FXTAS stands for Fragile X-associated Tremor/Ataxia syndrome (FXTAS) – a difficult word for a complex disorder. As a relatively “new” condition, described by Dr Randi Hagerman in 2001 for the first time, FXTAS is still under- and often misdiagnosed. Many physicians are unaware of FXTAS and the multifaceted problems these patients are facing. We want to raise awareness in the community as well as reaching out to the medical profession for a better understanding and recognition of this progressive, neurodegenerative condition and the implications it has for affected individual and their families.
What are the symptoms of FXTAS?
It was in Dr Hagerman’s paediatric clinic for Fragile X syndrome (FXS) where she first recognized that some of the children’s grandfathers seemed to have neurological symptoms, including tremor and memory problems.
FXTAS is named after its main symptoms:
Tremor: involuntary hand trembling, typically when performing an action like reaching for an object or writing, less often at rest
Ataxia: impaired coordination of walking and limb movements
These symptoms are often combined with other features such as cognitive changes (problems with thinking, memory and organizing), stiffness and slowness as seen in Parkinson’s. Damage of the nerves in the periphery (neuropathy) can cause pain, and may also affect the autonomic system (responsible for bladder, bowel, blood pressure and sexual function). Other symptoms like mood and personality changes, or fatigue can occur. But every person is different and not everyone will experience all of these symptoms. As symptoms worsen over time, day-to-day activities such as walking, getting dressed, using everyday objects like cutlery, a phone or computer, become increasingly difficult.
What causes FXTAS?
As it turned out, a premutation of the Fragile X gene is the cause of this adult onset (usually over the age of 50 years) progressive, neurological disorder. People with Fragile X Syndrome have an excessive number of repeats of the genetic code ‘CGG’ on the Fragile X (FMR1) gene. Usually the number of CGG repeats is under 44, but people with FXS have over 200 CGG repeats, and sometimes thousands. This typically causes the gene to become “switched off”, meaning it cannot produce the protein FMRP, which is important for brain development.
In comparison, people with the premutation have a longer CGG repeat size than the general population, but shorter than the full mutation that causes FXS, hence the term ‘premutation’ (55-200 CGG repeats). In FXTAS premutation carriers, the gene is not completely switched off like in FXS. In contrast, in FXTAS the gene still works well enough to produce some FMR1 protein, though not always enough to prevent mental health problems starting early in life. However, the actual symptoms of FXTAS are mainly due to the overproduction of the genetic messengers (mRNA). The mRNA is the messenger that reads and translates the information encrypted in the gene into the end product, the protein. The problem with the FMR1 premutation is the increase of mRNA in the cells where it has a toxic effect on the brain cells and peripheral nerves in the body. This toxic process is likely to cause dysfunction and loss of nerve cells especially in those areas of the brain which control movement and thinking. The FMR1 premutation triggers a lifelong process which over the years can lead to this progressive neurodegenerative disorder, becoming more and more apparent the older a person gets. This explains the onset of FXTAS later in life, usually after the age of 50 years of age.
Women who carry the premutation are less likely to develop FXTAS than male carriers. This is due to the fact that men have got only one X-chromosome (their additional Y-chromosome defining their gender as males) and thus fully rely on it, whereas women possess two X-chromosomes, one ‘X’ being able to partially compensate for the other ‘X’ if defect. As a result, their symptoms tend to be less severe, though this is not always the case.
How common is FXTAS?
The Fragile X premutation is more common than you might think: 1 in 250 women, and 1 in 800 men are carriers of the premutation. Every person with FXTAS has this FMR1 premutation. However, not every premutation carrier will develop FXTAS: about 60% of male and 15% of female carriers develop the condition. Therefore, in the general population FXTAS occurs approximately in one man in every 4,000 aged over 55 and possibly one woman in every 8,000. Thus FXTAS may be one of the most common neurological disease of adult onset that is caused by a single genetic change. Yet, it is still too often overlooked as a diagnosis.
How to diagnose FXTAS?
The diagnosis of FXTAS is based on the
Clinical features, which need to include either tremor, ataxia or both,
Radiological features: FXTAS-typical lesions in the brain detected with an MR brain scan
Positive genetic test: A blood test confirming that the person carries a Fragile X premutation.
For example, a man in his mid-50s, known to carry a premutation, develops intention tremor but no signs of ataxia as of yet. However, the MR scan shows a pattern of brain changes typical for FXTAS. He therefore fulfils all the relevant criteria for a definite diagnosis of FXTAS. In case he would have both tremor and ataxia but a normal MR brain scan, the diagnosis of FXTAS would be probable but not definite. So first of all, FXTAS is a clinical diagnosis based on a person’s symptoms, and the MR brain scan can be helpful in diagnosing FXTAS.
Getting the diagnosis right matters!
As shown above, the further the symptoms progress, the more disabling they become and the more they impact on day to day life. People with FXTAS become increasingly dependent on their families. Thus FXTAS not only has a huge impact on the patient’s health and quality of life, but has also massive implications for the entire family. So getting the right diagnosis early on is important. Knowing the reason for your difficulties, be it motor symptoms, mood swings or slowing of thinking for example, often comes as a relief as you now at least know why this is the case. The right diagnosis will allow access to adequate support, lead to a better management of the complex symptoms of FXTAS, including specific drug treatment, that is tailored to the individual needs. It enables people to become proactive and make informed decisions about their future. They can decide to take part in research studies and new therapies as they become available.
Because FXTAS is complex and “new”, many health professionals may be unsure how best to manage FXTAS and some might feel that little can be done for these patients. Therefore, these patients should be seen by a neurologist, movement disorder specialist or psychiatrist familiar with FXTAS.
What can we do about it?
Multidisciplinary team work is required to provide the best possible support. Some of the symptoms in FXTAS, such as mood changes, Parkinsonian features or to some extent tremor and neuropathic pain, can be treated and managed with a range of therapies, whereas there are only few drugs that may somewhat alleviate ataxia, usually the most disabling symptom. Thus physiotherapy is often the best approach as it addresses various aspects of this complex condition. Unfortunately, we neither have anything at hand to slow cognitive decline nor is there currently a cure available for FXTAS.
Why we need you?
Parkinson’s and Alzheimer’s disease, the two most frequent and well-known neurodegenerative disorders, have a lot in common with FXTAS. Nevertheless, FXTAS does not get the same recognition and resources that would be needed to work toward better care and drive research. If we want to improve the lives of people with FXTAS, we need to understand what causes the FXTAS, learn how to manage the complex problems of each patient and find efficient treatment that results in real life benefit. Let’s go for it, together, step by step.
Join in our campaign today to raise awareness of FXTAS and the other Fragile X-associated conditions, and help to raise vital funds to support those living with the condition: