Charcot-Marie-Tooth Disease Workup

Updated: Jan 28, 2021
  • Author: Divakara Kedlaya, MBBS; Chief Editor: Vinod K Panchbhavi, MD, FACS, FAOA, FABOS, FAAOS  more...
  • Print

Laboratory Studies

All routine laboratory tests are normal in individuals with Charcot-Marie-Tooth (CMT) disease. However, special genetic tests are available for some types of CMT disease.

About 70-80% of CMT 1 cases are designated CMT 1A, which is caused by alteration of the PMP22 gene (chromosome band 17p11). Pulsed field gel electrophoresis and a specialized fluorescent in-situ hybridization (FISH) assay are the most reliable genetic tests but are not widely available. [45] DNA-based testing for the PMP22 duplication (CMT 1A) is widely available and detects more than 98% of patients with CMT 1A (see the image below). [46] Point mutations in the PMP22 gene, which cause fewer than 2% of cases of CMT 1A, are identified by this technique.

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

Genetic testing for CMT 1B 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).

Very rarely, mutations occur in the EGR2 gene or the LITAF gene, causing CMT 1D and CMT 1C, respectively. Molecular genetic testing is also available clinically for these.

The four major subtypes of CMT 2 are indistinguishable clinically and are differentiated 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.

About 90% of cases of CMT X can be detected by means of molecular genetic testing of the GJB1 (Cx32) gene. Such testing is clinically available.

Genetic testing currently is not available for other types of CMT disease.

A study by Millere et al found that plasma neurofilament light chain (NfL) concentrations were higher in CMT patients than in healthy control subjects and suggested that NfL might prove useful as a biomarker in the setting of suspected CMT disease. [47]


Imaging Studies

In CMT 1A, high-resolution ultrasonography (US) of the median nerve and other peripheral nerves may serve as an adjunct to electrodiagnosis. Cartwright et al characterized US findings in peripheral nerves of patients with CMT 1B. [48] They found that persons with CMT 1B had larger median and vagus nerves than healthy individuals did, but there was no difference in cranial nerve size between CMT 1B patients who had cranial neuropathies and those who did not. [48]

Magnetic resonance imaging (MRI) of lower-limb muscles is used to follow the progression of the disease in patients with CMT neuropathies. [49]


Electrodiagnostic Studies

Electromyography (EMG) and nerve conduction studies should be performed first if CMT disease is suggested. [50] Findings vary, depending on the type of CMT disease present. In demyelinating types, such as CMT 1, diffuse and uniform slowing of nerve conduction velocities (NCVs) is observed (see the image below).

Nerve conduction study showing decreased nerve con Nerve conduction study showing decreased nerve conduction velocity in median nerve in 18-year-old woman with Charcot-Marie-Tooth disease type 1.

Harding and Thomas criteria for diagnosing CMT 1 include a median motor NCV of less than 38 m/s, with compound motor action potential (CMAP) and amplitude of at least 0.5 mV. No focal conduction block or slowing should be present, unless it is associated with other focal demyelinating processes.

All nerves tested, sensory and motor, show the same degree of marked slowing.

Absolute values for NCV 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, NCV is usually normal, but markedly low amplitudes are noted in sensory nerve (ie, sensory nerve action potential [SNAP]) and motor nerve (ie, CMAP) studies. 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.



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 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 2, axon loss with wallerian degeneration is generally 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.


Histologic Findings

Histologic findings vary according to the type of CMT disease present, as follows:

  • CMT 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
  • CMT 2 - Axonal degeneration is observed
  • CMT 3 - Demyelination with thinning of the myelin sheath can be seen

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