Case Study Monday - Charcot-Marie-Tooth Disease

I was thinking recently about what I could write about on the blog here, since for the most part a) I am busy and b) most of my personal experience as of late has been "STUDY STUDY STUDY AAHHHHHH".  Having spent a little time thinking about it, I thought that perhaps it would be a good idea to adapt some of the things I'm learning to the blog, as it would give me the opportunity to practice summarizing information and presenting it.

At the very least, it's a good exercise.

So, for the next few weeks (or when I feel like it and have the time) I present to you Case Study Monday.*

A 15-year old high school student is brought to the clinic for a neurological exam by her father.  The patient has had difficulty walking without stumbling, and is also suffering from cramps in her lower legs and feet.  She is found to have pes cavus (high arch), poor muscular development in her calves, and decreased ankle reflexes.  The remaining exam is normal.  A nerve conduction velocity study reveals that the conduction velocity in her legs is 24 m/s.  A family history reveals that her father has always been "a bit clumsy" and continues to have difficulty with fine skills such as buttoning shirts.  He appears to have "stork-like" legs and high arches.  He also walks with a high-stepping gait and has an audible foot slap when walking.  His daughter appears to be developing the same gait.

As a physician, where do you start?  Examining the symptoms, it appears that the patient is having some sort of lower limb motor disorder that is disrupting her mobility.  She also has some deformities in her feet and ankles, importantly the high arches and poor muscular development, that are indicative of some sort of muscular dystrophy or atrophy.  Combined with the family history of similar symptoms, especially in her father, it appears that she is suffering from some sort of genetically inherited muscular disorder.  The information in the case is suggestive of Charcot-Marie-Tooth disease. 

Charcot-Marie-Tooth is a clinically heterogeneous group of inherited disorders that affect the peripheral nervous system (i.e. the nervous system outside of your brain and spinal cord).  Symptoms of CMT disease include many of those mentioned above, including lower leg weakness, foot deformities (high arch, hammer toes), and foot slap with a high stepping gait.  Muscle wasting is also a problem, leading to the characteristic "stork leg" appearance.   In addition to muscular problems, there are also problems associated with loss of peripheral touch sensation, as well as possible secondary symptoms such as scoliosis, malformed hip sockets, and possible GI problems.

CMT is diagnosed based on a number of criteria, including the symptoms, biopsy of the nerve, genetic testing, and electromyography (the nerve conduction velocity study described above).  These criteria can be enhanced by taking of a family history (again, the disease is hereditary).  The underlying cause of the disease is genetic, and there are a number of genetic variations that can lead to the disease state.  Although it's classified as "one" disease, there are actually a number of different types with different forms that can be identified in part using the nerve conduction velocity test.  The two main divisions of this disease are demyelinating type and axonal type.

Demyelinating CMT Type 1 (CMT1) is a form of the disease in which a gene product (most commonly Peripheral Myelin Protein PMP22) is mutated in such a way that the insulating myelin sheath is degraded.  This loss of insulation affects the ability of electrical signals to conduct down neurons, such that the signal appears more slowly than under normal circumstances.  A normal peripheral nerve may conduct a signal at 40 m/s; when demyelination occurs, that same signal may be slowed to 20-25 m/s or even slower, indicating that the neuron is no longer insulated.  Along with a history and physical exam, this result can be helpful in diagnosing the disease.

Although demyelination is common in CMT, there are subtypes (most commonly CMT2) in which the myelin sheath is not affected, but rather the axon of the nerve.  In this form of the disease, a measurement of the nerve conduction velocity would reveal that the speed remains relatively unchanged, but the amplitude of the signal decreases.  This is because the axon is no longer able to generate a large action potential for conduction of a signal down the neuron.  Use of the nerve conduction velocity test is still helpful because it can help shed light on how well the signal is being conducted.  A good primer on neuron signals and action potentials can be found here. 

Understanding the genetic root of the disease and the associated symptoms, how can these patients be treated?  As of now, there is no real "cure" for the disease (like many neuromuscular diseases), but a suite of treatments that help to manage the disease and prevent further damage from occurring.  Although the disease doesn't directly lead to muscle wasting (i.e. the muscle tissue isn't being degraded), the lack of nervous input and movement problems can lead to patients losing muscle tone and physical movement.  The key treatments aim to maintain movement, strength, and flexibility, and include physical therapy and moderate, manageable activity.  Use of braces or stabilizing equipment can also be useful to aid in movement and encourage patients to use the muscle tone they still have.  In cases with more severe malformations, surgical stabilization of joints and repair of malformations can be beneficial and allow for increased movement.  A search of ClinicalTrials.gov reveals trials focusing treatments ranging from physical therapy to high doses of ascorbic acid.  Clearly, further research into this disease and a better understanding of the underlying genetic mechanisms is necessary to aid in developing a strong treatment plan and possible cure.

More information on CMT and ways to support CMT research can be found at the CMT Association website.  

So, there you go.  Hope you enjoyed learning a bit about this disorder, and that is was organized in such a way that it was at least a little understandable.  More practice!

*Case adapted from M1 Neuroscience course at the U of I