eMedicine Specialties > Physical Medicine and Rehabilitation > Peripheral Neuropathy

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
Contributor Information and Disclosures

Updated: Feb 16, 2009

Differential Diagnoses

Alcoholism
HIV Infection
Leprosy
Neurosyphilis
Thyroid Disease

Other Problems to Be Considered

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.

Workup

Laboratory Studies

  • Results of all routine laboratory tests are within the reference range in Charcot-Marie-Tooth disease (CMT). Special genetic tests are available for some types of CMT.
    • CMT-1A - Pulsed-field gel electrophoresis or a specialized fluorescent in situ hybridization (FISH) assay is the most reliable genetic test, but it is not widely available. 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 below and Image 2). 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 alteration of the PMP-22 gene (chromosomal locus 17p11).
    • 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).
    • 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.
    • Genetic testing is not currently available for other types of CMT.

Charcot-Marie-Tooth disease type 1A DNA test show...

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

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Charcot-Marie-Tooth disease type 1A DNA test show...

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


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.8,9,10,11,12,13

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)8,9,10,11,12,13
    • 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 image below and Image 3).
    • 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 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.

Nerve conduction study showing decreased nerve co...

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.

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Nerve conduction study showing decreased nerve co...

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.


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.
  • 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
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Further Reading

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Keywords

Charcot-Marie-Tooth disease, Charcot Marie Tooth, Charcot Marie Tooth disease, neuropathy, Charcot, Charcot Marie, pes cavus, connexin, Charcot Marie Tooth syndrome, hereditary motor sensory neuropathy, HMSN, peroneal muscular atrophy, PMA, CMT

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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
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

Milton J Klein, DO, MBA, Consulting Physiatrist, Sewickley Valley Hospital, Allegheny General Hospital, Harmarville Rehabilitation Center, Ohio Valley General Hospital, and Aliquippa Community Hospital
Milton J Klein, DO, MBA is a member of the following medical societies: American Academy of Disability Evaluating Physicians, American Academy of Medical Acupuncture, American Academy of Osteopathy, American Academy of Physical Medicine and Rehabilitation, American Medical Association, American Osteopathic Association, American Osteopathic College of Physical Medicine and Rehabilitation, American Pain Society, and Pennsylvania Medical Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Michael T Andary, MD, MS, Residency Program Director, Professor, Department of Physical Medicine and Rehabilitation, Michigan State University College of Osteopathic Medicine
Michael T Andary, MD, MS is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, and Association of Academic Physiatrists
Disclosure: allergan Honoraria Speaking and teaching

CME Editor

Kelly L Allen, MD, Regional Medical Director, IMX-Medical Management Services
Disclosure: Nothing to disclose.

Chief Editor

Robert H Meier III, MD, Director, Amputee Services of America; Active Medical Staff, Presbyterian/St Luke's Hospital, Spalding Rehabilitation Hospital, Select Specialty Hospital; Consulting Staff, Kindred Hospital
Robert H Meier III, MD is a member of the following medical societies: American Academy of Physical Medicine and Rehabilitation and Association of Academic Physiatrists
Disclosure: Nothing to disclose.

 
 
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