Introduction
For a long time, it has been known that fragile X syndrome could be passed to future generations from people with smaller variants (premutation) of the fragile X gene (FMR1), sometimes referred to as carriers. However, until quite recently, it was thought that there were no direct effects for carriers of the fragile X premutation. We are now becoming aware that both men and women with a premutation may experience features related to smaller changes in the FMR1 gene. This article focuses on results of a large survey designed to better understand the types of medical and reproductive challenges experienced by girls and women who have a premutation.
Why do we want to understand the possible features of being a carrier?
Everyone, including fragile X carriers, will experience health challenges during their lifetime. However, we are now learning that there are some features that female carriers may be more likely to experience. Of course, not all carriers have effects: the majority of girls and women with a premutation will experience no noticeable features of being a carrier or may experience subtle features that do not significantly affect their day-to-day life. However, for around a third of carriers the fragile X premutation may have one or more challenging effects. Therefore, we want to understand the possible effects of the fragile X premutation, for the following reasons:
If carriers and professionals are aware of the possible health effects, then particular indicators can be monitored to detect any changes early, which could allow for better treatment and reduced symptoms.
With greater understanding of the features and their causes,specific treatments that are more effective for symptoms of fragile X carriers may be found
Knowing the cause of particular features may be helpful for individuals themselves and also gives access to support a community of people who understand or who are experiencing similar challenges.
Understanding the possible features can help women to make informed choices and take steps to help to remain in the best health possible
There are likely to be undiagnosed girls and women experiencing symptoms related to having a variation in their fragile X gene. Therefore, there may be particular patterns of features which indicate that someone should have a fragile X test. Having the correct diagnosis is important for that person and their wider family, due to the inherited nature of Fragile X.
Why do some carriers experience effects and others do not?
There may be many reasons why some people experience features relating to being a carrier whilst others do not. We do not yet understand this variation in detail, but the reasons may include:
How expanded the fragile X gene is (how many CGG repeats the person has).
How much of the fragile X genetic messenger is being produced: when someone has a fragile X premutation they may produce higher than normal levels of a type of “genetic messenger” (mRNAs) which may interfere with the way some cells work.
How much of the Fragile X Protein (FMRP) is being produced. In people with Fragile X Syndrome, FMRP may be absent or greatly reduced. Carriers still produce FMRP but this may be at lower levels than in the general population.
Other “knock-on” effects of having an expanded fragile X gene
Which changes (typical variations or unusual differences) the person has of other genes
Environmental factors such as stress or exposure to things which could cause harm to the brain.
In the future, we hope to better understand the causes of the variation so that we can more accurately predict whether someone may be likely to experience a certain condition, and so that we can better prevent difficulties from occurring.
In addition, it is important to recognise that, though some health issues may be associated with being a carrier, support to manage and reduce these symptoms can and should be sought from your doctor and may be helpful, as they would be for anyone else experiencing similar symptoms.
Which features may be associated with being a carrier?
Fragile X-Associated Conditions
In the past 10-15 years, two fragile X-associated conditions have been discovered to affect some premutation carriers. These conditions have a specific set of symptoms and develop in a particular way
Fragile X Associated Tremor Ataxia Syndrome (FXTAS). In later life (typically, after the age of 50) some carriers may develop FXTAS. Features of the syndrome may include: tremor (especially when moving, compared to at rest), balance problems, decline in intellectual skills such as memory and learning. The condition is more common in men: over the age of 50, FXTAS is estimated to affect 30-40% of male carriers and 8-16% of female carriers in families in which a fragile X associated condition is already diagnosed (across all carriers, the true estimates are likely to be lower). The symptoms in females are typically less pronounced or may vary slightly in how they are experienced. For further information, see our introductory leaflet.
Fragile X Premature Ovarian Insufficiency (FXPOI). A minority of female carriers(20-25%) experience a condition in which they have decreased or abnormal ovarian function. This can result in infertility or fertility problems, irregular or absent periods, or premature ovarian failure (POF) with associated early menopause. For further information, see our introductory leaflet.
Associated Features
People who are fragile X carriers, like everyone, may experience health difficulties through their lives. Some of these health conditions will be unrelated to being a carrier, but we know that there are some features which may be more likely to occur as a result of having the pre-mutation. The following discussion focusses upon carrier-related features for girls and women, but there is some discussion about the possible effects for boys or men, too.
The following section reviews all of the evidence that we have at the moment on health (both physical and mental health) and reproductive features that may be associated with being a fragile X pre-mutation carrier. The evidence is from research and from experts’ experience.
The only way to find out whether there is an increased risk of a particular feature in fragile X carriers is to do comparisons between large groups of people with and without the fragile X premutation, but who otherwise have similar features (e.g. age, socio-economic status). Therefore, the associations are rated to show how strong the evidence is for a link with being a carrier according to the following criteria:
Definitely related: there is strong evidence, from several research studies directly comparing people with and without the fragile X premutation, which shows that there is an increased risk. NOTE: this does not mean that all carriers will experience this feature.
Probably related: there is some evidence for an association. This could either be because there is good evidence from just one study (i.e. it needs further research to confirm), there is not agreement between all research studies, or because better quality research is needed.
Possibly related: there is emerging or anecdotal evidence of an association, but more research is needed.
Not likely related: there is good evidence to show that the risk is not increased i.e. it is the same as in the general population. NOTE: some carriers may experience these features but it is very likely to be unrelated to being a carrier.
The following sections look at different types of features and review what we know about each, in fragile X carriers.
Medical Features
Table 1. Summary of evidence to show whether there is an increased risk of certain medical/ health features
Thyroid problems. The thyroid is a gland in the body. One of its main functions is to produce hormones that help regulate the body's metabolism (the process that turns food into energy). The thyroid can be both under- or over-active in people who are carriers, and in the general population.
Three research studies have looked at the frequency of thyroid problems in carriers, two found significantly higher thyroid problems in female carriers, but one did not. It may be that the link to thyroid problems gets stronger in older women. Problems include under-active thyroids (hypothyroidism)and, less commonly, over-active thyroids(hyperthyroidism) and may be related to the immune system attacking the gland. One study estimates that approximately 17% of carriers (without FXTAS) may have thyroid problems. In the general population, thyroid problems are estimated to affect around 1 in 20 people, so the rate in carriers does seem to be higher. These issues are thought to be more common in carriers with FXTAS.
What does this mean for me?
The NHS provide good advice on the features and treatment of both under and over active thyroids:
http://www.nhs.uk/Conditions/Thyroid-over-active/Pages/Symptoms.aspx
http://www.nhs.uk/conditions/Thyroid-under-active/Pages/Introduction.aspx
If you think you are experiencing any of these symptoms, speak to your GP about getting a check of your thyroid function, which involves a blood test.
If you know you are a carrier, ask your GP for regular thyroid checks, so that if there are any difficulties, they can be detected early and treated quickly.
Fibromyalgia. Fibromyalgia is a condition which is associated with long term pain and stiffness. These symptoms have been found to be higher in carriers than in the general population in two studies, but one did not find an association. More research is needed to determine whether there is an increased risk.
What does this mean for me?
There are no specific tests for fibromyalgia, as the exact causes are unknown. It is diagnosed based on symptoms.
The NHS provide further details about the features and management of fibromyalgia: http://www.nhs.uk/Conditions/Fibromyalgia/Pages/Introduction.aspx
High blood pressure. In female carriers without FXTAS, there does not seem to be a strong association (one study found an increased risk but two did not). However, one study has shown much higher rates in women with FXTAS than the non-carrier comparisons and it is thought that this may be due to a broader issue with the autonomic nervous system (which controls unconscious body processes like heart rate), specifically related to FXTAS.
What does this mean for me?
If you have been diagnosed with FXTAS, speak to your GP about ensuring that regular blood pressure checks are conducted, so that if there are any difficulties, they can be detected early and treated quickly.
More information can be found about high blood pressure at: http://www.nhs.uk/conditions/blood-pressure-(high)/pages/introduction.aspx
Migraines. Migraines are severe headaches which may be accompanied with symptoms such as nausea or sensitivity to light. Two studies have suggested that more (male and female) carriers experience headaches and migraines. However, this was not seen in carriers without children with FXS. It may be that migraines may be made worse with family stress issues (caused by caring for children or relatives with fragile X-related challenges), though this is not yet clear. As in the general population, it seems that migraines are most common in teenage/ young adult carriers and become less common with age.
What does this mean for me?
If you are experiencing regular headaches, which are not able to be controlled by over the counter painkillers (such as paracetamol) see your GP.
You can find advice on the management of migraines at: http://www.nhs.uk/conditions/migraine/pages/introduction.aspx
Neuropathy. Neuropathy is a group of conditions affecting the nerves (such as those who help you to feel or move). Symptoms of neuropathy can include: numbness, tingling and muscle pain in the extremities. There has been a good amount of research showing that female carriers are more likely to experience neuropathy. It is thought that these symptoms may start intermittently but become more consistent and enduring in people who develop FXTAS, though they are not necessarily an early sign of FXTAS.
Vestibular Issues. Four studies have shown an association between features such as feelings of spinning, dizziness, faintness and suddenly being unbalanced. More carriers appear to experience these symptoms more commonly than the general population, but these symptoms may be more common and severe in women who develop FXTAS.
What does this mean for me?
If you are experiencing features of neuropathy or vestibular issues to an extent that they are uncomfortable or they interfere with your daily life, speak to your doctor who can discuss methods which may help to manage the symptoms.
Mental health and psychological features
Table 2. Summary of evidence to show whether there is an increased risk of certain mental health/ psychological features
Depression. There is good evidence that carriers have a higher risk of experiencing depression or depressive symptoms. For instance, one study found that the the lifetime prevalence (i.e. the proportion of people who experienced depression once or more at some point in their lives) of major depressive disorder was 43% in female pre-mutation carriers, versus 32% of women in the general population.
Anxiety. A large recent piece of research compared carriers (with and without FXTAS) to people in the general population. It was found that carriers were more likely to experience social anxiety, and that carriers with FXTAS were at a higher risk of some other anxiety-related issues than individuals in the general population (though this did not apply to carriers without FXTAS). However, there were not differences between carriers and non-carriers in the frequency of some anxiety-related features, such as generalised anxiety disorder and obsessive compulsive disorder (OCD).
What does this mean for me?
It may be that there is a direct biological link between being a carrier and experiencing either anxiety or depression, or that supporting other family members with Fragile X Syndrome or FXTAS may also cause or contribute to these issues. Most likely is that there is an interaction between the biology of being a carrier and the challenges that can be associated with supporting a family member with additional needs.
As for all individuals experiencing mental health issues, there are a variety of supports available. Your GP can help to speak through these options with you. You can also find more information via the NHS website and via organisations such as Mind (http://www.mind.org.uk/)
Attention and hyperactivity. Research suggests that, on average, carriers are more likely to experience issues with inattention and impulsivity, though not more likely to experience issues with hyperactivity, when compared to non-carriers.
Reproductive Features
It has been known for a long time that Fragile X carriers have a change of passing Fragile X Syndrome to future generations. However, researchers have also investigated whether there are any other features related to reproduction for women who are carriers. For more information, read our introductory booklet.
Table 3. Summary of evidence to show whether there is an increased risk of certain reproductive health features
Ovarian Insufficiency. We know that female carriers have an increased risk for developing FXPOI, with features such as periods stopping early (before the age of 40), ovaries stopping releasing eggs before the age of 40 (premature ovarian insufficiency (POI) or failure) or other signs of the ovaries aging early or not working properly (skipping periods, irregular or short menstrual cycles, fertility difficulties). On average, the age of menopause is 5 years earlier in fragile X carriers. The risk for having an earlier menopause seems to be highest in women with mid-range numbers of CGG repeats (around 70-100)
Fertility issues. Women who experience POI experience reduced fertility, however, there is some evidence to suggest that even before POI, or in women who don’t develop POI, that there may be reduced fertility. Again, this appears to be most common in women in the mid-range CGG group.
Unlike women who have gone through menopause, there is a possibility that women with FXPOI may still become pregnant, which may have implications for birth control.
Oestrogen deficiency. Oestrogen is a hormone produced mainly in the ovaries, and levels are generally highest in women of reproductive age. When women go through POI, they also experience early reduction in levels of oestrogen (which is a normal feature of menopause). This comes with challenges typically associated with menopause and features such as earlier onset and greater frequency of osteoporosis (bone weakness) have been reported in female carriers
What does this mean for me?
If you are concerned about whether you may be experiencing FXPOI, speak to your GP who can do tests to check your hormone levels.
If you are a carrier and plan to have children, there is a chance that your fertility levels may decrease earlier than expected. This may influence family planning.
If you are experiencing oestrogen deficiency, your GP may recommend oestrogen replacement in the form of HRT or the combined pill.
http://www.guysandstthomas.nhs.uk/resources/patient-information/gynaecology/premature-ovarian-failure.pdf
Pregnancy and birth difficulties. There is very little known about these features in fragile X carriers and it is unclear whether there are any differences in risk. There does need to be more research, in particular into chances of preeclampsia.
What does this mean for me?
There are no differences in the management of pregnancies or birth for carriers, compared to other women.
Postnatal depression. One study has investigated whether rates of postnatal depression are higher in women who are carriers, and found no difference, though this needs to be investigated further.
What does this mean for me?
More information can be found about postnatal depression here: http://www.nhs.uk/conditions/postnataldepression/pages/introduction.aspx
Conclusion
Maintaining a good level of health, such as through eating, exercise and stress reduction techniques, is important for all (fragile X carrier or not) but may help to prevent or reduce the impact of some of the associated features with being a carrier.
Of note, being a carrier does not mean that these features are inevitable. If you are experiencing any of these challenges then contact your GP who will work to identify methods to help treat or manage these symptoms.
We hope that this research as well as future research into the fragile X premutation will help carriers to receive the best support possible, where required.
You can read the full version of the research review here
If you have questions about being a carrier, or want to talk to someone, you can contact our support workers on: 01371875100 or info@fragilex.org.uk