Charcot-Marie-Tooth disease

History

Charcot-Marie-Tooth disease (CMT) is an inherited disorder of progressive peripheral nerve dysfunction resulting in numbness and weakness. The first description of distal muscle weakness and wasting beginning in the legs was published by Jean Martin Charcot and Pierre Marie under the name of peroneal muscular atrophy in 1886. The same disease was described by Howard Henry Tooth in his Cambridge dissertation in 1886 under the name of peroneal progressive muscular atrophy. Tooth was the first to correctly attribute the symptoms to neuropathy, rather than myelopathy (spinal cord disease) as was previously believed. They Marinesco identified the presence of foot deformity and the familial nature of the disease, but incorrectly suggested that anterior horn cells may also be involved in the disease process.

The early designation of peroneal muscular atrophy later gave way to Charcot-Marie-Tooth disease. More recent nomenclature designated CMT as Hereditary Motor and Sensory Neuropathy type I (HMSN-I). Recent advances in genetic research have identified several types of CMT, which correspond with specific genetic mutations (see Genetics below).

Clinical Presentation

Epidemiology
The prevalence of CMT is 1 per 2,500 population, which results in 125,000 patients in USA, making CMT the most common inherited neurological disease. Because CMT is an inherited disorder, patients almost always have a family history of the disease. There are, however, rare sporadic cases without a family history, which likely represent spontaneous mutations. There does not appear to be any racial predominance.

Clinical Features
CMT is characterized by slowly progressive weakness beginning in the distal limb muscles, and typically in the legs before the arms. Symptoms usually appear in the first two decades of life. Patients may first complain of difficulty walking, especially with tripping due to foot and distal leg weakness. Ankle sprains are common in this stage. In its subtlest manifestation, patients may only note clumsiness with running or simply being not very athletic. As weakness becomes more severe foot drop commonly occurs, resulting in a "steppage" gait in which the patient must lift the leg in an exagerated fashion in order to clear the foot off the ground. Eventually, atrophy may develop, resulting in the characteristic "stork" leg appearance. Intrinsic foot muscle weakness commonly results in the foot deformity known as pes cavis.

Weakness in the upper extremities usually develops later than the lower extremities. Hand weakness results in complaints of poor finger control, poor hand writing, difficulty using zippers and buttons, and clumsiness with manipulating small objects. Despite the fact that the sensory nerves are affected as much as the motor nerve, patients do not complain of numbness. This is thought to be due to the fact that CMT patients never had normal sensation and therefore simply do not perceive their lack of sensation. Muscle cramping is a common complaint.

On neurological examination, deep tendon reflexes (DTR's) are markedly diminished or absent. Very early on in the disease, the DTR's will disappear in the ankles and knees first, and then in the arms. Weakness and atrophy in a distal > proximal and lower > upper extremity pattern is typical with pes cavis being common, as noted above. Despite the lack of complaints of numbness, vibration and proprioception are markedly decreased, and Romberg testing is usually positive. Spinothalamic (pain and temperature) sensation is usually intact. Essential tremor is present in 30-50% of CMT patients, neuronal hearing loss in 5% , and scoliosis in 20%. Phrenic nerve involvement with diaphragmatic weakness is rare but has been described.

Pathophysiology

CMT is really a heterogenous group of genetically distinct disorders with a similar clinical presentation. CMT Type 1 is a disorder of peripheral myelination resulting from a mutation in the peripheral myelin protein (PMP) 22 gene. The mutation results in abnormal myelin which is unstable and spontaneously breaks down. This results in segmental demyelination, which results in slowing of conduction velocity. It is the slowing of conduction in motor and sensory nerves which results in weakness and numbness. Spinothalamic nerves (pain and temperature) are not affected because they are unmyelinated (Type C) nerves. In response to the demyelination, schwann cells proliferate and form concentric arrays of remyelination. Repeated cycles of demyelination and remyelination result in a thickening layer of abnormal meylin around the peripheral axons, leading to so-called "onion bulbing."

CMT Type 2 is primarily an axonal disorder, not a demyelinating disorder. It results in peripheral neuropathy through direct axonal death and wallerian degeneration. CMT Type 3 ( also called Dejerine-Sottas disease) results in severe demyelination, is infantile in onset with delayed motor skills, and is basically a much more severe form than Type 1. On histological examination there is marked segmental demyelination with thinning of the myelin around the nerve

Diagnosis

Diagnosis is initially made based upon the clinical presentation. The key features here, as discussed above, are progressive weakness or clumsiness with markedly dimished or absent DTR's, no sensory complaints but marked vibratory and proprioception decrease on exam, and a positive family history. When the diagnosis is suspected based upon these clincial criteria, then laboratory investigation, including Electromyography (EMG), nerve biopsy, and genetic testing, is indicated to confirm the diagnosis.

Electromyography/Nerve Conduction Study (EMG/NCV)
The first study performed is usually EMG/NCV. The results will depend upon the type of CMT. For demyelinating types, the characteristic findings are diffusely and equally decreased conduction velocities. In every nerve tested, both sensory and motor, roughly the same degree of marked slowing is found. The amount of slowing is 60-80%, with absolute values around 20-25 m/s. Such slowing can also be found in asymptomatic individuals, and for this reason family members, even those who do not complain of weakness, are often tested to aid in the diagnosis.

Nerve Biopsy
Nerve biopsy is usually not necessary for diagnosis, especially since the availability of genetic testing. It is still helpful, however, for diagnostic dillemmas. Findings depend upon the type. Type 1 reveals demyelination and multiple layers of remyelination, called onion bulbing. Type 2 reveals axon loss with wallerian degeneration. Type 3 reveals demyelination with thinning of the myelin sheath. As important as what the biopsy shows, is what the biopsy should not show. There should be no inflammatory infiltrate indicating an autoimmune demyelinating process.

Genetic Testing
Genetic testing for CMT Type 1A is now commercially available. This allows for definitive diagnosis, even in asymptomatic individuals. Only 50-60% of cases, however, will be positive. The other 40-50% of patients with CMT have another genetic type.

Genetics

CMT is a heterogenous genetic disease with all different modes of inheritence. About 70% are autosomal dominant but recessive and X-linked varieties also exist. Below is delineated the currently known types of CMT with the identified genetics.

CMT1A - autosomal dominant, maps to 17p11.2-p12 (duplication)
- 1.5 million bases, results in 3 copies of gene
- double duplication with 4 copies results in more severe disease
- Peripheral Myelin Protein (PMP) 22 gene
- 50-60% of cases
- deletion (or frame shift mutation) at same site results in HNPP (Hereditary Neuropathy with Liability to Pressure Palsies) - point mutation at same site results in CMT1A
CMT1B - autosomal dominant, maps to 1q21-q23 (Po gene)
- myelin protein zero, integral membrane protein, most abundant in PNS myelin, role in compaction
- very rare, only 5 described families worldwide
CMT1C - autosomal dominant, gene unknown but not on 1 or 17
CMT2 - autosomal dominant, maps to 1p35--36
CMT3 - autosomal dominant, maps to PMP22 on chrom. 17 or the myelin Po gene on chrom. 1
CMT4 - autosomal recessive, maps to 8q13-q21.2
CMTX1 - X-linked dominant, maps to Xq12-q13
- codes for connexin 32, an intercellular gap junction protein found in PNS and CNS myelin
CMTX2 - X-linked recessive, maps to Xp22.2 CMTX3 - X-linked recessive, maps to Xq26

Treatment

Currently there is no treatment for the underlying disorder, nothing which can fix the abnormal myelin or prevent its degeneration. Improved understanding of the genetics and biochemistry of the disorder, however, offers hope for an eventual treatment. In the meantime, patients with CMT should be offered genetic counseling, so that they can make informed decisions regarding the potential risk of their children having the disease. Patients can also be helped with physical therapy to aid with ambulation and provide the necessary orthoses, such as an ankle-foot orthosis for foot drop. Surgery is also sometimes helpful for foot and joint deformities which may occur.

Support Groups

Muscular Dystrophy Association (MDA)
National Headquarters
3300 East Sunrise Drive
Tucson, Arizona 85718
Phone: 1-800-572-1717

The MDA supports research and patient care for over 40 diseases, including ALS. They can put patients and families in touch with local chapters and support groups.

Charcot-Marie-Tooth Association (CMTA)
Crozer Mills Enterprise Center
601 Upland Avenue
Upland, PA 19015
Phone: 1-610-499-7486

The CMTA was founded by Howard K. Shapiro, PhD, to support patients and families with CMT, fund research, and disseminate information about CMT.

CMT International

1 Springbank Drive
St. Catharines, Ontario, Canada L2S 2K1
Phone: (905) 687-3630 EST Monday-Thursday 10 a.m-4 p.m
Fax: (905) 687-8753 anytime
E-mail: cmtint@vaxxine.com

Internet Links to other CMT sites

• Charcot-Marie-Tooth Association
• CMT International
• MDA Australia CMT page
• CMT Net
  

Disclaimer

This page is intended for educational purposes only, to provide an overview of CMT for patients, their families, and health care providers. It is not intended to recommend any specific treatment, nor should it be used as a guide for self-treatment. Patients with CMT should consult their physician before making any changes to their treatment regimen.

© Copyright Department of Neurology, Yale School of Medicine.
All rights reserved.