FXTAS: Who, What, When, How?


Summary of above video (written by Jane Oliver, Fragile X Society Support Worker)

This article gives an overview about what is currently known about (Fragile X Associated Tremor and Ataxia Syndrome) FXTAS, broadly. It is important to note, however, that the severity of its symptoms is different for each individual.

What is FXTAS?

FXTAS is a neurological, progressive condition affecting some premutation carriers of fragile X. It was originally described in 2001 by Randi Hagerman who then involved the expertise of, amongst others, Maureen Leehey, a neurologist and movement disorder specialist.

FXTAS was originally described in older men who were premutation carriers. Amongst males, the symptoms of FXTAS are quite variable but the most common features are:

  • Movement and balance. Issues may include: ataxia (lack of coordination in walking and, later, movement of limbs), tremor when completing an action (intention tremor), and Parkinsonism (stiffness and rigid movements). FXTAS shares some similar features to Parkinson’s, and is often misdiagnosed as Parkinson’s. However, one of the differences between FXTAS and Parkinson’s is that the tremor seen in Parkinson’s is usually at rest. In contrast, in FXTAS the tremor is noticeable when someone is active, for example, when trying to pick up a cup.

  • Memory and cognition: Cognitive changes may include decline in the ability to think, remember and organize. Research shows that approximately 40% of men with FXTAS develop dementia, meaning that their ability to process information shows down more severely and that they may have difficulty controlling their behaviour. Research suggests that the likelihood of experiencing this cognitive decline increases in individuals with an increased number of CGG repeats (in the premutation range). Interestingly, however, the current research suggests that individual with more severe tremors are seem to have less severe cognitive issues, on the whole.

  • Mood and personality: There is an increased chance of premutation carriers experiencing mood disorders like anxiety or depression in general, which may increase in those who develop FXTAS. Men with FXTAS may also experience changes in their personality. For example, some men have become withdrawn when previously they were outgoing, or become hostile and disinhibited when they were mild mannered before.

FXTAS may also occur in women (there is an incidence of approximately 10% based on recent research). On the whole, women with FXTAS tend to have milder symptoms. This is because women have two X chromosomes so, to varying degrees, they have a mixture of premutation cells and cells with an unaffected FMR1 gene (this is known as the X inactivation ratio). Women experience varied neurological symptoms, and tend to have a more Parkinson’s type presentation. Women are much less likely to develop the symptoms of cognitive decline and dementia, compared to men. Of note, it has been observed that some women who are premutation carriers experience clumsiness and balance issues earlier in life (for instance in their 30s or 40s) and, though believed to be associated to being a carrier, this is not believed to be in the same class of symptoms as FXTAS. Though our understanding is increasing, much more research is needed on the effects of premutations on women and FXTAs in females.

Prior to developing movement disorders, people often experience numbness and tingling. There is some suggestion that the myelin sheath (the membrane or covering that wraps over the nerves) seems to be implicated as nerves are slower at conducting their messages.

What is the timeline for FXTAS?

The most common age of onset is in the over 70’s but onset can occur earlier, such in the 50’s and 60’s. The older the person is the more likely it is that they will develop FXTAS, especially over the age of 80.

There has been come research investigating the average timescales of the progression of characteristics of FXTAS. In terms of tremor, once it presents itself, on average it takes about 9 years before it impacts on daily life. In terms of balance this usually presents a couple of years after the tremor. About 5 years in to the diagnosis falls can become more prominent and by 15 years aids or adaptations might be needed to help with mobility. It is important to note that these are average figures and individuals’ experiences vary widely.

FXTAS can be described as step-like in its progression. People may experience periods of time with little changes in their symptoms , but, if they have a major life event or a setback like a stressful event, becoming unwell or needing surgery, this may be followed by an increase their symptoms and they may need longer to recover. More research is needed to investigate what may be associated with symptom changes.

Treatment

There is currently no specific treatment for FXTAS and the main aim of interventions are to treat and manage or slow the symptoms.

The first clinical trial for FXTAS was on Memantine (94 people participated). This drug is usually prescribed for Alzheimer’s patients, but, as it seems to have an impact on fragile X protein it was felt it might produce a good response. Outcomes measured were behaviours and tremor, but, there was no change. Verbal memory did improve, however. The conclusion drawn from this by the investigators was that the way outcomes were measured in the study may not have been appropriate. So they couldn’t measure what they hoped had changed in effect. It is thought that there may be patients with certain clusters of symptoms for whom this might be helpful, but more research is needed.

In addition, some premutation carrier men have responded to dopamine medication- which is the medication used for people with Parkinsons (a condition that shares some features with FXTAS). People with Parkinson’s have low levels of dopamine, and the medication helps to combat this. In contrast, however, later research has shown that many premutation carrier men have normal levels of dopamine.

In the USA, Beta blockers (to control the tremor) are the most common treatment in primary care.

However, the priority is to treat the symptoms and there are no medications that have shown to be effective for all patients. One medication at a time is tried and medication is chosen according to the presenting symptoms.

Treatment of motor problems

Physiotherapy can help to manage some of the movement issues and reduce the risk of falls prevention. Exercise generally has been seen to slow neurodegenerative disease. However, this this is very important in movement disorders, as it increases stamina and memory areas in the brain. As a result, thirty minutes of aerobic exercise 5 days a week is recommended.

Generally, it is recommended that once diagnosed all FXTAS patients should be under the care of a neurologist: a movement disorder specialist is the ideal professional. However, general neurologists are not yet likely to be aware of FXTAS. Contact us at the Fragile X Society for information about FXTAS which can be shared with professionals about the features, diagnosis and management of FXTAS.

What causes FXTAS?

For those interested, this section gives an overview of the underlying physical changes and causes of FXTAS. Unlike in individuals with full-mutation Fragile X syndrome, in a pre-mutation change the protein (FMRP) is still made. However, in people with the premutation, but too many of the messengers (mRNA) which work with the fragile X protein (FMRP) are made. This extra messenger can reach toxic levels affecting the cell structure. In effect the cells are “clogged up”- forming inclusions within the cells. An additional problem in FXTAS lies in the cell’s powerhouse. This is called the mitochondria and in FXTAS these structures function poorly. This also contributes to the “toxicity” within the cell.

These changes happen most commonly in brain areas that serve movement and thinking, hence the pattern of symptoms associated with FXTAS.

What is happening in the brain when someone gets FXTAS?

  • A defining feature of FXTAS is lesions in a part of the brain called the Middle Cerebellar Peduncles (MCP). This pattern of brain changes is known as the MCP sign and can be detected in an MRI brain scan and can be used to help diagnose FXTAS.

  • The brain gets smaller at a faster rate than normal bearing in mind that brain size does decrease as we get older.

  • White matter is the tissue that connects different parts of the brain, in people with FXTAS, we see widespread changes in this type of tissue.

You can read more about research into brain changes in pre-mutation carriers here.

Conclusion

I hope this has made some sense and has been a little helpful. Please look at the link if you can. She really is an engaging speaker.

There is still much to be discovered about FXTAS and how to provide the best support and we will continue to keep you up to date with new information as it becomes available. If you want to find out more or speak to someone about FXTAS, please do contact me on 01371875100 or jane@fragilex.org.uk.

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