Updated: Apr 3, 2019
Figure 1. An fMRI brain scan looking at activation in the brain of a person with the Fragile X Premutation (research by Stephanie Brown and Andrew Stanfield)
The fragile X premutation is a change in the genetic code in a gene called FMR1, which is located on the X chromosome. Normally, the FMR1 gene has a region of repeated DNA code called a ‘CGG repeat’ that is up to 55 repeats long. The premutation means that this repeat region is expanded to between 55-200 CGG repeats. The Fragile X full mutation is over 200 CGG repeats, and this causes the gene to be ‘turned off’, leading to Fragile X Syndrome .
Carriers of the fragile X premutation are at risk of developing a condition later in life called the Fragile X Tremor Ataxia Syndrome (FXTAS). FXTAS typically causes balance, movement and memory problems, which may gradually worsen over time. Males with the fragile X premutation have approximately a 40% chance of developing FXTAS, and females approximately an 8-16% chance [2,3]. Individuals with the premutation may start to exhibit signs of FXTAS at about 50-60 years of age, usually with problems in co-ordination and some forgetfulness . Carriers of the premutation may also have a slightly higher risk than the general population of experiencing some mental health difficulties (such as depression, anxiety or obsessive-compulsive disorder), as well as autism spectrum conditions .
Why does the premutation increase the risk for certain problems?
Genes provide the ‘instructions’ to make molecules called mRNA, which in turn convey information about how different proteins should be built (figure 2). The FMR1 gene produces FMR1 mRNA, from which the protein FMRP is produced. FMRP is an important protein mainly in brain development, but also has some roles in hormonal regulation in both men and women. The lack of FMRP in people with the Fragile X full mutation is what causes Fragile X Syndrome. However, the biological effects of having the fragile X premutation are a little different. It has been found that the levels of FMR1 mRNA can be higher than normal, and the levels of FMRP can be slightly lower .
Figure 2. Genes encode messenger RNA (mRNA), from which proteins are created in the cell .
It is because of these slightly decreased levels of FMRP and its important role in brain development that premutation carriers are at higher risk of mental health problems or autism during their lifespan. In comparison, higher than normal levels of FMR1 mRNA are thought to be the cause of FXTAS, as the molecules may accumulate in brain cells over time, causing problems in the way that the cells function (figure 3) .
Figure 3. A theory of how the fragile X (FMR1) premutation might cause symptoms.
Brain imaging in premutation carriers: the current research
Research into the fragile X premutation to date has centred around brain imaging, as it is one of the most useful and powerful tools available for gaining understanding into changes in the brain. The types of brain imaging scans that are most routinely used for this are structural MRI and functional MRI. Structural MRI produces images of the brain that allow us to understand sizes and shapes of brain regions, and some specific types of structural imaging allow researchers to look at the architecture of the brain tissue itself. Functional MRI produces images of brain activation and relies on changes in blood flow to certain areas of the brain in response to different types of stimuli. This allows researchers to understand how the brain is reacting and functioning in certain simulated situations.
Structural MRI findings
Research has revealed that there are some structural changes to the brain in premutation carriers both with and without signs of FXTAS.
One quite stereotypical brain change that occurs in premutation carriers is at the middle cerebellar peduncles (MCPs), which are areas in each half of the brain which communicate inputs and outputs from the cerebellum, an important area for movement. The MCPs can become structurally impaired and this pattern of brain changes is seen in around 60% of people with FXTAS, so scans to look for these brain changes are used to help diagnose FXTAS . In addition, structural imaging studies into the premutation and FXTAS have shown that FXTAS is also associated with some generalised brain volume loss. Often patients with more severe FXTAS will have a larger extent of brain volume loss and in general individuals with larger CGG repeat sizes have a higher risk of developing these structural changes to the brain [9,10].
These types of structural changes in the brain are the cause of the symptoms of FXTAS, as when some of the brain tissue becomes impaired, movement and cognition can become negatively affected as a result. Research has aimed to begin to more thoroughly characterise these changes – for example which specific brain regions are affected, when and why – so that signs of FXTAS can spotted early on. Early interventions could mean that symptoms can be managed more effectively and diagnosis of the condition can be more accurate. Knowing more about how FXTAS develops also means that researchers and clinicians can begin to create treatments that target the cause of the disease, and not just use medications that alleviate the symptoms.
Functional Imaging findings
Functional brain imaging research has shown that carriers of the premutation, both with and without FXTAS, also have some changes in their brain activation patterns in response to certain tasks carried out in the scanner compared to people without the premutation.
In memory tasks, carriers with and without FXTAS performed equally in comparison to comparison volunteers without the premutation, however carriers exhibited decreased brain activation in specific regions of the frontal cortex. The frontal cortex is an area which is important for decision-making, attention and short-term memory. Additionally, premutation groups generally showed increased activation in the parietal lobe of the brain in response to these memory tasks. The parietal lobe is a region which controls perception and integration of sensory inputs to the brain, and higher activation in premutation carriers may mean that this area of the brain is working harder than normal when engaging memory and decision-making processes . During numerical processing tasks, premutation carriers also generally showed lower fronto-parietal activations, although again performance was not significantly different in these tasks compared to the comparison group . In social and emotional tasks performed in the scanner, premutation carriers showed less activation than comparison subjects in the limbic system, which is the emotional centre of the brain [13, 14]. This finding could possibly be linked to the increased likelihood of premutation carriers to develop social or mental health difficulties such as autism spectrum disorder, depression or anxiety throughout their life-span.
Functional imaging is an important part of the research into the Fragile X premutation, as it helps us to understand the underlying brain changes, why these come about, when, and in what areas.
Other research methods
Researchers often use brain imaging to form the main part of their study, but often other measures are taken so that we can see whether brain changes relate to other characteristics. In the case of the premutation, this may include tests into movement, balance, memory and cognition and some blood based measures. Blood based measures will frequently involve a genetic test of the CGG repeat region of the FMR1 gene, as some evidence has suggested the length of this repeat may influence some clinical features of FXTAS. Protein and mRNA levels associated with the FMR1 gene may also be investigated in blood cells, as these measures may also show some correlations to features of FXTAS and the premutation, and understanding this may be important in developing new treatments.
The future of research into the premutation and FXTAS
FXTAS and the other effects premutation have only been discovered relatively recently, and because of this much more research needs to be done to begin to build our knowledge of it. At this stage, most studies have used small groups of participants to look at individuals with the premutation at a single point in time. To progress research further, we need to look at the effects of the premutation in big groups of individuals of different ages, over time. This research will allow more insight into how, when and why FXTAS develops. Also, it is important for us to further understand whether there may be life-style factors that can cause some symptoms to become worse, in both early and later life.
How will this type of research benefit people who carry the premutation?
Medical research often develops over a long period of time, especially with conditions that have only very recently been described. Practically, the research into the Fragile X premutation first aims to educate clinicians and fragile X families, so that individuals can be aware of the changes that occur due to the premutation and FXTAS and doctors can more effectively check for the presence of the premutation or other Fragile X related syndromes.
In addition, blood and imaging tests will hopefully become more refined in the future, meaning that individuals with the premutation know more about the possible effects on both themselves and their families. It is hoped also that research may begin to unravel some of the underlying causes of FXTAS, so that more effective treatments can be developed.
Patrick Wild Centre, Division of Psychiatry, School of Molecular and Clinical Medicine
University of Edinburgh, Royal Edinburgh Hospital, Edinburgh, EH10 5HF, UK.
This piece is a summary of a published research review. If you want to learn more about neuroimaging and the Fragile X premutation, the full version of this review is available at:
Alternatively, you can visit the Patrick Wild Centre website at:
If you are interested in taking part in research into fragile X, you can find out about projects which the Fragile X Society is supporting: http://www.fragilex.org.uk/#!research-involment/ck47
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