The Future of Fragile X Syndrome: CDC Stakeholder Meeting Summary
- Catharine Riley, PhD, MPHa,
- Marsha Mailick, PhDb,
- Elizabeth Berry-Kravis, MD, PhDc,d,e, and
- Julie Bolen, PhD, MPHa
- aNational Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia;
- bWaisman Center, University of Wisconsin, Madison, Wisconsin; and
- cDepartments of Pediatrics,
- dNeurological Sciences, and
- eBiochemistry, Rush University Medical Center, Chicago, Illinois
Dr Riley conceptualized and organized the stakeholder meeting, led the planning committee, and drafted and revised the manuscript; Drs Mailick and Berry-Kravis served on the planning committee and revised the manuscript; Dr Bolen contributed to the stakeholder meeting and revised the manuscript; and all authors approved final submission.
- ASD —
- autism spectrum disorder
- CDC —
- Centers for Disease Control and Prevention
- FMR1 —
- fragile x mental retardation 1
- FMRP —
- fragile X mental retardation protein
- FXD —
- fragile X–associated disorder
- FXS —
- fragile X syndrome
- ID —
- intellectual disability
Fragile X syndrome (FXS) is the most common known inherited cause of intellectual disability (ID). Males and females with FXS exhibit a wide range of intellectual ability and may experience various degrees of emotional, behavioral, sensory, learning, and social difficulties. In 1991, the gene responsible for FXS was identified on the X chromosome at q27.3 and named fragile x mental retardation 1 (FMR1) gene.1 FXS and fragile X–associated disorders (FXD) are caused by a trinucleotide repeat (CGG) expansion mutation in the promoter region (exon 1) of FMR1. Affected individuals with the full FXS mutation have >200 repeats. When the full mutation is present, FMR1 methylation occurs during gestation, which causes silencing of gene transcription.2 This in turn leads to a reduction or absence of fragile X mental retardation protein (FMRP), which is needed for brain development and function. Most males with FXS have ID. A small number of males have less impaired function due to methylation patterns or mosaicism. In females, FMRP levels depend on the X activation ratio, or the percent of cells expressing the normal allele on the active X chromosome,3 resulting in a range of normal intellectual ability to moderate ID.
Over the past 2 decades, scientists have made significant advancements in identifying and describing genetic, molecular, and cellular underpinnings of FXS, allowing for a more precise diagnosis of this condition. The present challenge is to move from accurate diagnosis to public health action for FXS, requiring better understanding of the natural history of FXS, a clear description of how this complex condition affects individuals and their families, and identification of interventions and treatments that can lead to better outcomes. The more we know about this population across the life span, both from a clinical and parent or caregiver perspective, the better we can design treatments, services, and care. The Centers for Disease Control and Prevention (CDC) hosted a meeting in May 2014 to engage FXS stakeholders in the process of framing a public health research agenda geared toward the CDC’s long-term goal of improving care and quality of life for individuals living with FXS and their families (Fig 1).
To identify needs and plan for the stakeholder meeting, the CDC supported a structured literature review for FXS and FXD, which identified what is known about conditions caused by an FMR1 mutation (see Raspa et al4 and Wheeler5 et al in this supplement). Working from the results of this literature review and an environmental data scan, the CDC, with input from a planning committee, identified 6 areas where public health research and programs could potentially contribute knowledge to benefit FXS patients and their relatives: (1) epidemiology, (2) early identification and screening, (3) impact on individuals and families, (4) FXS across the life span, (5) cooccurring conditions, and (6) interventions and outcome measures. To help delineate goals, the CDC gathered a broad range of 60 experts and stakeholders to discuss the future of public health research for FXS. Attendees included researchers, clinicians, public health professionals, behavior and education specialists, patient advocates, and affected individuals and their families. Over 2 days, this group discussed each of the 6 topic areas, while describing how to address limited areas of knowledge. In particular, participants were asked to identify potential challenges in developing and implementing research and strategies needed for overcoming these limitations. To start the discussion for each topic, a summary of the literature was presented, followed by a large group discussion on the topic and then small breakout workgroups for more in-depth discussion. A summary was then presented back to the large group to provide an opportunity for all attendees to share additional discussion points.
This process (see Fig 1), from describing what is known to incorporating ideas from stakeholders about overcoming challenges, helped the CDC plan and develop public health research and programmatic activities for FXS, providing information for broader FXS clinical and public health communities regarding FXS population needs.
The structured literature review presented noted the following limitations in our current knowledge base, thereby highlighting potential needs: (1) prevalence estimates for the full mutation lack precision; (2) there is no large-scale, population-based study on FXS; (3) there is a lack of complete consensus on prevalence of the premutation; (4) much is unknown about the sociodemographic characteristics of FXS and FXD populations; and (5) there are inadequate data regarding FXS and FXD variability among racial or ethnic groups.
Estimates of the prevalence of the full mutation vary, ranging from 1:2000 to 1:9000.6–11 Although the exact prevalence of FXS is unknown, the research community currently uses estimates between 1 in 4000 to 5000 for boys and about 1 in 6000 to 8000 for girls. These estimates have been based on relatively small samples and could be biased if they exclude higher functioning boys and girls with FXS. Additionally, little is known about whether FXS is more or less prevalent in population subgroups. Prevalence of the premutation has been estimated based on population-based samples, with converging evidence that between 1 in 150 to 200 females and 1 in 300 to 450 males carry the premutation.12–14
Early Identification and Screening
A summary of the literature noted that the average age of a child first diagnosed with FXS is 36 months15 and suggested that a delay in diagnosis could potentially reduce access to interventions and other support mechanisms,16 leading to emotional stress, increased financial burden for families,17 and delay in families receiving information about future risk. After discussing the literature more, areas for future research were identified. The first area identified was the need for the development of new models and strategies to increase frequency of genetic testing for individuals with global developmental or intellectual delay, which could result in the identification of individuals with FXS who currently are not accurately diagnosed. Another area with limited research is the development and validation of low-cost, effective approaches for population-based FXS screening. The benefits of early (ie, presymptomatic) detection and early intervention on health outcomes, compared with identification after clinical presentation, has not yet been studied. In addition, we have only a limited understanding of the benefits and risks of reporting carrier/premutation status versus only reporting full mutation status in a large-scale screening program. Attendees also noted the importance of identifying public health and medical system infrastructure needs in relation to implementing large-scale screening for FXS.
Part of enhanced infrastructure is the need to improve outreach to health care professionals, including psychologists, therapists, and educators, to promote early identification of FXS, as well as the type of data and information needed to determine if FXS is ready for newborn screening. More detail on potential research that could provide the evidence needed to assess the feasibility and utility of newborn screening for FXS can be found in a companion article by Riley and Wheeler in this supplement.18
Impact on Individuals and Families
A literature summary included studies on the impact of FXS on mothers, caregivers, and family units as a whole. With regard to mothers, the mental health effects of raising a child with FXS that have been reported are diverse, including increased levels of stress, depression, anger, and anxiety. Stress, in particular, appears related to child behavior and can vary among mothers, depending on their FMR1 mutation status.19–21 A few studies have indicated that most mothers that participated in the studies reported average or above average levels of hope, optimism, quality of life, well-being, and adaptation, noting that social support could play a role in this positive adaption.19,22,23 In relation to caregivers, a recent survey and subsequent comparison of these survey data with children with autism spectrum disorder (ASD), an ID, and both ASD and ID described high caregiver burden with regard to financial impact as well as impact on employment due to increased caregiving demands.24,25 Several studies described the possible effects of raising a child with FXS on marriages, family units, maternal interaction, and mother’s religiosity.26–32
Because most studies have focused on mothers, little is known about how FXS affects fathers, siblings, and other caregivers. The issue of stress on caregivers and family members was discussed as an area in need of additional research to provide insight into magnitude of the issue and options for addressing stress on families. Attendees noted that family-focused interventions are not readily available. Little evidence exists regarding factors that influence family and maternal outcomes. Future research on outcomes in premutation carrier mothers could address the need to separate the impact of caring for a child with FXS from the direct effects of the premutation itself. With improved understanding of these issues, strategies could be designed to lessen the impact of FXS. Attendees also discussed the need for more outreach to families, specifically focusing on resources caregivers need to navigate complex health, social, educational, and occupational systems.
A particular area in need of additional inquiry is the impact of FXS on individuals and families across the life span and potential issues related to aging with FXS. As children with FXS grow up, they experience areas of improved functioning, but also new challenges. Some studies report an age-related decline in scores on standardized measures of cognition in individuals with FXS. Limited information is available on this phenomenon in adults with FXS, but the decline in scores does not appear to reflect a loss of skills, rather an increasing divergence in performance relative to the normative group.33,34 FMRP levels or a codiagnosis of ASD are correlated with the magnitude of decline.35–40 A contrasting pattern of age-related changes has been described in the areas of adaptive behavior and behavior problems; a recent longitudinal study found that adaptive behavior improves and behavior problems decline in severity during adolescence and into adulthood.41
Once individuals with FXS reach adulthood, they still may require considerable care, based on limited research. Little has been reported on the behavioral functioning of adults with FXS. In 1 study that examined the independence level of a large sample of adults with FXS, findings indicated that a majority of adult males with FXS (70%) lived with their parents, and 50% of adult females were living at home at the time of the survey.42 Almost half (48%) of females were working full time compared with only 20% of males.42 In a cross-sectional study of adult men with FXS, findings suggested that there is a pattern of age-related improvement in many ASD symptoms across adulthood.43 However, the aging process and the impact of more frequently occurring coconditions on individuals as they age have not been adequately described. Only 1 paper has addressed this subject in a small cohort of individuals with FXS >40 years of age.44
Meeting attendees emphasized the need for more research and data collection that include longitudinal studies to better understand the natural history of FXS and how it impacts individuals across the life span. In particular, studies of older adolescents and adults are needed. Literature regarding the transition out of school, employment opportunities, daily living and functional skills, behavior problems, health, and social needs of adolescents and adults is limited. Issues related to guardianship and self-advocacy have also not been adequately explored. Attendees emphasized the importance of researching the health and social needs of adolescents and adults with FXS.
A range of behaviors that individuals with FXS exhibit has been described in the literature, including anxiety, aggression, self-injury, tactile defensiveness, hand flapping, poor eye contact, hyperactivity, distractibility, tantrums, perseveration, hyperarousal to sensory stimuli, and impulsivity.45–48 Information about attention problems, anxiety, and ASD in the FXS population is more robust, compared with other behaviors and conditions that have been reported to occur in the FXS population, such as self-injury, aggression toward others, and sleep problems. Additionally, limited information is available about effective interventions and treatments for these behaviors and conditions that have been observed in the FXS population.
Meeting attendees discussed the importance of identifying and describing conditions that occur most frequently in conjunction with FXS and the need for additional research on why these behaviors and conditions occur and how they can be addressed to improve health outcomes. Additionally, there is an overall need to better characterize the health status of individuals with FXS, including the presence of health disparities, health literacy, and health care decision-making.
Interventions and Outcome Measures
Developing interventions and understanding how to best measure their impact is an area of ongoing need in the FXS population. Reliable outcome measures for clinical trials of new-generation medications have not been identified or validated, so determining clinical end points that could be used to assess change is important. One difficulty in evaluating FXS treatment effectiveness is the lack of a feasible biomarker. Many of the outcome measures in FXS are related to behavioral or cognitive changes. There are few validated outcome measures that describe rates of learning that could be used to determine medication efficacy for improving cognition. Current research suggests several promising outcome measures. Efforts to validate them in the FXS population are currently being funded by the CDC.
Attendees discussed the need to identify new ways of measuring developmental changes in individuals and populations living with FXS to address short- and long-term changes achieved through interventions and treatments. In addition to pharmacologic treatments, there is a need for large randomized controlled trials on specific behavioral or educational interventions. No large randomized controlled trial for this type of intervention has been conducted to date. Attendees also discussed the need to identify end points and quality measures that can assess learning rate, rather than cognitive achievements that may not be sensitive to change. Finally, attendees agreed on the need for biomarkers that could be used to document target engagement or to determine the level of response to specific interventions for clinical trials and other types of research.
Even with major advances in basic and clinical research, there is still much to learn about the impact of public health efforts on FXS and how they can improve health outcomes and quality of life for those living with it. The efforts described have helped the CDC develop a public health research agenda for FXS. Part of this research agenda is being addressed through awards that began in September 2015 under a request for applications titled “Using Longitudinal Data to Characterize the Natural History of Fragile X Syndrome to Improve Services and Outcomes.” The purpose of these awards are to conduct research on the natural history of FXS across the life span; explore effective strategies to increase participation in longitudinal studies among minority, underserved, and adult populations living with FXS; and test approaches to measure cognitive and behavioral function in the FXS population. The CDC is also collaborating with the American Academy of Pediatrics to work on improving early identification of FXS. Addressing limited areas of knowledge will be a collective effort of the research, clinical, and patient communities. Federal agencies, academic researchers, health care professionals, private corporations, and FXS patient organizations all play an important role in addressing the identified needs of individuals and families impacted by this complex condition.
We thank the CDC Stakeholder Meeting cosponsors, the John Merck Fund and National Fragile X Foundation; Planning Committee members: Don Bailey, Elizabeth Berry-Kravis, W. Ted Brown, Katie Clapp, Jeffrey Cohen, Marsha Mailick, Catharine Riley, Nancy Stockford, Mark Swanson, and Tiina Urv; Facilitator: Rebecca Reeves; and RTI International: Don Bailey, Anne Wheeler, and Melissa Raspa (background materials) and Marjorie Margolis (note taker).
- Accepted January 24, 2017.
- Address correspondence to Julie Bolen, PhD, MPH, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, 4770 Buford Hwy (E-88), Atlanta, GA 30341. E-mail:
The findings and conclusions in this publication are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.
FUNDING: No external funding.
POTENTIAL CONFLICT OF INTEREST: Dr Mailick is Chair of the Scientific Advisory Board of the Developmental Disabilities Program of the John Merck Fund; Dr Berry-Kravis is a member of the Scientific and Clinical Advisory Board of the National Fragile X Foundation and is the recipient of 2 current grants “Acamprosate in Fragile X Syndrome” and “GABA-mediated Mechanisms of Altered Sensory Perception in Fragile X Syndrome” from the John Merck Fund; and Drs Riley and Bolen have indicated they have no potential conflicts of interest to disclose.
- Copyright © 2017 by the American Academy of Pediatrics