Fragile X-Associated Tremor/Ataxia Syndrome

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is an inherited neurodegenerative disorder characterized by tremors and problems with walking, balance (ataxia), memory, and mood disorders.¹ Those affected by FXTAS show damage in the brain’s cerebellum, the part that controls movement, and white matter lesions, which can be seen on an MRI. This damage leads to problems with movement and other impairments associated with FXTAS.²

FXTAS is a late-onset disorder, usually affecting males over 50.² Females account for a very small percentage of the FXTAS community, and their symptoms also tend to be milder.³ FXTAS is a significant cause of morbidity, especially ataxia (a group of disorders that affect co-ordination, balance and speech), in aging men. It is also the most commonly known single-gene cause of tremors, ataxia, and possibly dementia in the older population.⁴

What Causes Fragile X-Associated Tremor/Ataxia Syndrome?

FXTAS occurs due to mutations in the FMR1 gene on the X chromosome, which is responsible for making a protein called FMRP (Fragile X RNA-binding protein) needed for developing synapses. Synapses are essential for the transmission of nerve impulses.²

The FMR1 gene contains a DNA sequence known as the CGG triple repeat, generally repeated five to 40 times in unaffected individuals. In people with FXTAS, however, this segment is repeated between 55 to 200 times. This mutation is known as FMR1 gene premutation. An expansion of more than 200 repeats is known as a full mutation, which can lead to a more serious condition called Fragile X syndrome (FXS).² Females with an FMR1 permutation are also at risk of developing another Fragile X-associated disorder known as Fragile X-associated Primary Ovarian Insufficiency (FXPOI).¹

For reasons unknown, the premutation leads to excess production of the altered FMR1 mRNA, which contains the expanded CGG-repeat region. The FMR1 mRNA is the genetic blueprint for FMRP production. Researchers believe that the excess levels of this mRNA cause the symptoms of FXTAS. The mRNA has been detected in clumps of proteins and mRNA in brain and nerve cells in individuals with FXTAS. These clumps are believed to prevent the other proteins from performing their functions.²

It is important to note that not all Fragile X premutation carriers will develop FXTAS, but everyone with FXTAS has an FMR1 premutation. Researchers are studying other factors that may contribute to FXTAS in Fragile X premutation carriers.³

Prevalence of Fragile X-Associated Tremor/Ataxia Syndrome

Among premutation carriers, about 40% of males older than 50 and eight to 16% of females older than 40 develop FXTAS. However, the risk of FXTAS in any given individual depends on their:³

CGG repeat size – The larger the repeat size, the higher the risk.
Age – Symptoms are more prevalent as age increases.
Gender – Males are at a higher risk than females.

Based on these variables and the available literature, the lifetime prevalence of FXTAS in the general population is predicted to be 1 in 8,000. This suggests that FXTAS is far less common in the elderly than essential tremor or Parkinson’s disease.³

For male premutation carriers, the possibility of developing the core symptoms of FXTAS increases with age:³

For ages 50-59, the possibility is about 17%
For ages 60-69, the possibility is about 38%
For ages 70-79, the possibility is about 47%
For ages 80 and above, the possibility is about 75%

FXTAS may be one of the most common adult-onset, single-gene neurological disorders similar in prevalence to other neurodegenerative disorders such as ALS (Lou Gehrig’s disease). However, more research within the general population is required before an accurate prevalence can be determined.³

Symptoms of Fragile X-Associated Tremor/Ataxia Syndrome

The characteristic features of FXTAS include progressive cerebellar ataxia (sudden, uncoordinated muscle movement), parkinsonism, action tremor when using a muscle such as holding out an arm, generalized brain atrophy or shrinkage in the size of the brain, and cognitive decline, especially executive dysfunction such as inability to focus on a task or solving problems. Other features in affected individuals, which can be present in varying degrees, include psychiatric disturbances, autonomic dysfunction such as loss of bladder control, and peripheral neuropathy such as tingling or loss of feeling in legs. However, a few other clinical symptoms and presentations with varied dominating signs have also been reported in people with FXTAS. Even within families, affected individuals can have different clinical presentations. For example, one brother can have a presentation that looks like an essential tremor, while the other can have a classic FXTAS presentation.⁴

Cerebellar Gait Ataxia

The cerebellum is the part of the brain that coordinates and regulates muscle movements. Individuals diagnosed with FXTAS may experience various symptoms, but nearly all will experience increasingly challenging forms of cerebellar gait ataxia, which presents as a wide stance and imbalance when walking, as the syndrome advances. Unexpected falls are common, and the ability to walk in a straight line (tandem gait) is challenged in approximately 50% of male carriers over 50. While cerebellar dysfunction is mostly the factor that affects the gait, other impairments such as peripheral neuropathy, parkinsonism, and weakness also contribute to problems with balance.⁴

Action Tremor

Action tremor or tremor when using a muscle such as holding out an arm, is another common feature of FXTAS, but the severity can vary among individuals. While those close to the individual impacted may have noticed a mild, intermittent tremor for months or even years, many individuals with FXTAS are unaware of their tremors. Others have a rather apparent, severe tremor that affects their daily functioning. The tremor associated with FXTAS has not been extensively studied but appears similar to essential tremor (involuntary and rhythmic shaking, usually of the hands when in use).⁴

Parkinsonism

Another common motor sign of FXTAS is parkinsonism, which is usually mild and primarily manifested diminished facial expressivity, generalized rigidity, slow walking, and overall slowness of movement and speed. Occasionally, individuals with FXTAS have a parkinsonism-related abnormal stooped posture. Resting tremor is uncommon. Tremor, challenges walking, and parkinsonism worsen with age, and the severity of FXTAS is strongly related to the CGG repeat size through the premutation range.⁴

Cognitive Decline

A very disabling feature seen in many aging male carriers is cognitive dysfunction. Male carriers over 50 years, whether they do or do not have motor symptoms of FXTAS such as tremor, exhibit normal Intelligence Quotient (IQ) to mild IQ deficits and substantial memory and frontal executive dysfunction such as inability to focus, problem-solve or plan. Male carriers with motor signs show prominent executive function deficits. As the condition progresses, they may also develop dementia, affecting working memory, intelligence, speaking about things they have learned and memory, processing speed, and cognitive decline occurs in almost 40% of men, less often in women, and is more frequent in late-stage FXTAS.⁴

Psychiatric Symptoms

Some other disabling features of FXTAS include psychiatric and behavioral disorders. Male carriers over 50 exhibits increased anxiety, irritability, agitation, hostility, obsessive-compulsiveness, apathy, and depression. These affected males are usually unaware of their mood instability and personality changes and, thus, will not report or seek treatment for their psychiatric symptoms. In contrast, female carriers exhibit higher rates of depression, anxiety obsessive-compulsive disorder.3,4

Peripheral Neuropathy

Fragile X premutation carriers may also experience peripheral neuropathy, including symptoms such as tingling or loss of feeling in legs. Peripheral neuropathy symptoms may be the first symptoms of FXTAS that are noticed. Male carriers show a significant loss of reflexes in their lower legs compared to males who are not carriers. However, lower leg strength is usually unaffected. The loss of reflexes in the legs may contribute to difficulties walking in some people with FXTAS. ⁴

Autonomic Dysfunction

Autonomic dysfunction or loss of functions that work without thinking about them, has also been described in FXTAS, but more controlled studies are needed. In a study of 20 men with FXTAS, approximately 55%, and 30% reported urinary and bowel incontinence, respectively. Urinary and bowel incontinence usually occurs in late-stage FXTAS. Some people also have low blood pressure when standing and episodes of fainting.⁴

Comorbid Conditions

Certain medical conditions have been reported to be associated with FMR1 premutation. For example, hypertension (high blood pressure) is more common in male and female carriers. Anecdotal evidence suggests that heart dysfunction, such as abnormal heart beat and reduced heart function may often occur in male carriers. Other disorders also appear to be more common in people with FXTAS. For example, many males with progressing FXTAS have diet-controlled hyperglycemia (high blood sugar), which leads to diabetes requiring treatment with medication.⁴ Furthermore, many male carriers have episodes of dizziness, which can occur due to lightheadedness related to a drop-in blood pressure when standing or impaired sense of balance; however, more studies are needed to determine if and how they relate to FMR1 premutation.⁴

Female Premutation Carriers

FXTAS is less severe in female carriers due to the protective effect of their second, unaffected X chromosome. However, the available data on female carriers indicate that the premutation may cause different neurological symptoms and medical risks than males, possibly due to hormonal and other unknown factors.⁴

Typically, as discussed above, female carriers do not develop as much ataxia (challenge with walking) or tremor as males. Female carriers without FXTAS report more sensory loss, tremors, and chronic muscle pain.⁴

Some female carriers develop characteristic features of FXTAS, but even then, they tend to have distinct differences from male carriers. Female premutation carriers probably have less cognitive dysfunction than males, although individual case reports suggest that dementia and memory loss do occur. Moreover, affected females often report chronic muscle pain and fibromyalgia. Approximately 50% of female premutation carriers have been diagnosed with thyroid dysfunction, typically hypothyroidism.⁴

How Is Fragile X-Associated Tremor/Ataxia Syndrome Inherited?

FXTAS is inherited in an X-linked dominant pattern.² Male carriers will pass on their FMR1 gene premutation to all of their daughters but not to their sons. In contrast, female carriers have a 50% chance of passing the premutation to their sons and daughters.⁵

Diagnosing Fragile X-Associated Tremor/Ataxia Syndrome

FXTAS is frequently misdiagnosed for two reasons: 1) numerous physicians are unfamiliar with the condition, and 2) individual manifestations can vary, leading to a misdiagnosis. Fragile X premutation carriers and their families must have an accurate diagnosis to establish who is at risk for Fragile X syndrome and other Fragile X-associated disorders.⁴

Diagnosis of a Fragile X premutation carrier requires genetic counselling and DNA testing.⁴ Genetic testing will look for the expanded CGG repeat region in the FMR1 gene. This same test is performed to diagnose Fragile X syndrome. ⁷

Neuroimaging can also help facilitate the diagnosis of FXTAS. Neuroimaging is used to look for abnormalities in the structure of the brain in individuals impacted by FXTAS. ⁴

References

National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. Fragile X Associated Disorders. Retrieved Dec 1, 2022, from https://www.cdc.gov/ncbddd/fxs/associateddisorders.html
MedlinePlus. National Library of Medicine. Fragile X-associated tremor/ataxia syndrome. Retrieved Dec 1, 2022, from https://medlineplus.gov/genetics/condition/fragile-x-associated-tremor-ataxia-syndrome/#causes
National Fragile X Foundation. Fragile X-Associated Tremor/Ataxia Syndrome | FXTAS. Retrieved Dec 1, 2022, from https://fragilex.org/understanding-fragile-x/tremor-ataxia-syndrome-fxtas/
Leehey MA. Fragile X-associated tremor/ataxia syndrome: clinical phenotype, diagnosis, and treatment. J Investig Med. 2009 Dec;57(8):830-6. doi: 10.2310/JIM.0b013e3181af59c4. PMID: 19574929; PMCID: PMC2787702.
National Institute of Child Health and Human Development, National Institutes of Health. How is a change in the FMR1 gene related to Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)? Retrieved Dec 5, 2022, from https://www.nichd.nih.gov/health/topics/fxtas/conditioninfo/gene
National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. How Fragile X Syndrome Is Inherited. Retrieved Dec 5, 2022, from https://www.cdc.gov/ncbddd/fxs/inherited.html#:~:text=Fragile%20X%20syndrome%20(FXS)%20is,parents%20to%20children%20through%20genes.
Berry-Kravis E, Abrams L, Coffey SM, Hall DA, Greco C, Gane LW, Grigsby J, Bourgeois JA, Finucane B, Jacquemont S, Brunberg JA, Zhang L, Lin J, Tassone F, Hagerman PJ, Hagerman RJ, Leehey MA. Fragile x-associated tremor/ataxia syndrome: Clinical features, genetics and testing guidelines. https://doi.org/10.1002/mds.21493