Genetic FTD & Living At-risk

GENETIC FTD AND LIVING AT-RISK

Our work focuses on trying to improve the lives of those with FTD from birth through to the development of symptoms and beyond. This is particularly the case in genetic FTD where people often learn of their risk of developing genetic FTD at a young age. On this page we address some commonly asked questions. For a detailed review of genetic FTD click here.

In the UK, support for people at-risk of genetic FTD is available through the familial FTD support group – we meet once per year, with the opportunity to meet others in the same position. If you are interested in attending, contact Caroline Greaves from our team on caroline.greaves.14@ucl.ac.uk.

FTD is genetic in around one third of people and not genetic in the other two thirds.

The risk is highest in bvFTD where it is nearer to 40%, and much lower in PPA, where it is around 5-10% for nfvPPA and <1% for svPPA and lvPPA.

The risk can be quantified further based on the family history. For bvFTD, if there is a family history of dementia or MND in first-degree relatives of the person symptomatic with FTD the risk is:

  • ~75% (or 3 in 4) if there are at least 2 other people (and >90% if more than 2 other people),
  • ~50% (or 1 in 2) if there is 1 person with a young onset dementia (first symptoms below 65),
  • ~25% (or 1 in 4) if there is 1 person with an older age onset dementia (first symptoms above 65).
  • If there is no other family history of dementia or MND, the risk of finding a genetic cause is ~10% (or 1 in 10).
  • Whilst a 10% risk of a parent’s FTD being genetic is what we would quote to people with no family history, it is made a little bit more difficult to give an exact figure if parents of the person with FTD died at a relatively young age.

For anyone with bvFTD and anyone else with a strong family history we would offer genetic testing.

The majority of people who are symptomatic with FTD take up genetic testing when offered it, but some do not. Most people take up testing because: 1) it allows the family to plan (and this includes for some families the possibility of preimplantation genetic diagnosis i.e. having a child without the genetic mutation), and 2) it allows people to be involved in research studies of genetic FTD, which for people both with and without symptoms now includes drug trials.

If it happens to be a genetic form of FTD, then not testing for a genetic cause will not stop it being genetic – it just means the family will not know, and make it harder for people in the family to plan. However, sometimes the time at which the person is asked to undergo genetic testing does not feel to them (or to the family) like the right time to go forward it. In that case we suggest having a blood sample taken and for the DNA to be stored in the genetics lab until a time when people want to move forward with testing. This ensures that family members have all options open at a later time when they might want to know what their risk is.

When genetic testing is performed, all differences from the ‘normal’ genetic code are looked at. However, we all have variations at different points in our DNA, and many of these have no effect on our health at all. When these variations are rare enough to not be included in databases of ‘normal’ genetic code, but have yet to be shown to definitely cause FTD, they are called variants of unknown significance or VUS.

We are often asked to see people or families where there is a VUS. The question we are generally being asked is whether the variant is a definite cause of FTD. There is often no easy answer to this, and commonly not enough information to provide enough support to move it from being a VUS to a definite mutation. However, different bits of information can be supportive of the variant being a definite mutation including:

  • for progranulin mutations, very low levels of the progranulin protein in blood or spinal fluid have been shown to be signs of a definite mutation – such testing is only available in specialist centres like ours.
  • finding the variant in multiple members of the family who also have FTD (and not finding it in people without FTD).
  • checking special software programmes that predict if a variant is likely to be a definite mutation.
  • biological studies that show that the variant causes abnormal changes in brain cells.
  • examining for particular pathological findings consistent with the mutation (if brain tissue is available from someone with the mutation in the family).

For most people who have a genetic form of FTD their family members have been involved in the diagnostic process and are aware of the genetic nature of the illness. However, there are a number of situations when that is not the case.

When relatives did not attend the appointment.

Many people who are diagnosed with genetic FTD attend their appointment only with their partner and not with their children or siblings. It therefore falls on the person with FTD, or more commonly their partner, to tell other family members about the genetic nature of the ilness, and their own risk of developing it. Understandably, many people find this difficult and often delay telling family members.

There is no ‘right’ time to tell family members. It is worth thinking about finding a time when all family members are told at the same time so that everyone hears the same information. We will often provide a letter that people can show to family members with important information about their risk. This contains the following points:

  • Your relative has been diagnosed with a genetic form of FTD.
  • Genetic FTD has an ‘autosomal dominant’ pattern of inheritance, meaning that it passes from one generation to the next in a 1 in 2, or 50:50 manner.
  • In other words, if you are a child or sibling of someone with genetic FTD you have a 50% risk of carrying the same genetic mutation.
  • If you carry the genetic mutation then it is extremely likely that you will develop symptoms of FTD during your lifetime. For many people this can be at a similar age to the person who has FTD, but the age at which people develop symptoms can sometimes vary by at least ten years from their relative.
  • It is possible for you to find out whether you carry the genetic mutation – this is a process called presymptomatic testing and requires a referral from your GP or primary care physician to a specialist genetics clinic. People undergo genetic counselling before testing is performed in order to make sure that the right decision is made. In our experience, only about one third of people choose to have presymptomatic testing and two-thirds do not.
  • More information about familial FTD can be found on www.ftdtalk.org and through the national support group (in the UK at www.raredementiasupport.org).

We generally offer to meet with family members in our clinic as soon as we can after a genetic diagnosis has been given. This allows us to go through the points above and also talk about issues such as preimplantation genetic diagnosis if relevant. We can also go through any questions that have arisen from the information above.

When relatives are children below the age of 18.

The above information is generally applicable to adult relatives. For children below the age of 18, telling them about their risk can be more difficult. One key difference is that presymptomatic genetic testing is generally not performed on those under 18. There is no ‘right’ age at which to tell someone. Whilst some people advocate telling children at a young age, others feel that the mid- to late-teens is more appropriate. Whenever people do tell their children it is important to recognise that most specialist genetics clinics will provide support to children and the whole family for any issues that arise.

When relatives are not directly in touch with the family.

This can be difficult and people can understandably not be keen to contact family members they have not seen in a long time, or are barely in contact with, with such information. For people who do want to contact other family members we will usually provide a letter with text similar to below that people can take to their GP or primary care physician:

To whom it may concern:

A relative of your patient has been diagnosed with familial frontotemporal dementia (fFTD).
Frontotemporal dementia is a form of dementia predominantly affecting behaviour and personality. It can also affect language when it is generally called primary progressive aphasia (PPA). It can affect both men and women and usually starts in the 40’s, 50’s or 60’s. However it can also affect older people, and rarely, even younger people.

First degree relatives (brothers, sisters and children) of an affected individual are at risk of carrying the genetic alteration associated with familial frontotemporal dementia and, therefore, may be at risk of developing signs and symptoms.

More information regarding familial frontotemporal dementia is available at www.ftdtalk.org and from the national support group (in the UK: http://www.raredementiasupport.org/).

If your patient would like to discuss this in more detail please refer them to their local genetics centre. Genetic testing of unaffected individuals requires careful thought and generally occurs following several appointments. A referral does not oblige an individual to have a genetic test, it merely offers them an opportunity to discuss their options.

Please do contact us if you require any additional information.

If you have a first-degree relative (parent or sibling) with a known genetic mutation then it is clear that the risk of you also carrying the mutation is 1 in 2, or 50:50. This is because most forms of genetic FTD have an ‘autosomal dominant’ pattern of inheritance. The vast majority of people who carry one of these genetic mutations will develop symptoms during their lifetime.

If you do not have a first-degree relative with a known genetic mutation the answer is more complex. For people who contact us and say: “My parent (or sibling) has FTD – what is my risk?”, the first question to answer is whether their parent (or sibling) has a genetic form of FTD or not. When we think about this question, we usually make the following points:

  • FTD is genetic in around one third of people and not genetic in the other two thirds.
  • The risk is highest in people with bvFTD where it is nearer to 40%, and much lower in people with PPA, where it is around 5-10% for nfvPPA and <1% for svPPA and lvPPA.
  • The risk can be quantified further based on the family history. For people with bvFTD, if they have a first-degree relative who also has dementia or MND then the risk of their form of FTD being genetic is:
    • ~75% if there are at least 2 other people apart from them,
    • ~50% if there is 1 other person with a young onset dementia (first symptoms below 65),
    • ~25% if there is 1 other person with an older age onset dementia (first symptoms above 65).
    • If there is no other family history of dementia or MND, the risk of finding a genetic cause is ~10%.
  • Whilst a 10% risk of a parent’s FTD being genetic is what we would quote to people with no family history, it is made a little bit more difficult if both of the parents of the person with FTD died at a relatively young age.
  • For anyone worried about a genetic cause in their first-degree relative we recommend discussing the above information with their relative’s doctor. For anyone with bvFTD and anyone else with a strong family history we usually recommend that the person symptomatic with FTD is offered genetic testing.
  • Prior to any genetic testing, the risk of the child of a person with FTD is not quantifiable. If their parent turns out to have a genetic cause of his FTD then the child (and any siblings) risk of carrying the same genetic mutation is 50%. If their parent turns out not have a genetic cause of his FTD then their risk is zero.

The above advice is applicable when the person with FTD is alive and able to consent for genetic testing. If they are not, then things are even more complex:

  • If they are alive and unable to consent, our advice is to seek a referral to a clinical geneticist. It can be possible in this setting to take a DNA sample from either blood or saliva of the person with FTD in the best interests of the family, and then test the sample if all family members are in agreement, or store a sample for later testing.
  • If they are no longer alive, then we will search to see if a DNA sample can be found. This may have been taken from blood during life and stored in a genetics lab, or it can be taken from brain (or other) tissue after death if a post mortem was performed. We will then undertake genetic testing on that sample.
  • Unfortunately, if no DNA sample is available then genetic testing cannot be performed. In this situation clinical geneticists generally do not advise blind presymptomatic testing of first-degree relatives because of the risk of finding genetic variants whose significance is unclear.

Presymptomatic testing is the process by which people who currently do not have symptoms can find out if they carry the genetic mutation.

People undergo ‘genetic counselling’. This is usually a hospital appointment where you meet with a trained genetic counsellor and/or geneticist to discuss the pros and cons of having testing. It is important to note that this is not ‘counselling’ in the psychological sense that people often think of when they hear the word ‘counselling’.

Usually you will meet with the genetics team on a few occasions over a number of months to allow you to think about the decision to go for testing. You cannot ‘unknow’ the information once you’ve been told your genetic result so it is important to make sure you definitely want to find your result.

It is important to note that going for genetic counselling does not commit you to having presymptomatic testing. You can pull out of the process at any time if you change your mind about having the test. In our experience, only about one third of people who are at-risk choose to have presymptomatic testing and two-thirds do not.

Within the UK, the process of presymptomatic testing starts with your GP making a referral to one of the regional genetics services.

For FTD (and other neurological disorders), the neurogenetics team at the National Hospital for Neurology and Neurosurgery can also see people via a referral from their GP.

For people from families with a MAPT mutation, the age at which people develop symptoms is fairly well correlated with the average age at which other family members have previously developed symptoms. In other words, if the average age at onset of symptoms is 55 within the family, it is likely that symptom onset for the majority of presymptomatic mutation carriers in that family will be somewhere nearby to 55.

For people from families with a C9orf72 expansion the correlation is less than for MAPT, whilst for people from families with a GRN mutation, the correlation is even lower. This means that is not possible to accurately predict the age at which presymptomatic carriers of these mutations will develop symptoms. We have seen families with differences in age at symptom onset of more than 10 years, and in some cases 20 years, between different family members.

For both C9orf72 expansions and GRN mutations, the genetic phenomenon of age-related penetrance exists. This means that a small number of people, for reasons we don’t currently understand, do not develop symptoms by the time they die despite carrying the mutation. We have seen people from these families who have developed symptoms in their 80s or even 90s.

Less is known about the rarer genetic causes although research is underway to understand this better.

In each of the genetic groups, people can develop the same or different clinical syndrome as other members of the family:

  • For MAPT mutations, most people develop bvFTD, but some people develop a parkinsonian syndrome, which may be CBS, or less commonly, PSP.
  • For GRN mutations, bvFTD is the most common clinical syndrome, but others develop PPA (either nfvPPA or a PPA syndrome not otherwise specified) or in some cases a CBS.
  • For C9orf72 expansions, bvFTD or MND/ALS (or the combination of both) are the most common clinical syndromes, but more rarely PPA, or a movement disorder can occur.

For some people from each of the main genetic groups, memory problems similar to Alzheimer’s disease can be the first symptom.

Many people worry about passing on the risk to their future children of developing FTD. There are several choices available for those at-risk of FTD in families with definite mutations (but not for those with variants of unknown significance – see above):

  • Many people may will conceive naturally and give birth without taking up options for having children without the mutation. For known mutation carriers, their children will be at 50% risk of carrying the genetic mutation. For at-risk people unaware of their own genetic status, their children will be at 25% risk of carrying the genetic mutation.
  • For those who have conceived naturally, prenatal testing can be performed in some circumstances. This requires a process called chorionic villus sampling (CVS) or amniocentesis in early pregnancy – this sample is then tested for the genetic mutation. Prenatal testing is only offered where a couple feel certain that they will terminate the pregnancy should the foetus be a carrier of the mutation. This is because there is a miscarriage risk associated with prenatal testing which should be avoided if it will not alter management of a pregnancy. In addition, continuing a pregnancy at risk of FTD would take away the child’s right to choose whether or not to have genetic testing once they reach adulthood. A disadvantage of this method is that the time sensitive nature means that the at-risk person would most likely need to know their own genetic status prior to conception as CVS has to take place early on in the pregnancy.
  • Preimplantation genetic diagnosis (PGD) may be available to those at-risk of FTD. Preimplantation diagnosis is a form of in vitro fertilisation (IVF) with added screening of embryos for the mutation in question prior to implantation. This process carries risks similar to those of IVF. In most cases of PGD the potential parent knows their own genetic status, but this does not necessarily need to be the case – see exclusion testing below, with another less common (and more difficult option) being non-disclosure PGD. PGD is available only in most countries if the individual meets certain criteria, and in the UK is generally only funded on the NHS for the couple’s first child – see the figure for the different services within the UK, which require a referral from a specialist genetics clinic.
  • Alternative reproductive options may include sperm or egg donation. Under some circumstances adoption may also be an option.

Exclusion testing is an option for couples where the at-risk person does not wish to have predictive testing. It is possible to offer exclusion testing in both the prenatal and the PGD setting. In order to offer exclusion testing DNA samples from sufficient family members must be available, usually including the parents of the at-risk person (one of whom will be the person with FTD). Using a method of DNA fingerprinting, it is possible for example to work out whether the foetus has inherited a low-risk chromosome from their unaffected grandparent rather than a high-risk chromosome from their affected grandparent. This is explained well in this article about Huntington’s disease on the HD Buzz website.

In any of the above scenarios, or for discussion of reproductive options in general, an appointment with a specialist genetics clinic in order to understand the options and risks is recommended.

UK Preimplantation Genetic Diagnosis services

London