Charcot-Marie-Tooth Disease 

Updated: Apr 01, 2019
Author: Divakara Kedlaya, MBBS; Chief Editor: Vinod K Panchbhavi, MD, FACS 

Overview

Background

Charcot-Marie-Tooth (CMT) disease is the most common inherited neuromuscular disorder. It is characterized by inherited neuropathies without known metabolic derangements.[1, 2]  These disorders are also known as hereditary motor and sensory neuropathies (HMSNs); they are distinct from hereditary sensory neuropathies (HSNs) and hereditary motor neuropathies (HMNs).

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 two types, CMT 1 and CMT 2, on the basis of pathologic and physiologic criteria. It has been subdivided further on the basis of the genetic cause of the disease. With the advent of genetic testing, it is likely that all of the diseases currently falling under the heading of CMT syndrome will eventually become distinguishable.[3]

Pathophysiology

CMT disease is a heterogeneous group of genetically distinct disorders with similar clinical presentations.[1]  Its genetic spectrum spans more than 80 genes.[4] Gene discovery has been revolutionized by new high-throughput molecular technologies.[5]  CMT disease is divided into several types, as follows.

CMT 1

CMT type 1 is a disorder of peripheral myelination resulting from a mutation in the peripheral myelin protein-22 (PMP22) gene.[6, 7, 8] 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 et al suggested that neurologic dysfunction and clinical disability in CMT 1A are caused by loss of or damage to large-diameter motor and sensory axons.[9, 10, 11]

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.[12] 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

CMT type 2 primarily is a neuronal (ie, axonal) disorder, not a demyelinating disorder.[7, 13, 14, 15] It results in peripheral neuropathy through direct axonal death and wallerian degeneration. It has been associated with mutations in the ATP1A1 gene.[16]

CMT 3

Characterized by infantile onset, CMT type 3 (also known as Dejerine-Sottas disease) results in severe demyelination with delayed motor skills; it is much more severe than CMT type 1. Marked segmental demyelination with thinning of the myelin around the nerve is observed on histologic examination.

CMT X and CMT 4

CMT X (X-linked CMT) and CMT 4 also are demyelinating neuropathies.[17, 18]  CMT X has been associated with mutations in the PRPS1 gene.[19]

Etiology

HMSNs are classified by Online Mendelian Inheritance in Man (OMIM). A broad division may be made between HMSNs with diffusely slow nerve conduction velocity and those with normal or borderline abnormal nerve conduction velocity.[20]

HMSN with diffusely slow nerve conduction velocity (hypertrophic neuropathy)

HMSN I (ie, CMT 1) includes the following subtypes[6, 7] :

  • CMT 1A [10, 11, 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) is inherited in an autosomal recessive manner.

HMSN IV (Refsum syndrome, phytanic acid excess) has an autosomal recessive inheritance and is characterized by a tetrad of peripheral neuropathy, retinitis pigmentosa, cerebellar signs, and increased cerebrospinal fluid (CSF) protein.

HMSN with normal or borderline abnormal nerve conduction velocity (neuronal or axonal type)

HMSN II (ie, CMT 2) includes the following subtypes[7, 13, 15] :

  • CMT 2A - Band 1p35-36; typical type; no enlarged nerves; later onset of symptoms; feet are more severely affected than hands
  • CMT 2B [14, 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) is characterized by normal upper limbs and the absence of sensory symptoms. Roussy-Levy syndrome has an autosomal dominant inheritance and is characterized by essential tremor. HMSN VI is characterized by optic atrophy. HMSN VII is associated with retinitis pigmentosa. Prednisone-responsive hereditary neuropathy is the final HMSN of this type.

Genetic and clinical features of CMT disorders are listed in Table 1 below.

Table 1. Charcot-Marie-Tooth Disorders: Genetic and Clinical Feature Comparison (Open Table in a new window)

CMT Type

Chromosome; Inheritance Pattern

Age of Onset

Clinical Features

Average NCVs§

CMT 1A (PMP-22¶ dupl.)

17p11; AD*

First decade

Distal weakness

15-20 m/s

CMT 1B (P0 -MPZ)**

1q22; AD

First decade

Distal weakness

< 20 m/s

CMT 1C (non A, non B)

16p13;AD

Second decade

Distal weakness

26-42 m/s

CMT 1D (early growth response [EGR]-2)#[[25]

10q21; AD

First decade

Distal weakness

15-20 m/s

CMT 1E

17p11; AD

First decade

Distal weakness, deafness

15-20 m/s

CMT 1F

8p21; AD

First decade

Distal weakness

15-20 m/s

CMT X (Connexin-32)[26, 27, 28, 29, 30]

Xq13; XD‡

Second decade

Distal weakness

25-40 m/s

CMT 2A

1p36; AD

10 y

Distal weakness

>38 m/s

CMT 2B

3q; AD

Second decade

Distal weakness,

sensory loss, skin ulcers

Axon loss; Normal

CMT 2C

12q23-q24, AD

First decade

Vocal cord, diaphragm, and

distal weakness

>50 m/s

CMT 2D

7p14; AD

16-30 y

Distal weakness, upper limb predominantly

Axon loss; N††

CMT 2E

8p21; AD

10-30 y

Distal weakness, lower limb predominantly

Axon loss; N

CMT 2F

7q11-q21; AD

15-25 y

Distal weakness

Axon loss; N

CMT 2G

12q12-q13; ?AD

9-76 y

Distal weakness

Axon loss; N

CMT 2H

?; AR†

15-25 y

Distal weakness, Pyramidal features

Axon loss; N

CMT 2I

1q22; AD

47-60 y

Distal weakness

Axon loss; N

CMT 2J

1q22; AD

40-50 y

Distal weakness, hearing loss

Axon loss; N

CMT 2K

8q13-q21; AR

< 4 y

Distal weakness

Axon loss; N

CMT 2L

12q24; AD

15-25 y

Distal weakness

Axon loss; N

CMT R-Ax (Ouvrier)

AR

First decade

Distal weakness

Axon loss; N

CMT R-Ax (Moroccan)

1q21; AR

Second decade

Distal weakness

Axon loss; N

Cowchock syndrome

Xq24-q26

First decade

Distal weakness, deafness, mental retardation

Axon loss; N

HNPP|| (PMP-22)

Or tomaculous neuropathy

17p11; AD

All ages

Episodic weakness and numbness

Conduction Blocks

Dejerine-Sottas syndrome (DSS) or hereditary motor and sensory neuropathy (HMSN) 3

P0; AR

PMP-22; AD

8q23; AD

2 y

Severe weakness

< 10 m/s

Congenital

hypomyelination (CH)

P0, EGR2 or PMP-22

AR

Birth

Severe weakness

< 10 m/s

CMT 4A

8q13; AR

Childhood

Distal weakness

Slow

CMT 4B

(Myotubular in-related

protein-2)[18]

11q23; AR

2-4 y

Distal and proximal

weakness

Slow

CMT 4C

5q23; AR

5-15 y

Delayed walking

14-32 m/s

CMT 4D (Lom)

(N-myc Downstream-

Regulated Gene 1)

8q24; AR

1-10 y

Distal muscle wasting, foot and hand deformities

10-20 m/s

CMT 4E (EGR2)

10q21; AR

Birth

Infant hypotonia

9-20 m/s

CMT 4G

10q23.2; AR

8-16 years

Distal weakness

9-20 m/s

CMT 4H

12p11.21-q13.11; AR

0-2 years

Delayed walking

9-20 m/s

CMT 4F

19q13; AR

1-3 y

Motor delay

Absent

*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

Epidemiology

United States statistics

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

International statistics

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.[31, 32]

According to a Norwegian genetic epidemiologic study, CMT disease is the most common inherited disorder of the peripheral nervous system, with an estimated prevalence of 1 in 1214. CMT 1 and CMT 2 are equally frequent in the general population. The prevalence of PMP22 duplication and of mutations in Cx32, MPZ, and MFN2 is 19.6%, 4.8%, 1.1% and 3.2%, respectively. The ratio of probable de-novo mutations in CMT families was estimated to be 22.7%. Genotype-phenotype correlations for seven novel mutations in the genes Cx32 (2), MFN2 (3) and MPZ (2) are described.[33]

Prognosis

Prognoses for the different types of CMT disease vary and depend on clinical severity. Generally, CMT disease is a slowly progressive neuropathy that causes eventual disability secondary to distal muscle weakness and deformities. Motor performance deterioration in CMT 1A appears to accelerate after age 50 years.[34] In rare cases, phrenic nerve involvement of the diaphragm can cause ventilatory difficulties. CMT disease does not usually shorten the expected life span.

Shy et al 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 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. Genetic counseling should be offered to patients with CMT disease so that they can make informed decisions regarding the potential risk of passing the disease to their children.[22, 36]

Certain drugs and medications (eg, 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] No specific activity limitation is recommended.

Obesity should be avoided because it makes walking more difficult.

Daily heel-cord stretching exercises are warranted to prevent Achilles tendon shortening.

 

Presentation

History

Patients with Charcot-Marie-Tooth (CMT) disease have a significant family history. This history varies depending on the inheritance and penetrance pattern of the particular disorder (see Etiology). Spontaneous mutations also have been reported.

The age of presentation varies, depending on the type of CMT disease. Onset usually occurs in the first two decades of life.

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 1A may present with proximal muscle wasting and weakness.

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. The hand may be affected at all ages in children with CMT 1A; that hand problems in these patients may be underrecognized in the early stages of disease, causing potential delay in therapy.[38]

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.[39]

Autonomic symptoms usually are absent, but a few men with CMT disease have reported impotence.

Physical Examination

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 pes cavus (high-arch foot), probably analogous to the development of claw hand in ulnar nerve lesions. Pes cavus has an occurrence rate of 25% in the first decade of life and 67% in later decades. Selective denervation of intrinsic foot musculature (particularly of the lumbricals), rather than imbalance of lower-leg muscles, seems to be the initial mechanism causing reduced ankle flexibility and forefoot cavus deformity.[40] Other foot deformities also can occur (see the image below).

Foot deformities in 16-year-old boy with Charcot-M Foot deformities in 16-year-old boy with Charcot-Marie-Tooth disease type 1A.

Spinal deformities (eg, thoracic scoliosis) occur in 37-50% of patients with CMT 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 yields positive results. The Romberg test is performed by having the patient stand upright with the feet together and the eyes closed. The examiner observes the patient's body movement relative to a perpendicular object behind him or her (eg, a door or window). Pronounced, sometimes irregular swaying, or occasionally even toppling over, constitutes a positive result. The key point is that the patient's unsteadiness increases when his or her eyes are closed.

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.

Complications

Because of the loss of protective sensation distally in all four 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 of complications during delivery. This increase is related to a higher frequency of emergency interventions during birth.[36]

 

DDx

Diagnostic Considerations

In addition to the conditions listed in the differential diagnosis, other problems to be considered include the following:

  • Acquired nongenetic causes of peripheral neuropathies
  • Vitamin B12 deficiency
  • 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 Charcot-Marie-Tooth syndrome.

Differential Diagnoses

 

Workup

Laboratory Studies

All routine laboratory tests are normal in individuals with Charcot-Marie-Tooth (CMT) disease. However, special genetic tests are available for some types of CMT disease.

About 70-80% of CMT 1 cases are designated CMT 1A, which is caused by alteration of the PMP22 gene (chromosome band 17p11). Pulsed field gel electrophoresis and a specialized fluorescent in-situ hybridization (FISH) assay are the most reliable genetic tests but are not widely available.[41] DNA-based testing for the PMP22 duplication (CMT 1A) is widely available and detects more than 98% of patients with CMT 1A (see the image below).[42] Point mutations in the PMP22 gene, which cause fewer than 2% of cases of CMT 1A, are identified by this technique.

Charcot-Marie-Tooth disease type 1A DNA test showi Charcot-Marie-Tooth disease type 1A DNA test showing duplication in short arm of chromosome 17 (A); compared with normal (B).

Genetic testing for CMT 1B 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).

Very rarely, mutations occur in the EGR2 gene or the LITAF gene, causing CMT 1D and CMT 1C, respectively. Molecular genetic testing is also available clinically for these.

The four major subtypes of CMT 2 are indistinguishable clinically and are differentiated 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.

About 90% of cases of CMT X can be detected by means of molecular genetic testing of the GJB1 (Cx32) gene. Such testing is clinically available.

Genetic testing currently is not available for other types of CMT disease.

Imaging Studies

In CMT 1A, high-resolution ultrasonography (US) of the median nerve and other peripheral nerves may serve as an adjunct to electrodiagnosis. Cartwright et al characterized US findings in peripheral nerves of patients with CMT 1B.[43] They found that persons with CMT 1B had larger median and vagus nerves than healthy individuals did, but there was no difference in cranial nerve size between CMT 1B patients who had cranial neuropathies and those who did not.[43]

Magnetic resonance imaging (MRI) of lower-limb muscles is used to follow the progression of the disease in patients with CMT neuropathies.[44]

Electrodiagnostic Studies

Electromyography (EMG) and nerve conduction studies should be performed first if CMT disease is suggested.[45] Findings vary, depending on the type of CMT disease present. In demyelinating types, such as CMT 1, diffuse and uniform slowing of nerve conduction velocities (NCVs) is observed (see the image below).

Nerve conduction study showing decreased nerve con Nerve conduction study showing decreased nerve conduction velocity in median nerve in 18-year-old woman with Charcot-Marie-Tooth disease type 1.

Harding and Thomas criteria for diagnosing CMT 1 include a median motor NCV of less than 38 m/s, with compound motor action potential (CMAP) and amplitude of at least 0.5 mV. No focal conduction block or slowing should be present, unless it is associated with other focal demyelinating processes.

All nerves tested, sensory and motor, show the same degree of marked slowing.

Absolute values for NCV 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, NCV is usually normal, but markedly low amplitudes are noted in sensory nerve (ie, sensory nerve action potential [SNAP]) and motor nerve (ie, CMAP) studies. 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.

Biopsy

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 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 2, axon loss with wallerian degeneration is generally found. In CMT 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.

Histologic Findings

Histologic findings vary according to the type of CMT disease present, as follows:

  • CMT 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
  • CMT 2 - Axonal degeneration is observed
  • CMT 3 - Demyelination with thinning of the myelin sheath can be seen

No inflammatory infiltrate should be present, indicating an autoimmune demyelinating process.

 

Treatment

Approach Considerations

Charcot-Marie-Tooth (CMT) disease continues to be an incurable condition. Patients should be evaluated and treated symptomatically in a multidisciplinary approach by a team that includes the following[46] :

  • Neurologist
  • Physiatrist
  • Orthopedic surgeon
  • Physical therapist
  • Occupational therapist
  • Orthotists
  • Mental health provider
  • Genetic counselor

This approach is crucial for improving the quality of life of CMT patients.[47]  Specialists in neurogenetics may be consulted to order specific genetic tests and proper genetic counseling.

Nonoperative Therapy

Currently, no proven medical 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.[48] Improved understanding of the genetics and biochemistry of the disorder offers hope for an eventual treatment. Animal studies have suggested that targeting myelin lipid metabolism with lipid supplementation may be a potential therapeutic approach in CMT 1A.[49]

An insert with lateral posting and recession under the first ray can provide mechanical stability if the cavovarus deformity is flexible and correctible as tested with the Coleman block test. Additionally, the shoes can have a lateral flare along the outer border of the outsole, which can help in prevent the ankles from rolling over. High-top lace-up shoes can similarly provide additional stability. 

A pilot study by Knak et al suggested that aerobic antigravity exercise may be helpful in patients with CMT 1A or CMT X; however, further evaluation in larger cohorts is needed.[50]

Surgical Therapy

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

Cavovarus feet with heels visible from front ("pee Cavovarus feet with heels visible from front ("peekaboo" sign).
High arch typical of patients with cavus feet. High arch typical of patients with cavus feet.
Both heels showing varus deformity when observed f Both heels showing varus deformity when observed from back.

Surgical procedures consist of the following three types:

  • Soft-tissue procedures (plantar fascia release, tendon release or transfer)
  • Osteotomy (metatarsal, midfoot, calcaneal)
  • Joint-stabilizing procedures (triple arthrodesis)

Procedures are usually staged. The initial procedure is a radical plantar or plantar-medial release-plantar fasciotomy, 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.[51]  In a prospective study of 14 patients with CMT disease who had cavovarus foot deformity, Dreher et al found that tibialis posterior tendon transfer was effective at correcting the foot-drop component of cavovarus foot deformity; the transfer apparently worked as an active substitution.[52]

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 tendon to the first metatarsal head and arthrodesis of the interphalangeal (IP) joint of the great toe.

A review paper by Faldini et al concluded that plantar fasciotomy, midtarsal osteotomy, the Jones procedure, and dorsiflexion osteotomy of the first metatarsal yielded adequate correction of flexible cavus feet in patients with CMT disease in the absence of fixed hindfoot deformity.[53]  

The Coleman block test (see the image below) is sometimes used to help decide what type of surgery is best. In cases of cavovarus deformity, this test evaluates hindfoot flexibility.[54] It 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 plantarflexion and pronation.

Coleman block test showing lack of correction of h Coleman block test showing lack of correction of hindfoot varus malalignment when block is placed under outer border of foot.

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 plantarflexion 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 et al showed that this operation is a valuable salvage procedure in the management of the rigid cavus deformity in children with CMT disease.[55]

Wukich and Bowen reported that only 14% of patients with CMT disease required triple arthrodesis.[56] They also reported hindfoot stability with triple arthrodesis, and when the posterior tibial tendon was transferred 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.

Ward et al studied the long-term results of surgical reconstruction procedures for cavovarus foot deformity in 25 patients with CMT disease who had undergone the procedure between 1970 and 1994 and were evaluated at a mean follow-up of 26.1 years.[57] The authors found that the use of soft-tissue procedures and first metatarsal osteotomy resulted in lower rates of degenerative changes and reoperations in comparison with results obtained with triple arthrodesis.

Generally, spinal deformities in children with CMT disease can be treated with the same techniques used for idiopathic scoliosis.

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, 36]

A study of mitochondrial data from 442 patients suggested that MT-ATP6 mutations are an important cause of CMT disease and can be evaluated with a simple blood test.[58]

Long-Term Monitoring

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]

 

Medication

Medication Summary

Avoid drugs and medications known to cause nerve damage (eg, vincristine,[59] isoniazid, and 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 et al,[60] as well as Ginsberg et al,[61] have described a few individuals with Charcot-Marie-Tooth (CMT) disease type 1 and sudden deterioration in whom treatment with steroids (prednisone) or intravenous immunoglobulin produced variable levels of improvement. Sahenk et al studied the effects of neurotrophin-3 on individuals with CMT 1A.[62]

Passage et al reported benefit from ascorbic acid (vitamin C) in a mouse model of CMT 1.[63]  However, in adult patients with symptomatic CMT 1A, Pareyson et al found that ascorbic acid supplementation (1.5 g/day) had no significant effect on neuropathy compared with placebo after 2 years, suggesting that no evidence supports treatment with ascorbic acid in adults with CMT 1A.[48]  A 2015 Cochrane review did not find evidence of benefit in adults or children.[64]

An exploratory randomized double-blind and placebo-controlled phase 2 study of a combination of baclofen, naltrexone and sorbitol (PXT3003) in patients with CMT 1A confirmed that PXT3003 was a safe and well-tolerated treatment for adults with this condition.[65] The trial enrolled 80 CMT 1A patients in France who were randomly assigned to a low, medium, or high dose of PXT3003 or a placebo for 12 months. On the basis of that result, the PLEO-CMT phase 3 trial (NCT02579759) was conducted.

PLEO-CMT was a 15-month double-blind study that assessed the efficacy and safety of two doses of PXT3003 as compared with placebo in 323 patients (age range, 16-65 years) with mild-to-moderate CMT 1A. It was conducted at 30 sites across the United States, the European Union, and Canada. PXT3003 was given twice daily (morning and evening) with food as a liquid formulation. The higher dose contained baclofen 12 mg, naltrexone 1.4 mg, and sorbitol 420 mg; the lower contained baclofen 6 mg, naltrexone 0.7 mg, and sorbitol 210 mg. Official study results have not been published as of early spring 2019; however, the study sponsor, Pharnext, states that PXT3003 consistently eased disability in these patients.

An animal study published in 2019 found that early short-term PXT3003 combinational therapy delayed disease onset in a transgenic rat model of CMT 1A.[66] These results may suggest that PXT3003 therapy may be a bona fide option for children and young adolescent patients suffering from CMT 1A.

Nonsteroidal anti-inflammatory drugs

Class Summary

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.

Ibuprofen (Motrin, Ibuprin)

DOC for patients with mild to moderate pain. Inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Naproxen (Naprelan, Naprosyn, Anaprox)

For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.

Cyclooxygenase-2 inhibitors

Class Summary

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.

Celecoxib (Celebrex)

Inhibits primarily COX-2. COX-2 is considered an inducible isoenzyme, induced during pain and inflammatory stimuli. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited and thus, GI toxicity may be decreased. Seek lowest dose of celecoxib for each patient.

Tricyclic antidepressants

Class Summary

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.

Amitriptyline (Elavil)

Analgesic for certain chronic and neuropathic pain. Inhibits membrane pump responsible for uptake of norepinephrine and serotonin in adrenergic and serotonergic neuron.

Nortriptyline (Pamelor)

Has demonstrated effectiveness in the treatment of chronic pain. By inhibiting the reuptake of serotonin and/or norepinephrine by the presynaptic neuronal membrane, this drug increases the synaptic concentration of these neurotransmitters in the central nervous system.

Pharmacodynamic effects, such as the desensitization of adenyl cyclase and down-regulation of beta-adrenergic receptors and serotonin receptors, also appear to play a role in its mechanisms of action.

Doxepin (Sinequan)

Inhibits histamine and acetylcholine activity and has proven useful in treatment of various forms of depression associated with chronic and neuropathic pain.

Desipramine (Norpramin)

May increase synaptic concentration of norepinephrine in CNS by inhibiting reuptake by presynaptic neuronal membrane. May have effects in the desensitization of adenyl cyclase, down-regulation of beta-adrenergic receptors, and down-regulation of serotonin receptors.

Anticonvulsants

Class Summary

Used to manage pain and provide sedation in neuropathic pain.

Gabapentin (Neurontin)

Membrane stabilizer, a structural analogue of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), which paradoxically is thought not to exert effect on GABA receptors. Appears to exert action via the alpha(2)delta1 and alpha(2)delta2 subunit of the calcium channel.

Analgesics

Class Summary

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

Acetaminophen (Tylenol)

DOC for pain in patients with documented hypersensitivity to aspirin or NSAIDs, with upper GI disease, or who are taking oral anticoagulants.

 

Questions & Answers

Overview

How is Charcot-Marie-Tooth (CMT) characterized?

What is the historical background of Charcot-Marie-Tooth (CMT) disease?

What is Charcot-Marie-Tooth (CMT) disease?

What is Charcot-Marie-Tooth (CMT) disease type 1?

What is the pathophysiology of Charcot-Marie-Tooth (CMT) disease type 1?

What causes onion bulb appearance in Charcot-Marie-Tooth (CMT) disease type 1?

What is Charcot-Marie-Tooth (CMT) disease type 2?

What is Charcot-Marie-Tooth (CMT) disease type 3?

What are Charcot-Marie-Tooth (CMT) disease types X and 4?

What causes Charcot-Marie-Tooth (CMT) disease?

What are the subtypes of hereditary motor and sensory neuropathy (HMSN) I?

What is hereditary motor and sensory neuropathy (HMSN) III?

What is hereditary motor and sensory neuropathy (HMSN) IV?

What are the subtypes of hereditary motor and sensory neuropathy (HMSN) II?

What are hereditary motor and sensory neuropathies (HMSNs) V, VI, and VII?

What is the prevalence of Charcot-Marie-Tooth (CMT) disease in the US?

What is the prevalence of Charcot-Marie-Tooth (CMT) disease in Japan, Italy, and Spain?

What is the prevalence of Charcot-Marie-Tooth (CMT) disease in Norway?

What is the prognosis of Charcot-Marie-Tooth (CMT) disease?

What is the Charcot-Marie-Tooth (CMT) disease neuropathy score?

What is the role of genetic counseling in patient education for Charcot-Marie-Tooth (CMT) disease?

Which drugs and medications should patients with Charcot-Marie-Tooth (CMT) disease avoid?

What activity modifications are beneficial in the management of Charcot-Marie-Tooth (CMT) disease?

How does obesity affect patients with Charcot-Marie-Tooth (CMT) disease?

What is the role of stretching in the management of Charcot-Marie-Tooth (CMT) disease?

Presentation

What is characteristic about the history of patients with Charcot-Marie-Tooth (CMT) disease?

Which factor affects the age of presentation of Charcot-Marie-Tooth (CMT) disease?

What is the manifestation of muscle weakness in Charcot-Marie-Tooth (CMT) disease?

How does muscle weakness progress in Charcot-Marie-Tooth (CMT) disease?

What are the symptoms of structural foot abnormalities in Charcot-Marie-Tooth (CMT) disease?

What are the symptoms of hand muscle weakness in Charcot-Marie-Tooth (CMT) disease?

Do patients with Charcot-Marie-Tooth (CMT) disease experience numbness?

Do patients with Charcot-Marie-Tooth (CMT) disease experience pain or muscle cramping?

What are the autonomic symptoms of Charcot-Marie-Tooth (CMT) disease?

Which physical findings suggest distal muscle wasting in Charcot-Marie-Tooth (CMT) disease?

Which bony abnormalities suggest Charcot-Marie-Tooth (CMT) disease?

What is the prevalence of spinal deformities in patients with Charcot-Marie-Tooth (CMT) disease?

How are deep tendon reflexes (DTRs) affected in Charcot-Marie-Tooth (CMT) disease?

What is the role of a Romberg test in the diagnosis of Charcot-Marie-Tooth (CMT) disease?

What are possible complications of Charcot-Marie-Tooth (CMT) disease?

What are the complications of Charcot-Marie-Tooth (CMT) disease during delivery?

DDX

Which conditions should be considered in the differential diagnoses of Charcot-Marie-Tooth (CMT) disease?

What are the differential diagnoses for Charcot-Marie-Tooth Disease?

Workup

What is the role of routine lab tests in the evaluation of Charcot-Marie-Tooth (CMT) disease?

What is the role of DNA tests in the diagnosis of Charcot-Marie-Tooth (CMT) disease?

What is the role of genetic tests in the diagnosis of Charcot-Marie-Tooth (CMT) disease?

Which genetic tests are available for the diagnosis of Charcot-Marie-Tooth (CMT) disease?

What is the role of ultrasonography (US) in the workup of Charcot-Marie-Tooth (CMT) disease?

What is the role of magnetic resonance imaging (MRI) in the workup of Charcot-Marie-Tooth (CMT) disease?

What is the role of electromyography (EMGs) in the workup of Charcot-Marie-Tooth (CMT) disease?

What are the Harding and Thomas criteria for the diagnosis of Charcot-Marie-Tooth (CMT) disease type 1?

Which electromyographic (EMG) results are characteristic of Charcot-Marie-Tooth (CMT) disease?

What are the nerve conduction velocities (NCVs) for Charcot-Marie-Tooth (CMT) disease type 1?

Which nerve conduction velocities (NCVs) are characteristic of neuronal types of Charcot-Marie-Tooth (CMT) disease?

What is the role of nerve biopsy in the workup of Charcot-Marie-Tooth (CMT) disease?

Which nerve biopsy findings suggest Charcot-Marie-Tooth (CMT) disease type 1?

Which nerve biopsy findings suggest Charcot-Marie-Tooth (CMT) disease type 2?

Which histologic findings suggest Charcot-Marie-Tooth (CMT) disease?

Treatment

Which physicians should be included in a multidisciplinary approach to management of Charcot-Marie-Tooth (CMT) disease?

Why should patients with Charcot-Marie-Tooth (CMT) disease be treated by a multidisciplinary team?

Can nonoperative treatments reverse or slow Charcot-Marie-Tooth (CMT) disease?

What treatments may provide mechanical stability for patients with Charcot-Marie-Tooth (CMT) disease?

What is the role of surgery in the treatment of Charcot-Marie-Tooth (CMT) disease?

What are the surgical options for correction of flexible cavus feet in Charcot-Marie-Tooth (CMT) disease?

Which surgical procedures are used in the treatment of Charcot-Marie-Tooth (CMT) disease?

What is the initial procedure for the treatment of Charcot-Marie-Tooth (CMT) disease?

What is the role of posterior tibial tendon transfer in the treatment of Charcot-Marie-Tooth (CMT) disease?

What is the role of soft-tissue release in the surgical treatment of Charcot-Marie-Tooth (CMT) disease?

What is the role of the Coleman block test in the treatment of Charcot-Marie-Tooth (CMT) disease?

What are the indications for surgical correction of the hindfoot in Charcot-Marie-Tooth (CMT) disease?

What is the role of triple arthrodesis in the treatment of Charcot-Marie-Tooth (CMT) disease?

How are children with Charcot-Marie-Tooth (CMT) disease and supple hindfeet treated?

How are children with Charcot-Marie-Tooth (CMT) disease and rigid hindfoot deformities treated?

What is the role of Akron dome osteotomy in the treatment of Charcot-Marie-Tooth (CMT) disease?

What is the efficacy of triple arthrodesis for the treatment of Charcot-Marie-Tooth (CMT) disease?

What is the efficacy of soft-tissue procedures in the treatment of Charcot-Marie-Tooth (CMT) disease?

How are spinal deformities in children with Charcot-Marie-Tooth (CMT) disease treated?

How are joint contractures and deformities prevented in Charcot-Marie-Tooth (CMT) disease?

What are the benefits of Charcot-Marie-Tooth (CMT) disease genetic counseling?

How can MT-ATP6 mutations be identified in Charcot-Marie-Tooth (CMT) disease?

What is included in long-term monitoring of Charcot-Marie-Tooth (CMT) disease?

Medications

Which medications are used in the treatment of Charcot-Marie-Tooth (CMT) disease?

What is the role of prednisone in the treatment of Charcot-Marie-Tooth (CMT) disease?

What is the role of ascorbic acid (vitamin C) in the treatment of Charcot-Marie-Tooth (CMT) disease?

Which medications in the drug class Analgesics are used in the treatment of Charcot-Marie-Tooth Disease?

Which medications in the drug class Anticonvulsants are used in the treatment of Charcot-Marie-Tooth Disease?

Which medications in the drug class Tricyclic antidepressants are used in the treatment of Charcot-Marie-Tooth Disease?

Which medications in the drug class Cyclooxygenase-2 inhibitors are used in the treatment of Charcot-Marie-Tooth Disease?

Which medications in the drug class Nonsteroidal anti-inflammatory drugs are used in the treatment of Charcot-Marie-Tooth Disease?