Fragile X Premutation Conference 2023 – Lived Experience Perspective Summary Paper
Shining a Light on the FMR1 Premutation: What We Know, What We Think We Know, and What We Need to Know
Lived Experience Perspective Summary Paper
The 5th International Conference on FMR1 Premutation: Molecular Mechanisms, Clinical Involvements, and Target Treatments took place Feb 27 – Mar 02, 2023, at Waitangi, New Zealand.
The conference demonstrated a critical step forward in the inclusion of a lived experience perspective of those with the PM. This was in the form of inclusion of the consumer voice in group discussions, as well as two presentations from representatives of the FXS and PM community. Following presentations, discussion, and at times vigorous debate, a range of themes emerged at the conference. These included the importance of population screening and the information shared with individuals newly identified with the PM; development and use of terminology in this emerging field of study and the need for agreed, consistent use of terminology for both individuals with the PM, clinicians, and researchers; the concept of ‘at increased risk of’ when considering how to talk about the range of issues associated with the PM; recognizing the PM population currently studied is skewed towards families impacted by FXS; the importance of the lived-experience voice. The quantity and quality of research shared was impressive and highlighted the evolving understanding of what we know, what we think we know, and what we need to know about the PM.
Data from studies presented at the conference extend the current literature that has investigated health impacts linked to the PM. This includes FXPAC, FXPOI, FXTAS, and FXAND. These conditions range from subtle effects, that in some cases are difficult to measure, through to clinically diagnosed conditions. Issues identified in studies as having higher prevalence than the general population included anxiety, depression, executive function difficulties, autoimmune conditions, hypothyroidism, migraines, chronic pain, and sleep apnea. There is a recognized need for early diagnosis and management of these conditions. However, this is not necessarily occurring due to lack of awareness amongst healthcare providers about the broader impacts of the PM. Further research will be instrumental in elucidating and defining these effects on health, and developing strategies to improve support for people with the PM.
Other areas of significance discussed during the conference included:
- Fertility-related issues—the need for increased knowledge and better pathways for fertility-related issues associated with the PM gene, particularly for younger women;
- The CGG repeat number is recognized as only part of the evolving picture—research indicating AR, FMR1 mRNA, FMRP levels, AGG interruptions, and allelic instability as also important factors to consider;
- Lifestyle measures—multiple presenters mentioned the importance of healthy lifestyle as a protective measure against risk factors associated with the PM, including an emphasis on limiting alcohol, not smoking, the importance of exercise and a good diet, and avoiding excess environmental toxins and high stress;
- It was noted that many PMs have high levels of functioning and achievement;
- Many PMs also face the challenges of children with developmental issues and FXS.
There was much discussion about how to talk about the influence of the PM that may occur outside FXPOI and FXTAS. The concept of ‘at increased risk of’ was widely discussed as a way to share what is currently known about the health impacts associated with the PM. Talking about these conditions/effects as risk factors takes into account that there are still unknown elements, including the differences between males and females, the impact of CGG sizes, AR, FMRP levels, AGG interruptions, and environmental factors. Discussing the possible effects of the PM as elevated risk factors, compared to the general population, as opposed to labelling conditions, was an approach which received wide agreement.
Results from large-scale PM-reproductive-carrier screening in Australia has provided important information about the distribution of FMR1 alleles in the general population. Approximately 75% of females with a PM in this cohort had 55–69 CGG repeats . It is likely our understanding of the PM will evolve, and more research is needed as we widen the scope of research to increasingly capture those in the 55–69 CGG range. It was therefore recognized that our knowledge about the significance of the FMR1 alleles is possibly biased, coming mostly from families impacted by FXS. Clinicians raised the issue of what information is shared with those newly diagnosed with the PM, acknowledging most research to date has focused on individuals with families impacted by FXS and, by implication, predominately those above the 55–69 CGG repeat range.
NZ Fragile X Community Response to PM Research (Fragile X New Zealand)
Data were captured from 38 people from the NZ PM community via a Survey Monkey questionnaire. The results showed the community is: (a) interested in PM research; (b) experiencing a high personal value from the research; (c) able to easily access and digest the research; (d) making positive changes in lifestyle choice and behavior based on recommendations from specialists in the field (Figure 4a). These data emphasized that the knowledge gained through research is valuable to persons with a lived experience and is enabling informed choices.
In recent years, there has been debate about proposed terminology encompassing the broader health impacts of the PM, with the terms FXAND and FXPAC both used. As shown in Figure 4b, the preferred terminology in the survey respondents was FXPAC. As demonstrated by the quotes, there are many positive experiences from this community, and recognizing the possible impact of the PM is valued (Figure 4c), while others outlined concerns about negative terminology (Figure 4d, quote 1). The results suggest a wide variety of personal experiences and opinions amongst the community and highlight the importance of ongoing research in this space that includes the voices of those with lived experience.
What Is in a Name? (National Fragile X Foundation (NFXF) and Fragile X Association of Australia (FXAA)
The focus of this talk was on terminology, and to understand this more thoroughly, the team conducted a survey about the terminology related to the PM. Data were captured from 296 people from the NFXF and FXAA communities via a Survey Monkey questionnaire, 255 of whom reported having the PM.
Part 1 of the survey probed what terminology people with lived experience endorsed when talking about their own PM status. A “click all that applies” option was provided. The response with the highest endorsement was Fragile X Carrier (n = 148), followed by Fragile X PM Carrier (n = 110), and Fragile X PM (n = 85).
Part 2 of the survey delved into views as measured by a Likert scale ranging from very comfortable to very uncomfortable, about specific words, focusing on “Fragile X premutation carrier”, “Fragile X carrier”, “condition”, “conditions and disorders”, and “disorder”. As shown in Figure 5, not one of these options has strong support (~less than half of respondents were very or somewhat comfortable with these options). In the last section (part 3), an open text box was enabled to collect comments. These qualitative data demonstrate that the concerns of the community are, indeed, far more complex than initially assumed, extending to the words “premutation” and “carrier”, and this generated robust debate between the audience and speakers, which is still ongoing.
The Importance of Appropriate Terminology
Both surveys acknowledged the impact of language and terminology in the community. Both surveys highlighted challenges with terms such as ‘carrier’, which could imply that a person experiences no impact from the PM. Also identified were issues with terms such as ‘mutation’ and ‘PM’, and the desire for the use of neutral, nonstigmatizing language. The group reflected on learnings from other expansion condition fields, such as Huntington’s and myotonic dystrophy, which have also undergone phenotype and/or terminology updates. For example, the term ‘gene change’ is now used rather than mutation. In addition, the term most often used is “variant”. The variant may be neutral or increase the function of the gene (gain-of-function mutation) or decrease or inhibit its function (loss-of-function mutation). It was also noted in the autism field that the term disorder is no longer widely used. Both clinicians and researchers shared the need for consistent use of agreed language and terminology. It was recognized there was a focus by U.S. clinicians on the use of terminology that helps families and patients gain access to services they need in the U.S. Clinicians raised the challenges for practicing clinicians worldwide when terminology evolves and changes.
Fragile X International (FraXI) released a press statement during the International Premutation Conference sharing the position of 17 family led fragile X country organizations regarding the use of terminology. FraXI and many family led organizations have adopted the term Fragile X-premutation-associated conditions (FXPAC), a term which lists everything which may or may not affect a PM carrier, and aims to use neutral language which is nondiscriminatory. Dr. Randi Hagerman, in her summary of the discussion around premutation terminology, shared her view that the term FXPAC presented a sensible umbrella term to encompass the range of involvement from the PM, with FXAND sitting under the FXPAC umbrella.
We know more than we ever have about the FMR1 PM. However, there remains more to learn and understand. This is particularly important as screening becomes increasingly available and those diagnosed with the PM seek to understand what this means, and the implications. Research suggests that some people with the PM may experience health impacts outside the currently defined FXPOI and FXTAS. Using appropriate, consistent, and nonstigmatizing terminology was recognized as having important implications for the planned knowledge translation of these new findings. This includes the potential success of developed guidelines for testing for both adults and in childhood that aims to provide early detection to inform optimal management and outcomes. Emerging from the International Premutation Conference, where many experts in the field met (Figure 6) and discussed the related issues, was an overall agreement around the value of the concept of ‘at increased risk’ compared to the general population when referring to the range of conditions currently associated with the PM.
Andrea Lee (FXNZ), Dr Jonathan Cohen, Dr Claudine Kraan, Dr Alison Archibold, Karen Lipworth (FXAA), Robert Miller (NFXF), Dr Sarah Potter, Dr Lidia V. Gabis, Dr Dejan Budimirovic, Dr Reymundo Lozano
Australian FMRI Premutation Screening Study (Archibald et al, 2018)
Fragile X International (FraXI) Press Release Statement 27 February 2023 https://fraxi.org/FraXI_FXPAC_Press%20Release_27February2023.pdf
Dr Randi Jenssen Hagerman, M.D., F.A.A.P. Distinguished Professor, Department of Pediatrics, Endowed Chair in Fragile X Research, Medical Director of the MIND
Published as part of the paper ‘Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation’
The full paper can be read here: https://www.mdpi.com/2073-4409/12/18/2330/pdf