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Fragile X-associated tremor/ataxia (FXTAS)
FXTAS is a neurological disorder that typically affects older adults, more commonly males, causing movement difficulties and memory issues. It is linked to changes in the FMR1 gene, which also causes Fragile X syndrome.
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Overview
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurological condition that generally affects individuals as they get older. It is part of a group of disorders caused by specific changes in the FMR1 gene [PMID:17907572]. The main features of FXTAS include problems with movement, such as tremors and difficulty with balance (ataxia), alongside memory and thinking difficulties. While both males and females can be affected, FXTAS is seen more frequently and is often more severe in males who carry the specific FMR1 gene change.
FXTAS is not Fragile X syndrome, but they are related. Fragile X syndrome is a developmental disorder, often associated with intellectual disability, which is caused by a larger change in the same FMR1 gene. FXTAS, however, typically appears later in life and involves different neurological symptoms. Understanding the distinction is important for diagnosis and management.
Symptoms & clinical features
The symptoms of FXTAS usually develop gradually, often starting in middle to older age. The most common initial symptoms are an intentional tremor, which means shaking that occurs when a person tries to make a purposeful movement, and ataxia, which is difficulty with coordination and balance [PMID:17907572]. This can make walking unsteady and lead to falls.
Alongside movement difficulties, individuals with FXTAS may experience cognitive changes. These can include problems with executive function (planning and problem-solving), memory, and attention. Psychiatric symptoms such as anxiety, depression, and irritability are also reported in some individuals. Other possible features can include numbness or weakness in the limbs (peripheral neuropathy), and problems with the automatic functions of the body, such as blood pressure regulation or bladder control.
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Affected organs
FXTAS primarily affects the brain and nervous system. The changes seen in the brain include white matter lesions (areas of damage to the nerve fibres) and a reduction in brain volume, particularly in areas like the cerebellum, which is crucial for coordination, and the cerebral cortex, involved in higher-level thinking [PMID:17907572]. The nerve fibres in the limbs can also be affected, leading to peripheral neuropathy. Over time, these neurological changes contribute to the progressive symptoms observed in individuals with FXTAS.
Risks & severity
The risk of developing FXTAS is significantly higher for males who carry the specific FMR1 gene change, often referred to as a 'premutation'. Around 40% of males over the age of 50 with this premutation are thought to develop FXTAS [PMID:16524330]. For females with the premutation, the risk is lower and the symptoms tend to be less severe, with approximately 8-16% developing the condition.
The severity of FXTAS can vary widely between individuals. It is a progressive condition, meaning symptoms tend to worsen over time. The age of onset also varies, but symptoms most commonly begin after the age of 50. While FXTAS is not typically life-threatening, its progressive nature can significantly impact quality of life, affecting mobility, independence, and cognitive function. Regular monitoring and supportive care are important aspects of managing the condition.
Genetic causes
FXTAS is caused by specific genetic changes in the FMR1 gene. This gene provides instructions for making a protein called FMRP (Fragile X Mental Retardation Protein). FMRP is vital for normal brain development and function, particularly at the synapses, which are the connections between nerve cells.
In FXTAS, the FMR1 gene has an increased number of repeating DNA segments called CGG repeats. This is known as an FMR1 'premutation'. While a normal FMR1 gene typically has 5-44 CGG repeats, a premutation involves 55-200 repeats. This intermediate number of repeats does not usually completely switch off the FMR1 gene, as happens in Fragile X syndrome, but it leads to the production of an abnormal FMR1 messenger RNA (mRNA). This abnormal mRNA is thought to accumulate and become toxic to cells, particularly nerve cells, leading to the symptoms of FXTAS [PMID:17907572].
- FMR1 fragile X messenger ribonucleoprotein 1The FMR1 gene provides instructions for making the FMRP protein, which is vital for proper brain development, synaptic plasticity, and is associated with several inherited conditions including Fragile X syndrome.
Inheritance pattern
FXTAS follows an X-linked recessive (XLR) inheritance pattern. The FMR1 gene is located on the X chromosome. Males have one X chromosome and one Y chromosome, so if their single X chromosome carries the FMR1 premutation, they are at a higher risk of developing FXTAS. Females have two X chromosomes; if one X chromosome carries the premutation, the presence of a second, typically unaffected X chromosome often provides some protection, meaning they may have milder symptoms or not develop the condition at all.
Parents who carry the FMR1 premutation can pass it on to their children. A mother with the premutation has a 50% chance of passing the premutation to each child, regardless of gender. Sons who inherit the premutation will be at risk of developing FXTAS, and daughters will be carriers and also at a lower risk of developing FXTAS. A father with the premutation will pass it to all of his daughters, making them carriers, but none of his sons, as sons inherit their X chromosome from their mother. Genetic counselling can help families understand these inheritance risks.
X-linked recessive: sons of a carrier mother have a 50% chance of being affected. Daughters have a 50% chance of being carriers.
Diagnosis & testing
Diagnosing FXTAS typically involves a combination of clinical assessment and genetic testing. A neurologist may suspect FXTAS based on the presence of characteristic symptoms like tremor, ataxia, and cognitive changes, especially in an older individual. Brain imaging, such as an MRI scan, may show specific changes like white matter lesions, which can support the diagnosis.
The definitive diagnosis of FXTAS is confirmed by genetic testing of the FMR1 gene. This test looks for the specific 'premutation' range of CGG repeats. In the UK, genetic testing for FMR1 premutations can be accessed through the NHS Genomic Medicine Service, often following a referral from a specialist (e.g., a neurologist or clinical geneticist). The relevant NHS R-codes would be used for this genetic testing, which helps identify individuals at risk or confirm a diagnosis.
Management & lifestyle
Currently, there is no cure for FXTAS, so management focuses on alleviating symptoms and improving quality of life. Treatment strategies are individualised and often involve a multidisciplinary team. Physical therapy, occupational therapy, and speech therapy can help manage motor symptoms, improve balance, and assist with daily activities.
Medications may be used to treat specific symptoms, such as tremors, anxiety, or depression. Regular monitoring by a neurologist is important to track disease progression and adjust treatments as needed. Lifestyle adjustments, including exercise and cognitive stimulation, may also be beneficial. Individuals and families affected by FXTAS can also benefit from support groups and genetic counselling to help them understand the condition and its implications.
UK care pathway
In the UK, individuals suspected of having FXTAS typically enter the NHS care pathway through a referral to a specialist, such as a neurologist or a clinical geneticist. These specialists can assess symptoms, arrange necessary investigations like MRI scans, and refer for genetic testing for the FMR1 premutation through the NHS Genomic Medicine Service. The testing is guided by specific NHS R-codes, ensuring appropriate laboratory analysis. Following a diagnosis, individuals are usually supported by a multidisciplinary team. Access to genetic counsellors is available within clinical genetics services to provide information on inheritance, risks to family members, and support.
Frequently asked questions
Is FXTAS the same as Fragile X syndrome?
No, FXTAS and Fragile X syndrome are related but distinct conditions. Both are caused by changes in the FMR1 gene. Fragile X syndrome is typically a developmental disorder with intellectual disability, while FXTAS is a progressive neurological condition that usually affects older adults, causing movement and cognitive problems.
How common is FXTAS?
FXTAS typically affects males with the FMR1 premutation more commonly than females. Research suggests that about 40% of males over 50 years old with the premutation may develop FXTAS. For females with the premutation, the risk is lower and symptoms are often milder.
Can women get FXTAS?
Yes, women can develop FXTAS, although it is less common and often less severe than in men. Women who carry the FMR1 premutation have a lower risk of developing the condition, typically ranging from 8-16%.
What are the first signs of FXTAS?
The first signs of FXTAS often involve movement difficulties, such as an intentional tremor (shaking when trying to move) and problems with balance and coordination (ataxia). These symptoms usually develop gradually in middle to older age.
Is there a cure for FXTAS?
Currently, there is no cure for FXTAS. Management focuses on treating the symptoms to improve quality of life. This can include physical therapy, occupational therapy, and medications to help manage specific symptoms like tremor, anxiety, or depression.