AUTHOR AND EDITOR INFORMATION

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Charcot-Marie-Tooth (CMT) disease 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 attribute symptoms correctly to neuropathy rather than to myelopathy, as physicians previously had done.

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 disease was subdivided into 2 types, CMT 1 and CMT 2, based on pathologic and physiologic criteria. CMT disease has been subdivided further based on the genetic cause of the disease (see Table).

With the advent of genetic testing, all of the diseases that fall under the heading of CMT syndrome are likely to eventually become distinguishable.

Related eMedicine topics:
Charcot-Marie-Tooth and Other Hereditary Motor and Sensory Neuropathies
Charcot-Marie-Tooth Disease [Physical Medicine and Rehabilitation]
Hereditary Neuropathies of the Charcot-Marie-Tooth Disease Type

Pathophysiology

CMT disease is a heterogeneous group of genetically distinct disorders with similar clinical presentations.¹ The disease is divided into the following types:

• CMT type 1^{2, 3} - This form of CMT disease is a disorder of peripheral myelination resulting from a mutation in the peripheral myelin protein-22 (PMP22) gene. Mutations in the gene encoding the major PNS myelin protein, myelin protein zero (MPZ), account for 5% of patients with CMT disease. 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.

  Slowing of conduction in motor and sensory nerves was believed to cause weakness and numbness. However, a study by Krajewski and colleagues suggested that neurologic dysfunction and clinical disability in CMT 1A are caused by loss of or damage to large-diameter motor and sensory axons.^{4, 5, 6} 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 type 2^{3, 7, 8, 9} - This primarily is a neuronal (ie, axonal) disorder, not a demyelinating disorder. CMT type 2 results in peripheral neuropathy through direct axonal death and Wallerian degeneration.
• CMT type 3 (also known as Dejerine-Sottas disease) - Characterized by infantile onset, this condition results in severe demyelination with delayed motor skills; it is much more severe 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^{10, 11} - These also are demyelinating neuropathies.

Frequency

United States

The prevalence of CMT disease is 1 person per 2500 population, or about 125,000 people in the United States. The incidence of CMT type 1 is 15 persons per 100,000 population; the incidence of CMT type 1A is 10.5 persons per 100,000 population, or 70% of CMT type 1. The incidence of CMT type 2 is 7 persons per 100,000 population. Persons with CMT X represent at least 10-20% of people with the CMT syndrome.

International

In Japan, the prevalence is reported to be 10.8 cases per 100,000 population; in Italy, it is reported to be 17.5 cases per 100,000 population; and in Spain, it is 28.2 cases per 100,000 population.^{12, 13}

Mortality/Morbidity

Morbidity in CMT disease is mainly secondary to distal muscle weakness and foot deformities. In rare cases, phrenic nerve involvement of the diaphragm can cause ventilatory difficulties.

Race

No racial predilection is recognized.

Sex

No sex predilection is reported.

Age

The age of presentation varies depending on the type of CMT disease (see Table).

CLINICAL

Section 3 of 11  

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• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Patients have a significant family history. This history varies depending on the inheritance and penetrance pattern of the particular disorder (see Table). Spontaneous mutations also have been reported.
• Slowly progressing weakness beginning in the distal limb muscles generally is noted; it typically occurs in the lower extremities before it affects the upper ones. A subgroup of patients with CMT type 1A may present with proximal muscle wasting and weakness.
• Onset usually occurs in the first 2 decades of life.
• Patients initially may complain of difficulty walking and frequent tripping due to foot and distal leg weakness. Frequent ankle sprains and falls are characteristic.
• Parents may report that a child is clumsy or simply not very athletic.
• As weakness becomes more severe, foot drop commonly occurs. Steppage (that is, gait in which the individual must lift the leg in an exaggerated fashion to clear the foot off of the ground) also is common.
• Intrinsic foot muscle weakness commonly results in the foot deformity known as pes cavus. Symptoms related to structural foot abnormalities include calluses, ulcers, cellulitis, and lymphangitis.
• Hand weakness results in complaints of poor finger control, poor handwriting, difficulty using zippers and buttons, and clumsiness in manipulating small objects.
• Patients usually do not complain of numbness. This may be because patients with CMT disease never had normal sensation and, therefore, simply do not perceive their lack of sensation.
• Pain (musculoskeletal and neuropathic types) may be present. Muscle cramping is a common complaint.¹⁴
• Autonomic symptoms usually are absent, but a few men with CMT disease have reported impotence.

Related eMedicine topic:
Foot Drop

Physical

• Distal muscle wasting may be noted in the legs, resulting in the characteristic stork leg or inverted champagne bottle appearance.
• Bony abnormalities commonly seen in long-standing CMT disease include the following:
• • Pes cavus (high-arch foot), probably analogous to the development of claw hand in ulnar nerve lesion, has a 25% occurrence rate in the first decade of life and a 67% occurrence rate in later decades. Other foot deformities also can occur (see Image 1).
  • Spinal deformities (eg, thoracic scoliosis) occur in 37-50% of patients with CMT type 1.
• Deep tendon reflexes (DTRs) are markedly diminished or are absent.
• Vibration sensation and proprioception are significantly decreased, but patients usually have no sensory symptoms.
• Patients may have sensory gait ataxia, and a Romberg test usually is positive.
• Sensation of pain and temperature is usually intact.
• Essential tremor is present in 30-50% of patients with CMT disease.
• Sensory neuronal hearing loss is observed in 5% of patients.
• Enlarged and palpable peripheral nerves are common.
• Phrenic nerve involvement with diaphragmatic weakness is rare but has been described.
• Vocal cord involvement and hearing loss can occur in rare forms of CMT disease.

Causes

Hereditary neuropathies are classified by Mendelian Inheritance in Man (MIM).

Charcot-Marie-Tooth Disorders: Genetic and Clinical Feature Comparison

*Autosomal dominant

†Autosomal recessive

‡X-linked dominant

§Nerve conduction velocities

||Hereditary neuropathy with liability to pressure palsy

¶Peripheral myelin protein

#Early growth response

**Myelin protein zero

††Normal

• HMSN with diffusely slow nerve conduction velocity (hypertrophic neuropathy)¹
• • HMSN I (ie, CMT 1)^{2, 3}
    • CMT 1A^{5, 6, 21, 22, 23} - Autosomal dominant band 17p11.2-12 is most common; milder than CMT 1B
    • CMT 1B - Autosomal dominant band 1q21-25
    • CMT 1C - Unknown autosome
    • CMT X1 - X-linked dominant band Xq13-21
    • CMT X2 and CMT X3 - X-linked recessive
    • Autosomal recessive CMT 1 - Arm 8q
  • HMSN III (Dejerine-Sottas disease, hypertrophic neuropathy of infancy, congenital hypomyelinated neuropathy) - Autosomal recessive inheritance
  • HMSN IV (Refsum syndrome, phytanic acid excess) - Autosomal recessive inheritance; tetrad of peripheral neuropathy, retinitis pigmentosa, cerebellar signs, and increased cerebral spinal fluid (CSF) protein
• Hereditary motor and sensory neuropathy with normal or borderline abnormal nerve conduction velocity (neuronal or axonal type)
• • HMSN II (ie, CMT 2)^{3, 7, 9}
    • CMT 2A - Band 1p35-36; typical type; no enlarged nerves; later onset of symptoms; feet are more severely affected than hands
    • CMT 2B^{8, 24} - Band 3q13-22; typical type with axonal spheroids
    • CMT 2C - Not linked to any known loci; diaphragm and vocal cord weakness
    • CMT 2D - Band 7p14; muscle weakness and atrophy more severe in hands than in feet
    • Autosomal recessive CMT 2
  • HMSN V (ie, spastic paraplegia) - Normal upper limbs and no sensory symptoms
• Roussy-Levy syndrome - Autosomal dominant with essential tremor
• HMSN VI - With optic atrophy
• HMSN VII - With retinitis pigmentosa
• Prednisone-responsive hereditary neuropathy

DIFFERENTIALS

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Other Problems to Be Considered

Acquired nongenetic causes of peripheral neuropathies
Vitamin B-12 deficiency
Thyroid disease
Diabetes mellitus
Vasculitis
Amyloid associated with chronic inflammation
Occult malignancy
Heavy-metal intoxication
Chronic inflammatory demyelinating polyneuropathy
Motor neuropathy with multiple conduction block

Other genetic neuropathies

Familial brachial plexus neuropathy (ie, hereditary neuralgic amyotrophy)
Autosomal recessive genetic disorders, such as Refsum disease or metachromatic leukodystrophy
X-linked recessive genetic disorders, such as adrenomyeloneuropathy or Pelizaeus-Merzbacher disease
Amyloid neuropathies
Hereditary ataxias with neuropathy (eg, Friedreich ataxia)

Blindness, seizures, dementia, and mental retardation are not part of CMT syndrome.

WORKUP

Section 5 of 11  

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Lab Studies

• All routine laboratory tests are normal in individuals with CMT disease.

Imaging Studies

• In CMT 1A, high-resolution ultrasonography of the median nerve and other peripheral nerves may serve as an adjunct to electrodiagnosis.

Other Tests

• Special genetic tests are available for some types of CMT disease.
• • CMT 1A - Approximately 70-80% of CMT 1 cases are designated CMT 1A, which is caused by alteration of the PMP-22 gene (chromosome band 17p11). Pulsed field gel electrophoresis and a specialized fluorescent in situ hybridization (FISH) assay are the most reliable genetic tests, but they are not widely available.²⁵ DNA-based testing for the PMP-22 duplication (CMT 1A) is widely available and detects more than 98% of patients with CMT 1A (see Image 2).²⁶ Point mutations in the PMP-22 gene, which cause fewer than 2% of cases of CMT 1A, are identified by this technique.
  • CMT 1B - Genetic testing is performed primarily on a research basis, but it is available from a few commercial laboratories. Approximately 5-10% of CMT 1 cases are designated CMT 1B; they are caused by a point mutation in the myelin P0 protein (MPZ) gene (chromosome band 1q22).
  • CMT 1C and CMT 1D - Very rarely, mutations occur in the EGR-2 gene or the LITAF gene, causing CMT 1D and CMT 1C, respectively. Molecular genetic testing is also available clinically for these.
  • The 4 subtypes of CMT 2 are indistinguishable clinically and are distinguished solely on the basis of genetic linkage findings. Relative proportions of CMT 2A, 2B, 2C, and 2D have not yet been determined. The chromosomal loci for CMT 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2L have been mapped, but the genes have not been identified. Molecular genetic testing is clinically available only for CMT 2A, 2B1, 2E, and 2F.
  • CMT X - Molecular genetic testing of the GJB1 (Cx32) gene detects about 90% of cases. Such testing is clinically available.
  • Genetic testing currently is not available for other types of CMT disease.
• Nerve biopsy rarely is indicated for the diagnosis of CMT disease, especially with the availability of genetic testing. Biopsies sometimes are performed in cases of diagnostic dilemmas. Findings vary in different types of CMT disease.
• • In CMT type 1, peripheral nerves contain few myelinated fibers, and intramuscular nerves are surrounded by rich connective tissue and hyperplastic neurilemma. Lengths of myelin are atrophic along the fibers. Concentric hypertrophy of the lamellar sheaths is seen. Onion bulb formation is frequently observed and is made of circumferentially directed Schwann cells and their processes.
  • In CMT type 2, axon loss with wallerian degeneration is generally found.
  • In CMT type 3, or Dejerine-Sottas disease, demyelination with thinning of the myelin sheath is observed.
  • Inflammatory infiltrate, indicating an autoimmune demyelinating process, should not be present.

Procedures

• Electromyography/nerve conduction study²⁷
• • Perform these studies first if CMT disease is suggested. Findings vary depending on the type of CMT disease.
  • In demyelinating types, such as CMT 1, diffuse and uniform slowing of nerve conduction velocities is observed (see Image 3).
  • Harding and Thomas criteria for diagnosing CMT 1 include a median motor nerve conduction velocity of less than 38 m/s, with compound motor action potential (CMAP) and amplitude of at least 0.5 millivolts (mV). No focal conduction block or slowing should be present unless associated with other focal demyelinating processes.
  • All nerves tested, sensory and motor, show the same degree of marked slowing.
  • Absolute values vary, but they are approximately 20-25 m/s in CMT 1 and less than 10 m/s in Dejerine-Sottas disease and congenital hypomyelination. Slowing of nerve conduction also can be found in asymptomatic individuals.
  • In neuronal (ie, axonal) types, nerve conduction velocity is usually normal, but markedly low amplitudes are noted in sensory (ie, sensory nerve action potential [SNAP]) and motor nerve (ie, CMAP) studies.
  • In neuronal (ie, axonal) types, increased insertional activity is evident as fibrillation potentials and positive sharp waves are observed. Motor unit potentials show decreased recruitment patterns and neuropathic changes in morphology.

Histologic Findings

Findings according to type of CMT disease are as follows:

• In CMT type 1, peripheral nerves contain few myelinated fibers, and intramuscular nerves are surrounded by a rich connective tissue and hyperplastic neurilemma. Lengths of myelin are atrophic along the fibers. Concentric hypertrophy of the lamellar sheaths is seen. Formation of the typical onion bulb is noted and is made of circumferentially directed Schwann cells and their processes.
• In CMT type 2, axonal degeneration is observed.
• In CMT type 3, demyelination with thinning of the myelin sheath can be seen.
• No inflammatory infiltrate should be present, indicating an autoimmune demyelinating process.

TREATMENT

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Medical Care

• Currently, no treatment exists to reverse or slow the natural disease process for the underlying disorder. Nothing can correct the abnormal myelin, prevent its degeneration, or prevent axonal degeneration.
• Improved understanding of the genetics and biochemistry of the disorder offers hope for an eventual treatment.
• Patients often are evaluated and treated symptomatically by a team that includes a neurologist, physiatrist, orthopedic surgeon, physical therapist, and occupational therapist.

Surgical Care

Orthopedic surgery is required to correct severe pes cavus deformities, scoliosis, and other joint deformities. Treatment is determined by the age of the patient and the cause and severity of the deformity.

• Surgical procedures consist of the following 3 types:
• • Soft tissue (plantar fascia release, tendon release or transfer)
  • Osteotomy (metatarsal, midfoot, calcaneal)
  • Joint stabilizing (triple arthrodesis)
• Surgical procedures are usually staged. The initial procedure is a radical plantar or plantar-medial release, with a dorsal closing-wedge osteotomy of the first metatarsal base if necessary. Tendo calcaneus lengthening should not be performed as part of the initial procedure, because the force used to dorsiflex the forefoot causes the calcaneus to dorsiflex into an unacceptable position. If the hindfoot is flexible and a posterior release is not necessary, posterior tibial tendon transfer can be done as part of the initial procedure for severe anterior tibial weakness.²⁸
• When the hindfoot is flexible, early, aggressive treatment with soft-tissue releases can delay the need for more extensive reconstructive procedures. The Jones procedure includes transfer of the extensor hallucis longus and arthrodesis of the interphalangeal joint of the great toe.
• The Coleman block test is sometimes used to help decide what type of surgery is best. In cases of cavovarus deformity, this test evaluates hindfoot flexibility.²⁹ The Coleman block test is performed by placing the patient's foot on a wood block that is 2.5-4 cm thick, with the heel and lateral border of the foot on the block and bearing full weight while the first, second, and third metatarsals are allowed to hang freely into plantar flexion and pronation. If heel varus corrects while the patient is standing on the block, the hindfoot is considered flexible. If the subtalar joint is supple and corrects with the block test, then surgical procedures may be directed at correcting forefoot pronation, which is usually due to plantar flexion of the first metatarsal. If the hindfoot is rigid, then surgical correction of the forefoot and hindfoot is required.
• Triple arthrodesis serves as a salvage procedure for patients in whom other procedures have been unsuccessful, as well as in patients with untreated fixed deformities.
• Children younger than 8 years with supple hindfeet usually respond to plantar releases and appropriate tendon transfers. A first metatarsal osteotomy may be needed in some cases.
• Children younger than 12 years with rigid hindfoot deformities may need radical plantar-medial release, first metatarsal osteotomy, and Dwyer lateral closing-wedge osteotomy of the calcaneus to correct the deformities.
• In the early 1970s, the Akron dome osteotomy was developed as a salvage surgical option to manage rigid cavus deformity of the foot. In a retrospective study, Weiner and colleagues showed that this operation is a valuable salvage procedure in the management of the rigid cavus deformity in children with CMT disease.³⁰
• Wukich and Bowen reported that only 14% of patients with CMT disease required triple arthrodesis.³¹ They also reported hindfoot stability with triple arthrodesis, and when transferring the posterior tibial tendon anteriorly, this eliminated the need for a postoperative drop-foot brace. They reported good or excellent results in 88% of patients who were treated with this method.
• Generally, spinal deformities in children with CMT disease can be treated with the same techniques used for idiopathic scoliosis.

Consultations

• Consult specialists in neurogenetics to order specific genetic tests and proper genetic counseling.

Activity

• No specific activity limitation is recommended.

MEDICATION

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Avoid drugs and medications known to cause nerve damage (eg, vincristine,³² isoniazid, nitrofurantoin). Identify the cause of any pain as accurately as possible. Musculoskeletal pain may respond to acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). Neuropathic pain may respond to tricyclic antidepressants or antiepileptic drugs, such as carbamazepine or gabapentin.

Dyck and colleagues,³³ as well as Ginsberg and coauthors,³⁴ have described a few individuals with CMT 1 and sudden deterioration in whom treatment with steroids (prednisone) or intravenous immunoglobulin produced variable levels of improvement. Sahenk and colleagues studied the effects of neurotrophin-3 on individuals with CMT 1A.³⁵ Passage and co-investigators reported benefit from ascorbic acid (vitamin C) in a mouse model of CMT 1.³⁶

Drug Category: Nonsteroidal anti-inflammatory drugs

Have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known, but they may inhibit cyclooxygenase (COX) activity and prostaglandin synthesis. Other mechanisms may exist as well, such as inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, and various cell membrane functions.

Drug Category: Cyclooxygenase-2 inhibitors

Although increased cost can be a negative factor, the incidence of costly and potentially fatal GI bleeds is clearly less with COX-2 inhibitors than with traditional NSAIDs. Ongoing analysis of cost avoidance of GI bleeds will further define the populations that will find COX-2 inhibitors the most beneficial.

Drug Category: Tricyclic antidepressants

A complex group of drugs that have central and peripheral anticholinergic effects, as well as sedative effects. Tricyclic antidepressants have central effects on pain transmission, blocking the active reuptake of norepinephrine and serotonin.

Drug Category: Anticonvulsants

Used to manage pain and provide sedation in neuropathic pain.

Drug Category: Analgesics

Pain control is essential to quality patient care. Analgesics ensure patient comfort and have sedating properties, which are beneficial to patients who experience pain.

FOLLOW-UP

Section 8 of 11  

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• Follow-up
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Further Outpatient Care

• Patients should have regular follow-up visits to check for deterioration in function and the development of contractures. This follow-up allows early detection of complications. Proper interventions early in the disease course help to avoid significant and permanent functional limitations.³⁷

Deterrence/Prevention

• Regular and proper follow-up and therapeutic interventions are necessary to avoid joint contractures and deformities.
• Proper genetic counseling helps parents to understand the risk of having children with this disorder and gives them a chance to make informed decisions regarding pregnancy.^{22, 38}

Complications

• Due to loss of protective sensation distally in all 4 limbs, patients with CMT disease are susceptible to skin breakdown or burns, nonhealing foot ulcers, and in severe cases, bony deformities of bilateral feet. As mentioned previously, orthoses are required for treatment of foot drop or to accommodate bony foot deformities. If not fitted properly, the orthoses themselves become a source of skin breakdown secondary to associated distal sensory impairment.
• The presence of maternal CMT disease is associated with an increased risk for complications during delivery. This increase is related to a higher frequency of emergency interventions during birth.³⁸

Prognosis

• Prognoses for the different types of CMT disease vary and depend on clinical severity (see Table).
• Generally, CMT disease is a slowly progressive neuropathy that causes eventual disability secondary to distal muscle weakness and deformities.
• CMT disease does not usually shorten the expected life span.
• Shy and colleagues developed the CMT neuropathy score, which is a modification of total neuropathy score.³⁹ 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 of and clinical trials related to CMT disease.²³

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 CMT disease genetic counseling so that they can make informed decisions regarding the potential risk of passing the disease to their children.^{22, 38}
• Drugs and medications, such as vincristine, 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.³⁷
• Obesity should be avoided, because it makes walking more difficult.
• Daily heel-cord stretching exercises are warranted to prevent Achilles tendon shortening.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to make the proper diagnosis, including the genetic pattern, has significant medicolegal concerns.
• Informing parents about the genetic nature of the disease and the possibility of having a baby with the disorder is medicolegally important.

MULTIMEDIA

Section 10 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Foot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A.
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Media type:  Photo

Media file 2:  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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Media type:  Photo

Media file 3:  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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Media type:  Graph

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
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• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

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2. Bird TD, Ott J, Giblett ER, et al. Genetic linkage evidence for heterogeneity in Charcot-Marie-Tooth neuropathy (HMSN type I). Ann Neurol. Dec 1983;14(6):679-84. [Medline].
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11. Bolino A, Muglia M, Conforti FL, et al. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat Genet. May 2000;25(1):17-9. [Medline].
12. Kurihara S, Adachi Y, Wada K, et al. An epidemiological genetic study of Charcot-Marie-Tooth disease in Western Japan. Neuroepidemiology. Sep-Oct 2002;21(5):246-50. [Medline].
13. Morocutti C, Colazza GB, Soldati G, et al. Charcot-Marie-Tooth disease in Molise, a central-southern region of Italy: an epidemiological study. Neuroepidemiology. Sep-Oct 2002;21(5):241-5. [Medline].
14. Carter GT, Jensen MP, Galer BS, et al. Neuropathic pain in Charcot-Marie-Tooth disease. Arch Phys Med Rehabil. Dec 1998;79(12):1560-4. [Medline].
15. Pareyson D, Taroni F, Botti S, et al. Cranial nerve involvement in CMT disease type 1 due to early growth response 2 gene mutation. Neurology. Apr 25 2000;54(8):1696-8. [Medline].
16. Bergoffen J, Scherer SS, Wang S, et al. Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science. Dec 24 1993;262(5142):2039-42. [Medline].
17. Birouk N, LeGuern E, Maisonobe T, et al. X-linked Charcot-Marie-Tooth disease with connexin 32 mutations: clinical and electrophysiologic study. Neurology. Apr 1998;50(4):1074-82. [Medline].
18. Bone LJ, Dahl N, Lensch MW, et al. New connexin32 mutations associated with X-linked Charcot-Marie-Tooth disease. Neurology. Oct 1995;45(10):1863-6. [Medline].
19. Lewis RA. The challenge of CMTX and connexin 32 mutations. Muscle Nerve. Feb 2000;23(2):147-9. [Medline].
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