Charcot-Marie-Tooth Disease Clinical Presentation

  • Author: Divakara Kedlaya, MBBS; Chief Editor: Jason H Calhoun, MD, FACS   more...
 
Updated: Jul 7, 2011
 

History

  • Patients have a significant family history. This history varies depending on the inheritance and penetrance pattern of the particular disorder (see Table). Spontaneous mutations also have been reported.
  • Slowly progressing weakness beginning in the distal limb muscles generally is noted; it typically occurs in the lower extremities before it affects the upper ones. A subgroup of patients with Charcot-Marie-Tooth type 1A may present with proximal muscle wasting and weakness.
  • Onset usually occurs in the first 2 decades of life.
  • Patients initially may complain of difficulty walking and frequent tripping due to foot and distal leg weakness. Frequent ankle sprains and falls are characteristic.
  • Parents may report that a child is clumsy or simply not very athletic.
  • As weakness becomes more severe, foot drop commonly occurs. Steppage (that is, gait in which the individual must lift the leg in an exaggerated fashion to clear the foot off of the ground) also is common.
  • Intrinsic foot muscle weakness commonly results in the foot deformity known as pes cavus. Symptoms related to structural foot abnormalities include calluses, ulcers, cellulitis, and lymphangitis.
  • Hand weakness results in complaints of poor finger control, poor handwriting, difficulty using zippers and buttons, and clumsiness in manipulating small objects.
  • Patients usually do not complain of numbness. This may be because patients with CMT disease never had normal sensation and, therefore, simply do not perceive their lack of sensation.
  • Pain (musculoskeletal and neuropathic types) may be present. Muscle cramping is a common complaint.[20]
  • Autonomic symptoms usually are absent, but a few men with CMT disease have reported impotence.
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Physical

Distal muscle wasting may be noted in the legs, resulting in the characteristic stork leg or inverted champagne bottle appearance.

Bony abnormalities commonly seen in long-standing Charcot-Marie-Tooth disease include the following:

  • Pes cavus (high-arch foot), probably analogous to the development of claw hand in ulnar nerve lesion, has a 25% occurrence rate in the first decade of life and a 67% occurrence rate in later decades. Selective denervation of intrinsic foot musculature, particularly of the lumbricals, and not imbalance of lower-leg muscles seems to be the initial mechanism that causes reduced ankle flexibility and forefoot cavus deformity.[65] Other foot deformities also can occur (see image below). Foot deformities in a 16-year-old boy with CharcotFoot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A.

Spinal deformities (eg, thoracic scoliosis) occur in 37-50% of patients with CMT type 1.

Deep tendon reflexes (DTRs) are markedly diminished or are absent.

Vibration sensation and proprioception are significantly decreased, but patients usually have no sensory symptoms.

Patients may have sensory gait ataxia, and a Romberg test usually is positive.

Sensation of pain and temperature is usually intact.

Essential tremor is present in 30-50% of patients with CMT disease.

Sensory neuronal hearing loss is observed in 5% of patients.

Enlarged and palpable peripheral nerves are common.

Phrenic nerve involvement with diaphragmatic weakness is rare but has been described.

Vocal cord involvement and hearing loss can occur in rare forms of CMT disease.

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Causes

Hereditary neuropathies are classified by Mendelian Inheritance in Man (MIM). Table. Charcot-Marie-Tooth Disorders: Genetic and Clinical Feature Comparison

(Open Table in a new window)

CMT TypeChromosome; Inheritance PatternAge of OnsetClinical FeaturesAverage NCVs§
CMT 1A (PMP-22 dupl.)17p11; AD*First decadeDistal weakness15-20 m/s
CMT 1B (P0 -MPZ)**1q22; ADFirst decadeDistal weakness< 20 m/s
CMT 1C (non A, non B)16p13;ADSecond decadeDistal weakness26-42 m/s
CMT 1D (early growth response [EGR]–2)#[21] 10q21; ADFirst decadeDistal weakness15-20 m/s
CMT 1E17p11; ADFirst decadeDistal weakness, deafness15-20 m/s
CMT 1F8p21; ADFirst decadeDistal weakness15-20 m/s
CMT X (Connexin-32)[22, 23, 24, 25, 26] Xq13; XD‡Second decadeDistal weakness25-40 m/s
CMT 2A1p36; AD10 yDistal weakness>38 m/s
CMT 2B3q; ADSecond decadeDistal weakness,



sensory loss, skin ulcers



Axon loss; Normal
CMT 2C12q23-q24, ADFirst decadeVocal cord, diaphragm, and



distal weakness



>50 m/s
CMT 2D7p14; AD16-30 yDistal weakness, upper limb predominantlyAxon loss; N††
CMT 2E8p21; AD10-30 yDistal weakness, lower limb predominantlyAxon loss; N
CMT 2F7q11-q21; AD15-25 yDistal weaknessAxon loss; N
CMT 2G12q12-q13; ?AD9-76 yDistal weaknessAxon loss; N
CMT 2H?; AR†15-25 yDistal weakness, Pyramidal featuresAxon loss; N
CMT 2I1q22; AD47-60 yDistal weaknessAxon loss; N
CMT 2J1q22; AD40-50 yDistal weakness, hearing lossAxon loss; N
CMT 2K8q13-q21; AR< 4 yDistal weaknessAxon loss; N
CMT 2L12q24; AD15-25 yDistal weaknessAxon loss; N
CMT R-Ax (Ouvrier)ARFirst decadeDistal weaknessAxon loss; N
CMT R-Ax (Moroccan)1q21; ARSecond decadeDistal weaknessAxon loss; N
Cowchock syndromeXq24-q26First decadeDistal weakness, deafness, mental retardationAxon loss; N
HNPP|| (PMP-22)



Or tomaculous neuropathy



17p11; ADAll agesEpisodic weakness and numbnessConduction Blocks
Dejerine-Sottas syndrome (DSS) or hereditary motor and sensory neuropathy (HMSN) 3P0; AR



PMP-22; AD



8q23; AD



2 ySevere weakness< 10 m/s
Congenital



hypomyelination (CH)



P0, EGR2 or PMP-22



AR



BirthSevere weakness< 10 m/s
CMT 4A8q13; ARChildhoodDistal weaknessSlow
CMT 4B



(Myotubular in-related



protein-2)[17]



11q23; AR2-4 yDistal and proximal



weakness



Slow
CMT 4C5q23; AR5-15 yDelayed walking14-32 m/s
CMT 4D (Lom)



(N-myc Downstream-



Regulated Gene 1)



8q24; AR1-10 yDistal muscle wasting, foot and hand deformities10-20 m/s
CMT 4E (EGR2)10q21; ARBirthInfant hypotonia9-20 m/s
CMT 4G10q23.2; AR8-16 yearsDistal weakness9-20 m/s
CMT 4H12p11.21-q13.11; AR0-2 yearsDelayed walking9-20 m/s
CMT 4F19q13; AR1-3 yMotor delayAbsent
*Autosomal dominant



†Autosomal recessive



‡X-linked dominant



§Nerve conduction velocities



||Hereditary neuropathy with liability to pressure palsy



¶Peripheral myelin protein



#Early growth response



**Myelin protein zero



††Normal



HMSN with diffusely slow nerve conduction velocity (hypertrophic neuropathy) [1]

  • HMSN I (ie, CMT 1)[8, 9]
    • CMT 1A[11, 12, 27, 28, 29] - Autosomal dominant band 17p11.2-12 is most common; milder than CMT 1B
    • CMT 1B - Autosomal dominant band 1q21-25
    • CMT 1C - Unknown autosome
    • CMT X1 - X-linked dominant band Xq13-21
    • CMT X2 and CMT X3 - X-linked recessive
    • Autosomal recessive CMT 1 - Arm 8q
  • HMSN III (Dejerine-Sottas disease, hypertrophic neuropathy of infancy, congenital hypomyelinated neuropathy) - Autosomal recessive inheritance
  • HMSN IV (Refsum syndrome, phytanic acid excess) - Autosomal recessive inheritance; tetrad of peripheral neuropathy, retinitis pigmentosa, cerebellar signs, and increased cerebral spinal fluid (CSF) protein

Hereditary motor and sensory neuropathy with normal or borderline abnormal nerve conduction velocity (neuronal or axonal type)

  • HMSN II (ie, CMT 2)[9, 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, 30] - Band 3q13-22; typical type with axonal spheroids
    • CMT 2C - Not linked to any known loci; diaphragm and vocal cord weakness
    • CMT 2D - Band 7p14; muscle weakness and atrophy more severe in hands than in feet
    • Autosomal recessive CMT 2
  • HMSN V (ie, spastic paraplegia) - Normal upper limbs and no sensory symptoms
  • Roussy-Levy syndrome - Autosomal dominant with essential tremor
  • HMSN VI - With optic atrophy
  • HMSN VII - With retinitis pigmentosa
  • Prednisone-responsive hereditary neuropathy
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Contributor Information and Disclosures
Author

Divakara Kedlaya, MBBS  Clinical Associate Professor, Department of Physical Medicine and Rehabilitation, Loma Linda University School of Medicine; Medical Director, Physical Medicine and Rehabilitation and Pain Management, St Mary Corwin Medical Center

Divakara Kedlaya, MBBS is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Association of Neuromuscular and Electrodiagnostic Medicine, American Paraplegia Society, and Colorado Medical Society

Disclosure: Nothing to disclose.

Specialty Editor Board

James K DeOrio, MD  Director of Foot and Ankle Fellowship Program, Assistant Professor of Orthopedic Surgery, Orthopedic Surgery, St Lukes Hospital, Jacksonville, Florida

James K DeOrio, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American Orthopaedic Foot and Ankle Society, Florida Medical Association, and German Society of Neurology

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Shepard R Hurwitz, MD  Executive Director, American Board of Orthopaedic Surgery

Shepard R Hurwitz, MD is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American Association for the Advancement of Science, American College of Rheumatology, American College of Sports Medicine, American College of Surgeons, American Diabetes Association, American Orthopaedic Association, American Orthopaedic Foot and Ankle Society, Association for the Advancement of Automotive Medicine, Eastern Orthopaedic Association, Orthopaedic Research Society, Orthopaedic Trauma Association, and Southern Orthopaedic Association

Disclosure: Nothing to disclose.

Dinesh Patel, MD, FACS  Associate Clinical Professor of Orthopedic Surgery, Harvard Medical School; Chief of Arthroscopic Surgery, Department of Orthopedic Surgery, Massachusetts General Hospital

Dinesh Patel, MD, FACS is a member of the following medical societies: American Academy of Orthopaedic Surgeons

Disclosure: Nothing to disclose.

Chief Editor

Jason H Calhoun, MD, FACS  Frank J Kloenne Chair in Orthopedic Surgery, Professor and Chair, Department of Orthopedics, The Ohio State University Medical Center

Jason H Calhoun, MD, FACS is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American College of Surgeons, American Diabetes Association, American Medical Association, American Orthopaedic Association, American Orthopaedic Foot and Ankle Society, Missouri State Medical Association, Musculoskeletal Infection Society, Southern Medical Association, Southern Orthopaedic Association, Texas Medical Association, and Texas Orthopaedic Association

Disclosure: Nothing to disclose.

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Foot deformities in a 16-year-old boy with Charcot-Marie-Tooth disease type 1A.
Charcot-Marie-Tooth disease type 1A DNA test showing duplication in the short arm of chromosome 17 (A); compared with normal (B).
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.
Table 1
CMT TypeChromosome; Inheritance PatternAge of OnsetClinical FeaturesAverage NCVs§
CMT 1A (PMP-22 dupl.)17p11; AD*First decadeDistal weakness15-20 m/s
CMT 1B (P0 -MPZ)**1q22; ADFirst decadeDistal weakness< 20 m/s
CMT 1C (non A, non B)16p13;ADSecond decadeDistal weakness26-42 m/s
CMT 1D (early growth response [EGR]–2)#[21] 10q21; ADFirst decadeDistal weakness15-20 m/s
CMT 1E17p11; ADFirst decadeDistal weakness, deafness15-20 m/s
CMT 1F8p21; ADFirst decadeDistal weakness15-20 m/s
CMT X (Connexin-32)[22, 23, 24, 25, 26] Xq13; XD‡Second decadeDistal weakness25-40 m/s
CMT 2A1p36; AD10 yDistal weakness>38 m/s
CMT 2B3q; ADSecond decadeDistal weakness,



sensory loss, skin ulcers



Axon loss; Normal
CMT 2C12q23-q24, ADFirst decadeVocal cord, diaphragm, and



distal weakness



>50 m/s
CMT 2D7p14; AD16-30 yDistal weakness, upper limb predominantlyAxon loss; N††
CMT 2E8p21; AD10-30 yDistal weakness, lower limb predominantlyAxon loss; N
CMT 2F7q11-q21; AD15-25 yDistal weaknessAxon loss; N
CMT 2G12q12-q13; ?AD9-76 yDistal weaknessAxon loss; N
CMT 2H?; AR†15-25 yDistal weakness, Pyramidal featuresAxon loss; N
CMT 2I1q22; AD47-60 yDistal weaknessAxon loss; N
CMT 2J1q22; AD40-50 yDistal weakness, hearing lossAxon loss; N
CMT 2K8q13-q21; AR< 4 yDistal weaknessAxon loss; N
CMT 2L12q24; AD15-25 yDistal weaknessAxon loss; N
CMT R-Ax (Ouvrier)ARFirst decadeDistal weaknessAxon loss; N
CMT R-Ax (Moroccan)1q21; ARSecond decadeDistal weaknessAxon loss; N
Cowchock syndromeXq24-q26First decadeDistal weakness, deafness, mental retardationAxon loss; N
HNPP|| (PMP-22)



Or tomaculous neuropathy



17p11; ADAll agesEpisodic weakness and numbnessConduction Blocks
Dejerine-Sottas syndrome (DSS) or hereditary motor and sensory neuropathy (HMSN) 3P0; AR



PMP-22; AD



8q23; AD



2 ySevere weakness< 10 m/s
Congenital



hypomyelination (CH)



P0, EGR2 or PMP-22



AR



BirthSevere weakness< 10 m/s
CMT 4A8q13; ARChildhoodDistal weaknessSlow
CMT 4B



(Myotubular in-related



protein-2)[17]



11q23; AR2-4 yDistal and proximal



weakness



Slow
CMT 4C5q23; AR5-15 yDelayed walking14-32 m/s
CMT 4D (Lom)



(N-myc Downstream-



Regulated Gene 1)



8q24; AR1-10 yDistal muscle wasting, foot and hand deformities10-20 m/s
CMT 4E (EGR2)10q21; ARBirthInfant hypotonia9-20 m/s
CMT 4G10q23.2; AR8-16 yearsDistal weakness9-20 m/s
CMT 4H12p11.21-q13.11; AR0-2 yearsDelayed walking9-20 m/s
CMT 4F19q13; AR1-3 yMotor delayAbsent
*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



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