By Anna DeSonia

A note to readers:

The summary below gives a broad overview of the main themes discussed at the 5th International Conference on FMR1 Premutation in early 2023. More detailed summaries of conference topics can be found in the “Session Summaries” section below.

For the sake of this paper, the term “Fragile X premutation” will be abbreviated with the acronym “FXPM”.

Title: Insight and Recommendations for Fragile X Premutation Associated Conditions from the 5th International Conference on FMR1 Premutation

Authors: Flora Tassone, Dragana Protic, Emily Graves Allen, Alison D Archibald, Anna Baud, W. Ted Brown, Dejan B. Budimirovic, Jonathan Cohen, Brett Dufour, Rachel Eiges, Nicola Elvassore, Lidia V. Gabis, Samantha J Grudzien, Deborah A. Hall, David Hessl, Abigail Hogan, Jessica Ezzell Hunter, Peng Jin, Poonnada Jiraanont, Jessica Klusek, R. Frank Kooy, Claudine Kraan, Cecilia Laterza, Andrea Lee, Karen Lipworth, Molly Losh, Danuta Loesch, Reymundo Lozano, Marsha R. Mailick, Apostolos Manolopoulos, Veronica Martinez-Cerdeno, Yingratana McLennan, Robert M. Miller, Alice Montanaro, Matthew W. Mosconi, Sarah Nelson Potter, Melissa Raspa, Susan M. Rivera, Katharine Shelly, Peter Todd, Katarzyna Tutak, Jun Yi Wang, Anne Wheeler, Tri Indah Winarni, Marwa Zafarullah, and Randi Hagerman


Discovery and genetic sequencing of the Fragile X messenger ribonucleoprotein 1 (FMR1) gene have led to new molecular testing to facilitate the diagnosis of Fragile X syndrome (FXS). While people with FXS have more than 200 CGG repeats, individuals with the Fragile X premutation (FXPM), sometimes called “carriers”, are found to have 55 to 200 CGG repeats. Individuals with the FXPM can pass on the full mutation (more than 200 CGG repeats) to their children.

Previously, there was a misconception that individuals with the FXPM were unaffected by their genetic variations because their FMRP levels, the protein made by the FMR1 gene, were considered within the normal range. The term Fragile X carrier reflected the “lack” of any clinically presented symptoms associated with the FXPM. However, over time, our understanding of the risks associated with having the FXPM has significantly changed.

Research into the FXPM really developed out of anecdotes and coincidences that raised questions. Mothers of sons with FXS described early menopause and there were reports of older individuals with the FXPM who presented with motor tremors (involuntary, shaking movements in parts of the body) and ataxia (balance issues).

Subsequent studies have confirmed the presence of Fragile X-associated primary ovarian insufficiency (FXPOI) in females with the FXPM. Diagnosis of FXPOI is associated with the number of CGG repeats; those with repeats between 85 and 100 have the highest risk and earliest onset of FXPOI.

Drs. Flora Tassone and Paul Hagerman discovered elevated levels of FMR1 messenger RNA (mRNA) in those with the FXPM compared to controls, the opposite of what was thought and expected. Blood from individuals with the FXPM had between 2 to 8 times the normal values of FMR1 mRNA. Researchers found a positive association between repeat number and mRNA, meaning the higher the CGG repeat number, the higher the FMR1 mRNA value was in the individual with the FXPM.

In 2000, Dr. Randi Hagerman’s team presented case summaries from five aging males with the FXPM who had a history of tremor, ataxia, and brain atrophy (loss of neurons and connections between neurons) seen on MRI scans. During this presentation over 50% of the audience revealed that they also had relatives with similar problems. This led to a multitude of studies documenting the phenotype of what we now know as Fragile X-associated tremor/ataxia syndrome (FXTAS). FXTAS is now well recognized as an adult-onset neurodegenerative disorder with tremor, ataxia, neuropathy, Parkinsonian features, and cognitive changes beginning with memory problems and executive function deficits.

Further research into the FXPM expanded the phenotype beyond FXPOI and FXTAS. A notable study by Coffey and colleagues studied 128 individuals with the FXPM and 18 women with FXTAS compared to age-matched controls (people without the FXPM who are the same age as the study participants). The authors found multiple common medical conditions including neuropathy, hypertension, autoimmune thyroid disease, chronic muscle pain, intermittent tremor, and fibromyalgia. These conditions were significantly increased in individuals with the FXPM than those without, and many of these issues were seen in individuals with the FXPM without FXTAS. These findings led to further studies of problems that occur in those with the FXPM before the onset of FXTAS.

Although most individuals with the FXPM have typical intellectual abilities and are without neuropsychological issues, studies have shown that a subgroup of individuals with the FXPM have conditions like anxiety, attention-deficit/hyperactivity disorder (ADHD), social deficits, and even autism spectrum disorder (ASD) in childhood. Interestingly, for those with the FXPM who experience seizures, there is a higher incidence of ASD or intellectual disability (ID) compared to those without seizures. Over the last two decades, mental health impacts have been documented, particularly in females with the FXPM, that include anxiety, depression, obsessive-compulsive behavior, ADHD-inattentive type and the broad autism phenotype. Evidence supports that these symptoms can become more common in adulthood. However, women have expressed that their physicians do not always take their concerns seriously and usually attribute these problems to the stress of raising a child with FXS, even though these problems can be seen in individuals with the FXPM without children or without children with FXS.

Although many scientists doubted that psychological/psychiatric problems could be related to the FXPM, the work of Dr. Marsha Mailick and colleagues helped to validate some of these findings. Their research found elevated rates of agoraphobia (the fear of being in open or crowded spaces; the fear of leaving home), social anxiety or social phobia, and panic disorder – but not higher rates of major depression episodes – in those with the FXPM compared to those without. These psychological difficulties can be severe and can occur in up to 50% of adults with the FXPM. The name Fragile X-associated neuropsychiatric disorders (FXAND) was coined by Dr. Randi Hagerman as an umbrella term to encompass the problems that are increased in those with the FXPM. However, there has been some disagreement with the term FXAND, and a new term was proposed by the European Fragile X Network: Fragile X premutation-associated conditions (FXPAC). The variety of physical and mental conditions mentioned above, and any of the problems associated with the FXPM can fall under FXPAC.

The goal of the paper is to document the presentations and discussions from the 5th International Premutation Conference in New Zealand in 2023, which covered all facets of the FXPM.

Why this matters:

Today we know more about the FXPM than ever before; however, this does not mean we know it all. There is still much to be learned and understood. This knowledge gap is particularly important as those who are diagnosed with the FXPM seek to understand what it means and what implications it may have on their lives and the lives of their loved ones. With genetic screening for FXS becoming more and more available, there will only be more and more individuals identified, so further research and understanding of the FXPM is crucial.

Furthermore, current research suggests that some people with the FXPM experience health effects that do not fit the classifications of FXPOI and FXTAS. These new findings have opened the door to conversations about the importance of using appropriate, consistent, and non-stigmatizing terminology. Experts in the field who attended the 2023 International Premutation Conference overall agreed with the concept of ‘at increased risk’ compared to the general population, when referring to the range of conditions currently associated with the FXPM.

Next steps:

To continue learning about the health impacts of the FXPM and to bridge current knowledge gaps in this area, individuals with the Fragile X premutation and their loved ones are encouraged to join the International Fragile X Premutation Registry. People with the FXPM are encouraged to join the Registry to support future research projects, including treatment trials, and be connected with a group of professionals and individuals who are interested in the advancement of knowledge around the Fragile X premutation, FXTAS, and FXPOI.

There are several other research initiatives in the Fragile X premutation space. The largest FXTAS grant to date was awarded by the Department of Defense (DOD) for a FXTAS trial, there have been several small-scale drug trials, and there are ongoing studies looking at the progression of FXTAS. While we still have a lot to learn about FXTAS, FXPOI, and the Fragile X premutation in general, there have been significant strides over the past few years.

Acknowledgements: The authors and contributors want to thank the participants of the community-based studies who donated their time for many of the studies presented here.

Read more in depth session summaries below or the full pre-print of the publication here.

Session Summaries: 

More in-depth summaries of conference topics are provided below. Please note that the title of each “Topic” has been pulled directly from the original paper; however, the title may not perfectly align with the content in the summary. If you are interested in reading the full article, it can be found here. Finally, if you have any questions, you can email the corresponding authors listed at the beginning of the article.


Topic: Molecular basis of FXPAC

Researchers have done a lot of work looking at FXTAS on a molecular level (inside the cell), focusing on specific areas on and within the FMR1 gene, CGG repeat lengths, proteins, mRNA, etc. Researchers are particularly interested in studying the mechanisms that have been identified that explain the development of FXTAS.

An allele is an alternative version of a specific gene. FXPM alleles are characterized by increased levels of FMR1 mRNA. FXPM alleles in females are unstable and are prone to expansion through intergenerational transmission (having a child), with expansion into alleles with CGG repeats greater than 200, which then leads to FXS. Instability of alleles observed in individuals with FMR1 mutations leads to tissue mosaicism and may account for some of the variability observed in the clinical phenotype of individuals with the FXPM. This means that the symptoms that someone with the FXPM may have can vary from person to person. Unstable alleles are seen among many females and males with the FXPM. Molecular research has also given experts a look into how CGG repeats prompt the development and progression of FXTAS.

There are currently no FDA (Food and Drug Administration) approved drugs to slow FXTAS progression or delay its onset. There is a critical need for the discovery of reliable biomarkers (measurable substances found in the body that indicate problem or disease, i.e. CGG repeat in FXS or A1C in diabetes) to accurately understand what it looks like before someone has FXTAS (pre-disease onset states) and predict the clinical progression of FXTAS. Some promising work suggests that metabolomic and/or proteomics biomarkers (biomarkers derived from analyzing metabolites and proteins in the body) may serve this purpose. A type of gene therapy called antisense oligonucleotides (ASOs) is a promising candidate for FXTAS treatment even though the underlying neurobiological mechanisms of FXTAS are very complex and not fully understood. Because of the complexity of FXTAS, more studies are needed to understand the development and progression of the disease.

Clinical involvement in children who have a premutation

A key theme at the conference was the increased understanding of the phenotype (an individual’s observable traits, such as height and eye color) in children with the FXPM and how to manage it clinically.

There may be an increased risk of ASD, developmental characteristics and speech and language disorders in children with the FXPM; however, it is not clear how common and severe these conditions may be.

There is new evidence that suggests children with the FXPM may have: increased risk for sensory challenges, generalized anxiety, specific and social phobia, and obsessive-compulsive disorder.

Clinicians believe learning difficulties that may impact school performance and minor ASD traits are also elevated in children with the FXPM. These outcomes largely map onto what is being observed in adult studies, providing additional evidence and validity to trends observed in studies of children.

It appears that most children with the FXPM largely have typical development and function. However, our understanding of learning difficulties, clinical symptoms, and neuropsychiatric presentations is emerging. Therefore, experts stress that when a child with the FXPM is identified, clinicians should be cognizant about potential learning, behavioral and psychiatric difficulties, even if the symptoms are below the threshold for clinical diagnosis.

Based on emerging literature and conference presentations, there is a growing consensus that some difficulties in sensorimotor (the sensory and motor functions of the body) and visuospatial processing (the ability to tell where objects are in space), social inhibition (altering behavior in a social setting for fear of being judged by others), social anxiety/phobia, ADHD, and learning disabilities may manifest developmentally in some children with the FXPM. These children should be offered appropriate individualized assessment, treatment, and management options to optimize their outcomes. New knowledge about these characteristics is likely to impact testing indications within current genetic testing pathways. Newborn screening studies may help clarify questions about penetrance and developmental timing.

FXPAC and relationships with genetic markers

The relationships of FXPAC to genetic markers was a popular topic covered at the conference. Presentations on FXTAS, FXAND, and other FXPAC-related symptoms and conditions were given in detail.

The original core features of FXTAS focused on motor features including cerebellar gait ataxia and intention tremor in men over the age of 60 with the FXPM. Parkinsonism was also described, in addition to neuropathy (when nerve damage leads to pain, weakness, numbness or tingling in one or more parts of your body) and, later, cognitive changes in the form of executive dysfunction progressing (behavioral symptom that disrupts a person’s ability to manage their own thoughts, emotions and actions) into dementia at the final stage of this disorder.

The physical/motor presentation of FXTAS has been laid out for years but it was not until the work of Grigsby and colleagues that a clearer picture of the cognitive phenotype associated with FXTAS was recognized. Through standardized neuropsychological assessments and specialized tests that measure the frontal/executive control of movement, these studies revealed that while verbal skills are relatively unaffected, measures assessing general mental wellbeing, regulation of movement, verbal fluency, memory, and cognitive flexibility all showed significant deficits.

In addition to motor and cognitive impairments a high rate of psychiatric changes such as anxiety and depression were reported in both males and females with FXTAS.

Apart from the major risk factor of age, CGG repeat sizes of higher than 70 were shown to be associated with greater risk of developing features of FXTAS, while lower repeat sizes were correlated with later onset of tremor and ataxia. These data show that CGG repeat expansion size may be predictive of the severity of the phenotype, as well as of the age of onset and presence/absence of signs, rather than just severity of the motor signs, as reported in earlier studies.

Several studies have related the results of cognitive/executive assessments to the CGG repeat expansion size showing that the middle range of the repeats (80-110) is generally related to the highest risk for the impairments, including executive function and memory difficulties, digestive health, sleep quality and maternal depressive symptoms.

The umbrella of FXPAC includes major psychiatric issues. Elevated risks of psychiatric symptoms reported in males and females with the FXPM are the most prominent illustration of how common Fragile X-associated changes occur across non-FXTAS and FXTAS clinical categories. The group of problems, meeting clinical criteria for a psychiatric disorder, has been termed FXAND (Fragile X-Associated Neuropsychiatric Disorders).

FXAND includes anxiety, depression, insomnia, obsessive compulsive disorder, chronic pain, chronic fatigue, and potentially substance abuse. Studies suggest that one or more of these problems occur in up to 50% of individuals with the FXPM across the lifespan and in both sexes. However, results vary by the methodology and there is minimal population level data. Using a broader approach, if anxiety and depression do not meet the DSM- 5 criteria in severity for FXAND, then they fall under FXPAC which uses the term “condition” instead of disorder. FXAND can also include ADHD and ASD-related social-personality, language, and neuropsychological features.

Additionally, there are other symptoms and conditions that people with the FXPM may be at an increased risk for, including: hypertension, metabolic syndrome, chronic fatigue, chronic pain and fibromyalgia, and sleep problems.

Hypertension is the medical term for high blood pressure. It is a common medical condition that affects approximately half of all adults in the United States. Individuals with hypertension have an elevated risk of experiencing serious health problems, such as heart attacks, strokes, and kidney disease. Previous research suggests that individuals with the FXPM seem to be at a higher risk for developing hypertension relative to the general population, possibly due to diminished or absent levels of FMRP. Additional findings indicate that all individuals with the FXPM with FXTAS should undergo routine monitoring of hypertension and receive treatment if needed. Healthy lifestyle habits – including not smoking, eating well, exercising, and managing stress – can help prevent or manage hypertension, and are encouraged to help offset the development of hypertension.

Metabolic syndrome is a cluster of conditions that occur together and increase the risk of heart disease, stroke, insulin resistance, impaired glucose regulation, dyslipidemia (abnormal fat levels), obesity and type 2 diabetes in the general population. This clustering reflects overnutrition (a form of malnutrition or imbalanced nutrition arising from excessive intake of nutrients, leading to accumulation of body fat that impairs health), sedentary lifestyles, excess fat tissues, insulin resistance, dyslipidemia (abnormal fat levels) and elevated blood pressure. Studies have suggested that there may be an increased risk of metabolic syndrome in individuals with the FXPM. These metabolic disturbances can contribute to the development of metabolic syndrome. The risk of metabolic syndrome and other endocrine abnormalities may vary among individuals, and additional research is needed to better understand the underlying mechanisms and identify specific risk factors. Overall, the association between metabolic syndrome and the FXPM highlights the importance of monitoring metabolic health in individuals with the FXPM.

Chronic fatigue significantly affects the daily lives of some individuals with the FXPM, whether they have FXTAS or not. Studies show that those with FXTAS experience the most chronic fatigue, likely due to high instances of sleep apnea, while those without FXTAS exhibit intermediate levels of fatigue, falling between FXTAS patients and control groups.

Chronic pain and fibromyalgia have been reported by females with the FXPM. However, these associations have not been confirmed by research studies. Larger screening studies have been conducted to identify women who have the FXPM, but screening studies in other chronic pain conditions have not been done. Completed studies do suggest that additional work related to central sensitivity syndromes in these women is warranted.

Sleep difficulties are usually observed in individuals with the FXPM even before the onset of any neuropsychiatric problems. These are especially problematic among adult women with the FXPM who are also daughters of men with FXTAS; these women had significantly increased incidence of sleep problems compared to controls. Sleep problems among individuals with the FXPM may be associated with sleep apnea. Increased prevalence of sleep problems observed in individuals with the FXPM can be associated with some co-occurring conditions, such as ADHD and anxiety in young individuals with the FXPM.

FXTAS clinical and protective mechanisms

Not all individuals with the FXPM will develop FXTAS. Since most clinical research on FXTAS has focused on the symptoms and course of the disease, much less is known about possible protective mechanisms – the factors that can reduce the likelihood of a FXTAS diagnosis or the progression of symptoms. Yet some evidence points to the possibility of neuroprotection.

Having CGG repeats in the 50s and 60s may be protective for FXPM associated issues and even FXTAS because the FMR1 mRNA levels are lower than a higher end FXPM CGG repeat number; the higher the CGG repeat, the earlier the onset of FXTAS. There are likely other genetic factors that can be protective against FXPM associated issues.

Besides the genetic risks on development of FXTAS, there is evidence that stress and one’s lifestyle can lead to more frequent FXPM associated- issues. Researchers have also documented that other life events such as surgery with anesthesia, alcoholism, opioids, and other toxins can be linked to the onset of FXTAS. Individuals with the Fragile X premutation are encouraged to speak with their provider(s) about any concerns with any anesthesia and could also consider sharing this article: General Anesthetic Use in Fragile X Spectrum Disorders – PMC (

We know that oxidative stress and dysfunction of mitochondria in the cells are seen in FXTAS, and even in pre-FXTAS individuals, as compared to controls. Additionally, brain volume changes and white matter disease in those with the FXPM has been linked to decreases in mitochondrial mass and lowered ATP production (ATP is the energy source manufactured by mitochondria).

There is consensus that treatments that improve genetic, lifestyle, and mitochondrial factors are likely to be helpful for FXTAS and possibly additional FXPM associated issues. We know that daily exercise can improve mitochondrial function, and a healthy diet and supplements such as sulforaphane can improve oxidative stress. However, these interventions have not yet been studied thoroughly in the treatment of FXTAS. Avoidance or early treatment of excess stress, obesity, hypothyroidism, hypertension, diabetes, and other diseases, including psychiatric problems, can influence brain health and potentially delay or prevent the onset of FXTAS.

Higher education is yet another mechanism that has been seen to help stave off age-related cognitive decline across neurodegenerative diseases like Alzheimer’s and Parkinson’s. Research results are consistent in showing that higher education appears to be a significant protective mechanism.

Recent studies suggested a neuroprotective effect of higher education that was evident decades after college attendance. Ongoing research exploring additional experiences that may be cognitively enriching enough to provide those neuroprotective qualities outside of college is encouraged.

Among the risk factors for developing FXTAS-type symptoms are older age and being male. (Although females can also develop FXTAS.) Additionally, genetic factors can affect the likelihood of a diagnosis of FXTAS or FXTAS-type symptoms. Having mid-range or higher CGG repeats in the FXPM range increases the likelihood of cognitive and motor symptoms of FXTAS. The phenotypic presentation at symptom onset is clinically important, with those who have tremor as a first sign having milder impairment than those with ataxia + tremor when first diagnosed.

These identified protective factors propose strategies for reducing the age of onset and the severity of FXTAS-type symptoms that can be helpful, in addition to medical treatments. The protective effects of higher education and adhering to a healthy lifestyle point to potential socioeconomic factors that differentiate the healthier members of the FXPM community from those who are more symptomatic.

Neuroimaging findings in FXTAS

There are decades worth of research on those with the FXPM that have revealed many structural features of the FXTAS brain through medical imaging. Findings from this research have shed light on the anatomy of the brain, areas of the brain that are most affected by FXTAS, and relationships with these brain structures and CGG repeat length.

Early MRI work has reported the following findings: generalized brain atrophy, thinning of the corpus callosum, widespread white matter disease, and enlarged ventricles. The most prominent brain regions showing consistent structural changes are the cerebellum and brainstem. Separate studies have documented reduced volumes in the cerebellum and brainstem in individuals with the FXPM without FXTAS, suggesting structural differences may precede the onset of FXTAS, or manifest in those with the FXPM independent of disease status. Other prominent brain regions involved in FXTAS include the thalamus and basal ganglia. Generally, the thalamus shows atrophy in males with FXTAS, and this thalamic volume loss has been linked to increased gait variability. The basal ganglia are a group of structures interconnected with the thalamus and cerebellum, forming cerebellar networks that are important for motor, executive, and emotional processing. The relationship between the brain and CGG repeat length has also been studied, indicating structural brain differences affecting cerebellum and brainstem may disproportionately impact those with the FXPM and mid-range CGG expansions.

Understanding the fundamental mechanisms of changes in brain structure is vital for the discovery of effective therapies for FXTAS. However, despite the accumulating knowledge of structural brain differences associated with FXTAS, understanding of the functional brain changes that bolster clinical decline remains limited. This knowledge gap critically slows treatment development because key brain targets for new therapeutics have not been identified. Further, data sensitive to target engagement and treatment outcome in clinical trials are not yet available. Understanding of functional brain changes has accelerated the development and validation of targeted therapeutics in other neurodegenerative conditions, such as Parkinson’s and Alzheimer’s. This suggests that a greater focus on functional brain changes is needed to better track clinical decline in FXTAS.

There are a few ways researchers are currently studying the functional brain differences associated with FXTAS. Studies using electroencephalography (EEG), event-related potentials (ERP), and functional magnetic resonance imaging (fMRI) have been conducted. EEG/ERP studies offer very precise approaches for testing neurophysiological changes in FXTAS. However, they are limited in their potential to explain functional brain differences in the cerebellar and brainstem circuits, which we know are major brain structures affected by FXTAS. fMRI approaches offer greater spatial resolution than EEG/ERP and can measure changes in activation and functional connectivity across different brain networks. Despite these advantages, few fMRI studies of FXTAS patients have been conducted, and only two known studies have examined the primary behavioral features of FXTAS: motor impairment.

The neuropathology of FXTAS

Neurologically, FXTAS is characterized by clumps of protein found in nerve cells and other cells in systems across the body. These “clumps” are called intranuclear inclusions, and evidence shows that these inclusions are positively correlated with FMR1 CGG repeat length. This means that the higher the inclusion load, the higher the CGG repeats.

Radiology and neuropathology studies have further demonstrated changes in the FXTAS brain that indicate widespread neurodegeneration and inflammation. In these studies, neurodegeneration is seen through regional decreases in brain volume, white matter disease, iron accumulation, and microbleeds. Grey matter deterioration also occurs in the brain, which is particularly severe in the cerebellum. The cerebellum is in control of coordinating and regulating muscular activity in the body, and considering the characteristic motor symptoms of FXTAS, the involvement of the cerebellum is prominent.

Neuroinflammation is largely regulated by two specific types of cells in the central nervous system. These cells, called astrocytes and microglia, use substances called cytokines to coordinate a neuroinflammatory response. In a recent study of FXTAS brain samples, researchers found a significant increase of two types of cytokines that are major mediators of inflammation and regulators of immune responses.

Recent studies have showed the frequent coexistence of FXTAS with other neurodegenerative disorders like dementia, Alzheimer’s disease and Parkinson’s disease. These studies found about 50% of people with FXTAS develop dementia, and that it is fairly common to find classic Parkinsonian features, including bradykinesia (the slowness of movement) and muscle rigidity, during clinical evaluations. There is limited data that highlights a faster progression of motor and cognitive abilities, and faster-than-normally seen brain atrophy in individuals clinically diagnosed with FXTAS and Alzheimer’s disease.

FXTAS Treatment

Researchers have been doing a lot of work to clarify and understand the pathophysiology and neuropathology of FXTAS, as well as discover meaningful biomarkers for onset and progression of FXTAS.  However, there are currently no targeted treatments available to specifically treat or reverse FXTAS.  Instead, current treatment for FXTAS is symptom specific.  Clinical management includes off-label use of medications for movement disorders like tremors and ataxia, and monitoring/treatment of other neurological disorders such as cognitive decline, memory loss, chronic pain, and issues like anxiety and depression. 

There have been a handful of specific treatment trials carried out in people with FXTAS; however, many of these have been small studies that used open-label designs, meaning all participants receive the study medication during the study.  Only a few clinical trials with a control group and/or placebo have been conducted.  These treatment-targeted studies have tested out a variety of treatments such as memantine, allopregnanolone, citicholine, and sulforaphane, and although some participants found benefits, none of these studies had statistically significant, clinically favorable results. 

As previously mentioned, the bulk of FXTAS management currently focuses on medications and non-medication therapies to target the symptoms of FXTAS, not FXTAS itself.  However, since FXTAS symptoms are highly variable between individuals, symptomatic treatment is prescribed based on the signs and concerns of the individual with FXTAS.  Some of the major symptoms people with FXTAS seek treatment for include tremors, ataxia, executive dysfunction and cognitive decline, and neuropathy. 

Tremors are a major symptom of FXTAS.  Different types of FXTAS tremors have been treated with different substances including the following: propranolol and/or primidone, gabapentin, topiramate, amantadine, carbidopa/levodopa, and levetiracetam or zonisamide.  However, primidone can worsen balance in patients with FXTAS, and topiramate has unfavorable cognitive side effects.  Like other dementias, the FXTAS symptoms of executive dysfunction and cognitive decline are fairly common.  Therefore, the treatment of these symptoms in FXTAS is very similar to the treatment given for other dementias.  Treatments include memantine and acetylcholinesterase inhibitors for memory loss.   

Some individuals with FXTAS complain of nerve pain or discomfort/numbness in their feet, but this is not a common symptom.  Gabapentin has been found to be a good first-line treatment and it can also be beneficial for tremor and balance.  For both cognitive symptoms and neuropathy, an appropriate workup should be conducted in FXTAS patients to rule out other reversible causes of their symptoms, as treatment for those disorders may also be helpful for symptomatic improvement. 

A subset of people with FXTAS have undergone a type of Deep Brain Stimulation (DBS), but most reports describe clinical decline in people with FXTAS after bilateral DBS, so this treatment has been greatly reduced.  However, more recent DBS treatment that stimulates only one side of the brain (called “unilateral” DBS) has shown less worsening of ataxia and cognition after surgery. 

Treating the symptom of ataxia has proven to be more challenging, with medications typically used for other ataxias being considered for FXTAS.  However, most of these medications only work in isolated cases.  More widespread treatment options for ataxia include physical therapy to manage the imbalance seen in FXTAS, and assistive devices like a walking device or a wheelchair. 

Finally, some lifestyle changes have been identified that are thought to improve the symptoms of FXTAS.  Of note, how much these modifiable lifestyle changes would apply to slow the development and progression of FXTAS has not been specifically studied, but they could play a significant role.  These lifestyle changes include exercise – specifically resistance training – and a healthy, well-balanced diet full of vegetables, fruits, whole grains, some dairy items, lean meats, eggs, beans and nuts for protein, and healthy oils like olive oil. 

While most of the research done in FXTAS has been in small populations with less-than-ideal results, there is still hope for the future.  Potential future molecular therapies for CGG repeat disorders and FXTAS have been discussed and include  AntiSense Oligonucleotides (ASOs), RNA Interference (RNAi), Small Molecules, and Gene Editing using CRISPR approaches.  Some of these approaches are currently being clinically trialed in other diseases like amyotrophic lateral sclerosis (ALS), myotonic dystrophy I, Huntington’s disease, and frontotemporal dementia, but for FXTAS there are still several technical difficulties that need to be overcome.  According to recent research, there may be pharmacological interventions that can mitigate the progression of neurodegenerative disorders in their early stages.  The U.S. FDA has recently granted accelerated approval for two medications (Lecanemab and Aducanuma) that could potentially slow the progression of Alzheimer’s in individuals with mild disease, although their usefulness in early Alzheimer’s is still under investigation.  Therefore, early diagnosis and intervention with such medications could potentially delay or mitigate the severity of FXTAS.  While we are still on the journey, there is a lot on the horizon for FXTAS research and treatment. 


Screening for Fragile X and associated conditions and disorders

There are several potential avenues by which individuals with the FXPM may find out their genetic status. These include diagnosis via cascade testing (testing immediate and extended family members), newborn screening for FXS, carrier and prenatal screening, and genetic testing pathways. Presently, boys who are most severely affected by FXS are diagnosed around age 3 on average; girls with FXS are, on average, diagnosed later, and individuals with the FXPM are rarely diagnosed in childhood. Fewer than 20% of children with symptoms received a diagnosis within the first year of concerns.

The American Academy of Pediatrics in the United States recommends testing for FXS for any individual who presents with intellectual disability, developmental delay, autism, family history or other features common in FXS. Testing for the presence of the FMR1 mutation is recommended for patients with cerebellar ataxia and intention tremors, especially if they are male, and for women who have ovarian insufficiency or elevated FSH (Follicle Stimulating Hormone) levels. Despite these existing guidelines and increased efforts to bring awareness about FXS to physicians, an extensive diagnostic odyssey is still common for families seeking answers.

Historically, the most common pathway to a diagnosis has been through cascade testing, with the diagnosis of FXS in a family member leading to other family members getting screened. Around a quarter of families with a child with FXS will have a second child with FXS before the first is diagnosed. Once a child with FXS has been diagnosed, genetic counseling recommendations include testing of all immediate family members who are at risk for an expanded FMR1 gene based on hereditary patterns. One of the parents of a child with FXS has the FXPM, but screening is necessary to determine the size of the mutation (full vs. premutation) and for guidance regarding prognosis and health risks. There are rare cases of de novo Fragile X syndrome, meaning FXS spontaneously occurred and was not hereditary.

Newborn screening for FXS is supported by many developmental and behavioral pediatricians, though it is not widely available. However, one main barrier remains for full-scale newborn screening for FXS: FXS has not made it onto the panel of standard conditions that states screen for. Despite this and other roadblocks, there have been overall improvements in newborn screening techniques and early diagnosis. Diagnosis shortly after birth has led to work to understand early symptom onset which helps to document the natural history of FXS.

Prenatal screening is another avenue to screen for FXS and the FXPM. 76% of women voiced their preference of preconception carrier screening over prenatal fetal screening. Screening prior to pregnancy allows for more informed decision making about reproductive options. Because the presence of a FXPM can lead to risk of developmental disability in future generations, carrier screening has important reproductive and mental health implications for prospective parents, and it is relevant for early detection, intervention, and family planning. Importantly, the identification of women with the FXPM who are at risk for FXPOI could lead to more effective reproductive interventions for those who want to have a child.

Shining a light on the FMR1 premutation:  what we know, what we think we know and what we need to know

Discussions and even some passionate dialogues that occurred at the conference demonstrated a critical step forward in the inclusion of a lived experience perspective of those with the FXPM. Areas of significance discussed during the conference included: the importance of population screening, the type of information shared with individuals newly identified with the FXPM, the development and use of terminology in this emerging field of study and the need for agreed, consistent use of terminology around the FXPM. The concept of “at increased risk of” when considering how to talk about the range of issues associated with the FXPM was debated, recognizing the individuals with the FXPM currently studied is skewed towards families impacted by FXS. The importance of the lived experience voice was also discussed at length. Clinicians raised the issue of what information is shared with those newly diagnosed with the FXPM, acknowledging that most research to date has focused on individuals with families impacted by FXS and predominately those carrying a mutation above the 55-69 CGG repeat range. Further research will be instrumental in interpreting and defining various health implications and developing strategies to improve support for individuals with the FXPM.

What’s in a name (National Fragile X Foundation (NFXF) and Fragile X Association of Australia (FXAA))

With more and more understanding of FXPAC, it is important to find universally agreed upon terminology.  To understand this more thoroughly, representatives from patient advocacy organizations in the U.S. and Australia conducted a survey about the terminology related to the FXPM.  Data were captured from 296 people from the NFXF and FXAA communities via a survey questionnaire, 255 of whom reported having the FXPM. 

The survey was split up into three parts.  Part 1 of the survey probed what terminology people with lived experience endorsed when talking about their own Fragile X status.  A “click all that applies” option was provided, and survey takers were instructed to select which term they endorsed from the following options:  Fragile X Carrier (148 endorsements), FXPM Carrier (110 endorsements) and Fragile X Premutation (85 endorsements).  Part 2 of the survey probed into views measured by a Likert scale ranging from “very comfortable” to “very uncomfortable”, about specific words, focusing on “Fragile X premutation carrier”, “condition”, “conditions and disorders” and “disorder”.  Data showed that not one of these options has strong support; less than half of respondents were very or somewhat comfortable with these options.  In Part 3 of the survey, an open text field was enabled to collect comments from survey takers.  These qualitative data demonstrate that concerns of the community are far more complex than initially assumed, extending to the words “premutation” and “carrier”, which generated a robust discussion between the audience and speakers.  The discussion is still ongoing. 

The survey highlighted the impact and importance of language and terminology in the Fragile X community.  It identified challenges with terms like “carrier”, which implies that a person experiences no associated symptoms from the FXPM.  Other terms like “mutation” and “premutation” were identified as problematic, and the desire for the use of neutral, non-stigmatizing language was noted.   

Both clinicians and researchers shared the need for consistent use of agreed language and terminology.  It was recognized there was a focus by US clinicians on the use of terminology that helps families and patients gain access to services they need in the US.  Some clinicians raised the challenges caused by terminology that is vague or nonspecific and/or not recognized by the medical world.  The term Fragile X Premutation Associated Conditions (FXPAC) has most recently been adopted by Fragile X International and 17 family-led FXS organizations.  The overall feeling is that this term encompasses everything which may or may not affect an individual with the FXPM and aims to use neutral, non-discriminatory language.  

Author Hilary Rosselot

Hilary Rosselot
Hilary joined the NFXF team in 2019. Prior to joining the NFXF team, she worked at the Cincinnati Fragile X Research and Treatment Center for over five years. She has experience as a clinical research coordinator across many types of clinical trials and served as the clinical research manager for the Cincinnati program. She earned a bachelor’s degree in psychology, a master’s, and is a SOCRA certified clinical research professional (CCRP). She enjoys time with family and friends, a great book, a strong cup of coffee and, of course, a good laugh!

learn more