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Charcot Marie Tooth - CMT or Hereditary Motor and Sensory Neuropathy

This is a disease of the peripheral nerves. There is a defect in the sheaths of the nerves that conduct electrical stimuli from the brain to the muscles, and because of this damage to the nerve sheath (the myelin sheath), there is abnormal conduction of electrical signals, similar to what happens with un-insulated electrical wiring. Different types exist, and some of these are described below:

Types transmitted by autosomal dominant inheritance:
  • CMT type 1 - this type includes the most common type, called 1A.; Other types are 1B and 1C.

  • A relatively mild type in which the nerve damage is exacerbated mainly by external pressure (prolonged flexion, etc.).

  • CMT type 2 - there are two types - 2A and 2B. Clinically, these are more severe than type 1. They involve characteristic changes in nerves that can be seen microscopically; onion-like bodies (Dejerine Sottas bodies) appear. These bodies are myelin fragments that have not reached their normal positions.

  • CMT with deafness.

Types transmitted by autosomal recessive inheritance:
  • Type 4. CMT4A.

  • A complete absence of myelin (nerve sheath). These types are characterized by a severe clinical picture.

Types transmitted by X-linked inheritance:
  • CMTX2.

  • CMT with deafness and retardation.

  • CMT with muscular dystrophy and missing skin.

Clinical signs

In the classic form (CMT1), signs of the disease can appear in childhood, when the main sign is usually an increased plantar arch of the foot.

Between the ages of 20 and 40 years, signs appear in the lower legs, which appear thin and have a typical shape, resembling an inverted champagne bottle.

This results from the "disappearance" of the calf muscles. The disease progresses slowly.

There are milder forms, where clinical signs only appear at a later age, with slower and sometimes unilateral progress, if any.

An example is the type that occurs as a result of pressure.

There are more severe types, especially those transmitted by autosomal recessive or X-linked inheritance. Of the types transmitted by autosomal dominant inheritance, CMT2 is more severe.

A precise diagnosis is important, and a diagnosis made in the past is not always accurate by today's standards. Because of this, the diagnosis must always be confirmed in a genetic institute by examining the patient, or at least by reviewing the results of neurological tests, laboratory and/or EMG results, and other data.

Even though we know a lot about the inheritance patterns, the risk of recurrence, the mechanism of the manifestations of the disease, etc., most of these diseases have exceptions, and each case/family must be examined individually in a genetic institute. It must be remembered that a diagnosis of the various types of CMT is very difficult to make, and even if the clinical criteria stated above are present, the diagnosis cannot necessarily be confirmed by the diagnostic methods and techniques available today.

Inheritance pattern

As mentioned above, all three patterns of Mendelian inheritance are possible: autosomal dominant, autosomal recessive, and X-linked.


The penetrance of the disease is usually full in the types transmitted by autosomal recessive and X-linked inheritance. The autosomal dominant type may be milder and may not always appear.

Associated features that can be demonstrated in tests performed during pregnancy

In families in whom the genetic defect has been defined, a reliable genetic test can be performed on the fetus. This will be done if the geneticist finds that there is a high risk that the fetus will be affected. The condition cannot be diagnosed by ultrasound examination in pregnancy or by regular amniocentesis.

What is the risk of recurrence in a subsequent pregnancy?

For the autosomal dominant type, patients have a 50% risk of having a child with the same condition. In a family with members affected by this form of CMT, even those who do not have any clinical signs may well develop these at a later age; meaning, that healthy members of such a family may be at risk of having a child with the disease - the exact risk is determined individually within genetic counseling. In some cases, instead of the child's inheriting the mutation from a parent, a new mutation can appear for the first time in the child (a de novo mutation). This happens in some cases of CMT2. In the types transmitted by autosomal recessive inheritance, a couple who has already had an affected child has a 25% recurrence risk in every pregnancy. Other family members do not have a high risk (usually less than 1%); this can be determined within genetic counseling for each person individually according to their pedigree.

In the X-linked type, the recurrence risk for a mother of an affected son is 50% in every pregnancy with a male fetus. Fifty percent of the daughters of such mothers will be carriers and 50% will be normal.

For all the inheritance patterns, the exact risk for distant relatives of patients depends on the number of patients in the family, the degree of relatedness of the applicants to affected family members, consanguinity (blood relationship) between the partners, if present, etc., and can be ascertained in genetic counseling.

Molecular genetic information:

The genes for the diseases and the locations of the genes

In the types transmitted by autosomal dominant inheritance:
  • Type 1 - in type 1A the gene involved is PMP22 on chromosome 17q13. The defect is a duplication of a segment of this gene.

  • In the relatively mild form in which the nerve damage is exacerbated by external pressure, the defect is also in gene PMP22, but here the defect is a deletion rather than duplication in the gene.

  • In type 2 (Dejerine Sottas type) the defect is in gene MPZ on chromosome 1q22.

  • In the X-linked form, the gene involved is connexin-32 (CX32) (GJB1) on chromosome Xq13.1.

  • Other genes are responsible for the rarer types.

Diagnostic testing

In about 70% of classic CMT patients, the genetic defect, a duplication of part of the PMP22 gene on chromosome 17q13, can be demonstrated with relative ease. For other patients the diagnosis is not simple and takes considerable time and laboratory effort as it involves the examination of a number of genes: see: Indirect testing of genetic markers with a number of patients in the family - when there are a number of different genes, each of which can cause the disease - all the genes have been located / detected / mapped - autosomal dominant disease

Carrier testing

In families in whom the gene responsible for the disease has been located and the mutation identified, other family members can be examined for signs of the disease or carrier status. Carrier tests are not usually conducted in the healthy general population.

Fetal testing

See diagnostic testing above.

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