Health and Reproductive Features Related to Being a Female Fragile X Carrier

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:

  1. 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.

  2. With greater understanding of the features and their causes,specific treatments that are more effective for symptoms of fragile X carriers may be found

  3. 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.

  4. Understanding the possible features can help women to make informed choices and take steps to help to remain in the best health possible

  5. 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?