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Charcot-Marie-Tooth Disease: Differential Diagnoses & Workup

Author: Divakara Kedlaya, MBBS, Clinical Associate Professor, Department of Physical Medicine and Rehabilitation, Loma Linda University School of Medicine; Medical Director, PM&R and Pain Management, St. Mary Corwin Medical Center, Pueblo, CO
Contributor Information and Disclosures

Updated: Sep 9, 2009

Differential Diagnoses

Alcoholism
Human Immunodeficiency Virus Infection
Leprosy
Neurosyphilis

Other Problems to Be Considered

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

Other genetic neuropathies

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

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

Workup

Laboratory Studies

  • All routine laboratory tests are normal in individuals with Charcot-Marie-Tooth disease.

Imaging Studies

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

Other Tests

  • Special genetic tests are available for some types of CMT disease.
    • CMT 1A - Approximately 70-80% of CMT 1 cases are designated CMT 1A, which is caused by alteration of the PMP-22 gene (chromosome band 17p11). Pulsed field gel electrophoresis and a specialized fluorescent in situ hybridization (FISH) assay are the most reliable genetic tests, but they are not widely available.31 DNA-based testing for the PMP-22 duplication (CMT 1A) is widely available and detects more than 98% of patients with CMT 1A (see Image 2).32 Point mutations in the PMP-22 gene, which cause fewer than 2% of cases of CMT 1A, are identified by this technique.
     
    • CMT 1B - Genetic testing is performed primarily on a research basis, but it is available from a few commercial laboratories. Approximately 5-10% of CMT 1 cases are designated CMT 1B; they are caused by a point mutation in the myelin P0 protein (MPZ) gene (chromosome band 1q22).
    • CMT 1C and CMT 1D - Very rarely, mutations occur in the EGR-2 gene or the LITAF gene, causing CMT 1D and CMT 1C, respectively. Molecular genetic testing is also available clinically for these.
    • The 4 subtypes of CMT 2 are indistinguishable clinically and are distinguished solely on the basis of genetic linkage findings. Relative proportions of CMT 2A, 2B, 2C, and 2D have not yet been determined. The chromosomal loci for CMT 2A, 2B, 2C, 2D, 2E, 2F, 2G, and 2L have been mapped, but the genes have not been identified. Molecular genetic testing is clinically available only for CMT 2A, 2B1, 2E, and 2F.
    • CMT X - Molecular genetic testing of the GJB1 (Cx32) gene detects about 90% of cases. Such testing is clinically available.
    • Genetic testing currently is not available for other types of CMT disease.
  • Nerve biopsy rarely is indicated for the diagnosis of CMT disease, especially with the availability of genetic testing. Biopsies sometimes are performed in cases of diagnostic dilemmas. Findings vary in different types of CMT disease.
    • In CMT type 1, peripheral nerves contain few myelinated fibers, and intramuscular nerves are surrounded by rich connective tissue and hyperplastic neurilemma. Lengths of myelin are atrophic along the fibers. Concentric hypertrophy of the lamellar sheaths is seen. Onion bulb formation is frequently observed and is made of circumferentially directed Schwann cells and their processes.
    • In CMT type 2, axon loss with wallerian degeneration is generally found.
    • In CMT type 3, or Dejerine-Sottas disease, demyelination with thinning of the myelin sheath is observed.
    • Inflammatory infiltrate, indicating an autoimmune demyelinating process, should not be present.

Procedures

  • Electromyography/nerve conduction study2
    • Perform these studies first if Charcot-Marie-Tooth disease is suggested. Findings vary depending on the type of CMT disease.
    • In demyelinating types, such as CMT 1, diffuse and uniform slowing of nerve conduction velocities is observed (see Image 3).
     
    • Harding and Thomas criteria for diagnosing CMT 1 include a median motor nerve conduction velocity of less than 38 m/s, with compound motor action potential (CMAP) and amplitude of at least 0.5 millivolts (mV). No focal conduction block or slowing should be present unless associated with other focal demyelinating processes.
    • All nerves tested, sensory and motor, show the same degree of marked slowing.
    • Absolute values vary, but they are approximately 20-25 m/s in CMT 1 and less than 10 m/s in Dejerine-Sottas disease and congenital hypomyelination. Slowing of nerve conduction also can be found in asymptomatic individuals.
    • In neuronal (ie, axonal) types, nerve conduction velocity is usually normal, but markedly low amplitudes are noted in sensory (ie, sensory nerve action potential [SNAP]) and motor nerve (ie, CMAP) studies.
    • In neuronal (ie, axonal) types, increased insertional activity is evident as fibrillation potentials and positive sharp waves are observed. Motor unit potentials show decreased recruitment patterns and neuropathic changes in morphology.

Histologic Findings

Findings according to type of Charcot-Marie-Tooth disease are as follows:

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

More on Charcot-Marie-Tooth Disease

Overview: Charcot-Marie-Tooth Disease
Differential Diagnoses & Workup: Charcot-Marie-Tooth Disease
Treatment & Medication: Charcot-Marie-Tooth Disease
Follow-up: Charcot-Marie-Tooth Disease
Multimedia: Charcot-Marie-Tooth Disease
References
Further Reading
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Keywords

Charcot-Marie-Tooth, CMT, CMT 1, CMT 2, hereditary motor and sensory neuropathy, HMSN, peroneal muscular atrophy, PMA, peroneal progressive muscular atrophy, peroneal muscular atrophy with thickened nerves, Hoffman disease, Charcot-Marie-Tooth-Hoffman disease

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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, PM&R and Pain Management, St. Mary Corwin Medical Center, Pueblo, CO
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.

Medical Editor

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.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

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.

CME Editor

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, American Association of Physicians of Indian Origin, American College of International Physicians, and American College of Surgeons
Disclosure: Nothing to disclose.

Chief Editor

Jason H Calhoun, MD, FAAOS, Chairman, J Vernon Luck Distinguished Professor, Department of Orthopedic Surgery, University of Missouri
Jason H Calhoun, MD, FAAOS is a member of the following medical societies: American Academy of Orthopaedic Surgeons, American College of Surgeons, and American Orthopaedic Foot and Ankle Society
Disclosure: Nothing to disclose.

 
 
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