Is MND hereditary?

This is a common question and concern, and the answer has been made more complicated by recent discoveries. This is only a summary of some of the issues and the field is changing rapidly.

Genes and disease

Many neurological diseases, including MND, are thought to arise through a complex mix of factors. One factor can be harmful variations in our genes, which make up a 'blueprint' for the development and maintenance of our brain, spinal cord, and nerves.

When there are faults in the genes, they can contribute to diseases like MND developing. Other factors include environmental exposure, and random damaging events in cells that tend to occur more commonly as we age.

Although we have learned a great deal about the genetic factors that might influence whether someone is at risk of developing MND later in life, environmental and age-related factors have been more difficult to identify. This means that people seem to develop MND because of a mix of factors amounting to 'bad luck', rather than because of a single major lifestyle factor, such as their occupation or diet.

Familial and sporadic MND

Approximately one in 15 people with MND will be aware of another close family member (parent, brother or sister, grandparent, aunt, uncle or cousin) with the disease, or with a related condition, frontotemporal dementia (FTD). When this happens, we say the person has familial MND, meaning a genetic contribution is the major factor in causing the disease.

Sometimes people talk about this type of MND as 'running in the family'. This is clearly not the whole story, since people carrying faulty genes related to MND grow and develop normally into adulthood and later life before the disease reveals itself. Sometimes it is not possible to know with certainty if MND is familial, for example if someone was adopted or because medical problems in the family have not been talked about openly. We have also found that occasionally MND that causes walking problems has been misdiagnosed as multiple sclerosis (MS), and FTD has been misdiagnosed as Alzheimer's disease or just 'dementia'.

Most patients who can be sure that there is no other affected family member can assume that their case is a 'one off'. We call this 'sporadic MND', and studies so far suggest that the overall risk for their children is only very slightly increased compared with the children of a person who does not have MND. Since the absolute lifetime risk of any individual developing MND is roughly 0.3 percent, a small increase in risk still means that the chance of developing the disease for anyone with a relative with sporadic MND is still very low.

Genetic testing

We can easily test for faults in the four commonest genes in those MND patients who have also had a close family member with the condition (this is called having a 'family history' of MND). These genes are called C9orf72, SOD1, FUS and TARDBP. There are a growing number of other genes which have been associated with MND (more than 20 at present), but these are very rare, and currently routine testing is not available. Those with a faulty C9orf72 gene more commonly have family members with dementia (FTD).

We each have two copies of every gene. Those carrying a fault in a gene leading to MND have a 50 percent (one in two) chance of passing the genetic error on to their children. However, the risk of someone carrying the faulty gene actually developing MND may be lower than 50 percent in some cases. Individuals carrying the faulty gene may still live long lives and then die of more common illnesses, without ever getting MND or FTD. For this reason, we do not usually recommend testing family members who do not have any symptoms of MND as this can cause unnecessary worry.

Occasionally those who have a family member with MND, and are planning to have their own children, want to consider screening their embryos for the faulty gene to ensure only those without the faulty gene are implanted. This requires in vitro fertilization (IVF). However, this situation is unusual and needs a detailed discussion with a genetic counsellor. It is important to bear in mind that MND is unlikely to remain so difficult to treat. The prospect for treatment and even prevention of conditions like MND is likely to greatly increase during the lifetime of anyone born today.

Should all MND patients have genetic testing?

When, in a research setting, we test the genes of every MND patient who does not have a family history of MND or FTD, we find that a small number (less than five percent) have a faulty gene after all, most often an enlargement of part of the gene called C9orf72.

This means that their children have a 50 percent risk of carrying the same faulty gene. The fact that we can find people who carry a faulty gene, but who do not have any family history of MND, makes us more uncertain about whether or not carrying the faulty gene always leads to MND. This is called imcomplete penetrance.

Genetic testing is not a way to try to rule in or rule out a diagnosis of MND. Genetics will not explain the cause of MND in most patients. Some people find the identification of a faulty gene can help by explaining why MND has arisen, and can provide information to other family members, especially those thinking about planning their own families.

However, it can also cause anxiety for other family members. Because we do not understand the exactly how faulty genes might lead to MND, it is not possible to say for sure that someone has no risk of the disease by carrying out genetic testing, unless the specific faulty gene has been identified as the cause of the disease in the relative who has MND.

New drugs, called antisense oligonucleotides, are becoming available for testing in clinical trials as specific treatments targeting the familial forms of MND. One drug, called tofersen, has been licensed in the USA for the treatment of some people with changes in the SOD1 gene causing their MND. While it is not yet clear if all of such drugs will be successful in slowing or reversing the symptoms of MND, the wish to participate in this sort of clinical trial is another reason that many people with MND might still want to have genetic testing, whether or not they have a family history.

Genetic testing in MND is generally only for those who have developed symptoms. It is an individual decision for each person to make, based on a discussion with your neurologist, and sometimes also a genetic counsellor trained to explain other details of genetic testing.

FaTHoM

We think that studying families where there is a known faulty gene will provide us with a way to see and understand the very earliest changes in MND, and develop better tests and treatments. Importantly, these vital studies can be done without the need for a person to know whether or not they have a faulty gene linked to MND.

The Oxford MND Centre began an initiative called Families for the Treatment of Hereditary MND (FaTHoM), involving study days for families with multiple members affected by MND.

Oxford is leading a UK registry for those families affected by C9orf72 gene expansion, as the commonest genetic cause of MND. This includes studying people who have no symptoms, but have a close relative affected by C9orf72 MND. It's called A C9ORf72 National study (ACORN).

Further information

If you would like to know more about the genetic factors causing MND, or are worried about your own risk because someone in your family had MND, in the first instance you should ask the advice of your GP.

Depending on where you live it may be possible for you to be referred for an appointment at this clinic to discuss this with one of our MND consultants.

Research

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