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.
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.