Charcot-Marie-Tooth Disease Workup
- Author: Divakara Kedlaya, MBBS; Chief Editor: Vinod K Panchbhavi, MD, FACS more...
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 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 are 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 the image below). Point mutations in the PMP-22 gene, which cause fewer than 2% of cases of CMT 1A, are identified by this technique.
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 EGR-2 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.
In CMT 1A, high-resolution ultrasonography of the median nerve and other peripheral nerves may serve as an adjunct to electrodiagnosis. Cartwright et al characterized the ultrasonographic findings in peripheral nerves of patients with CMT 1B. 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.
Magnetic resonance imaging (MRI) of lower-limb muscles is used to follow the progression of the disease in patients with CMT neuropathies.
Electromyography (EMG) and nerve conduction studies should be performed first if CMT disease is suggested. 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 is observed (see the image below).
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 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 velocity 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 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 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.
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|CMT Type||Chromosome; Inheritance Pattern||Age of Onset||Clinical Features||Average NCVs§|
|CMT 1A (PMP-22¶ dupl.)||17p11; AD*||First decade||Distal weakness||15-20 m/s|
|CMT 1B (P0 -MPZ)**||1q22; AD||First decade||Distal weakness||<20 m/s|
|CMT 1C (non A, non B)||16p13;AD||Second decade||Distal weakness||26-42 m/s|
|CMT 1D (early growth response [EGR]–2)#[ 24]||10q21; AD||First decade||Distal weakness||15-20 m/s|
|CMT 1E||17p11; AD||First decade||Distal weakness, deafness||15-20 m/s|
|CMT 1F||8p21; AD||First decade||Distal weakness||15-20 m/s|
|CMT X (Connexin-32)[23, 24, 25, 26, 27]||Xq13; XD‡||Second decade||Distal weakness||25-40 m/s|
|CMT 2A||1p36; AD||10 y||Distal weakness||>38 m/s|
|CMT 2B||3q; AD||Second decade||Distal weakness,
sensory loss, skin ulcers
|Axon loss; Normal|
|CMT 2C||12q23-q24, AD||First decade||Vocal cord, diaphragm, and
|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||?; AR†||15-25 y||Distal weakness, Pyramidal features||Axon loss; N|
|CMT 2I||1q22; AD||47-60 y||Distal weakness||Axon loss; N|
|CMT 2J||1q22; AD||40-50 y||Distal weakness, hearing loss||Axon loss; N|
|CMT 2K||8q13-q21; AR||<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|
Or tomaculous neuropathy
|17p11; AD||All ages||Episodic weakness and numbness||Conduction Blocks|
|Dejerine-Sottas syndrome (DSS) or hereditary motor and sensory neuropathy (HMSN) 3||P0; AR
|2 y||Severe weakness||<10 m/s|
|P0, EGR2 or PMP-22
|Birth||Severe weakness||< 10 m/s|
|CMT 4A||8q13; AR||Childhood||Distal weakness||Slow|
|11q23; AR||2-4 y||Distal and proximal
|CMT 4C||5q23; AR||5-15 y||Delayed walking||14-32 m/s|
|CMT 4D (Lom)
Regulated Gene 1)
|8q24; AR||1-10 y||Distal muscle wasting, foot and hand deformities||10-20 m/s|
|CMT 4E (EGR2)||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|
§Nerve conduction velocities
||Hereditary neuropathy with liability to pressure palsy
¶Peripheral myelin protein
#Early growth response
**Myelin protein zero