genetic Diagnosis in the July 2007 issue of Quest and Love Letters and Preimplantation Genetic Diagnosis” in the April 2011 issue.)

In addition, there are clinical trials being developed that will require that participants have a specific genetic mutation.

On the “con” side of genetic testing, says Shy, is the fact that it isn’t perfect at predicting disease course; doesn’t test for every possible CMT-related gene mutation; and can be extremely expensive.