Abstract
Women who carry a fragile X premutation are at risk for at least two major health conditions and for transmitting fragile X syndrome (FXS) to their children. The two health concerns include fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS). The aim of this study was to evaluate whether written educational information about these conditions would increase knowledge and facilitate communication. Women with a premutation (N=142) completed an online pre-test to assess their knowledge of premutation-associated conditions, and 135 women who provided an address received a booklet titled Women’s Health and the Fragile X Premutation. After three months, 51.1% completed the post-test. Major gaps in knowledge were related to FXPOI and factors associated with repeat expansion. To determine whether the booklet helped to fill gaps in knowledge, we compared pre- and post-test scores. Scores were significantly increased after receipt of the booklet (p<0.05, Wilcoxon signed rank test). Participants answered that the booklet was “very helpful” (44.6%) or “somewhat helpful” (38.5%). Twenty-four participants (34.8%) reported using the booklet to explain concepts to family members. Although we found that the booklet provided women with needed information, we found that gaps in knowledge still exist.
Keywords: Communication, Education, Health literacy, Intellectual disability, Fragile X syndrome, Fragile X premutation, Ovarian insufficiency, FXPOI, FXTAS
Introduction
Fragile X disorders are caused by an expansion of the CGG repeat tract in the 5’ untranslated region of the X-linked FMR1 gene. There are four categories of FMR1 alleles that are defined by the number of CGG repeats: normal, intermediate, premutation, and full mutation. The full mutation causes fragile X syndrome (FXS) and is characterized by >200 hypermethylated CGG repeats near the promotor of FMR1, leading to silencing of the gene. FXS is the most common single-gene cause of inherited intellectual disability. It can cause developmental delay, learning disabilities, autism, behavioral problems, and specific physical characteristics. A premutation allele has 55–200 CGG repeats and remains unmethylated. About 1 in 300 women and 1 in 850 men carry a fragile X premutation, although there is wide variation in these estimates across studies (Hunter et al., 2014). While both men and women can carry premutation alleles, it is only through maternal transmission that a premutation allele can expand to a full mutation in offspring. The chance of expansion from a premutation in the mother to a full mutation in her offspring depends primarily on two factors: 1) the length of her CGG repeat, with larger repeats being more likely to expand during transmission, and 2) the number of AGG interruptions within the CGG tract, with increasing number of AGG interruptions stabilizing the repeat during transmission (Nolin et al., 2015).
In addition to the chance of having a child with FXS, there are personal health risks associated with a fragile X premutation. Women with a premutation are at risk of fragile X-associated primary ovarian insufficiency (FXPOI) and fragile X-associated tremor/ataxia syndrome (FXTAS). Approximately 20% of women with a fragile X premutation will experience FXPOI, which is defined as cessation of menses before age 40 (Sherman, 2000; Wittenberger et al., 2007). Symptoms of FXPOI can include irregular or ceased menstruation, irregular ovulation, infertility, altered hormone profile (e.g., decreased levels of anti-Müllerian hormone (AMH) and increased levels of follicle stimulating hormone (FSH)), and menopausal symptoms, (e.g., hot flashes and night sweats)(Hipp, Charen, Spencer, Allen, & Sherman, 2016). Despite hormonal changes and irregular ovulation, some women with FXPOI can still become pregnant. In addition to FXPOI, women who are carriers have an 8–17% chance of developing fragile X-associated tremor/ataxia syndrome (FXTAS) (Coffey et al., 2008; Rodriguez-Revenga et al., 2009). FXTAS is a progressive neurological disorder that can affect both male and female carriers, but is more common and more severe among men. Symptoms of FXTAS can present as balance problems, tremors, Parkinsonism, or executive function deficits (Hagerman & Hagerman, 2015). Women may have different manifestations of FXTAS and other health conditions related to the FMR1 premutation as compared to men. These may include thyroid problems, autoimmune disorders, neuropathy, and fibromyalgia (Wheeler et al., 2014). Women with a fragile X premutation are also predisposed to depression, anxiety, migraines, social phobias, math difficulties, affective disorders, and attention-deficit/hyperactivity disorder (ADHD) (Hagerman et al., 2018; Hunter, Epstein, Tinker, Abramowitz, & Sherman, 2012; Hunter et al., 2012; Kenna et al., 2013; Wheeler et al., 2014).
There are no cures for FXPOI, FXTAS, or the other related health issues, but timely treatment and management of symptoms can improve health overall. Women with FXPOI should receive hormone replacement therapy until the typical age of natural menopause (Hipp, Charen, Spencer, Allen, & Sherman, 2016). This will mitigate risks of osteoporosis, cardiovascular disease, and premature cognitive decline due to deficits of estrogen. Measuring FSH and AMH levels can be used as a screen for FXPOI leading to early detection. This also may allow women to pursue fertility preservation before reaching a point of infertility. Women who understand the inheritance pattern and factors influencing allele expansion can be aware of their chance to have a child affected by FXS and make family planning decisions. Awareness, early intervention, and proper management of other related health issues, such as anxiety and depression, can greatly improve quality of life.
A previous study assessed barriers to women understanding health implications and accessing personal healthcare related to their fragile X premutation (Espinel, Charen, Huddleston, Visootsak, & Sherman, 2016). This study found a lack of knowledge among healthcare providers and a lack of targeted educational material were two barriers to personal healthcare. A 29-page informational booklet, titled “Women’s Health and the Fragile X Premutation”, was created in response to these findings (Online Resource 4). Our current study was designed to determine the effectiveness of that booklet in improving fragile X premutation-related health knowledge among women with a fragile X premutation. We conducted a pre- and post-survey after providing the booklet to assess the change in level of knowledge of personal health risks. We also asked about other information sources and patient experiences in sharing their gained knowledge.
Methods
Participants
Participants included women age 18 and older who are carriers of a fragile X premutation. They were recruited through online social media, the Fragile X Clinic at Emory University, and by word of mouth. The vast majority was recruited from several Facebook groups.
Procedures
All aspects of this study were approved by the Institutional Review Board at Emory University. Consent was obtained before entering the pre-test survey. Women completed a pre-test survey through REDCap online survey system. They were then mailed a booklet titled “Women’s Health and the Fragile X Premutation” (Online Resource 4). Three months after the receipt of the booklet, participants were sent a link, via email, to the post-test survey. Survey responses were collected from April 2016 to February 2017. We refer to results obtained prior to the receipt of the booklet as “pre-test” results and those obtained three months after the receipt of the booklet as “post-test” results.
Instrumentation
The pre-test contained questions about demographics, fragile X-related health knowledge, and resource use. All demographic information, including number of CGG repeats, was self-reported. The health knowledge questions were presented in four sections and were scored to assess the level of understanding. These sections included: inheritance and family planning, FXPOI, FXTAS, other premutation-related health symptoms. Knowledge questions were asked in both multiple-choice and open-ended formats. Open-ended questions were used to assess a woman’s current awareness regarding the symptoms of FXPOI, FXPOI symptom management, the age range for FXPOI diagnosis, and symptoms of FXTAS. At the end of the FXPOI and FXTAS sections, participants were asked to rate their satisfaction with their knowledge of that topic on a scale from 0 to 100 with 0 being very unsatisfied and 100 being highly satisfied. Participants were also asked to describe experiences sharing fragile X-related information with family members. Lastly, the pre-test survey included an open-ended section for participants to share any information, experiences, or thoughts about being a premutation carrier. The post-test survey contained identical questions for the four scored sections described above. Additionally, the post-test survey contained questions about booklet use, perceived helpfulness, and further informational needs. The Flesch-Kincaid readability tests indicated that the surveys were understandable at a 6th to 7th grade reading level. Pre- and post-test surveys can be found in Online Resource 1A and 1B, respectively.
Data Analysis
A scoring guide was created to assign points to specific responses (Online Resource 2). Pre- and post-test surveys were given a total score out of 37 points possible. We determined scores for each of the following sections: inheritance/family planning (18 points), FXPOI (9 points), FXTAS (8 points), and other symptoms (2 points). Demographic information was analyzed with descriptive statistics. We used an independent t-test (continuous variables) or a chi-square test (grouped variables) to compare the demographics of participants who completed the pre-test survey only and those who completed both the pre- and post-test surveys to identify possible biases among these groups. An independent t-test was also used to determine whether the section and overall test scores on the pre-test survey were significantly different between those who went on to complete the post-test survey and those who did not. The association between satisfaction of participant’s knowledge of FXPOI and FXTAS and their pre-test scores in the corresponding category was obtained using Pearson’s correlation.
To understand predictors of knowledge, linear regression was used to identify significant associations of overall pre-test scores with demographic variables: β-coefficients and partial R2 were reported for significant predictors. Answers from the open-ended section of the pre-test survey, where participants were asked to list other health concerns related to the premutation aside from FXPOI and FXTAS, were ranked by frequency.
To assess the effectiveness of providing the informational booklet, pre- and post-test survey scores were compared using a Wilcoxon signed ranks test, as post-test scores were not normally distributed. A linear regression was used to determine whether the demographic variables associated with higher pre-test scores were associated with changes in score from pre- to post-test.
Two independent analysts analyzed responses to the open-ended comments section. They each independently reviewed the responses to identify common themes. Once consensus of themes was obtained, each response was re-categorized into the appropriate consensus theme. Representative quotes are provided with their identification number in parentheses.
The human subjects protocol and related issues involved in this project were reviewed and approved by the Emory University School of Medicine Institutional Review Board (IRB).
Results
Characteristics of participants
Pre-test surveys were completed by 142 women with a fragile X premutation. Four participants reported CGG repeat sizes that were outside the premutation range; three participants were intermediate alleles carriers (one reported having 54 CGG repeats and having a child with FXS); and one participant was a full mutation allele carrier. We included these participants in the analyses because of their belief that they were premutation carriers. None of these four participants completed the post-test survey. Of the 142 participants, 135 participants included a mailing address, which was necessary to receive the informational booklet (Online Resource 4). Of the 135 participants who received the booklet, 69 completed the post-test survey (51.1%). Of those 69 participants, five indicated they did not read any of the booklet and were excluded from post-test analyses and paired analyses. Demographic information revealed that participants who at least completed the pre-test were mostly white, college graduates, had a household income greater than the U.S. median, and had at least one child with FXS (Table 1). We compared demographics of those who completed the pre-test survey only and those who completed both the pre- and post-test surveys and found that a significantly larger proportion of those who completed both surveys had a higher annual household income compared with those who completed the pre-test only (p=0.019).
Table 1.
Demographics of all participants and stratified by those who completed only the pre-test survey and those who completed both the pre- and post-test surveys (p-values relate to tests of differences between the stratified groups).
| All (n=142) | Pre-test only (n=78) | Pre-&Post-test (n=64) | p-value | ||
|---|---|---|---|---|---|
| Age [mean (SD; range)] | 43.8 (10.8; 25–70) | 43.4 (10.6; 26–70) | 44.2 (11.1; 25–68) | 0.661 | |
| # of CGG repeats [mean (SD; range)] | 92.1 (34.1; 46–205) | 97.3 (41.1; 46–205) | 85.7 (21.1; 55–155) | 0.096 | |
| Years since carrier
diagnosis [mean (SD; range)] |
10.8 (7.9; <1–33) | 10.8 (7.8; <1–28) | 10.9 (8.7; <1–34) | 0.939 | |
| Race/Ethnicity | White | 89.4% | 89.7% | 89.1% | 0.896 |
| Not White | 10.6% | 10.3% | 10.9% | ||
| Annual household income | <$50,000 | 25.4% | 33.3% | 15.9% | 0.019 |
| ≥$50,000 | 74.6% | 66.7% | 84.1% | ||
| Education | Less than Bachelor’s degree | 40.0% | 45.5% | 33.3% | 0.147 |
| Bachelor’s degree or higher | 60.0% | 54.5% | 66.7% | ||
| Children with FXS | No | 21.4% | 22.1% | 20.6% | 0.837 |
| Yes | 78.6% | 77.9% | 79.4% | ||
| Adequate healthcare access | Yes | 83.8% | 82.1 | 85.9% | 0.535 |
| No | 16.2% | 17.9% | 14.1% | ||
| Overall good health | Yes | 80.9% | 77.9% | 84.4% | 0.336 |
| No | 19.1% | 22.1% | 15.6% | ||
| Genetic counseling for PM | Yes | 52.8% | 50.0% | 56.3% | 0.461 |
| No | 47.2% | 50.0% | 43.7% | ||
| Ever received written material on PM | Yes | 40.0% | 36.4% | 44.4% | 0.335 |
| No | 60.0% | 63.6% | 55.6% | ||
(Abbreviations: SD=standard deviation, FXS = fragile X syndrome, PM = premutation)
We compared sub-scores and total scores on the pre-test survey for women who completed the pre-test only and women who completed both pre- and post-test surveys. We found that women who completed both surveys had higher mean pre-test scores for FXPOI and FXTAS sections than those who only completed the pre-test survey, although only the difference in FXTAS sub-sections scores reached statistical significance (p=0.002; Table 2). For both groups, the mean level of satisfaction of their knowledge of FXPOI or of FXTAS on the pre-test was “neutral” to “dissatisfied” (<45 on a scale of 0–100), and their level of satisfaction was highly correlated with their pre-test score (Table 2).
Table 2.
Correlation between section knowledge scores and level of satisfaction with knowledge and comparison of mean scores between participants who did versus did not complete the post-test survey.
| Section | Score [Mean (SD)] | Satisfaction [Mean (SD)] | Pearson Correlation (p-value) | |
|---|---|---|---|---|
| FXPOI | All Participants | 3.32 (2.08) | 29.58 (24.51) | 0.543 (<0.001) |
| Pre-test Only | 3.08 (2.13) | 24.34 (23.11) | 0.497 (<0.001) | |
| Pre- and Post-test | 3.62 (2.00) | 36.25 (24.84) | 0.555 (<0.001) | |
| p-value* | 0.124 | 0.009 | --- | |
| FXTAS | All Participants | 3.85 (2.21) | 34.64 (25.78) | 0.550 (<0.001) |
| Pre-test Only | 3.33 (2.24) | 28.33 (22.19) | 0.594 (<0.001) | |
| Pre- and Post-test | 4.47 (2.02) | 42.26 (27.88) | 0.438 (0.001) |
|
| p-value* | 0.002 | 0.003 | --- |
Independent t-test comparing mean scores of participants who completed the pre-test only and those who completed both the pre- and post-test
(Abbreviations: FXPOI = fragile X-associated primary ovarian insufficiency, FXTAS = fragile X-associated tremor/ataxia syndrome)
Pre-test results: Level of knowledge and associated predictors
We examined the following variables to determine whether they were associated with pre-test scores using linear regression: age, having at least child with FXS, being white, having income of $50,000 or more, having a Bachelor’s degree or higher, living in the United States, having adequate access to healthcare, personally having FXPOI and/or FXTAS, and being in good health overall. We found that education of Bachelor’s degree or higher (β=0.217, p=0.018) and household income of $50,000 or higher (β=0.273, p=0.003) were statistically significantly associated with total pre-test scores. These two variables accounted for 16.9% of the variance in pre-test overall score.
To identify the areas with the biggest gaps in knowledge, we ranked questions by the percentage of participants who provided incorrect answers. We found that many women could not correctly identify factors affecting repeat expansion. Specifically, one question asked: “What factors influence if a fragile X premutation expands to a full mutation when passed on to the child? That is, what affects repeat stability? Check all that apply.” Answer choices given included: number of AGG interruptions within the premutation carried by the parent (40.0% correct), gender of the parent with the premutation (43.0% correct), repeat length of the premutation carried by the parent (54.8%); 24.4% incorrectly checked “none of the above; it is only random chance”. With respect to FXPOI, 48 of 142 women (33.8%) were aware of the age for which the diagnosis of FXPOI was based (i.e., cessation of menses prior to age 40). Importantly, only 38 of 142 women (26.8%) were aware of the need to take hormone replacement treatment for early menopause. The open-ended question to list symptoms related to FXPOI identified misconceptions. For example, four participants listed miscarriages as a symptom of FXPOI. To date, no study has identified an increased rate of miscarriages among premutation carriers (Schwartz et al., 1994).
An open-ended question asked participants to list other health and well-being concerns related to a premutation. This question yielded answers citing 40 unique symptoms (Online Resource 3). The five most common responses (and number who stated this symptom in their list) were: anxiety (84), depression (68), fibromyalgia (21), thyroid issues (20), and autoimmune diseases (19). The assessment of the strength of evidence for the association between each symptom and being a female premutation carrier (definitely, probably and possibly associated) used by Wheeler et al. is as follows: anxiety – possibly related; depression – probably related; fibromyalgia and thyroid issues – probably related in women with FXTAS and possibly related in women without FXTAS; and autoimmune-related diseases were possibly or probably related (Wheeler et al., 2014).
Pre-test Results: Communication of knowledge
The pre-test survey assessed communication with physicians about carrying a fragile X premutation and communication of fragile X-related topics to family members. Participants reported speaking with their primary care physician (73.7%), gynecologist (56.4%), and genetic counselor (42.1%) about carrying a fragile X premutation. However, in the open-ended comments section, 15 of 142 women (10.6%) stated difficulties with their physicians without any prompt to discuss such experiences. Difficulties included: 1) the physician’s lack of knowledge about fragile X-related topics, 2) feeling as if the physician lacked interest or did not care, and 3) receiving incorrect information about how fragile X disorders affect females. A representative quote that describes difficulties in communication follows:
“Trying to get doctors to understand is the hardest part. It took almost 8 years for anyone to believe me that I was experiencing FXPOI. Even after taking them literature on it, they kept telling me I was too young…” (ID13)
The pre-test survey asked participants about their experiences sharing fragile X-related information with family members. Responses were categorized as being positive, neutral/mixed, or negative. Of 94 participants who answered this open-ended question, 28 (29.8%) had a positive experience, 28 (29.8%) had a neutral or mixed experience, and 38 (40.4%) had a negative experience. Common positive experience themes were: 1) supportive response from family, 2) participants researched fragile X extensively to be prepared to discuss with their family, and 3) family members who understood the importance of this information pursued genetic testing.
“I drew out diagrams to show them how it is passed to make it less confusing. My sisters are going to get tested when planning to have children. I had to do a lot of studying and also two sessions with a genetic counselor to make sure I understood it before trying to explain it to my family. It’s been an ongoing conversation. When I learn something new about it, or understand an aspect of it better, I open the conversation again. I also look up the answers to their questions.” (ID48)
Participants who had negative experiences cited: 1) their family members’ reactions of anger, denial, and disinterest; 2) the stress of sharing this information; and 3) the difficulty of explaining concepts. Some family members refused to have genetic testing. Three participants stated that when they reached out to family members to share information about the diagnosis, the family members already knew about FXS in the family and had not told the participant.
“I had one cousin who had already had two boys with FX and had chosen not to share the results. Had my cousin … shared the information at the time she found out, I could have gotten tested and had options before I got pregnant. It’s a sore spot for us.” (ID56)
Pre-test Results: Additional needs
Within the same open-ended comments section on the pre-test survey, 13 women (9%) expressed additional informational needs. Informational needs included: 1) wanting information about additional testing, such as the availability of a predictive test for FXTAS; 2) testing of personal FMRP levels; and 3) testing for allele stability (AGG interruption testing). Many participants expressed difficulties finding a physician who was knowledgeable about issues related to being a premutation carrier and expressed a desire for resources, including primary literature to educate their physicians. With respect to medical management, one participant wanted to know if symptoms, such as migraines, should be treated differently because she is a premutation carrier. Participants wanted to know the effects of a premutation on children, about resources to help children understand the impacts of being a premutation carrier, and resources to share more general fragile X-related information with children.
Post-test results: Increase in knowledge based on receipt of the informational booklet
Sixty-four women completed a post-survey about three months after receipt of the informational booklet and indicated that they read at least some of the booklet. Overall scores increased from a median of 24.0 on the pre-test to 28.0 on post-test out of a possible score of 37 (Table 3). All scores increased significantly with the intervention of the booklet. Linear regression analysis found the pre-test score was not associated with change in score from pre- to post-test. The section-test scores on FXTAS had the largest median increase after receipt of the informational booklet, increasing from 4.0 to 6.0 out of 8 possible points.
Table 3.
Changes in paired scores from pre- to post-test.
| Pre-Test Score n=64 | Post-Test Score n=64 | Wilcoxon Signed Ranks Test | |
|---|---|---|---|
| Median (Range) | Median (Range) | p-value | |
| Inheritance and Family Planning (18 points possible) | 14.5 (7–18) | 15.0 (5–18) | 0.042 |
| FXPOI (9 points possible) | 4.0 (0–7) | 5.25 (0–9) | 0.001 |
| FXTAS (8 points possible) | 4.0 (0–8) | 6.0 (0–8) | 0.008 |
| Overall Score (37 points possible) | 24.0 (11–34) | 28.0 (8–36) | 0.001 |
(Abbreviations: FXPOI = fragile X-associated primary ovarian insufficiency, FXTAS = fragile X-associated tremor/ataxia syndrome)
Notable improvements were made from pre- to post-test scores on questions that were identified as gaps in knowledge on the pre-test. These included the factors influencing repeat expansion, the critical age for FXPOI diagnosis, and the identification of hormone replacement therapy as a treatment for FXPOI. For example, the number of correct responses in the pre- compared with the post-test regarding the influence of parent’s gender when passing on a premutation increased from 46.9% to 57.8%. The number of correct responses regarding the influence of AGG interruptions on expansion increased from 45.3% to 53.1%. The number of correct responses regarding the influence of the premutation size on chance of expansion increased from 59.4% to 71.9%. In the FXPOI section, 24 participants on pre-test and 31 participants on post-test stated age 40 was the age before which FXPOI symptoms must occur to receive a diagnosis (37.5% to 48.4% correct). When asked about the treatment for FXPOI, 18 participants on pre-test and 31 participants on post-test correctly answered hormone replacement therapy (28.1% to 48.4% correct).
Satisfaction scores (on a scale of 0–100, higher being more satisfied) for FXPOI knowledge increased from 36.3 to 51.6 (p<0.001) and satisfaction with FXTAS knowledge increased from 43.8 to 51.3 (p=0.122).
Assessment and use of booklet:
Participants answered that the booklet was “very helpful” (44.6%), “somewhat helpful” (38.5%), or “neutral” (16.9%). No participant reported that the booklet was “somewhat unhelpful” or “very unhelpful”. Forty-eight of 69 participants (71.6%) stated that they learned new information from the booklet. Twenty-four participants (34.8%) reported using or sharing the booklet to explain concepts to family members or friends. Of those who had been to the doctor since receiving the booklet, 11 of 34 participants (32.4%) shared it with their doctors. When asked on which topics participants still wanted more information (participants were able to select more than one response), the most frequent responses were: FXTAS (40.0%), the inheritance of the mutation (30.8%), and FXPOI (26.2%). However, 33.8% indicated that the booklet contained all the information that they wanted.
Participants were asked to identify their top three preferred modes of receiving information about the fragile X premutation. The most preferred modes of receiving information were ranked by percent of participants choosing that mode as one of their top-three choices. The most popular modes were: written material (75%), short online videos (44%), e-book (38%), and presentations by experts in the field (38%).
Discussion
This booklet was the first thorough, printed resource developed specifically for women with a fragile X premutation. It was developed based on input from women who carry a premutation and was reviewed and revised by them and health professionals in the field of fragile X (Espinel, Charen, Huddleston, Visootsak, & Sherman, 2016). This approach to include the intended community in the development of the education material has been shown to be effective (e.g.,(Ali, Salway, Such, Dearden, & Willox, 2019)). The booklet addressed the identified barrier reported by women: “lack of targeted educational material” (Espinel, Charen, Huddleston, Visootsak, & Sherman, 2016). Our work presented here evaluates the usefulness of this booklet with respect to reducing the gap in knowledge about the health consequences of the premutation carried by women. Our study indicated that its use narrowed many of the identified gaps, as assessed by a pre-test survey completed prior to receiving the booklet. The increased knowledge scores obtained in the post-surveys corroborate the perceived helpfulness. Participants had a high level of understanding of the X-linked inheritance pattern. Since having a child with FXS is the often considered the largest impact of being a premutation carrier, it is logical that women would understand the chances of passing on the gene with the expanded CGG tract and the importance of cascade testing. However, one of the critical gaps in knowledge included what factors influence CGG repeat expansion. The complexity of these factors influencing repeat expansion beyond simple X-linked inheritance may hinder understanding; however, this concept is important for informed reproductive decision-making. Another important gap in knowledge included the lack of awareness of the diagnostic criteria for FXPOI and the need for hormone replacement therapy to treat FXPOI symptoms. Increased awareness, as a result of the booklet, will empower women to seek medical care for their symptoms. Additional printed materials with more specific information about each of these topics and different modes of distributing this information may continue to improve understanding.
The importance of health literacy, in general, has been shown by many studies (Bostock & Steptoe, 2012; Dewalt, Berkman, Sheridan, Lohr, & Pignone, 2004; Dewalt & Pignone, 2005; Rowlands & Protheroe, 2012). Low-health literacy leads to reduced access to health care services, poorer communication with health care professionals and poorer self-management of symptoms. Health literacy is critical for those with a genetic condition that increases the risk for unique health conditions. Moreover, many women with a premutation report that they encounter physicians who have little knowledge of the health consequences of a fragile X premutation (Espinel, Charen, Huddleston, Visootsak, & Sherman, 2016; Hipp, Charen, Spencer, Allen, & Sherman, 2016); thus, it is essential that carrier women themselves understand possible premutation-associated health symptoms in order to be more directive in seeking their care.
Study Limitations
Limitations of this study include the source of participants. First, our recruitment strategy that invited women who participated in our previous fragile X studies or those who were members of three Facebook groups associated with fragile X probably resulted in a sample of more informed women. For example, members of these groups most likely were exposed to information on premutation-associated health conditions and to women who have experienced them. Also, the relatively high socio-economic demographics of this study sample may have led to a more health literate group in general. Thus, we suspect that participants may not be representative of all premutation carriers, as they would be more informed about fragile X disorders compared with the general population of premutation carriers.
In addition, this booklet was understandable at a 6th to 7th grade reading level; thus it may have included language that was difficult for some participants comprehend. This may explain why women with a Bachelor’s degree or higher scored better and may have limited increases in post-test scores. Premutation-associated traits reported by some carriers, such as anxiety, depression, and ADHD (Coffey et al., 2008; Hunter et al., 2008), may also limit the ability to read higher-level materials. Other studies that assessed education materials for genetic conditions (e.g., prenatal screening for Down syndrome (Smith et al., 2018) or neurofibromatosis disorders (Merker et al., 2018)) noted a strong association with health knowledge and gain in health knowledge after an intervention with education level. Thus, more work should be done with a more heterogeneous group of women, with respect to education level, health literacy level and culture/ethnicity, to determine whether the information in our booklet is accessible to all.
Research Recommendations
Future research regarding health knowledge may use other modes of disseminating health information related to the premutation. Some participants indicated that their preferred modes would be e-book and short online videos. These modes of education were also found to be preferable by clients for other health topics (e.g., (Hernan et al., 2019; Zhao et al., 2019). However, the effectiveness of each medium needs to be tested. For example, a short video that explained exome sequencing for clinical testing shown prior to talking with a genetic counselor was not found to be beneficial (Hernan et al., 2019); thus, the effectiveness of each mode of communication must be tested prior to implementation.
Due to the reported lack of physicians’ knowledge regarding premutation-related health issues, developing educational materials for physicians may be another important area for research, along with improved education materials for the women themselves. Future research topics requested by participants included: information about the late stages of FXTAS, predictive tests for FXTAS, and the effects of carrying a fragile X premutation on children. In addition, as research findings about the fragile X premutation become established, the healthcare community must find effective and accessible means of distributing this new information, thus bringing translational research findings to premutation carriers.
Practice Implications
Providing premutation carriers with quality informational materials will empower them to seek out and receive better healthcare, as has been shown for improved health literacy in general (Dewalt, Berkman, Sheridan, Lohr, & Pignone, 2004; Rowlands & Protheroe, 2012). With fragile X-associated health knowledge, women will feel more confident and empowered when speaking with their healthcare providers, who may not be experts on this topic; allow for more informed reproductive decision-making; and may increase the rate of seeking medical care in response to symptoms associated with the fragile X premutation, such as early menopausal symptoms, anxiety or depression.
Our study may also help healthcare providers better understand the informational needs of women with a fragile X premutation, enabling them to provide better care to their patients. Women who are newly diagnosed with a fragile X premutation can receive anticipatory guidance from the genetic counselor, in combination with this written informational material, to help reduce the negative experiences reported by some participants in communicating with relatives about fragile X-associated topics or with healthcare providers who have incorrect or out dated information.
Supplementary Material
Online Resource 1A: Pre-test survey
Online Resource 1B: Post-test survey
Online Resource 2: Scoring guide
Online Resource 3: Reported “other health/well-being conditions” related to a fragile X premutation
Online Resource 4: “Women’s Health and the Fragile X Premutation” booklet
Acknowledgements
This project was supported by the Fragile X Association of Georgia, and the award (NS091859) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Neurological Disorders and Stroke (NINDS). We also want to thank the women who participated in this study for their invaluable contribution.
Study data were collected and managed using REDCap (Research Electronic Data Capture) electronic data capture tools hosted at Emory University.
Footnotes
Human Studies and Informed Consent: All procedures and protocols were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and the Helsinki Declaration of 1975, as revised in 2000. The Emory School of Medicine’s Institutional Review Board (IRB) reviewed and approved this project.
Animal Studies: No animal studies were carried out by the authors for this research.
Conflict of Interest: All authors declare that they have no conflicts of interest.
References
- Ali PA, Salway S, Such E, Dearden A, & Willox M (2019). Enhancing health literacy through co-design: development of culturally appropriate materials on genetic risk and customary consanguineous marriage. Primary Health Care Research & Development, 20, e2. doi: 10.1017/S1463423618000038 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bostock S, & Steptoe A (2012). Association between low functional health literacy and mortality in older adults: longitudinal cohort study. The BMJ, 344, e1602. doi: 10.1136/bmj.e1602 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Coffey SM, Cook K, Tartaglia N, Tassone F, Nguyen DV, Pan R, et al. (2008). Expanded clinical phenotype of women with the FMR1 premutation. American Journal of Medical Genetics Part A, 146(8), 1009–1016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dewalt DA, Berkman ND, Sheridan S, Lohr KN, & Pignone MP (2004). Literacy and health outcomes: a systematic review of the literature. Journal of General Internal Medicine, 19(12), 1228–1239. doi: 10.1111/j.1525-1497.2004.40153.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- Dewalt DA, & Pignone MP (2005). The role of literacy in health and health care. American Family Physician, 72(3), 387–388. [PubMed] [Google Scholar]
- Espinel W, Charen K, Huddleston L, Visootsak J, & Sherman S (2016). Improving Health Education for Women Who Carry an FMR1 Premutation. Journal of Genetic Counseling, 25(2), 228–238. doi: 10.1007/s10897-015-9862-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hagerman PJ, & Hagerman RJ (2015). Fragile X-associated tremor/ataxia syndrome. Annals of the New York Academy of Sciences, 1338, 58–70. doi: 10.1111/nyas.12693 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hagerman RJ, Protic D, Rajaratnam A, Salcedo-Arellano MJ, Aydin EY, & Schneider A (2018). Fragile X-Associated Neuropsychiatric Disorders (FXAND). Frontiers in Psychiatry, 9, 564. doi: 10.3389/fpsyt.2018.00564 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hernan R, Cho MT, Wilson AL, Ahimaz P, Au C, Berger SM, et al. (2019). Impact of patient education videos on genetic counseling outcomes after exome sequencing. Patient Education and Counseling. doi: 10.1016/j.pec.2019.08.018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hipp HS, Charen KH, Spencer JB, Allen EG, & Sherman SL (2016). Reproductive and gynecologic care of women with fragile X primary ovarian insufficiency (FXPOI). Menopause, 23(9), 993–999. doi: 10.1097/GME.0000000000000658 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hunter J, Rivero-Arias O, Angelov A, Kim E, Fotheringham I, & Leal J (2014). Epidemiology of fragile X syndrome: a systematic review and meta-analysis. American Journal of Medical Genetics Part A, 164A(7), 1648–1658. doi: 10.1002/ajmg.a.36511 [DOI] [PubMed] [Google Scholar]
- Hunter JE, Allen EG, Abramowitz A, Rusin M, Leslie M, Novak G, et al. (2008). Investigation of phenotypes associated with mood and anxiety among male and female fragile X premutation carriers. Behavioral Genetics, 38(5), 493–502. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hunter JE, Epstein MP, Tinker SW, Abramowitz A, & Sherman SL (2012). The FMR1 premutation and attention-deficit hyperactivity disorder (ADHD): evidence for a complex inheritance. Behavioral Genetics, 42(3), 415–422. doi: 10.1007/s10519-011-9520-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hunter JE, Leslie M, Novak G, Hamilton D, Shubeck L, Charen K, et al. (2012). Depression and anxiety symptoms among women who carry the FMR1 premutation: impact of raising a child with fragile X syndrome is moderated by CRHR1 polymorphisms. American Journal of Medical Genetics Part B, Neuropsychiatric Genetics, 159B(5), 549–559. doi: 10.1002/ajmg.b.32061 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kenna HA, Tartter M, Hall SS, Lightbody AA, Nguyen Q, de los Angeles CP, et al. (2013). High rates of comorbid depressive and anxiety disorders among women with premutation of the FMR1 gene. A American Journal of Medical Genetics Part B, Neuropsychiatric Genetics, 162B(8), 872–878. doi: 10.1002/ajmg.b.32196 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Merker VL, McDannold S, Riklin E, Talaei-Khoei M, Sheridan MR, Jordan JT, et al. (2018). Health literacy assessment in adults with neurofibromatosis: electronic and short-form measurement using FCCHL and Health LiTT. Journal of Neuro-Oncology, 136(2), 335–342. doi: 10.1007/s11060-017-2657-8 [DOI] [PubMed] [Google Scholar]
- Nolin SL, Glicksman A, Ersalesi N, Dobkin C, Brown WT, Cao R, et al. (2015). Fragile X full mutation expansions are inhibited by one or more AGG interruptions in premutation carriers. Genetics in Medicine, 17(5), 358–364. doi: 10.1038/gim.2014.106 [DOI] [PubMed] [Google Scholar]
- Rodriguez-Revenga L, Madrigal I, Pagonabarraga J, Xuncla M, Badenas C, Kulisevsky J, et al. (2009). Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. European Journal of Human Genetics, 17(10), 1359–62. doi: 10.1038/ejhg.2009.51 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rowlands G, & Protheroe J (2012). SAPC Hot Topic: the importance of ‘health literacy’ in primary care. Primary Health Care Research & Development, 13(2), 186–188. doi: 10.1017/S1463423612000126 [DOI] [PubMed] [Google Scholar]
- Schwartz CE, Dean J, Howard-Peebles PN, Bugge M, Mikkelsen M, Tommerup N, et al. (1994). Obstetrical and gynecological complications in fragile X carriers: a multicenter study. American Journal of Medical Genetics, 51(4), 400–402. [DOI] [PubMed] [Google Scholar]
- Sherman SL (2000). Premature ovarian failure among fragile X premutation carriers: parent-of-origin effect? [comment] [editorial]. American Journal Human Genetic, 67(1), 11–13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Smith SK, Cai A, Wong M, Sousa MS, Peate M, Welsh A, et al. (2018). Improving women’s knowledge about prenatal screening in the era of non-invasive prenatal testing for Down syndrome - development and acceptability of a low literacy decision aid. BMC Pregnancy Childbirth, 18(1), 499. doi: 10.1186/s12884-018-2135-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wheeler AC, Bailey DB Jr., Berry-Kravis E, Greenberg J, Losh M, Mailick M, et al. (2014). Associated features in females with an FMR1 premutation. Journal of Neurodevelopmental Disorders, 6(1), 30. doi: 10.1186/1866-1955-6-30 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wittenberger MD, Hagerman RJ, Sherman SL, McConkie-Rosell A, Welt CK, Rebar RW, et al. (2007). The FMR1 premutation and reproduction. Fertility and Sterility, 87(3), 456–465. [DOI] [PubMed] [Google Scholar]
- Zhao S, Chen WJ, Dhar SU, Eble TN, Kwok OM, & Chen LS (2019). Needs assessment in genetic testing education: A survey of parents of children with autism spectrum disorder in the united states. Autism Research, 12(8), 1162–1170. doi: 10.1002/aur.2152 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Online Resource 1A: Pre-test survey
Online Resource 1B: Post-test survey
Online Resource 2: Scoring guide
Online Resource 3: Reported “other health/well-being conditions” related to a fragile X premutation
Online Resource 4: “Women’s Health and the Fragile X Premutation” booklet