Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease 

Updated: Feb 06, 2019
Author: Divakara Kedlaya, MBBS; Chief Editor: Elizabeth A Moberg-Wolff, MD 

Overview

Background

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.

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.[3, 4]  PMP22 -related neuropathies should be viewed as the consequence of impaired neuron–Schwann cell interactions that are likely to be operative during fetal development.[5]

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.[6]

Mutation in the gene encoding the major peripheral nervous system myelin protein, myelin protein zero (MPZ),[7, 8] 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), CMT neuropathy) account for 60-70% of families with CMT.[9]

Slowing of conduction in motor and sensory nerves was believed to cause weakness and numbness. A study by Krajewski and colleagues suggested that neurologic dysfunction and clinical disability in CMT-1A are caused by loss or damage to large-diameter motor and sensory axons.[10] 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.[11] Some cases of CMT-2 have also been linked to mutations in the MPZ gene.[12] 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.[13]  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.[14]

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.[15] CMT-1 incidence is 15 persons per 100,000 population. CMT-1A incidence is 10.5 persons per 100,000 population, or 70% of CMT-1 cases. CMT-2 incidence is 7 persons per 100,000 population. CMT-X represents at least 10-20% of persons with the CMT syndrome.

International

In Japan, the prevalence of CMT is reportedly 10.8 cases per 100,000 population.[16] In Italy, the prevalence is reported to be 17.5 cases per 100,000 population,[17] 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.[18]

Mortality/Morbidity

Morbidity in Charcot-Marie-Tooth disease (CMT) is mainly secondary to distal muscle weakness and foot deformities.[19, 20] Neuropathic pain is also one of the reasons for significant morbidity.[21] 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.

 

Presentation

History

Patients usually have a significant family history of Charcot-Marie-Tooth disease (CMT).[22] This history varies, depending on the inheritance and penetrance pattern of the particular disorder. Spontaneous mutations also have been reported.

Slow-progressing weakness beginning in the distal limb muscles, typically in the lower extremities before the upper extremities, generally is noted.[20] The most common clinical phenotype is the CMT syndrome with distal muscle wasting and weakness, tendon areflexia, usually mild sensory loss, and foot deformity.[23] A subgroup of patients with CMT-1A can present with proximal muscle wasting and weakness.[24] Cranial nerve deficits in a member of a CMT-1 family carrying an EGR2 mutation have been reported.[25]

  • Onset usually is in the first 2 decades of life.

  • Patients' initial complaints may be difficulty walking and frequent tripping because of foot and distal leg weakness. Frequent ankle sprains and falls are characteristic.[20]

  • Parents may report that a child is clumsy or simply not very athletic.

  • As weakness becomes more severe, foot drop commonly occurs. Steppage (ie, gait in which patient must lift the leg in an exaggerated fashion to clear the foot off the ground) also is common.[20]

  • Intrinsic foot muscle weakness commonly results in the foot deformity known as pes cavus.[19, 20] Symptoms related to structural foot abnormalities include calluses, ulcers, cellulitis, or lymphangitis.

  • Hand weakness results in complaints of poor finger control, poor handwriting, difficulty using zippers and buttons, and clumsiness in manipulating small objects.[26, 27, 28]

  • Patients usually do not complain of numbness. This phenomenon may be due to the fact that CMT patients will have never had normal sensation and therefore, simply do not perceive their lack of sensation.

  • Musculoskeletal pain may be present due to significant deformities. Neuropathic pain is also quite common and can cause significant disability.[21, 29, 30] Muscle cramping is a common complaint.

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

A prospective cohort study by Kennedy et al conservatively estimated that the incidence of falls in children and adolescents with Charcot-Marie-Tooth disease (CMT) is 33 times greater than that of peers undergoing typical development. Moreover, falls in the study’s patients with CMT more commonly resulted in injury than did those in the control group (34.2% of falls vs 11.5%, respectively).[31]

Physical

In patients with Charcot-Marie-Tooth disease (CMT), 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 include the following:

  • In 25% of cases, pes cavus (high-arch foot), which is probably analogous to the development of claw hand in ulnar nerve lesion, occurs in the first decade of life; in 67% of cases it arises in later decades. Other foot deformities also can occur (see following images).[19, 20]

    Foot deformities in a 16-year-old boy with Charcot Foot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A.
    Foot of 29-year-old with advanced Charcot-Marie-To Foot of 29-year-old with advanced Charcot-Marie-Tooth disease type 1.
  • Hand deformities can occur with wasting of intrinsic hand muscles and claw hand. See the following image.

    Hands of 29-year-old with advanced Charcot-Marie-T Hands of 29-year-old with advanced Charcot-Marie-Tooth disease type 1.
  • Spinal deformities (eg, thoracic scoliosis) occur in 37-50% of patients with CMT-1.

Other characteristics of CMT include the following:

  • Deep tendon reflexes (DTRs) are markedly diminished or absent
  • Vibration sensation and proprioception are decreased significantly, although patients usually have no sensory symptoms
  • Patients may have sensory gait ataxia, and Romberg test is usually positive
  • Sensation of pain and temperature usually is intact
  • Essential tremor is present in 30-50% of CMT patients
  • Sensory neuronal hearing loss is observed in 5% of patients [32, 33]
  • Enlarged and palpable peripheral nerves are common
  • Phrenic nerve involvement with diaphragmatic weakness is rare, but it has been described
  • Vocal cord involvement and hearing loss can occur in rare forms of CMT [32, 33]

A study by Reynaud et al indicated that in patients with CMT-1A, the isokinetic muscle strength (IMS) of the knee extensors correlates with walking speed, while for patients under age 50 years, IMS of the knee flexors also relates to speed.[34]

Causes

Hereditary neuropathies are classified by Mendelian Inheritance in Man (MIM). More than 900 mutations in 60 genes are associated with the disease.[35, 36] The list can be found at http://www.molgen.vib-ua.be/CMTMutations/Home/IPN.cfm.

Table. 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.)

17p11.2; AD*

First decade

Distal weakness

15-20 m/s

CMT-1B (P0 -MPZ)**

1q23.3; AD

First decade

Distal weakness

< 20 m/s

CMT-1C (non-A, non-B) (LITAF)

16p13.13;AD

Second decade

Distal weakness

26-42 m/s

CMT-1D (EGR-2)#

10q21.3; AD

First decade

Distal weakness

15-20 m/s

CMT-1E (PMP22)

17p11.2; AD

First decade

Distal weakness, deafness

15-20 m/s

CMT-1F (NEFL)

8p21.2; AD

First decade

Distal weakness

15-20 m/s

CMT-X (connexin-32)[37, 38, 39, 40]

Xq13; XD‡

Second decade

Distal weakness

25-40 m/s

CMT-2A

1p36; AD

10 y

Distal weakness

>38 m/s

CMT-2B

3q21; 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

8q21; AD

15-25 y

Distal weakness, pyramidal features

Axon loss; N

CMT-2I

1q23; AD

47-60 y

Distal weakness

Axon loss; N

CMT-2J

1q23; AD

40-50 y

Distal weakness, hearing loss

Axon loss; N

CMT-2K

8q13-q21; AD

< 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 deletion)[41]

or tomaculous neuropathy

17p11; AD

All ages

Episodic weakness and numbness

Conduction Blocks

Dejerine-Sottas-syndrome (DSS) or HMSN-3[42]

P0; AR

PMP-22; AD

8q23; AD

2 y

Severe weakness

< 10 m/s

Congenital

hypomyelination (CH)

P0, EGR-2 or PMP-22

AR

Birth

Severe weakness

< 10 m/s

CMT-4A[43]

8q13; AR

Childhood

Distal weakness

Slow

CMT-4B

(myotubularin- related

protein 2)[44, 45]

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 (EGR-2)

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

The above classification is the most specific, up-to-date, and comprehensive classification for Charcot-Marie-Tooth disease (CMT). In the past, CMT was classified as hereditary motor and sensory neuropathy (HMSN).[46, 47] Hereditary neuropathy with diffusely slow nerve conduction velocity (hypertrophic neuropathy) is HMSN-I.

  • HMSN-I (CMT-1) with different subclassifications.[48]

  • 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 cerebrospinal fluid (CSF) protein

  • Hereditary motor and sensory neuropathy with normal or borderline abnormal nerve conduction velocity (neuronal or axonal type)[49] :

    • HMSN-II (CMT-2)

      • CMT-2A - Chromosome 1(p35-36) - Typical type, no enlarged nerves, later onset of symptoms, feet more severely affected than hands

      • CMT-2B - Chromosome 3(q13-22) - Typical type with axonal spheroids

      • CMT-2C - Not linked to any known loci; diaphragm and vocal cord weakness

      • CMT-2D - Chromosome 7(p14) - Muscle weakness and atrophy is more severe in hands than 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

A study by Rose et al of 30 pediatric patients with CMT indicated that a significant association exists between functional ankle instability in children with disease and cavus foot structure, female sex, and impaired balance.[50]  

 

DDx

Diagnostic Considerations

These include the following:

  • Acquired nongenetic causes of peripheral neuropathies

  • Vitamin B-12 deficiency

  • 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 Charcot-Marie-Tooth syndrome.

Differential Diagnoses

 

Workup

Laboratory Studies

Results of all routine laboratory tests are within the reference range in Charcot-Marie-Tooth disease (CMT). Specific genetic tests are available for some types of CMT. A study by Murphy et al demonstrates that a molecular diagnosis can currently be achieved in over 60% of patients with CMT.[51] A molecular diagnosis is much more likely in patients with CMT-1 rather than CMT-2. Four genes commonly available for testing, PMP22 ( CMT-1A-PMP22 gene duplication; HNPP-PMP22 gene deletion), GJB1 ( CMT-1X), MPZ ( CMT-1B ), and MFN2 ( CMT-2A) account for over 90% of all CMT molecular diagnoses.

It is possible to narrow down the most likely gene based on nerve conduction studies and family history. Flow charts have been published using nerve conduction velocities to direct genetic testing, usually with the aid of family history information.[52]

  • CMT-1A - Pulsed-field gel electrophoresis or a specialized fluorescent in situ hybridization (FISH) assay is the most reliable genetic test to detect PMP22 gene duplication in CMT-1A and PMP22 gene deletion in HNPP.[53] DNA-based testing for the PMP22 duplication (CMT-1A) is widely available and detects more than 98% of patients with CMT-1A (see following image). Point mutations in the PMP-22 gene cause fewer than 2% of cases of CMT-1A and are identified by this technique. Approximately 70-80% of cases of CMT-1 are designated as CMT-1A, caused by duplication of the PMP-22 gene (locus 17p11).[3, 54] See the image below.

    Charcot-Marie-Tooth disease type 1A DNA test showi Charcot-Marie-Tooth disease type 1A DNA test showing duplication in the short arm of chromosome 17 (A) compared with normal (B).
  • 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 is designated CMT-1B and is caused by a point mutation in the myelin P0 protein (MPZ) gene (chromosomal locus 1q22).[7, 55]

  • CMT-1C and CMT-1D - Very rarely, mutations occur in the EGR-2 (early growth response 2) gene or in the LITAF gene, causing CMT-1D and CMT-1C, respectively, for which molecular genetic testing also is clinically available.

  • CMT-2 - Clinically indistinguishable, the 4 subtypes of CMT-2 are distinguished solely from genetic linkage findings. The relative proportions of CMT-2A, CMT-2B, CMT-2C, and CMT-2D have not yet been determined. The chromosomal loci for CMT-2A, CMT-2B, CMT-2C, CMT-2D, CMT-2E, CMT-2F, CMT-2G, and CMT-2L have been mapped, but the genes have not been identified. Molecular genetic testing is clinically available only for CMT-2A, CMT-2B1, CMT-2E, and CMT-2F.

  • CMT-X - Molecular genetic testing of the GJB1 (Cx32) gene detects about 90% of cases. Such testing is clinically available.

Imaging 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.[56, 57, 58, 59, 60, 61]

Other Tests

Nerve biopsy rarely is indicated for the diagnosis of Charcot-Marie-Tooth disease (CMT), especially because genetic testing is available. Biopsies sometimes are performed in cases of diagnostic dilemmas. Findings vary in different types of CMT, as follows:

  • 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, made up of circumferentially directed Schwann cells and their processes, frequently is observed.

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

Procedures

Electromyography/nerve conduction study (EMG/NCS)[56, 57, 58, 59, 60, 61]

  • If Charcot-Marie-Tooth disease (CMT) is suggested, perform an 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 (see following images).

    Nerve conduction study showing decreased nerve con 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.
    Right ulnar motor nerve conduction study in a 29-y Right ulnar motor nerve conduction study in a 29-year-old patient with advanced Charcot-Marie-Tooth disease type 1.
    Left ulnar motor nerve conduction study in 29-year Left ulnar motor nerve conduction study in 29-year-old patient with advanced Charcot-Marie-Tooth disease type 1.
  • Harding and Thomas criteria for diagnosing CMT-1 include median motor nerve conduction velocity of less than 38 meters per second (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 sensory and motor nerves that are tested 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 in Dejerine-Sottas disease and congenital hypomyelination. Slowing of nerve conduction can also be found in asymptomatic individuals. In X- linked CMTs, motor nerve conduction velocities are faster than in CMT1A.[62]

  • 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, CMAP) nerve studies.

  • In neuronal (ie, axonal) types of CMT, increased insertional activity is evident, with fibrillation potentials and positive sharp waves seen. Motor unit potentials show decreased recruitment patterns and neuropathic changes in morphology.

Histologic Findings

In Charcot-Marie-Tooth disease type 2 (CMT-1), peripheral nerves contain few myelinated fibers, intramuscular nerves are surrounded by a rich connective tissue and hyperplastic neurilemma, and lengths of myelin are atrophic along the fibers.

Concentric hypertrophy of the lamellar sheaths is seen. Formation of the typical onion bulb, made up of circumferentially directed Schwann cells and their processes, is noted.

In CMT-2, axonal degeneration is observed.

In CMT-3, Dejerine-Sottas disease, demyelination with thinning of the myelin sheath can be seen.[63]

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

 

Treatment

Rehabilitation Program

Physical Therapy

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).[64]

Patients often require an AFO to correct foot drop and to aid walking.[65] It is important to address the biomechanical needs of a CMT patient, since there may be bilateral strength differences due to progression of the disease. Optimizing the mechanical characteristics of the AFO to patient needs can be challenging. One strategy is to design AFOs of varying stiffness and allow patients to experience range energy storage and release characteristics prior to selecting the stiffness they prefer.

Patients with CMT discard AFOs because they highlight their disability, are not essential for their limited daily walking, and are uncomfortable. Prescription of AFOs should be accompanied with psychological support, noting that research of more comfortable and cosmetically acceptable solutions for the problem of footdrop in CMT is ongoing.[66]

Patients with CMT who regularly wore AFOs were more severely affected, had a slower maximum walking speed, higher energy cost of walking, and worse perceived walking ability.[67]

Custom carbon-fiber composite AFOs have been reported to improve gait of CMT patients[68] AFO prescription appears relevant for improving balance and gait performance in CMT patients, particularly when the model adequately compensates for specific muscle deficits. Custom polypropylene AFOs have shown to improve walking speed and gait parameters in patients with CMT.[69, 70]

Transcutaneous electrical nerve stimulator (TENS) units can be used to improve muscle functions in patients with CMT.[71]

Some patients require the use of forearm crutches or a cane for improved gait stability, but fewer than 5% of patients need wheelchairs. Advise patients with Charcot-Marie-Tooth disease (CMT) about weight management, because obesity makes ambulation more difficult. Encourage exercise within each individual patient's capability.[72] Most patients with CMT usually remain physically active.

A literature review by Sman et al suggested that even though studies have shown exercise-related strength and function changes in patients with CMT, these results should be considered cautiously since few such studies are available and their quality of evidence is only moderate.[73]

Occupational Therapy

An occupational therapist may recommend the use of adaptive equipment for activities of daily living (ADL) and self-care. Fitting of a proper orthosis and keeping the wrist and hand in functional position may be required. Vocational and avocational training regarding the importance of career and employment implications may be needed because of persistent weakness of the hands and/or feet.[26, 27]

Medical Issues/Complications

In Charcot-Marie-Tooth disease (CMT), no treatment currently exists to reverse or slow the natural disease process for the underlying disorder. Nothing can correct the abnormal myelin, prevent the myelin's degeneration, or prevent axonal degeneration.

Stem-cell and gene-transfer therapies are the most promising forms of treatment for the cure of CMT.[74] Some promising results have been reported for antiprogesterone therapy and ascorbic acid treatment for CMT-1A in animal CMT-1A models. Progesterone-receptor antagonists have reduced PMP-22 overexpression and clinical severity in a CMT-1A rat model. Furthermore, ascorbic acid treatment reduced premature death and demyelination in a CMT-1A mouse model. (A literature review by Gess et al, however, suggested that ascorbic acid does not improve outcomes in adults with CMT-1A, as measured by the neuropathy score at 12 months.[75] ) There is also the prospect of developing drugs to reduce the effects of PMP-22 overexpression in gene duplications by down-regulation via the promoter. Improved understanding of the genetics and biochemistry of the disorder offers hope for an eventual treatment.

Charcot-Marie-Tooth disease increases the risk for complications during delivery, which is linked to a higher occurrence of emergency interventions during birth.[76]

Patients often are evaluated and managed symptomatically by a team that includes a physiatrist, a neurologist, an orthopedic surgeon, and physical and occupational therapists.

Surgical Intervention

Orthopedic surgery may be required to correct severe pes cavus deformities, scoliosis, and other joint deformities.[19, 77, 78]

Consultations

Consult a specialist in neurogenetics to order specific genetic tests and proper genetic counseling.

 

Medication

Medication Summary

Avoid drugs and medications known to cause nerve damage (eg, vincristine,[79, 80] 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[81] and Ginsberg and coauthors[82] described a few individuals with Charcot-Marie-Tooth disease type 1 (CMT-1) and sudden deterioration in whom treatment with steroids (prednisone) or intravenous immunoglobulin produced variable levels of improvement.

Sahenk and colleagues had studied the effects of neurotrophin-3 (NT3), a neurotrophic factor, on individuals with CMT-1A. It was known to promote axonal growth and was tested with favorable results in 2 animal models and in a pilot study involving 8 CMT-1A patients.[83, 84]

Passage and coauthors[85] reported therapeutic benefits from the administration of ascorbic acid (vitamin C) in a mouse model of CMT-1. Based on these results, clinical trials were undertaken at different centers worldwide, and 4 of them have been completed; unfortunately, however, none of them resulted in significant clinical improvements.[86, 87, 88, 89]

The progesterone antagonist onapristone proved to be effective in a rat model of CMT-1A; unfortunately, currently available progesterone antagonists are too toxic to be safely used in humans.[90, 91, 92]

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 in 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; thus, GI toxicity may be decreased. Seek lowest dose of celecoxib for each patient.

Analgesics

Class Summary

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

Tricyclic Antidepressants

Class Summary

A complex group of drugs that has central and peripheral anticholinergic effects, as well as sedative effects. They 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 or 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.

 

Follow-up

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.[65]

Deterrence

Regular and proper follow-up and therapeutic interventions are necessary to avoid joint contractures and deformities.[65]

Proper genetic counseling helps parents to understand the risk of having a child with this disorder and gives them a chance to make informed decisions about having children.

Use of Vincristine is clearly contraindicated in patients with known or possible CMT-1A and most likely HNPP. Use of vincristine in other CMT subtypes should be considered with caution. Other agents that have reported to exacerbate CMT-related neuropathy in the Charcot-Marie-Tooth Association (CMTA) database include nitrous oxide, metronidazole, nitrofurantoin, phenytoin, statins and sertraline.[93]

Complications

Due to a loss of protective sensation distally in all 4 limbs, patients with Charcot-Marie-Tooth disease (CMT) are susceptible to skin breakdown, burns, nonhealing foot ulcers, and in severe cases, bony, bilateral foot deformities. As mentioned previously, orthoses are required for the treatment of foot drop or to accommodate bony foot deformities. If not fit properly, the orthoses themselves become a source of skin breakdown secondary to associated distal sensory impairment.

Maternal CMT increases the risk for complications during delivery; this risk is linked to a higher occurrence, in such cases, of emergency interventions during birth.

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.[94] 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.[95]

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.[96]

Certain drugs and medications, such as vincristine,[79, 80] 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.

 

Questions & Answers

Overview

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

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

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

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

What is the morbidity associated with Charcot-Marie-Tooth disease (CMT)?

What are the racial predilections of Charcot-Marie-Tooth disease (CMT)?

What are the sex predilections of Charcot-Marie-Tooth disease (CMT)?

Which age group has the highest incidence of Charcot-Marie-Tooth disease (CMT) onset?

Presentation

Which clinical history findings are characteristic in Charcot-Marie-Tooth disease (CMT)?

Which physical findings are characteristic of Charcot-Marie-Tooth disease (CMT)?

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

DDX

Which conditions are included in the differential diagnoses of Charcot-Marie-Tooth disease (CMT)?

What are the differential diagnoses for Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease?

Workup

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

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

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

What is the role of EMG/NCS in the workup of Charcot-Marie-Tooth disease (CMT)?

Which histologic findings are characteristic of Charcot-Marie-Tooth disease (CMT)?

Treatment

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

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

What is the role of stem-cell and gene-transfer therapies in the treatment of Charcot-Marie-Tooth disease (CMT)?

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

Which specialist consultations are beneficial to patients with Charcot-Marie-Tooth disease (CMT)?

Medications

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

Which medications in the drug class Anticonvulsants are used in the treatment of Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease?

Which medications in the drug class Tricyclic Antidepressants are used in the treatment of Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease?

Which medications in the drug class Analgesics are used in the treatment of Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease?

Which medications in the drug class Cyclooxygenase-2 Inhibitors are used in the treatment of Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease?

Which medications in the drug class Nonsteroidal Anti-inflammatory Drugs are used in the treatment of Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease?

Follow-up

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

How is Charcot-Marie-Tooth disease (CMT) prevented?

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

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

What is included in the patient education about Charcot-Marie-Tooth disease (CMT)?