What is the role of genetic testing in the workup of Charcot-Marie-Tooth (CMT) disease?

Updated: Feb 19, 2019
  • Author: Francisco de Assis Aquino Gondim, MD, PhD, MSc, FAAN; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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When the clinical and neurophysiologic phenotype and the family history suggest CMT, the patient should undergo genotyping. This is important because clinical examination and electrodiagnostic study findings often cannot definitively establish a precise diagnosis because of the overlap between clinical syndromes and the significant variability between family members with an identical genotype. Genotyping permits sound genetic and prognostic counseling and advances the scientific understanding of phenotypes. To date, there are at least 50 different genes linked to CMT subtypes

Although fresh blood samples are routinely required for DNA analysis, a recent report documented that chromosomal changes of the PMP22 gene can be diagnosed in highly degraded DNA from sural nerve biopsy specimens that are up to 12 years old.

The limitations of genotyping must be recognized because they do not exclude mutations with 100% certainty. Laboratory errors such as mislabeling occur. When a result is counterintuitive, the test should be repeated with a new blood sample, and, typically, the testing laboratory does not charge for a second test. The PMP22 gene, until recently, was only tested for deletion and duplication, not for point mutation, as is now the case, but this test must be requested separately. Point mutation analysis is limited to the open reading frame, ie, the protein coding sequences. It does not include search for changes in promoter, enhancer, and silencer and other nontranslated sequences, which could result in too much or too little RNA.

As stated before, de novo mutations are particularly common with PMP22, but they can occur with any gene. In other words, a general tenet holds for the family history: absence of evidence is not evidence of absence. Testing is possible only for mutations in known genes that are sufficiently common to make commercialization feasible, usually after 3 independent pedigrees have been identified. As indicated by the ever-increasing number of mutations, which makes a publication instantaneously obsolete, many additional genes exist that will be discovered in the future. Updated information is readily available at Victor McKusick's web site National Center for Biotechnology Information.

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