The Future of Fragile X Syndrome: CDC Stakeholder Meeting Summary Catharine Riley, PhD, MPH,a Marsha Mailick, PhD,b Elizabeth Berry-Kravis, MD, PhD, c,d, e Julie Bolen, PhD, MPHa

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

a National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia; bWaisman Center, University of Wisconsin, Madison, Wisconsin; and Departments of cPediatrics, 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 fi nal submission. The fi ndings and conclusions in this publication are those of the authors and do not necessarily represent the offi cial position of the Centers for Disease Control and Prevention. DOI: https://doi. org/ 10. 1542/ peds. 2016- 1159B Accepted for publication Jan 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: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2017 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no fi nancial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: Dr Mailick is Chair of the Scientifi c Advisory Board of the Developmental Disabilities Program of the John Merck Fund; Dr Berry- Kravis is a member of the Scientifi c 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 confl icts of interest to disclose.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 139 , Number s3 , June 2017:e 20161159 SUPPLEMENT ARTICLE FIGURE 1 Framing a public health research agenda for FXS. research agenda geared toward the (2) early identification and screening, start the discussion for each topic, CDC’s long-term goal of improving (3) impact on individuals and a summary of the literature was care and quality of life for individuals families, (4) FXS across the life span, presented, followed by a large group living with FXS and their families (5) cooccurring conditions, and (6) discussion on the topic and then (Fig 1). interventions and outcome measures. small breakout workgroups for more To help delineate goals, the CDC in-depth discussion. A summary was To identify needs and plan for gathered a broad range of 60 experts then presented back to the large the stakeholder meeting, the CDC and stakeholders to discuss the group to provide an opportunity supported a structured literature future of public health research for for all attendees to share additional review for FXS and FXD, which FXS. Attendees included researchers, discussion points. identified what is known about clinicians, public health professionals, conditions caused by an FMR1 mutation (see Raspa et al 4 and behavior and education specialists, This process (see Fig 1), from Wheeler5 et al in this supplement). patient advocates, and affected describing what is known Working from the results of individuals and their families. Over 2 to incorporating ideas from this literature review and an days, this group discussed each of the stakeholders about overcoming environmental data scan, the 6 topic areas, while describing how to challenges, helped the CDC plan CDC, with input from a planning address limited areas of knowledge. and develop public health research committee, identified 6 areas where In particular, participants were and programmatic activities for public health research and programs asked to identify potential challenges FXS, providing information for could potentially contribute in developing and implementing broader FXS clinical and public knowledge to benefit FXS patients research and strategies needed for health communities regarding FXS and their relatives: (1) epidemiology, overcoming these limitations. To population needs.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 S148 RILEY et al DISCUSSION area identified was the need for the Stress, in particular, appears related development of new models and to child behavior and can vary among Epidemiology strategies to increase frequency of mothers, depending on their FMR1 – The structured literature review genetic testing for individuals with mutation status. 19 21 A few studies presented noted the following global developmental or intellectual have indicated that most mothers limitations in our current knowledge delay, which could result in the that participated in the studies base, thereby highlighting potential identification of individuals with FXS reported average or above average needs: (1) prevalence estimates for who currently are not accurately levels of hope, optimism, quality the full mutation lack precision; (2) diagnosed. Another area with limited of life, well-being, and adaptation, there is no large-scale, population- research is the development and noting that social support could play based study on FXS; (3) there is validation of low-cost, effective a role in this positive adaption. 19,22, 23 a lack of complete consensus on approaches for population-based FXS In relation to caregivers, a recent prevalence of the premutation; screening. The benefits of early (ie, survey and subsequent comparison (4) much is unknown about the presymptomatic) detection and early of these survey data with children sociodemographic characteristics of intervention on health outcomes, with autism spectrum disorder FXS and FXD populations; and (5) compared with identification after (ASD), an ID, and both ASD and ID there are inadequate data regarding clinical presentation, has not yet described high caregiver burden FXS and FXD variability among racial been studied. In addition, we have with regard to financial impact as or ethnic groups. only a limited understanding of well as impact on employment due to the benefits and risks of reporting 24,25 Estimates of the prevalence of the full increased caregiving demands. carrier/premutation status versus Several studies described the mutation vary, ranging from 1:2000 only reporting full mutation status 6–11 possible effects of raising a child to 1:9000. Although the exact in a large-scale screening program. prevalence of FXS is unknown, the with FXS on marriages, family units, Attendees also noted the importance ’ research community currently uses maternal interaction, and mother s of identifying public health and – religiosity.26 32 estimates between 1 in 4000 to 5000 medical system infrastructure needs for boys and about 1 in 6000 to 8000 in relation to implementing large- Because most studies have focused for girls. These estimates have been scale screening for FXS. based on relatively small samples on mothers, little is known about and could be biased if they exclude Part of enhanced infrastructure how FXS affects fathers, siblings, and higher functioning boys and girls is the need to improve outreach other caregivers. The issue of stress with FXS. Additionally, little is known to health care professionals, on caregivers and family members about whether FXS is more or less including psychologists, therapists, was discussed as an area in need prevalent in population subgroups. and educators, to promote early of additional research to provide Prevalence of the premutation has identification of FXS, as well as the insight into magnitude of the issue been estimated based on population- type of data and information needed and options for addressing stress based samples, with converging to determine if FXS is ready for on families. Attendees noted that evidence that between 1 in 150 to newborn screening. More detail on family-focused interventions are 200 females and 1 in 300 to 450 potential research that could provide not readily available. Little evidence males carry the premutation. 12 – 14 the evidence needed to assess the exists regarding factors that influence feasibility and utility of newborn family and maternal outcomes. Early Identifi cation and Screening screening for FXS can be found in Future research on outcomes in a companion article by Riley and A summary of the literature noted premutation carrier mothers could Wheeler in this supplement. 18 that the average age of a child first address the need to separate the 15 impact of caring for a child with diagnosed with FXS is 36 months Impact on Individuals and Families and suggested that a delay in FXS from the direct effects of the diagnosis could potentially reduce A literature summary included premutation itself. With improved access to interventions and other studies on the impact of FXS on understanding of these issues, support mechanisms,16 leading to mothers, caregivers, and family strategies could be designed to lessen emotional stress, increased financial units as a whole. With regard to the impact of FXS. Attendees also burden for families,17 and delay mothers, the mental health effects discussed the need for more outreach in families receiving information of raising a child with FXS that to families, specifically focusing on about future risk. After discussing have been reported are diverse, resources caregivers need to navigate the literature more, areas for future including increased levels of stress, complex health, social, educational, research were identified. The first depression, anger, and anxiety. and occupational systems.

Downloaded from www.aappublications.org/news by guest on September 28, 2021 PEDIATRICS Volume 139 , number s3 , June 2017 S149 Lifespan/Transition/Aging Population addressed this subject in a small and conditions occur and how they cohort of individuals with FXS >40 can be addressed to improve health A particular area in need of additional years of age.44 outcomes. Additionally, there is an inquiry is the impact of FXS on overall need to better characterize individuals and families across the Meeting attendees emphasized the the health status of individuals with life span and potential issues related need for more research and data FXS, including the presence of health to aging with FXS. As children with collection that include longitudinal disparities, health literacy, and health FXS grow up, they experience areas studies to better understand the care decision-making. of improved functioning, but also natural history of FXS and how it impacts individuals across the new challenges. Some studies report Interventions and Outcome an age-related decline in scores on life span. In particular, studies Measures standardized measures of cognition of older adolescents and adults in individuals with FXS. Limited are needed. Literature regarding Developing interventions and information is available on this the transition out of school, understanding how to best measure phenomenon in adults with FXS, but employment opportunities, daily their impact is an area of ongoing the decline in scores does not appear living and functional skills, behavior need in the FXS population. Reliable to reflect a loss of skills, rather an problems, health, and social needs outcome measures for clinical trials increasing divergence in performance of adolescents and adults is limited. of new-generation medications relative to the normative group. 33, 34 Issues related to guardianship and have not been identified or FMRP levels or a codiagnosis of ASD self-advocacy have also not been validated, so determining clinical are correlated with the magnitude adequately explored. Attendees end points that could be used of decline.35 – 40 A contrasting pattern emphasized the importance of to assess change is important. of age-related changes has been researching the health and social One difficulty in evaluating FXS described in the areas of adaptive needs of adolescents and adults with treatment effectiveness is the lack behavior and behavior problems; FXS. of a feasible biomarker. Many of a recent longitudinal study found the outcome measures in FXS are that adaptive behavior improves Cooccurring Conditions related to behavioral or cognitive and behavior problems decline in A range of behaviors that individuals changes. There are few validated severity during adolescence and into with FXS exhibit has been described outcome measures that describe adulthood. 41 in the literature, including anxiety, rates of learning that could be used aggression, self-injury, tactile to determine medication efficacy Once individuals with FXS reach defensiveness, hand flapping, for improving cognition. Current adulthood, they still may require poor eye contact, hyperactivity, research suggests several promising considerable care, based on limited distractibility, tantrums, outcome measures. Efforts to validate research. Little has been reported on perseveration, hyperarousal to them in the FXS population are the behavioral functioning of adults sensory stimuli, and impulsivity. 45 – 48 currently being funded by the CDC. with FXS. In 1 study that examined Information about attention the independence level of a large Attendees discussed the need to problems, anxiety, and ASD in the sample of adults with FXS, findings identify new ways of measuring FXS population is more robust, indicated that a majority of adult developmental changes in individuals compared with other behaviors and males with FXS (70%) lived with and populations living with FXS to conditions that have been reported to their parents, and 50% of adult address short- and long-term changes occur in the FXS population, such as females were living at home at the achieved through interventions self-injury, aggression toward others, time of the survey.42 Almost half and treatments. In addition to and sleep problems. Additionally, (48%) of females were working full pharmacologic treatments, there is a limited information is available time compared with only 20% of need for large randomized controlled about effective interventions and males. 42 In a cross-sectional study trials on specific behavioral or treatments for these behaviors and of adult men with FXS, findings educational interventions. No large conditions that have been observed suggested that there is a pattern of randomized controlled trial for in the FXS population. age-related improvement in many this type of intervention has been ASD symptoms across adulthood.43 Meeting attendees discussed the conducted to date. Attendees also However, the aging process and the importance of identifying and discussed the need to identify end impact of more frequently occurring describing conditions that occur points and quality measures that coconditions on individuals as most frequently in conjunction with can assess learning rate, rather than they age have not been adequately FXS and the need for additional cognitive achievements that may described. Only 1 paper has research on why these behaviors not be sensitive to change. Finally,

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FMR1 and the fragile X syndrome: and clinical research, there is still (background materials) and Marjorie human genome epidemiology much to learn about the impact of Margolis (note taker). review. Genet Med. 2001;3(5): public health efforts on FXS and how 359–371 they can improve health outcomes 9. Crawford DC, Meadows KL, Newman and quality of life for those living ABBREVIATIONS JL, et al. Prevalence of the fragile X with it. The efforts described have ASD: autism spectrum disorder syndrome in African-Americans. Am J – helped the CDC develop a public CDC: Centers for Disease Control Med Genet. 2002;110(3):226 233 health research agenda for FXS. and Prevention 10. Jacobs PA, Bullman H, Macpherson J, Part of this research agenda is FMR1: fragile x mental retarda- et al. Population studies of the fragile being addressed through awards tion 1 X: a molecular approach. 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Downloaded from www.aappublications.org/news by guest on September 28, 2021 The Future of Fragile X Syndrome: CDC Stakeholder Meeting Summary Catharine Riley, Marsha Mailick, Elizabeth Berry-Kravis and Julie Bolen Pediatrics 2017;139;S147 DOI: 10.1542/peds.2016-1159B

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