Physical Medicine and Rehabilitation for Charcot-Marie-Tooth Disease Clinical Presentation

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

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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]

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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]  

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