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Supporting people affected by Charcot-Marie-Tooth disease.

Genetic Testing for CMT

What do we do?Of the 22,000 genes in the human body, 80+ have been identified as causes of CMT as of November 2014. The first causative gene for CMT – CMT1A secondary to the chromosome 17 duplication – was identified in 1991, but in the last three years there have been huge advances in the technology to look for new genes. The new techniques currently being used, called Next Generation Sequencing (NGS) mean that new genes are being identified much more quickly than previously – currently at a rate of about one new gene a month.

We now know about 65% of the causative genes for all types of CMT, HSN and distal HMN. This means that around two thirds of people with CMT in the UK can get an accurate genetic diagnosis. This figure is the same in the US and in other parts of Europe and is expected to increase in the next few years as new genes are identified with NGS. By 2020 all the causative genes are likely to have been identified.

Up until 2014, only four genes were commonly tested in most clinics in the UK but with NGS this has completely changed and it is now much easier to check all the genes in one go. Two laboratories now offer this in the UK. Testing vast numbers of genes is no longer the challenge it used to be. What is now more challenging is working out if the mutations identified are the real cause of the CMT in an individual patient. This is particularly difficult with the rare genes. For this reason, doctors often ask if they can see other members of your family (both with and without CMT) to trace the gene.

Testing for the genes that cause CMT is usually done in one of four circumstances:

Diagnostic: Somebody has symptoms and signs of CMT and wants to know which gene is causing their CMT i.e. the genetic cause.

Pre-symptomatic: This is where a person with no symptoms and signs of CMT but who has a relative with a confirmed genetic diagnosis of CMT wants to know if they have the same causative genetic mutation as their relative so that they can get information about their likelihood of developing the condition. This is not a common request in CMT as there is no treatment. If treatments become available, an early diagnosis will become more important.

Ante-natal diagnosis: This is where a pregnant women who either has CMT herself or whose partner has it, screens the pregnancy (usually at about 12 weeks by CVS testing) to see if the foetus carries the mutated gene.

Pre-implantation diagnosis: This is where the sperm and the egg of parents (one of whom has CMT) are fertilised outside the womb (by IVF). The resulting embryos are then tested to see if they carry the mutated gene and only the embryos without the mutated gene are implanted into the mother’s womb.

Where can you get advice?

Genetic testing for the underlying cause of CMT in different families is changing. Testing for the commonest cause – the duplication of chromosome 17 – can be done very readily. Testing several other genes can be arranged through the 22 regional genetic centres (find a list of centres on the NHS website) throughout the country (and the Republic of Ireland). It can also be done in specialised neuropathy clinics. Your neurologist or your family doctor can make the appropriate referral for you and any relatives who are concerned.

Testing for less common causes of CMT is improving rapidly but may require referral to a specialist research laboratory. Much of the CMT research is done in the neurogenetics unit at The Institute of Neurology.

To make the most of any genetic findings you need to have your results interpreted by your consultant neurologist or by a geneticist with an interest in neurology. They will be able to find out the implications for your particular diagnosis and give a spectrum of likely symptoms and how the condition is likely to change over the years.

Planning a family: how developments in genetics can play a part

From the twelfth week of pregnancy onwards it is possible to test a foetus for those forms of CMT for which the causative gene is known. Investigations of affected family members may be needed before the tests are done. Unless you are considering ending the pregnancy if the foetus is affected, there may be little advantage in discovering at this stage whether or not the child will have the gene that causes CMT, because the test itself carries a risk of miscarriage. Tests in pregnancy may improve dramatically over the next few years and be available earlier in pregnancy and without risk of miscarriage.

Pre-implantation genetic diagnosis (PGD)

PGD is a method of screening embryos before they are implanted into the womb during in-vitro fertilisation (IVF). After the embryo is created in the laboratory from the eggs and sperm of a couple, it is then tested for the relevant genetic disorder – in this case CMT. One or two unaffected embryos are then transferred into the womb, in the hope that a pregnancy will occur.

PGD is a complex procedure involving time and emotional and physical commitment, but it does avoid the need for termination of an affected pregnancy. This is the main reason given by those who request PGD.

Couples will first have an appointment with a PGD Genetic Counsellor to discuss the procedure. For CMT, laboratory work is needed to prepare the genetic test that will be used on the embryos. Couples will also need a pre-treatment appointment with an IVF doctor in the Assisted Conception Unit (ACU). Preparation for a PGD cycle takes some time and after an initial discussion it is likely to be around eight to nine months before a treatment cycle can start, sometimes even longer.

As PGD involves using IVF, the success rate is relatively low compared with the chance of conceiving naturally. Approximately one in three cycles of PGD will result in a baby. If a couple get as far as having embryos transferred, then there is approximately a one in two chance of success.

You will need a referral by a geneticist or genetic counsellor to a PGD clinic for an initial discussion appointment. This will give you the opportunity to ask questions and find out more about PGD before reaching your decision. NHS funding for PGD may or may not be available.

Each separate type of CMT must be licenced for PGD separately by the Human Fertilisation and Embryology Authorities, and currently licences are in place for only a small number of genetic types. Therefore, when considering PGD, bear in mind that it may take a considerable time to gain the appropriate licence for your type.


Watch Professor Mary Reilly answering a question about early testing and PGD.

My husband’s father has CMT and we are thinking about starting a family.  My husband doesn’t appear to have any symptoms – what are the risks to my future children?

The simple answer to your question is – if your husband doesn’t have CMT, he can’t pass it onto his children.  It does NOT skip generations – he has to have a genetic mutation in order to pass it onto your children.

However, unfortunately with CMT, the simple answer may not be the whole story.  Many people don’t develop symptoms of CMT until later in life and therefore, there is a possibility that your husband may have the gene, in which case, even though he appears unaffected at present, he could still pass it onto future children.  The most common form of inheritance is autosomal dominant, giving a 50/50 risk of passing it on.  The only way to find out for sure, would be for your husband to be tested – but again, there is no simple answer.

Does his father know what specific genetic type he has?  If he does, then depending on the type, your husband could ask for a referral to a geneticist and ask for a blood test to determine if he is carrying the same gene.  In the UK at present, routine testing can be done at any genetic department for Type 1A and Type 1X – more specialist centres may be able to test for a few more types, and major Centres of Excellence, such as the MRC Centre for Neurology at the National Hospital for Neurology can do genome sequencing and find a wide range of types.   If your father-in-law doesn’t know, and it’s very common for people diagnosed many years ago not to know (the gene fault for Type 1A was only discovered in 1992), then HE would have to be tested.  And for most of the Type 2s, genetic testing is not yet routinely available in the UK

So there is a whole process of steps to take before we can answer the question definitively.  There would be no point in your husband just asking for genetic testing without knowing the type that is in the family, because there is quite a high chance of getting a false negative result.

Will knowing the precise genetic cause of my CMT help me understand how my CMT is likely to affect me in the years to come?

How you experience CMT is likely to be specific to you – people within the same family can have very different symptoms. But certain genes give a spectrum of likely symptoms and suggest how the condition is likely to change over the years. So, even though there is a spectrum within a family, there is a bigger difference between genes. There are certain genes that cause CMT to present in the first year or two of life, whereas others cause it to present at 20 or 30. Your consultant neurologist will be able to tell you more about this.

I’ve just had a child and would like to find out whether they have CMT. Is it possible to have a genetic test?

This is a matter of debate. Most doctors do not recommended genetic tests on children who have no signs of CMT. Children can make their own decision as to whether they want testing when they are 18. If they do develop possible signs or symptoms of CMT during childhood, they should have a genetic test in the same way as adults to confirm the diagnosis.

However, many people with CMT believe that parents should be able to ask for genetic testing to be carried out on their children – a case of forewarned is forearmed. CMT United Kingdom’s position on this sensitive issue is that asymptomatic testing (i.e. before there are any noticeable symptoms) ought to be available to any parent who requests it – after suitable genetic counselling. It is possible that very early diagnosis could lead to earlier interventions (like physiotherapy or orthotics), ultimately having a positive long-term effect.

What is a chromosome?

A chromosome is the biological equivalent of an enormous volume of instructions or recipes: each individual recipe or instruction is called a gene. Our chromosomes are responsible for the way that each of the 10,000 trillion cells which form the human body behaves.

Apart from the sex cells (sperm and egg) each human cell has two copies of each of the 23 types of human chromosome. This amounts to 46 single chromosomes in each cell nucleus. We inherit a single full set of 23 chromosomes from each of our parents.

Twenty-two of our chromosomes are known as autosomal and these are the same in boys and girls. The twenty third pair is our pair of sex chromosomes, the X and the Y chromosomes. If we have two Xs we become female and if we have an X and a Y, we become male.

If we have children, one of our sex cells (a sperm cell or an egg cell) merges with our partner’s sex cell. This newly-fertilised egg cell then contains the full 23 pairs of chromosomes. This cell divides and multiplies and eventually forms a new human being.

Can women get ‘X-linked’ CMT?

If you are a woman and carry the X-linked gene you may be completely unaffected, in which case you are known as a carrier. If you are affected, this is usually more mildly than in a male. This variability occurs because women use only one of their two X chromosomes in any one cell: which X is used in each patch of tissue is decided early in development and varies randomly. The two copies of the CMT-X gene may be employed about equally (in which case the woman will be affected more mildly than a male) but sometimes the affected copy is used predominantly and then she may be affected much as a man might be.


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