Practice Essentials
Charcot-Marie-Tooth disease (CMT) is the most common inherited neurologic disorder. CMT is characterized by inherited neuropathies without known metabolic derangements. In 1886, Professor Jean Martin Charcot of France (1825-1893) and his student Pierre Marie (1853-1940) published the first description of distal muscle weakness and wasting beginning in the legs, calling it peroneal muscular atrophy.
Howard Henry Tooth (1856-1926) described the same disease in his Cambridge dissertation in 1886, calling the condition peroneal progressive muscular atrophy. Tooth was the first to correctly attribute the disorder's symptoms to neuropathy rather than to myelopathy, as physicians had done before him. In 1912, Hoffman identified a case of peroneal muscular atrophy with thickened nerves. This disease was referred to as Hoffman disease and later was known as Charcot-Marie-Tooth-Hoffman disease.
In 1968, CMT was subdivided into 2 types, CMT-1 and CMT-2, based on pathologic and physiologic criteria. [1, 2] CMT has been further subdivided, based on the genetic cause of the disease. With the advent of genetic testing, all of the different diseases that fall under the heading of CMT syndrome eventually are likely to become distinguishable.
Signs and symptoms of Charcot-Marie-Tooth disease
Slow-progressing weakness beginning in the distal limb muscles, typically in the lower extremities before the upper extremities, generally is noted. [3] The most common clinical phenotype is the CMT syndrome with distal muscle wasting and weakness, tendon areflexia, (usually) mild sensory loss, and foot deformity. [4]
Workup in Charcot-Marie-Tooth disease
If CMT is suggested, perform an electromyography/nerve conduction study (EMG/NCS) first. Findings vary depending on the type of CMT.
In demyelinating types of CMT, such as CMT-1, diffuse and uniform slowing of nerve conduction velocities is observed.
In neuronal (ie, axonal) types of CMT, nerve conduction velocity usually is normal, but markedly low amplitudes are noted in sensory (ie, sensory nerve action potential [SNAP]) and motor (ie, compound motor action potential [CMAP]) nerve studies.
High-resolution ultrasonography of the median nerve and other peripheral nerves may serve as an adjunct to electrodiagnosis in Charcot-Marie-Tooth disease type 1A. [5, 6, 7, 8, 9, 10]
Management of Charcot-Marie-Tooth disease
Daily heel-cord stretching exercises are desirable to prevent Achilles tendon shortening. Special shoes with good ankle support may be needed. Physical therapy can assist with ambulation and provide necessary evaluation and training with orthoses, such as an ankle-foot orthosis (AFO). [11]
Transcutaneous electrical nerve stimulator (TENS) units can be used to improve muscle functions in patients with CMT. [12]
Some patients require the use of forearm crutches or a cane for improved gait stability, but fewer than 5% of patients need wheelchairs. An occupational therapist may recommend the use of adaptive equipment for activities of daily living (ADL) and self-care.
Orthopedic surgery may be required to correct severe pes cavus deformities, scoliosis, and other joint deformities. [13, 14, 15]
Pathophysiology
Charcot-Marie-Tooth disease (CMT) is actually a heterogeneous group of genetically distinct disorders with a similar clinical presentation. CMT-1A is a disorder of peripheral myelination resulting from a duplication in the peripheral myelin protein-22 (PMP22) gene. [16, 17] PMP22 -related neuropathies should be viewed as the consequence of impaired neuron–Schwann cell interactions that are likely to be operative during fetal development. [18]
A study by Duchesne et al indicated that in addition to myelinated nerve fibers, small unmyelinated fibers are also involved in CMT-1A, with the authors finding significantly reduced intraepidermal nerve fiber density in patients with CMT-1A compared with healthy controls. The study also reported epidermal Langerhans cell density to be significantly lower in patients with CMT-1A, possibly demonstrating that Langerhans cells are associated with the neuropathic pain some patients experience. The study’s results, according to the investigators, may reveal that along with PMP22 dosage, other factors influence the development of CMT-1A. [19]
Mutation in the gene encoding the major peripheral nervous system myelin protein, myelin protein zero (MPZ), [20, 21] causes CMT-1B, and it accounts for 5% of patients with CMT. The mutation results in abnormal myelin that is unstable and spontaneously breaks down. This process results in demyelination, leading to uniform slowing of conduction velocity.
Autosomal dominant hereditary motor and sensory neuropathies (HMSNs) account for 60-70% of families with CMT. [22]
Slowing of conduction in motor and sensory nerves was formerly believed to cause weakness and numbness. However, a study by Krajewski and colleagues suggested that neurologic dysfunction and clinical disability in CMT-1A result when large-diameter motor and sensory axons are lost or damaged. [23] . Hence, this loss or damage is currently accepted as the cause for clinical disability and weakness in CMT-1A. Pain and temperature sensations usually are not affected, because they are carried by unmyelinated (type C) nerve fibers.
In response to demyelination, Schwann cells proliferate and form concentric arrays of remyelination. Repeated cycles of demyelination and remyelination result in a thick layer of abnormal myelin around the peripheral axons. These changes cause what is referred to as an onion bulb appearance.
CMT-2 is primarily a neuronal (ie, axonal) disorder, not a demyelinating disorder. Type 2 results in peripheral neuropathy through direct axonal death and wallerian degeneration. CMT-2 is likely to display much more genetic heterogeneity than CMT-1. [24] Some cases of CMT-2 have also been linked to mutations in the MPZ gene. [25] CMT-3 (also known as Dejerine-Sottas disease) is characterized by infantile onset.
Type 3 results in severe demyelination with delayed motor skills and is a much more severe form than type 1. Marked segmental demyelination with thinning of the myelin around the nerve is observed on histologic examination.
CMT-X (X-linked CMT) and CMT-4 are also demyelinating neuropathies.
CMT type 4C appears to be the most prevalent (18%) autosomal recessive CMT subtype. Common features of CMT-4C include childhood onset, thoracic spine scoliosis, moderate-to-severe neuropathy, and cranial nerve deficits. [26] A report by Jerath et al delineated the clinical and physiologic features of five patients with CMT-4C, each of whom demonstrated biallelic private mutations of SH3TC2. Scoliosis occurred universally, and nerve conduction studies pointed to the existence of demyelination. Three new mutations in the patients were described, and the presence of at least two different genetic diseases in the same patient was observed. [27]
Epidemiology
Frequency
United States
The prevalence of Charcot-Marie-Tooth disease (CMT) is 1 person per 2500 population. CMT is the most common inherited disorder that involves the peripheral nerves, affecting an estimated 150,000 people in the United States. [28]
About half of all diagnosed cases of CMT are in the form of CMT-1A, making it the most prevalent type of CMT. The second most common form, CMT-X, makes up approximately 7-15% of cases. The predominant axonal subtype of CMT, CMT-2A, represents about 4-7% of cases of CMT. [29, 30]
International
In Japan, the prevalence of CMT is reportedly 10.8 cases per 100,000 population. [31] In Italy, the prevalence is reported to be 17.5 cases per 100,000 population, [32] and in Spain, it is 28.2 cases per 100,000 population. In Norway, estimated prevalence of CMT is 1 in 1214 and the prevalence of PMP22 duplication and of mutations in Cx32, MPZ, and MFN2 is 19.6%, 4.8%, 1.1%, and 3.2%, respectively. [33]
Mortality/Morbidity
Morbidity in Charcot-Marie-Tooth disease (CMT) is mainly secondary to distal muscle weakness and foot deformities. [13, 3] Neuropathic pain is also one of the reasons for significant morbidity. [34] In rare cases, phrenic nerve involvement of the diaphragm can cause ventilatory difficulties.
Race
No race predilection is recognized in Charcot-Marie-Tooth disease.
Sex
There is no known sex predilection in Charcot-Marie-Tooth disease.
Age
The age of presentation for Charcot-Marie-Tooth disease (CMT) varies depending on the type of CMT. Please refer to the table under Causes.
Prognosis
The prognosis for the different types of Charcot-Marie-Tooth disease (CMT) varies; it depends on the condition's clinical severity (see the table under Causes).
Generally, CMT is a slowly progressive neuropathy, with eventual disability occurring secondary to distal muscle weakness and deformities.
CMT usually does not shorten a patient's expected life span.
Shy and colleagues developed the CMT neuropathy score, which is a modification of the total neuropathy score. [35] This has been shown to be a validated measure of length-dependent axonal and demyelinating CMT disability and can be investigated as an end point for longitudinal studies and clinical trials of CMT.
The Inherited Neuropathies Consortium developed an 11-item CMT Pediatric Scale (CMTPedS) to measure impairment of children with CMT. Testing showed the scale to be a reliable, valid, and sensitive global measure of disability for children from the age of 3 years. [36]
Patient Education
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance patterns, and implications of genetic disorders in order to help them make informed medical and personal decisions. Offer patients with Charcot-Marie-Tooth disease (CMT) genetic counseling so that they can make informed decisions regarding the potential risk of passing the disease to their children. [37]
Certain drugs and medications, such as vincristine, [38, 39] isoniazid, paclitaxel, cisplatin, and nitrofurantoin, are known to cause nerve damage and should be avoided.
Routine exercise within the individual's capability is encouraged; many individuals remain physically active.
Obesity should be avoided, because it makes walking more difficult.
Daily heel-cord stretching exercises are warranted to prevent Achilles tendon shortening.
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Foot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A.
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Charcot-Marie-Tooth disease type 1A DNA test showing duplication in the short arm of chromosome 17 (A) compared with normal (B).
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Nerve conduction study showing decreased nerve conduction velocity in the median nerve in an 18-year-old woman with Charcot-Marie-Tooth disease type 1.
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Foot of 29-year-old with advanced Charcot-Marie-Tooth disease type 1.
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Hands of 29-year-old with advanced Charcot-Marie-Tooth disease type 1.
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Right ulnar motor nerve conduction study in a 29-year-old patient with advanced Charcot-Marie-Tooth disease type 1.
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Left ulnar motor nerve conduction study in 29-year-old patient with advanced Charcot-Marie-Tooth disease type 1.
