Basic Mechanisms and Clinical Involvement
The NFXF was one of multiple co-sponsors of this important gathering organized by Drs. Flora Tassone and Paul Hagerman of the UC Davis School of Medicine and MIND Institute. Executive Director Robert Miller attended as one of the few non-scientists so that he could report back to you in a family-friendly manner. His comments follow.*
The setting for the meeting may have been extraordinary (Perugia, Italy) but the topic was even more so. It was exciting and inspiring to see the number of basic and clinical researchers (approximately 70, including young researchers and senior researchers new to the field) who have become interested in the Fragile X premutation (55 to 199 CGG repeats). The growing cadre of motivated scientists bodes well for developing a much greater understanding of the premutation and the development of treatments of all types.
It has been approximately half a century since researchers began discussing their observations of something that would ultimately be known as Fragile X syndrome (FXS), which results from the “full” mutation (200+ CGG repeats). Reproductive problems in female carriers of the premutation were recognized and documented soon after the Fragile X gene was discovered in the early 1990s, in what ultimately came to be called FXPOI (Fragile X-associated primary ovarian insufficiency). At the time, most researchers considered those with the premutation to be problem-free, at least when it came to other medical or psychological problems related to the mutation.
It is true that some clinicians and researchers, and many mothers of children with FXS, openly talked about their own problems that they believed to be related to the premutation, but, in most cases, the hard data, including a description of the responsible biological process, were simply lacking. That situation began to change dramatically around the year 2000 with the discovery of FXTAS (Fragile X-associated tremor/ataxia syndrome), which was initially described in older men who carry the premutation. Since that time, much effort has gone into trying to fully understand the biological cause of FXTAS, with a goal of developing treatments.
Concurrently, it was determined that women who carry the premutation are also at risk for FXTAS, though with lower likelihood of disease and usually with different and less severe symptoms. Later in that same decade the term “Fragile X-associated Disorders” (FXDs) was coined to highlight all Fragile X conditions including, but not limited to, FXS.
Finally, as part of the normal scientific process, some researchers and clinicians have begun to describe and examine evidence for other medical, learning and psychological problems for which some premutation carriers of both genders may be at risk. Thus the need for, and importance of, a meeting dedicated to the premutation!
Opening remarks by longtime Italian Fragile X researcher Giovanni Neri included a history of FXS research and the oft-shared “Welcome to Holland” story about parenting a child with special needs. Dr. Neri concluded his history with a heartfelt comment based on his lifetime of dedication to a better understanding of Fragile X, “The key is acceptance and care.”The conference began in the beautiful and historical setting of Palazzo dei Priori (Priors’ Palace), built in 1293. On a humorous note, one of my tasks during the registration process was to station myself at the doors of the palace and politely inform the tourists who were arriving with their guidebooks in hand, “Mi scusi. È chiuso per una riunione. Mi dispiace.” (“Excuse me. It is closed for a meeting. I am sorry.”)
The remaining three days of the conference took place in a more modern conference room within the equally unique and historical setting of Castello di Monterone on the outskirts of Perugia. Although one might think that the setting would lend itself to distractions, the meeting was, on the contrary, focused and intense.
It is important to be aware that this was a scientific conference only, in which participants were encouraged to brainstorm and probe the comments and observations of fellow scientists. Appropriately, some of the presentations were speculative in nature. With the exception of consensus around FXPOI and FXTAS, at this time there was only limited consensus about possible additional disorders related to the premutation, and many attendees expressed the critical importance of communicating that point to families!
Here are some of my takeaway points that may be of interest to families. Some of these will be followed up in the future by more descriptive articles to be shared by the NFXF, as well as in scientific publications.
- As has been previously established, the number of people with the premutation far exceeds those with the full mutation.
- The boundary between the premutation (55-199 repeats) and the full mutation (200+ repeats), may be more “fuzzy” than previously believed.
- Those with the premutation may be more susceptible to the effects of environmental and lifestyle stressors such as smoking, excessive alcohol consumption and environmental toxins. Although the evidence is inconsistent at this point with respect to specific stressors, all individuals should be encouraged to live healthy lives and continue to use preventive health care measures.
- A recent survey suggests that some children with the premutation may have developmental problems. The effect appears to be much milder than that caused by the full mutation. If this finding is borne out in future studies, it will have implications for early diagnosis and intervention.
- While the CGG repeat number in the full mutation is known to have little relevance to the developmental trajectory of those with FXS, the number is seen as having increasingly important relevance for those with the premutation, as it pertains to FXTAS and FXPOI.
- Efforts to better understand the premutation have led to questions about the biological impact of intermediate alleles (also known as the “gray zone”) involving 45-54 CGG repeats. What are known as “AGG interruptions” within the CGG repeat sequence has been shown to significantly affect the risk of the CGG sequence becoming unstable and expanding when passed from parent to child. More accurate risk estimates are now possible for gray zone and small premutations. (For more about “AGG interruptions” please read .
- Some studies found that medical conditions unrelated to FXPOI and FXTAS, such as irritable bowel syndrome, restless leg syndrome, migraine headaches, social phobias, panic disorder, hypertension, anxiety, depression, sleep apnea, fatigue, joint pain and other seemingly unrelated problems such as autoimmune conditions, may be associated with the premutation. Other studies did not find these same relationships. Unbiased population studies are needed to confirm or refute these relationships; studies are continuing in these areas.
- FXTAS-like symptoms that do not fully meet the diagnostic criteria for FXTAS have been seen in some carriers of the premutation.
- Neuropathways in the brain that are similar to those implicated in FXS could play a role in FXTAS.
- Ongoing mouse studies along with the development of new animal models have suggested the possibility of developing drugs that halt or reverse the progression of the disease.
- The drug allopregnanolone will be studied as a potential treatment for some of the problems associated with FXTAS and other possible premutation disorders.
- Memantine, a symptomatic therapy already available, may improve auditory processing.
- Research suggests that intervention early in the course of FXTAS could be critically important.
- The Fragile X premutation is considered to be the most frequent genetic cause of premature ovarian failure.
- Women who carry the premutation have an average age of menopause 4 to 6 years earlier than the average age of 51. One’s repeat size matters in determining whether or not one develops FXPOI, with the highest risk shown to be for those with 65-90 repeats.
- Smoking reduces the age at menopause for all women, with and without the premutation, but more so for women with the premutation, since their ovarian function may already be at risk.
Other Possible Premutation-Related Problems
- Ample evidence exists regarding the overlap of autism and FXS (i.e. those with the full mutation). There is also growing evidence, though it is not yet confirmed, regarding an increased risk for autistic behaviors and other “neuro-dysfunctions” for some individuals with the premutation.
- Despite the lack of scientific certainty, some researchers emphasized that we may already know enough about environmental factors to begin emphasizing prevention—where possible—and not just treatment.
- There are several controlled studies regarding psychiatric problems in a subgroup of premutation carriers, with MRI evidence showing changes in the brain related to the premutation even before FXTAS develops. Studies continue in sorting out which changes are related to elevated FMR1-mRNA and which to mildly lowered FMRP.
- Additional premutation problems currently being studied include extensive work in animals and cells, in addition to humans.
There was much discussion about “other” possible problems related to the premutation (besides FXTAS and FXPOI), with attendees expressing support both for and against the evidence for these associations. In the end, there was general agreement about the possibility of a relationship between the premutation and other problems, but that convincing scientific evidence does not yet exist. Only large-scale population studies will bring clarity.
This author’s comment to the group was that certain beliefs about the premutation are already held to be true simply because they are repeated often enough on the web and in social media. It will be important that researchers do not perpetuate those beliefs without clear evidence. That said, I would now add that researchers need to provide accurate new information as it becomes available to the estimated 20 million carriers worldwide who struggle with, at best, the uncertainties that come with being a carrier.
An additional concern of the NFXF’s, and one that was discussed at the conference, was the inconsistent use of terminology pertaining to conditions related to the premutation. Terms such as “affected,” “at-risk,” and “disorder” may mean one thing to one medical professional, something slightly different to another, and something wholly different to a family member. Many clinical professionals are aware of this problem, and there was general agreement that the current situation could be improved upon. As it has in the past, the NFXF will help provide leadership on this issue.
The National Fragile X Foundation was proud to contribute to the success of the conference and looks forward to helping ensure steady progress in the field of Fragile X-associated Disorders.
has been the executive director of the National Fragile X Foundation since 1999. He has over 40 years experience as a teacher and administrator in the fields of early intervention, special education, mental health and nonprofit/human service administration. His work has included programs for children from abuse and neglect backgrounds as well as work in economically disadvantaged areas as part of the Federal Head Start program.
Vocabulary note: Throughout this article, the terms “carrier” and “premutation” are used interchangeably unless otherwise noted. Readers are encouraged to read NFXF Genetic Counselor Brenda Finucane’s article, What Defines a Carrier? for additional insights into the premutation.
* Selected members of the NFXF’s and others who were present at the conference reviewed this article for accuracy. This report reflects their and the author’s observation of general agreements among conference participants.