Genetics

Yes. For example, mutations in the GARS gene (CMT2D) often (though not always) affect hands first.

Variants of Unknown Significance (VUS) have not been determined to be disease-causing. A subtype is determined when something causative is found. As such, CMT2 means axonal hereditary neuropathy which has yet to be genetically defined.

It is rare to have two types of CMT as the person affected would need mutations in two or more genes that each cause CMT. Please see a licensed genetic counselor (www.nsgc.org) to better understand your genetic testing results. The statistic is that about 1.5 percent of people will have two types of CMT. Not all variants are disease-causing. In many cases, the results of the genetic tests are often very difficult to decipher and seeing a trained CMT expert who also performs a physical exam is key for an accurate diagnosis.

CMT does not skip generations genetically. For people with autosomal dominant and X-linked conditions, a person will either have the condition or not. If a parent has CMT that has been genetically confirmed, a child can be tested when that child is at least 18 years of age and with appropriate genetic counseling. It is not recommended to test children who do not have any symptoms for CMT, as that child could be stigmatized or could be treated differently due to a label. If a person does not inherit the condition from a parent, that person will not have CMT and cannot pass it on in the future. If your kids have been confirmed to not have CMT, your grandkids will not be able to inherit the mutation in the family.

There is one situation where CMT can seem to skip a generation. Recall that a person needs to have two copies of the gene with a mutation in order to have CMT and that all children of a person who has an autosomal recessive form of CMT will be carriers of the condition (one gene has the mutation, and one does not). If that child’s partner is a person who is also a carrier for the same condition, there is a one in four or 25 percent chance of having a child who is affected with the condition. In this situation, the grandparent and grandchild are affected, but the parent is not. Thus the CMT symptoms have skipped a generation, but the genetics behind the condition have not skipped. This is more likely to occur in relationships where family members marry each other, as it is more likely in these groups that the mutation in the gene has been passed on through carriers than in the general population.

CMT Type 2O (CMT2O) is caused by mutations in the dynein cytoplasmic 1 heavy chain 1 gene (DYNC1H1). It is a rare form of an axonal neuropathy which is inherited in an autosomal dominant pattern. It is important to determine whether or not the variant identified is in fact disease causing if it has not been reported in the literature, this can be done through familial studies looking for the mutation in affected and unaffected family members. The gene is located on chromosome 14 and helps the cell to create a subunit of the dynein-dynactin complex which is a complex inside the cell’s cytoplasm which helps with transporting things within the cell and communicating with other cells. Mutations in this gene are known to usually cause a pure motor form of CMT, that is weakness more than sensory impairment.

We no longer use the term CMT3 or Dejerine Sottas. It just means a severe type of CMT. Your neurologist should be able to help you find the type of CMT you have.

A diagnosis of CMT 5 can mean:

(1) In most cases, CMT 5 is another name for Hereditary Motor and Sensory Neuropathy (HMSN) 5. A diagnosis of HMSN 5 used to be the common way to say that a patient had CMT and displayed upper motor neuron signs such as brisk reflexes. Upper motor neuron signs can occur in patients with several types of CMT, including some patients with CMT2A. It can even happen in patients with CMT1X.

(2) There are rare forms of X-linked CMT, defined as CMTX5 with mutations in the PRPS1 gene.

(3) Some patients with CMT2D (mutations in the GARS gene) have weakness, but not sensory loss. These patients are sometimes classified as having Distal Hereditary Motor Neuropathy type V (dHMNV).

In a perfect world, yes, this would be ideal, but not all the Centers of Excellence are equipped for both pediatrics and adults. However, a few do cater to families. See: https://www.cmtausa.org/living-with-cmt/find-help/cmta-centers-of-excellence

Females have two X chromosomes. A woman affected with CMT1X has a 50/50 chance of passing on the X chromosome with the changed gene in each pregnancy, no matter the sex of the child. Traditionally, females have been thought to have no to mild symptoms, but we have seen women whose symptoms resemble those of their male relatives. Overall, the severity is less than males, but females can, and usually do, have symptoms. This is likely because while one gene isn’t working, the other copy of the gene on the other X-chromosome is working well and makes up for the other one.

A male offspring, on the other hand, has one X chromosome and one Y chromosome. If he inherits the copy of the X-chromosome with non-working gene from his mother, he has no other X chromosome to compensate, and he will develop CMT. (See also, Genetics and Inheritance.)

23andMe’s genetic testing will not be helpful in detecting CMT. While this type of testing is approved to look for some conditions, such as Bloom syndrome, CMT is not one of them. Moreover, 23andMe testing does not perform a full gene sequence of any conditions, nor is it certified to be used for clinical actionability. This means that if a condition is found using 23andMe testing, that finding would still need to be confirmed in a CLIA-certified lab before the information could be used for clinical purposes (such as treatment or clinical trials).

Instead, get tested at a genetic testing company because they do test for CMT. Additionally, those labs are CLIA-certified, which means that they have passed government inspection of their processes and proven that they can perform the specific test with almost zero false positives or negatives (genetic testing has a 99.9% success rate). Also, genetic testing companies have specialized individuals who work on variant interpretation with intimate knowledge of the genes and variants tested. This is important because the genetic testing itself is not usually the hard part; the challenge lies in the analysis of those results. Interpretation by a specialized team is vital to procuring accurate results that provide personally and clinically meaningful information to patients and families.

Genetic testing does not need to be expensive. Ask your health care professionals about different laboratories that provide genetic testing services to patients at low out-of-pocket cost. Also, note that many insurances will cover genetic testing, particularly if testing is sought for family planning purposes or if the results of testing could change management. To find a genetic counselor, go to www.nsgc.org.

Mutations in the LMNA gene can cause symptoms that are typical of CMT as well as symptoms that are not so typical, such as weakness in the parts of the limbs close to the body (e.g. the upper thigh). It is difficult to state what any given mutation in the gene will do. A small fiber neuropathy can cause sensory symptoms, including pain, and can be caused by mutations in the LMNA gene. It is possible that your symptoms are due to CMT, but it is also possible that they are due to a different cause of neuropathy. Your doctor, or a CMT specialist, may be able to help determine the cause of your symptoms.