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Inherited Peripheral Neuropathies
By Phillip F. Chance, MD, FACMG 

Hereditary (or genetic) neuropathies represent a special category of neuropathies resulting from alterations in the DNA making up our chromosomes. Some inherited neuropathies may affect predominantly motor nerves, leading to muscle weakness, wasting, gait abnormalities or difficulties with hand function. Some mainly affect sensory nerves, leading to abnormalities of sensation, including pain or numbness. And still others appear to affect both motor and sensory functions, and cause a combination of various symptoms related to those nerves affected.

Neuropathy Researcher

"Today, CMT is known 
to affect approximately 1
in 2,500 individuals in the
U.S., and 2.6 million people
worldwide--although experts
believe the number could be
much higher." 

Charcot-Marie-Tooth Diseases
The largest category of inherited peripheral neuropathies affecting both motor and sensory nerves is the Charcot-Marie-Tooth (also called “CMT”) diseases. CMT designates a large group of inherited diseases first described in 1886 by three physicians—Jean-Martin-Charcot, Pierre Marie, and Howard Henry Tooth. Today, CMT is known to affect approximately 1 in 2,500 individuals in the United States.

Types of CMT
The various forms of CMT are broadly subdivided into two categories, each of which leads to peripheral nerve degeneration:

  • CMT Type I (or CMT1) – those types of CMT affecting the myelin membrane (or the insulation surrounding the nerve) resulting in the slowing of the nerves’ ability to conduct electrical impulses.
  • CMT Type II (or CMT2) – those types of CMT causing degeneration of the actual nerve (the axon) itself.

CMT Inheritance Patterns
Genetically speaking, there are a number of ways a gene causing CMT can be inherited. The various forms of CMT may be passed down through a family in a dominant gene expression, meaning the gene for CMT can occur in male and female family members. Some forms of CMT, however, may result when an individual inherits an abnormal copy of a gene from both parents, who themselves are unaffected; this pattern is termed recessive gene expression. And there are still other forms of CMT known as having X-linked inheritance patterns, meaning they appear to be passed on through the X-chromosome, which causes these neuropathies to affect primarily males, while still having some milder manifestations in females.

To date, there are no effective treatments for any form of inherited peripheral neuropathy; however, there has been an explosion of progress made in the last twenty years regarding identification of the various genes which, when abnormal, can lead to a form of CMT. Presently, there are over 50 different forms of CMT that have been assigned to various chromosomal regions; for about 25 of these disorders, a specific gene is known to be involved.

Ultimately, finding the genes causing the various forms of CMT means finding the key to unlocking future therapies for CMT…to develop a rational therapy, first the basic underlying genetic abnormality will need to be known. In addition, identifying the specific gene can, in some cases, lead to the development of better diagnostic tools and improved genetic counseling for patients and families with CMT.

Living With CMT
Current clinical efforts are directed at improving a patient’s activities of daily living, keeping them active and leading productive lives. The lifespan for a patient with CMT is normal. Most CMT patients remain able to walk, however, there are rare forms that in may require use of walkers or wheelchairs. Lower leg braces are commonly prescribed, and can significantly aid walking or even restore a normal gait. It seems most likely that in the near future, pharmacological interventions will come about to help patients with CMT.

More recently, vitamin C has been found to be therapeutically useful in an animal model for a particular form of CMT (CMT1A); as a result, there are therapeutic trials underway in both the United States and Europe. However, a tremendous amount of research is yet to be done to uncover more causes of CMT, to gain further needed insights into the basic disease mechanisms involved, and to translate this knowledge into therapies that will be helpful in either preventing the onset of the neuropathy or slowing its progression.

Dr. Chance is Chief and Allan and Phyllis Truer Endowed Chair of the Division of Genetics and Developmental Medicine at the Children’s Hospital and Regional Medical Center in Seattle, Washington. He is also Professor of Pediatrics and Neurology and Director of the Neurogenetics Lab at the University of Washington School of Medicine. Dr. Chance is a past Neuropathy Association research grant recipient for his investigation of the causal gene for hereditary neuralgic amyotrophy (HNA).

 

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