public health literature review of fragile x syndrome

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Abstract review and refinement, developmental profile, social-emotional profile, medical profile, treatments and interventions, impact on the family, gaps in the research literature, implications for pediatricians, acknowledgments, public health literature review of fragile x syndrome.

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: Dr Raspa received funds from the John Merck Fund for travel to a meeting co-sponsored with the Centers for Disease Control and Prevention; the other authors have indicated they have no financial relationships relevant to this article to disclose

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Melissa Raspa , Anne C. Wheeler , Catharine Riley; Public Health Literature Review of Fragile X Syndrome. Pediatrics June 2017; 139 (Supplement_3): S153–S171. 10.1542/peds.2016-1159C

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The purpose of this systematic literature review is to describe what is known about fragile X syndrome (FXS) and to identify research gaps. The results can be used to help inform future public health research and provide pediatricians with up-to-date information about the implications of the condition for individuals and their families.

An electronic literature search was conducted, guided by a variety of key words. The search focused on 4 areas of both clinical and public health importance: (1) the full mutation phenotype, (2) developmental trajectories across the life span, (3) available interventions and treatments, and (4) impact on the family. A total of 661 articles were examined and 203 were included in the review.

The information is presented in the following categories: developmental profile (cognition, language, functional skills, and transition to adulthood), social-emotional profile (cooccurring psychiatric conditions and behavior problems), medical profile (physical features, seizures, sleep, health problems, and physiologic features), treatment and interventions (educational/behavioral, allied health services, and pharmacologic), and impact on the family (family environment and financial impact). Research gaps also are presented.

The identification and treatment of FXS remains an important public health and clinical concern. The information presented in this article provides a more robust understanding of FXS and the impact of this complex condition for pediatricians. Despite a wealth of information about the condition, much work remains to fully support affected individuals and their families.

Fragile X syndrome (FXS) is the most common single-gene cause of inherited intellectual disability. FXS is caused by an expanded trinucleotide repeat (CGG) on the 5′ untranslated region of the fragile x mental retardation 1 ( FMR1 ) gene. A normal range is between 6 and 44 repeats. Individuals with 45 to 54 repeats are considered to have a gray zone or intermediate expansion. Those with 55 to 200 repeats have the premutation, which is likely to become unstable in future generations. Affected individuals with the full mutation FXS have >200 repeats. In the full mutation, methylation occurs during gestation, silencing FMR1 transcription. 1 This silencing leads to a reduction or absence of fragile X mental retardation protein (FMRP), which is needed for normal brain development. In a small number of males with the full mutation, there are no methylation patterns observed, resulting in residual levels of FMRP, which results in less impaired functioning. In females, FMRP levels are related to the X activation ratio and the amount of FMRP produced. 2 FXS results in cognitive and adaptive limitations that impact everyday function. Given that FXS is inherited, there are numerous implications for families, ranging from carrier issues and testing to family adaptation to the condition.

Policy documents by the American Academy of Pediatrics (AAP) suggest ways to identify and treat individuals with FXS. The Committee on Genetics published a clinical report on the comprehensive genetic evaluation of children with general development delays or intellectual disabilities. 3 The report recommends FXS testing as a first-line test for all boys and girls with general developmental delay or intellectual disability of unknown origin. The AAP also provides clinical guidelines on health supervision of children with FXS, 4 including information on genetic testing, recommended examinations for well-care visits, and anticipatory guidance. However, these guidelines do not provide for treatment of FXS, including the use of medications.

The purpose of this review is to describe the state of the science on FXS and research gaps to help pediatricians support patients with FXS and their families.

Four overarching themes of both public health and clinical importance in FXS guided the systematic literature review: (1) epidemiology, (2) impact, (3) health care delivery, and (4) genetics. Of the topics included under these overarching areas, we focused the search on 4 topic areas for this manuscript: (1) the full mutation phenotype, (2) developmental trajectories across the life span, (3) available interventions and treatments, and (4) the impact on the family. Given that there are other reviews of the FXS phenotype, we focused on literature published in the past 6 years, but also included seminal articles outside the search dates. The other areas had more inclusive search dates. Table 1 details the search terms and inclusion/exclusion criteria for all 4 areas.

Search Terms and Inclusion/Exclusion Criteria by Topic Area

An electronic literature search was conducted by using search terms in PubMed, CINAHL, and Embase. All iterations of the search terms were combined within each topic area. For example, the interventions and treatment topic search combined either “fragile X syndrome,” or “fragile X,” with any 1 of the following: “treatment,” “intervention,” “pharmacological,” “educational,” behavioral,” “medication,” or “clinical trial.” A total of 878 unique citations matched the search criteria ( Fig 1 ). We reviewed titles and abstracts to determine studies appropriate for inclusion. We excluded articles that either did not meet the inclusion criteria ( Table 1 ), had a focus on basic rather than social science, or were not research studies (eg, letters to the editor). These exclusions resulted in a total of 661 articles that were reviewed. Of these, 20 were excluded because the content focused exclusively on the fragile X premutation. In sum, 203 are summarized in this review. The information from the first 2 areas of focus are presented below by profile type: (1) developmental profile, (2) social-emotional profile, and (3) medical profile. The last 2 are summarized in the Treatments and Interventions section and the Impact on the Family section.

FIGURE 1. Articles included in the public health literature review. (Adapted from Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med. 6(7):e1000097.)

Articles included in the public health literature review. (Adapted from Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group. Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med . 6(7):e1000097.)

The results are organized into 5 sections. The Developmental Profile section provides an overview of research on cognitive and academic skills, language ability, functional skills, and the transition to adulthood. The Social-Emotional Profile section details the behavioral phenotype of FXS, including cooccurring conditions and other behavioral problems. The Medical Profile section describes the literature on physical features associated with FXS, seizures, sleep issues, other health issues, and physiologic characteristics. The Treatments and Interventions section summarizes research on behavioral and educational interventions, allied health services, and pharmacologic treatments. Finally, the Impact on the Family section includes research on family adaptation, such as impacts on the family environment and the financial impact of FXS.

Cognitive Development and Academic Skills

The neurocognitive profile of individuals with FXS is well described, including several recent reviews. 5 , – 11 Boys typically have moderate to severe intellectual disability, with average IQ scores <55. Other areas of weakness include short-term and working memory, spatial memory, auditory and sequential processing, abstract thinking, executive function, and mathematical thinking. 5 , – 11 Areas of strength for boys include receptive vocabulary, visual memory, simultaneous processing, experiential learning, and imitation. 5 , – 11 This profile of cognitive challenges persists across groups of high-, mid-, and low-functioning individuals. 12

Boys exhibit a unique cognitive profile compared with other types of intellectual or developmental disabilities or with typically developing peers. When compared with individuals with Down syndrome, boys with FXS have greater impairments in object discrimination learning, but better performance on object recognition memory and egocentric spatial learning tasks. 13 They also have significant deficits in all areas of executive function (ie, inhibition, working memory, cognitive flexibility, and planning) compared with typically developing peers. 14 , 15 Boys with FXS show relatively stable deficits across most developmental domains, whereas boys with autism show more varying ability levels. 16

Girls with FXS may demonstrate similar patterns of strengths and weaknesses to boys, but are often less severely affected. 17 Girls have a higher rate of learning disability in mathematics than grade-matched comparisons. 18 Mathematical tasks requiring a conceptual understanding of numbers or amounts are most challenging for girls, 19 which may be related to delays in spatial location skills. 20

Several longitudinal studies have demonstrated that IQ scores are lower in adolescents and adults with FXS when compared with younger children with FXS. 21 , – 26 Children make steady cognitive growth through early adolescence, at which point mental age plateaus and IQ declines. 27 Older children with FXS have a developmental growth rate 2.2 times slower than their non-FXS siblings. 27 A pattern of cognitive decline holds even when assessed by using nonverbal measures. 28 , 29 The increasing gap in IQ scores from typical development may be due to the nature of standardized tests (ie, increased importance of symbolic language in adolescence) as opposed to the loss of skills. 30 However, studies examining these variable rates in cognitive decline 30 , 31 have suggested that methylation level, delayed frontal lobe maturation, level of FMRP production, comorbid autistic behaviors, and maternal education may be contributing factors. 28 , 29 , 32 , 33

More recently, other longitudinal studies starting as young as infancy have explored the earliest age of onset of decline. Roberts et al 34 found delays beginning as early as 9 months of age. The rate of development did not change dramatically over time; however, autistic behavior was strongly related to development. Two other studies 35 , 36 found global delays in boys, with the rate of development being approximately half that of typically developing peers. Across these studies communication and cognition were the most affected domains of functioning.

Language Development

Many areas of language development appear to be affected in FXS, and therefore this area has been studied extensively; recent reviews provide a summary of research findings to date. 37 , – 39

Prelinguistic

Young children with FXS often have delays in attaining early language milestones 40 , 41 as well as delays in nonverbal communication (ie gestures and reciprocal/symbolic behavior). 42 Children with more autistic behaviors have a negative pattern of development; initial gesture use may be negatively associated with later rates of words used. 43

Studies of receptive language have shown mixed results. Some have found receptive vocabulary in boys with FXS to be below that of typically developing peers, even after controlling for nonverbal cognitive ability. 44 , 45 However, other studies report vocabulary skills on par with mental age–matched peers. 46 , 47 Receptive language ability does appear to improve over time. 48

Recent work has compared receptive language in individuals with FXS with other groups who have an intellectual or developmental disability. Receptive language is similar between individuals with FXS and those with autism. 49 In another set of studies, girls, but not boys, with FXS had higher receptive syntax scores than those with Down syndrome. 50 , 51 Girls with FXS also have been shown to have higher scores on receptive vocabulary than on nonverbal IQ, indicating a relative strength in this area. 52

Individuals with FXS outperform individuals with Down syndrome or autism on global measures of expressive language 53 and in general are more talkative and more intelligible. 54 When compared with mental age (MA)-matched peers, individuals with FXS often have equivalent overall expressive language skills 53 and numbers of communication units. 55 A relative strength in phonological memory may be associated with higher expressive language scores. 56

Zajac et al 57 , 58 examined articulation in young boys with FXS compared with typically developing peers. In the first study, boys with FXS did not differ from MA-matched peers with regard to articulation rate. However, boys with comorbid FXS and autism had faster rates than the chronologically matched peers. Another study found that those with FXS, regardless of autism status, performed better than those with Down syndrome and did not differ from typically developing peers on phonological accuracy. 59 On a measure of intelligibility, those with FXS had a lower percentage of words that were understood when compared with MA-matched peers but did not differ from those with Down syndrome.

Syntax also appears to be a challenge for individuals with FXS. Boys with FXS have shorter, less complex utterances than MA-matched peers. 53 , 57 , 60 No differences existed between boys with and without a codiagnosis of autism, but those with FXS did perform better than individuals with Down syndrome. 60 , 61 Sterling et al 62 found that boys with lower receptive vocabulary scores were more likely to make grammatical tense errors (eg, “She walk home.”) than those with higher receptive vocabulary scores. Nonverbal cognition and phonological working memory are other key factors that play a role in syntactic ability. 63

Pragmatic development, or the ability to use language in social interactions, is an area of deficit in FXS for both boys and girls. Individuals with FXS engage in fewer conversational turns and ask fewer clarifying questions to continue the conversational topic than typically developing peers. 64 , 65 Boys with both FXS and autism also appear to struggle with pragmatics. 61 When narrative language is examined, however, individuals with FXS perform similarly or better than MA-matched peers, suggesting an area of strength. 66 , 67 Early and sustained levels of maternal responsivity, an interaction style characterized by warmth and sensitivity, appears to play a role in many language outcomes. 68 , 69

Functional Skills

Studies on functional skills and adaptive behavior in FXS have been limited. Using a large sample of parents of individuals with FXS, Bailey et al 70 reported on skill attainment in 7 areas: eating, dressing, toileting, bathing/hygiene, communication, articulation, and reading. Most adult males and females were verbal and independently used the toilet, bathed, dressed themselves, and ate. However, skills, such as using complex sentences, reading, or speaking at a typical rate, were weaknesses. Hatton et al 71 showed steady improvements in adaptive behavior over time for children up to age 12 years. Those with fewer autistic behaviors and higher levels of FMRP showed more improvements over time. In adolescents and adults, delays in communication, socialization, and daily living skills for both males and females have been documented. 72 , – 74 Individuals codiagnosed with autism exhibit the biggest declines in adaptive scores over time. 75 , – 77

Transition to Adulthood

The majority of research on FXS to date has focused on children and adolescents, and therefore information about adults with FXS is limited. A large national survey showed that the majority of adult males (70%) lived with their parents, and even 50% of adult females still lived at home. 78 Many females were working full time (48%) compared with only 20% of males. More males (57%) than females (19%) needed moderate to considerable assistance with everyday life. The strongest predictor of independence was functional skill level (males) and the ability to interact appropriately (females). Adolescents and young adults with more autism symptoms had lower independent living skills, especially managing money, health and safety, and problem solving, relative to typically developing peers even after controlling for IQ. 79

Cooccurring Psychiatric Diagnoses

Research on conditions that cooccur with FXS has focused primarily on attention, anxiety, autism, and other behavioral problems. These are now well-described features of the FXS phenotype that have broad implications for treatment and family adaptation.

In a large national survey of parents, 84% of males and 67% of females with the full mutation had attention problems. 80 When compared with boys with Down syndrome and typically developing peers, boys with FXS had more difficulty with attention, impulsivity and inhibition control. 81 , 82 A detailed exploration of these difficulties using a touch screen search task revealed several differences between boys with FXS and typically developing peers. Although there were no differences in overall search speed, boys with FXS made more errors. 83 Boys with FXS also show overall lower levels of attention, especially auditory attention, when compared with a MA-matched peers. Using a multimodal approach of visual and auditory stimuli did not improve performance. 84 Boys with FXS show slight declines over time in sustained attention and larger declines in response inhibition when compared with their MA-matched peers on both visual and auditory continuous performance tests. 85 Auditory attention was associated with later IQ. 86

Recent work has studied underlying physiologic attention processes in very young children with FXS. Infants and toddlers display lower heart rate variability and shallower heart rate decelerations during attentional tasks when compared with typically developing peers. 87 This finding suggests a hampered capacity to regulate arousal levels and thus attentional behavior. 87 Visual attention was associated with the severity of autistic behaviors. 87

Anxiety is a pervasive concern among providers, caregivers, and individuals living with FXS. 88 , – 90 Early work found high rates of anxiety in girls with FXS compared with typically developing peers and those with other developmental disabilities. 91 , – 93 In a national survey, 70% of boys and 56% of girls were reported to have been treated or diagnosed with anxiety. 80 Other studies have found similarly high rates. 89 , 94 A recent study described an association between negative affect, a temperament construct, and later anxiety in preschool boys with FXS providing an early diagnostic method. 95 A study of brain activity in the prefrontal regions found that social anxiety in FXS may be related to challenges in higher-level social cognition. 96 These findings may also explain other phenotypic traits associated with anxiety in FXS, such as poor eye contact, gaze aversion, excessive shyness, hand flapping, self-injurious behaviors, aggression, and autistic symptoms. 10 , 88 , 97

FXS is the most common known inherited single-gene condition associated with autism. 98 Individuals with FXS can exhibit several behaviors commonly associated with autism, including difficulties with social communication, self-injurious behavior, perseverative or restricted behavior, motor stereotypies, poor eye contact, and odd or delayed speech. 99 , 100 Depending on the presentation of symptoms, individuals with FXS can be codiagnosed with autism spectrum disorder (ASD). Reports of comorbidity of ASD diagnoses range from 15% to 52%. 80 , 101 Additionally, an estimated 90% of boys with FXS exhibit at least 1 autistic behavior. 102

A series of studies suggests that children with FXS without ASD share similar profiles with children diagnosed with developmental delay, whereas children with FXS and comorbid ASD (FXS+ASD) are more similar to children with idiopathic autism. 100 , 103 , 104 Children with FXS+ASD exhibit poorer developmental outcomes, including late-onset language milestones, weaker communication and social skills, lower adaptive behavior scores, greater behavior problems, and greater cognitive impairment than boys with FXS only or those with idiopathic autism. 16 , 41 , 105 In addition, individuals with FXS only have profiles of higher receptive than expressive language, whereas those with FXS+ASD do not exhibit this strength. 106 , 107

Social impairments may be the most significant predictor differentiating individuals with FXS+ASD from individuals with FXS only. 102 Specifically, social withdrawal (eg, avoidance and indifference) and adaptive socialization behaviors (eg, recognizing emotions or appropriate social interactions) are often independent predictors of ASD in individuals with FXS. 105 , 108 , – 110 In cross-sectional 105 and longitudinal studies, 101 impaired socialization was the greatest contributor to ASD diagnosis and severity in the FXS population, more so than communication or cognition. 110 Per parent report, however, repetitive and stereotyped behaviors were the strongest predictors of ASD in FXS. 102 Boys with FXS+ASD exhibited significantly less ritualistic and compulsive behavior, but increased repetitive motor behaviors compared with boys with idiopathic autism. 111

Few studies have examined the severity of ASD symptoms in individuals with FXS over time, and conflicting evidence exists. Two longitudinal studies showed that behavioral profiles did not change significantly over time, with lower levels of FMRP correlated with more ASD symptoms. 99 , 112 However, these studies did not use gold standard ASD measures, which is the use of Diagnostic and Statistical Manual of Mental Disorders criteria by an experienced clinician, using the Autism Diagnostic Observation Schedule with or without the Autism Diagnostic Interview-Revised. More recently, the Autism Diagnostic Interview-Revised was used to examine current versus lifetime behaviors, with current scores subtracted from lifetime scores to gauge age-related improvement. By using this method, autism symptoms improved with age, with the least improvement in the Restricted Interests and Repetitive Behaviors domain. 113 In this and 1 other study 114 once IQ was controlled for, levels of FMRP were not related to ASD.

Physical Features

Boys often present with long, narrow faces; high-arched palates; prominent ears; macroorchidism (during and after puberty); hypermobility of joints; hypotonia; and flat feet. 129 , – 131 Other conditions that are found at increased rates include cleft palates and orthopedic abnormalities, such as scoliosis or severe flat feet. 5 Adults with FXS have a shorter average height than that of the general population. 132 Girls with FXS have similar physical features to boys with FXS although at lower rates. 133

The incidence of epilepsy is between 10% and 20% for boys with FXS, with lower percentages for girls. 134 A national survey of parents found that 14% of boys and 6% of girls had experienced at least 1 seizure, 135 similar to earlier reports. 136 , 137 The first seizure commonly occurs between 4 and 10 years of age, and the seizures are typically focal or localized. 135 Most seizures occur while awake, but approximately one-third of individuals with FXS have seizures when sleeping. 135 A key factor associated with the occurrence of seizures is whether the individual is codiagnosed with autism. 135 , 138

Over time, providers and caregivers anecdotally reported sleep problems in the FXS population, prompting several studies to explore sleep problems in FXS. 139 , – 141 In a national survey, 32% of individuals with FXS were reported by the caregiver to experience sleep difficulties, with 85% having at least 2 problems (eg, trouble falling asleep and frequent night awakenings). Of those with problems, 47% of boys and 40% of girls were taking at least 1 medication to help with sleep. A study of sleep architecture in FXS revealed less time in bed and less time in REM sleep. 141

Physiologic Features

Studies of brain structure using MRI have shown several enlarged regions in the brains of individuals with FXS compared with typically developing controls, including the hippocampus, amygdala, caudate nucleus, and thalamus. 119 These regions are critical in regulating cognitive and behavioral functions, such as memory and learning, information and sensory processing, and social and emotional behavior, all of which are known to be impaired in individuals with FXS. However, the cerebellar vermis and the superior temporal gyrus are smaller than those in typically developing controls. 119 MRIs of young boys with FXS show increased caudate volume when compared with typically developing peers. 146 Amygdala volume in those with FXS, although larger than controls, was not as enlarged as in individuals with ASD. 146 However, other studies have shown no differences in amygdala volume between individuals with FXS and typically developing peers. 147 Functional MRIs, which predominantly have been conducted on girls, have shown different neural activity, which may help to explain the cognitive delays in the FXS population. 119 , 148

In a review of neuroendocrinology studies, 119 individuals with FXS were reported to have impaired hypothalamic functioning due to decreased levels or absence of FMRP. These studies may help explain the abnormal stress responses, sleep abnormalities, and physical growth patterns commonly seen in affected individuals. Other work has examined the relationship between an individual’s genetic expression, brain structure, and behavior. 149 , 150

Other physiologic features have also been reported. Roberts et al 151 found that the blink rate in boys with FXS was much higher than typically developing peers during passive tasks. The blink rate was correlated with problem behaviors and physiologic arousal, indicating possible underlying pathophysiological differences in dopamine functioning in individuals with FXS. 151 Studies of heart rate activity and its relationship with sensory processing have shown that boys with FXS have increased cardiac reactivity to auditory stimulus compared with typically developing peers. 152 Studies of prepulse inhibition have shown significant deficits in individuals with FXS. 153 , 154 Miller et al 155 demonstrated enhanced electrodermal reactivity to sensory stimuli in those with FXS, and this reactivity correlated inversely with the level of FMRP. Taken together, these results suggest that individuals with FXS have atypical physiologic characteristics when compared with typically developing peers and that these differences may be related to the behavioral profile of FXS.

Behavioral Interventions

Anecdotal reports suggest that reducing anxiety or sensory issues may reduce challenging behaviors in some children with FXS. 156 Several case studies suggest the use of behavioral principles, such as positive reinforcenement. 157 , 158 Behavioral interventions can be effective for children with FXS through the development of individualized multicomponent intervention plans implemented by parents and supported by professionals. 126 Although these studies differ in approach, they suggest that behavioral techniques can be useful for reducing challenging behaviors in children with FXS.

Cognitive/Educational Interventions

Few studies have examined cognitive or educational interventions for individuals with FXS. One interview study of professionals working with young children with FXS 159 reported that learning strategies that incorporate visually based, experiential or holistic learning were most successful. A recent case study 160 found a combination of early pharmacologic treatment combined with intensive educational interventions resulted in improved behavior and normal IQ in 2 young children with FXS. The intensive interventions included cognitive and memory games, visualized math tasks, and supplemental occupational therapy, speech-language therapy, and social skills training.

The use of a self-paced computer program (Discrete Trial Trainer [DTT]) to assess learning of basic math and geography skills by using a match-to-sample teaching procedure has been tested as a possible intervention technique. 161 , – 164 Results showed that basic mathematical relations could be taught and were comparable with those of the control group; however, improved outcomes were not maintained, and more complex concepts (eg, equality and congruence concepts) were not learned at a rate similar to that of the control group. Additional studies using the DTT software suggest that it may be a promising approach for outcome measurement. 164 , 165

These studies of DTT exemplify a shift toward technological mechanisms for assessing and treating cognitive and learning impairments. Another example is the use of the Cogmed program, which can improve working memory and is being tested with individuals with FXS. 166 These computerized tools have the advantage of providing increased independent learning, are generally highly motivating, and reduce social pressure, which may affect learning in children whose anxiety is increased with social interactions. In addition, computerized protocols may be useful for research design with this population; they theoretically could be implemented anywhere at any time, thereby reducing geographical challenges.

Allied Health Services

Given the high rates of intellectual disability and comorbidities, such as autism, anxiety, and attention-deficit/hyperactivity disorder (ADHD), individuals with FXS have significant needs for specialized therapies and services, including speech-language, occupational, and physical therapies; special education services; and behavior management. In addition, individuals with FXS frequently require specialized medical care, such as consultations with developmental-behavioral pediatricians or neurologists.

Despite the clear need for services for individuals with FXS, the intensity and use of health or therapeutic services has not been well described. Three papers reporting on early intervention services 40 , 99 , 159 all suggest that children with FXS <3 years of age commonly use speech-language, occupational, and physical therapy services. More recently, allied health service use was reported based on findings from a large survey. 160 The use of, intensity of, and parent satisfaction with speech-language, occupational, and physical therapies, as well as behavior management therapy, were examined across sex and age groups. Almost all males and half of females were receiving at least 1 of these therapies at the time of the survey. Clear declines in service use occurred across age groups, with those no longer in school (>20 years of age) receiving few services. Parents were generally satisfied with the amount and quality of services received.

One study examined parent reports of medical services and procedures that their child with FXS received during the previous year. 167 This study found that most boys and girls had at least 1 visit with their primary care physician, with an average of 2.5 visits for boys and 2.1 visits for girls in the year. Although there were few emergency department visits or inpatient care, almost all individuals with FXS required some medical specialist care (97% of boys, 95% of girls). The most common specialists seen were ophthalmologists, psychiatrists, developmental-behavioral pediatricians, and neurologists. The majority of both boys and girls were taking at least 1 prescription medication for FXS-related problem.

Pharmacologic Treatments

Pharmacotherapy is frequently used as a primary intervention to target specific symptoms for individuals with FXS. Guidelines for the suggested treatment of neuropsychiatric symptoms of FXS have been published suggesting that stimulants or selective serotonin reuptake inhibitors (SSRIs) typically work to decrease hyperactivity, cognitive deficits, and psychiatric symptoms. 115 , 168 A recent article reviews the treatment strategies found to be most effective for specific symptoms. 169

Anxiety Symptoms

SSRIs are the most common first-line treatment of anxiety in FXS, which is the most common reason parents seek medication treatment. 167 Case reports and survey studies suggest SSRIs are effective ∼50% of the time at reducing anxiety in FXS. 170 , – 172 No controlled studies on the efficacy of SSRIs for reducing anxiety in FXS have been conducted. In addition, side effects, including weight loss or gain, and behavioral activation for those on SSRIs, specifically fluoxetine, have been reported. 115 , 172

Attention-Deficit/Hyperactivity Disorder Symptoms

Impulsivity and hyperactivity are 2 common challenges for individuals with FXS, and stimulant medications are the most common type of medication prescribed to individuals with FXS. 173 However, only 1 controlled trial conducted years ago has been carried out demonstrating efficacy. 133 In addition, stimulant use for children <5 years old can often cause irritability and, according to the AAP, is not the recommended treatment for children ≤5 years of age. 115 , 174 Typical doses have been found to be effective at reducing impulsivity and hyperactivity and increasing attention in a controlled trial of boys with FXS. 175 Second-line treatments, recommended for those who do not respond to stimulants, include α-adrenergic receptor agonists (eg, clonidine and guanfacine). 115 Although surveys and case studies suggest clonidine can be effective 171 , 176 and clinical experience suggests guanfacine 115 can be helpful, no controlled trials have examined the efficacy of these medications for ADHD symptoms in FXS specifically. Two controlled studies of L-acetyl-carnitine 177 , 178 suggest some reduction of ADHD symptoms in FXS compared with placebo. More recently, valproic acid, the antiepileptic drug, was found to reduce ADHD symptoms in an open-label trial. 179

Aggression and Mood Symptoms

Aggression and irritability are behaviors of great concern to parents of individuals with FXS and are often the primary outcome of clinical trials. 169 Antipsychotic medications have been the first-line treatment of these behaviors and are effective at reducing irritability, aggression, mood instability, and perseverative behaviors in individuals with FXS. 115 In survey studies, both risperidone and aripiprazole have been reported to be effective at reducing aggression and self-injurious behaviors in FXS. 170 , 171 In a recent pilot, open-label study of aripiprazole, 180 10 out of 12 participants showed improvement in irritability, hyperactivity, and social behavior. Risperidone has a positive effect on irritability symptoms in individuals with autism compared with placebo. 181 However, no controlled trials of antipsychotics have been completed with individuals with FXS.

Sleep issues are a significant concern for families of a subsample of individuals with FXS. 140 So far, melatonin is the only treatment that has been studied for individuals with FXS, with findings suggesting efficacy for increased sleep onset and duration compared with placebo. 182

Next Generation Treatments

Recent discoveries in the pathophysiology of FXS have led to excitement in the field about the development of possible therapeutic agents. Multiple reviews summarize these discoveries and the preclinical and clinical trials that are under way to examine the efficacy of these treatments. 183 , – 187

The metabotropic glutamate receptor (mGluR) theory of FXS, first formulated by Bear et al, 188 suggests that the absence of FMRP in FXS leads to enhanced glutamatergic signaling via mGluR5, which subsequently results in increased protein synthesis and defects in synaptic plasticity. The resulting weakening of the synapse and increased number of longer immature dendritic spines is thought to explain the intellectual disability found in FXS. 130 Based on this theory, there has been a heavy focus on developing and testing agents that target mGluR5 modulation. 189 , – 193

Based on promising findings in FMR1 knockout mice, 184 several agents have been or are currently being tested in human clinical trials. These agents include the following, which are in clinical development in open-label phase II or higher clinical trials 183 : (1) glutamatergics (ie, mavoglurant/AFQ056, RG7090/RO4917523, STX107, and fenobam/NPL-2009), (2) GABAergics (ie, arbaclofen, ganaxolone, and acamprosate), (3) atypical antipsychotics (ie, aripiprazole), (4) antidepressants/anxiolytics (ie, sertraline), (5) mood stabilizers (ie, lithium), and (6) antibiotics (ie, minocycline). Trials of mavoglurant (AFQ056), RG7090/RO4917523, and STX107 were proven ineffective in comparison with placebo and have been terminated. In addition, given the heterogeneity of the FXS phenotype, debate is ongoing regarding the most appropriate target patients and outcome measures that will allow for valid efficacy results.

Minocycline is a targeted treatment in FXS that lowers matrix metalloproteinase 9, an important protein for synaptic development that is elevated in FXS. A controlled trial of minocycline demonstrated efficacy in young children with improvements in behavior and moodiness. 194 Side-effects included graying of the permanent teeth, the rare occurrence of swollen joints, rash, or a lupus-like syndrome that resolves once the minocycline is discontinued.

In a retrospective study of young children on low-dose sertraline, a commonly used SSRI, those treated demonstrated improvements on both receptive and expressive language development compared with controls. 160 Sertraline stimulates neurogenesis in addition to increasing brain-derived neurotrophic factor, which can improve connectivity in the developing central nervous system. The current thinking is that low-dose sertraline may also improve anxiety and sensory hyperarousal in children <5 years of age.

Family Environment

The stress of raising a child with FXS on carrier mothers may have an impact on the family unit as well as the maternal-child relationship. Maternal depression, anxiety, and stress are related to both marital satisfaction and family cohesion in families affected by FXS. 120 , 195 , 196 Family cohesion was slightly higher than previously reported levels of families of individuals with developmental disabilities or ASD. 195 Research on the family environment has also examined molar levels of maternal responsivity (ie, overall interaction styles), including levels of warmth, positive affect, expressed emotion, and criticism. Mothers of children with FXS display high levels of warmth and positive affect with little to no negative behaviors exhibited. 197 , 198 These behaviors appear to be related to many child variables, as observed in unaffected populations as well, such as a child’s rate of communication 199 or developmental level. 200 Child age and frustration or help-seeking behaviors also predicted maternal encouraging/responsive behaviors. 201 Mothers of younger children and those whose children had more behavior problems had higher levels of criticism of their children. 197

Financial Impact

Results of a national survey indicated that approximately half of all families experienced at least some financial burden, with almost 60% stating that someone in the family had to change work hours or stop work as a result of having a child with FXS. 202 Family (ie, not having adequate health insurance or having multiple affected sons) and child (ie, higher numbers of cooccurring conditions) factors were associated with financial burden and employment. The median out-of-pocket expenditures for families were $1900 per year, which included expenses for transportation (31%), therapy (31%), medications or other medical needs (25%), supervision (6%), recreation (4%), or other needs (3%). 202 A second survey examined the amount of paid and unpaid time spent in providing care to individuals with FXS. 124 On average, parents spent 9.2 hours per day in care or support for sons and 4.8 hours per day for daughters. The average boy with FXS also received 5.5 hours per day of paid support, and the average girl received 1.9 hours. Caregivers also had to take an average of 19.4 hours off from work each month to care for their child’s needs. In a study comparing survey responses by parents of children with FXS to those with ASD only, intellectual disability only, and ASD and intellectual disbaility, 203 a higher percentage of caregivers of children with FXS reported a negative financial and employment impact than caregivers of children with ASD only or intellectual disability only. The negative financial and employment impact of FXS was comparable to that of caring for children with ASD and intellectual disability. Greater financial and employment impact were associated with increased anxiety, seizures, irritability, and reduced thinking, reasoning, or learning ability regardless of condition.

Despite extensive literature on FXS, there are gaps that need to be addressed. Below we outline key remaining questions, which can be used to shape future research.

Are there subtypes of the FXS phenotype? There is strong evidence for the impact of FXS on cognitive and language development. Less is known about behavior problems, self-injury, and sleep issues. Research has shown differences in cognitive and behavioral profiles for individuals with FXS only and those with FXS+ASD. However, little information exists about other phenotypic subgroups within FXS. Do certain cooccurring conditions form clusters or profiles? Are there biomarkers that correlate with certain subgroups? Answering these questions is critical to additional understanding the FXS phenotype.

What are the needs of young adults, middle-aged adults, and seniors living with FXS? The vast majority of research on FXS has been conducted with children and adolescents. Longitudinal studies of age-related decline in adolescence in cognition and adaptive behavior have shown mixed results. Moreover, a large evidence base is emerging on the premutation phenotype in older adults, specifically the impact of fragile X–associated tremor-ataxia syndrome and fragile X–associated primary ovarian insufficiency. However, much less is known about FXS across the life span; in particular, studies on young adults, middle-aged adults, and seniors are lacking. Although some studies include individuals with FXS in this age range, they often focus on non–age-related topics (eg, language abilities and autism symptoms). Little is known about the transition out of school, employment opportunities, daily living and functional skills of adults, caregiving demands on families who provide assistance to adult children who are living at home, and guardianship issues. Moreover, studies examining the health and social needs of these individuals are needed.

What are the greatest public health needs of individuals with FXS? The physical features and medical problems associated with FXS have been well documented. However, little research has been conducted on public health issues related to the fragile X population, including areas such as health disparities, health literacy, access to preventative health care, health promotion activities, and health care decision-making. The communication of important health-related information to individuals with FXS is also understudied. Finally, little is known about the prevalence of noncommunicable diseases among individuals with FXS and how it compares to other intellectual and developmental disability groups as well as the general population.

What educational, behavioral, and pharmacologic treatments offer the most promise for individuals with FXS? There is a shortage of evidence regarding service use, intensity, or efficacy for school-age and preschool children with FXS, including special education eligibility and the types of educational services most commonly provided. More detailed descriptive information would lead to the development of targeted treatment options. The ability to conduct a high-quality intervention study targeting specific behaviors or learning issues in FXS is challenging given the wide range of locations of individuals with FXS. However, promising interventions targeting similar issues in populations that share symptomology (eg, ASD), as well as increasing use of technological options, suggest some directions for future intervention research. In addition, little is known regarding the efficacy of treatments. Pharmacological treatments for symptoms have been reported to be beneficial for reducing some of the core features of FXS, including impulsivity, hyperactivity, anxiety, and irritability. However, few randomized controlled trials have been conducted to prove efficacy of these medications in the FXS population. Recent work has focused on pharmacologic treatments that target the core mechanism in FXS. Much work remains not only for basic scientists but also for social scientists before FXS-specific medications are commonplace. Finally, there is a need to examine the use of medications and/or behavioral interventions in the first year of life. The efficacy of earlier treatment will need to be described if large-scale screening, like newborn screening, is to be considered. Most importantly, it has been hypothesized that the benefit of combining educational interventions with targeted psychopharmacologic interventions may prove to be more efficacious. Research on the combination of these interventions is needed.

What are the core risk and protective factors for families of individuals with FXS? What are the combinations of factors that lead to positive or negative adaptation in families of individuals with FXS? Although the field has begun to explore the economic burden of behavioral/educational and medical services, it is not well characterized for a representational sample of families affected by FXS. In addition, the cost associated with FXS has not been studied relative to other conditions. Finally, the cumulative health and financial consequences of multiple family members being affected by FMR1 mutations have not been studied. Although mental and physical health in carrier mothers is fairly well documented, it is difficult to tease apart variance caused by parenting a child with FXS versus premutation carrier status. In addition, factors such as family cohesion and marital satisfaction have not been well studied and could provide more information on possible mediating variables that may contribute to or lessen the impact on maternal outcomes. Likewise, knowledge about how FXS affects fathers and siblings, both carriers and noncarriers, is lacking. Finally, no research has been conducted on family-focused interventions that aim to improve both family and child functioning.

The identification and treatment of FXS remains an important concern for pediatricians. In addition to the AAP clinical reports and recommendations already referenced, pediatricians can find clinical practice recommendations for individuals with FXS and their families developed by the Fragile X Clinical and Research Consortium ( www.fragilex.org/treatment-intervention/consensus-on-clinical-practices/ ). The consensus documents are based on expert opinions of fragile X researchers and clinicians. The documents cover a variety of topics, such as educational guidelines, the diagnosis and treatment of associated medical conditions, and information about genetic testing. This review of the research as well as the consensus documents and AAP publications provide a wealth of information for pediatricians to help better understand and treat FXS and its associated conditions. Pediatricians can help coordinate care/therapies, provide psychopharmacologic interventions, and identify those with FXS by ordering a fragile X DNA test. In addition, pediatricians may be called on to support the larger family system, because a diagnosis of 1 individual can impact many other family members. 204 These basics are reviewed in this article, although if the pediatrician feels uncomfortable regarding these points, they can refer to a specialist, such as a developmental-behavioral pediatrician or psychiatrist, for psychopharmacologic intervention or a genetic counselor to discuss extended family involvement and reproductive options.

American Academy of Pediatrics

attention-deficit/hyperactivity disorder

autism spectrum disorder

Discrete Trial Trainer

fragile X mental retardation 1

fragile X mental retardation protein

fragile X syndrome

fragile X syndrome with comorbid autism spectrum disorder

metabotropic glutamate receptor

selective serotonin reuptake inhibitors

Drs Raspa and Wheeler conceptualized and designed the study, conducted the literature review, drafted the initial manuscript; Dr Riley conceptualized and designed the study and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted.

FUNDING: This work was supported in part by Centers for Disease Control and Prevention (CDC) contract 200-2007-22644-0013. The findings and conclusions in this publication are those of the authors and do not necessarily represent the views of CDC.

We thank Don Bailey, Randi Hagerman, and Julie Bolen for reviewing earlier drafts of the manuscript.

Competing Interests

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Research Gaps in Fragile X Syndrome: An Updated Literature Review to Inform Clinical and Public Health Practice

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1 RTI International, Genomics, Ethics, and Translational Research Program, Research Triangle Park, NC.
PMID: 36219479
PMCID: PMC9770151
DOI: 10.1097/DBP.0000000000001134

Objective: The phenotypic impact of fragile X syndrome (FXS) has been well-documented since the discovery of the fragile X messenger ribonucleoprotein 1 gene 30 years ago. However, gaps remain in clinical and public health research. The purpose of this literature review was to determine the extent to which these gaps have been addressed and identify targeted areas of future research.

Methods: We conducted an electronic search of several scientific databases using a variety of key words. The search focused on 5 areas identified as research gaps by an earlier review: (1) diagnosis, (2) phenotypic presentation, (3) familial impact, (4) interventions and treatments, and (5) life span perspectives. Inclusion criteria included publication between 2014 and 2020, focus on human subjects, and publication in English. A total of 480 articles were identified, 365 were reviewed, and 112 are summarized in this review.

Results: Results are organized into the following categories: (1) FXS phenotype and subtypes (FXS subtypes, medical profile, cognitive/developmental profile, social and behavioral profile); (2) needs of adults; (3) public health needs (clinical diagnosis and newborn screening, health care needs, and access); (4) treatment (treatment priorities, pharmacological treatments, and behavioral and educational interventions); and (5) families (economic burden and mother-child relationship).

Conclusion: Despite the progress in many areas of FXS research, work remains to address gaps in clinical and public health knowledge. We pose 3 main areas of focused research, including early detection and diagnosis, determinants of health, and development and implementation of targeted interventions.

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Research Support, U.S. Gov't, P.H.S.
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Evidence Gaps
Fragile X Syndrome* / diagnosis
Fragile X Syndrome* / therapy
Infant, Newborn
Public Health Practice

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Research gaps in fragile x syndrome

An updated literature review to inform clinical and public health practice

Raspa, M. , Wheeler, A. , Okoniewski, K. C. , Edwards, A. , & Scott, S. (2023). Research gaps in fragile x syndrome: An updated literature review to inform clinical and public health practice . Journal of Developmental and Behavioral Pediatrics , 44 (1), e56-e65. https://doi.org/10.1097/DBP.0000000000001134

OBJECTIVE: The phenotypic impact of fragile X syndrome (FXS) has been well-documented since the discovery of the fragile X messenger ribonucleoprotein 1 gene 30 years ago. However, gaps remain in clinical and public health research. The purpose of this literature review was to determine the extent to which these gaps have been addressed and identify targeted areas of future research.

METHODS: We conducted an electronic search of several scientific databases using a variety of key words. The search focused on 5 areas identified as research gaps by an earlier review: (1) diagnosis, (2) phenotypic presentation, (3) familial impact, (4) interventions and treatments, and (5) life span perspectives. Inclusion criteria included publication between 2014 and 2020, focus on human subjects, and publication in English. A total of 480 articles were identified, 365 were reviewed, and 112 are summarized in this review.

RESULTS: Results are organized into the following categories: (1) FXS phenotype and subtypes (FXS subtypes, medical profile, cognitive/developmental profile, social and behavioral profile); (2) needs of adults; (3) public health needs (clinical diagnosis and newborn screening, health care needs, and access); (4) treatment (treatment priorities, pharmacological treatments, and behavioral and educational interventions); and (5) families (economic burden and mother-child relationship).

CONCLUSION: Despite the progress in many areas of FXS research, work remains to address gaps in clinical and public health knowledge. We pose 3 main areas of focused research, including early detection and diagnosis, determinants of health, and development and implementation of targeted interventions.

10.1097/DBP.0000000000001134

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Wheeler AC 2

ORCIDs linked to this article

Wheeler AC | 0000-0003-2693-5616
Raspa M | 0000-0003-3791-3367

Pediatrics , 01 Jun 2017 , 139(Suppl 3): S153-S171 https://doi.org/10.1542/peds.2016-1159c PMID: 28814537 PMCID: PMC5621610

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Abstract

Conclusions, free full text .

Public Health Literature Review of Fragile X Syndrome

Melissa raspa.

a RTI International, Research Triangle Park, North Carolina

Anne C. Wheeler

Catharine riley.

b National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia

CONCLUSIONS

The purpose of this review is to describe the state of the science on FXS and research gaps to help pediatricians support patients with FXS and their families.

Search Terms

Search Terms and Inclusion/Exclusion Criteria by Topic Area

Abstract Review and Refinement

Developmental Profile

Cognitive development and academic skills.

The neurocognitive profile of individuals with FXS is well described, including several recent reviews. 5 – 11 Boys typically have moderate to severe intellectual disability, with average IQ scores <55. Other areas of weakness include short-term and working memory, spatial memory, auditory and sequential processing, abstract thinking, executive function, and mathematical thinking. 5 – 11 Areas of strength for boys include receptive vocabulary, visual memory, simultaneous processing, experiential learning, and imitation. 5 – 11 This profile of cognitive challenges persists across groups of high-, mid-, and low-functioning individuals. 12

Several longitudinal studies have demonstrated that IQ scores are lower in adolescents and adults with FXS when compared with younger children with FXS. 21 – 26 Children make steady cognitive growth through early adolescence, at which point mental age plateaus and IQ declines. 27 Older children with FXS have a developmental growth rate 2.2 times slower than their non-FXS siblings. 27 A pattern of cognitive decline holds even when assessed by using nonverbal measures. 28 , 29 The increasing gap in IQ scores from typical development may be due to the nature of standardized tests (ie, increased importance of symbolic language in adolescence) as opposed to the loss of skills. 30 However, studies examining these variable rates in cognitive decline 30 , 31 have suggested that methylation level, delayed frontal lobe maturation, level of FMRP production, comorbid autistic behaviors, and maternal education may be contributing factors. 28 , 29 , 32 , 33

Language Development

Many areas of language development appear to be affected in FXS, and therefore this area has been studied extensively; recent reviews provide a summary of research findings to date. 37 – 39

Prelinguistic

Functional Skills

Studies on functional skills and adaptive behavior in FXS have been limited. Using a large sample of parents of individuals with FXS, Bailey et al 70 reported on skill attainment in 7 areas: eating, dressing, toileting, bathing/hygiene, communication, articulation, and reading. Most adult males and females were verbal and independently used the toilet, bathed, dressed themselves, and ate. However, skills, such as using complex sentences, reading, or speaking at a typical rate, were weaknesses. Hatton et al 71 showed steady improvements in adaptive behavior over time for children up to age 12 years. Those with fewer autistic behaviors and higher levels of FMRP showed more improvements over time. In adolescents and adults, delays in communication, socialization, and daily living skills for both males and females have been documented. 72 – 74 Individuals codiagnosed with autism exhibit the biggest declines in adaptive scores over time. 75 – 77

Transition to Adulthood

Social-Emotional Profile

Cooccurring psychiatric diagnoses.

Anxiety is a pervasive concern among providers, caregivers, and individuals living with FXS. 88 – 90 Early work found high rates of anxiety in girls with FXS compared with typically developing peers and those with other developmental disabilities. 91 – 93 In a national survey, 70% of boys and 56% of girls were reported to have been treated or diagnosed with anxiety. 80 Other studies have found similarly high rates. 89 , 94 A recent study described an association between negative affect, a temperament construct, and later anxiety in preschool boys with FXS providing an early diagnostic method. 95 A study of brain activity in the prefrontal regions found that social anxiety in FXS may be related to challenges in higher-level social cognition. 96 These findings may also explain other phenotypic traits associated with anxiety in FXS, such as poor eye contact, gaze aversion, excessive shyness, hand flapping, self-injurious behaviors, aggression, and autistic symptoms. 10 , 88 , 97

Social impairments may be the most significant predictor differentiating individuals with FXS+ASD from individuals with FXS only. 102

Specifically, social withdrawal (eg, avoidance and indifference) and adaptive socialization behaviors (eg, recognizing emotions or appropriate social interactions) are often independent predictors of ASD in individuals with FXS. 105 , 108 – 110 In cross-sectional 105 and longitudinal studies, 101 impaired socialization was the greatest contributor to ASD diagnosis and severity in the FXS population, more so than communication or cognition. 110 Per parent report, however, repetitive and stereotyped behaviors were the strongest predictors of ASD in FXS. 102 Boys with FXS+ASD exhibited significantly less ritualistic and compulsive behavior, but increased repetitive motor behaviors compared with boys with idiopathic autism. 111

Medical Profile

Physical features.

Boys often present with long, narrow faces; high-arched palates; prominent ears; macroorchidism (during and after puberty); hypermobility of joints; hypotonia; and flat feet. 129 – 131 Other conditions that are found at increased rates include cleft palates and orthopedic abnormalities, such as scoliosis or severe flat feet. 5 Adults with FXS have a shorter average height than that of the general population. 132 Girls with FXS have similar physical features to boys with FXS although at lower rates. 133

Over time, providers and caregivers anecdotally reported sleep problems in the FXS population, prompting several studies to explore sleep problems in FXS. 139 – 141 In a national survey, 32% of individuals with FXS were reported by the caregiver to experience sleep difficulties, with 85% having at least 2 problems (eg, trouble falling asleep and frequent night awakenings). Of those with problems, 47% of boys and 40% of girls were taking at least 1 medication to help with sleep. A study of sleep architecture in FXS revealed less time in bed and less time in REM sleep. 141

Physiologic Features

Miller et al 155 demonstrated enhanced electrodermal reactivity to sensory stimuli in those with FXS, and this reactivity correlated inversely with the level of FMRP. Taken together, these results suggest that individuals with FXS have atypical physiologic characteristics when compared with typically developing peers and that these differences may be related to the behavioral profile of FXS.

Treatments and Interventions

Behavioral interventions.

Cognitive/Educational Interventions

The use of a self-paced computer program (Discrete Trial Trainer [DTT]) to assess learning of basic math and geography skills by using a match-to-sample teaching procedure has been tested as a possible intervention technique. 161 – 164 Results showed that basic mathematical relations could be taught and were comparable with those of the control group; however, improved outcomes were not maintained, and more complex concepts (eg, equality and congruence concepts) were not learned at a rate similar to that of the control group. Additional studies using the DTT software suggest that it may be a promising approach for outcome measurement. 164 , 165

Allied Health Services

Pharmacologic Treatments

Anxiety Symptoms

SSRIs are the most common first-line treatment of anxiety in FXS, which is the most common reason parents seek medication treatment. 167 Case reports and survey studies suggest SSRIs are effective ~50% of the time at reducing anxiety in FXS. 170 – 172 No controlled studies on the efficacy of SSRIs for reducing anxiety in FXS have been conducted. In addition, side effects, including weight loss or gain, and behavioral activation for those on SSRIs, specifically fluoxetine, have been reported. 115 , 172

Attention-Deficit/Hyperactivity Disorder Symptoms

Impulsivity and hyperactivity are 2 common challenges for individuals with FXS, and stimulant medications are the most common type of medication prescribed to individuals with FXS. 173 However, only 1 controlled trial conducted years ago has been carried out demonstrating efficacy. 133 In addition, stimulant use for children <5 years old can often cause irritability and, according to the AAP, is not the recommended treatment for children ≤5 years of age. 115 , 174 Typical doses have been found to be effective at reducing impulsivity and hyperactivity and increasing attention in a controlled trial of boys with FXS. 175 Second-line treatments, recommended for those who do not respond to stimulants, include α-adrenergic receptor agonists (eg, clonidine and guanfacine). 115 Although surveys and case studies suggest clonidine can be effective 171 , 176 and clinical experience suggests guanfacine 115 can be helpful, no controlled trials have examined the efficacy of these medications for ADHD symptoms in FXS specifically. Two controlled studies of L-acetylcarnitine 177 , 178 suggest some reduction of ADHD symptoms in FXS compared with placebo. More recently, valproic acid, the antiepileptic drug, was found to reduce ADHD symptoms in an open-label trial. 179

Aggression and Mood Symptoms

Next Generation Treatments

Impact on the Family

Family environment.

Financial Impact

Gaps in the Research Literature

Despite extensive literature on FXS, there are gaps that need to be addressed. Below we outline key remaining questions, which can be used to shape future research.

Implications for Pediatricians

Acknowledgments

We thank Don Bailey, Randi Hagerman, and Julie Bolen for reviewing earlier drafts of the manuscript.

ABBREVIATIONS

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

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J Dev Behav Pediatr , 44(1):e56-e65, 11 Oct 2022

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Bailey DB , Raspa M , Bishop E , Holiday D

Pediatrics , 124(2):527-533, 05 Jul 2009

Cited by: 94 articles | PMID: 19581269

Health supervision for children with fragile X syndrome.

Hersh JH , Saul RA , Committee on Genetics

Pediatrics , 127(5):994-1006, 25 Apr 2011

Cited by: 49 articles | PMID: 21518720

Checklist assessments of FMR1 gene mutation phenotypes.

J Cult Divers , 15(3):117-131, 01 Jan 2008

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Public Health Literature Review of Fragile X Syndrome

2017, Pediatrics

OBJECTIVES: The purpose of this systematic literature review is to describe what is known about fragile X syndrome (FXS) and to identify research gaps. The results can be used to help inform future public health research and provide pediatricians with up-to-date information about the implications of the condition for individuals and their families. METHODS: An electronic literature search was conducted, guided by a variety of key words. The search focused on 4 areas of both clinical and public health importance: (1) the full mutation phenotype, (2) developmental trajectories across the life span, (3) available interventions and treatments, and (4) impact on the family. A total of 661 articles were examined and 203 were included in the review. RESULTS: The information is presented in the following categories: developmental profile (cognition, language, functional skills, and transition to adulthood), social-emotional profile (cooccurring psychiatric conditions and behavior problems),...

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Journal of Psychology & Clinical Psychiatry

Kathryn Yoo

Advances in the care of patients with fragile X syndrome (FXS) have been hampered by lack of data. This deficiency has produced fragmentary knowledge regarding the natural history of this condition, healthcare needs, and the effects of the disease on caregivers. To remedy this deficiency, the Fragile X Clinic and Research Consortium was established to facilitate research. Through a collective effort, the Fragile X Clinic and Research Consortium developed the Fragile X Online Registry With Accessible Research Database (FORWARD) to facilitate multisite data collection. This report describes FORWARD and the way it can be used to improve health and quality of life of FXS patients and their relatives and caregivers. FORWARD collects demographic information on individuals with FXS and their family members (affected and unaffected) through a 1-time registry form. The longitudinal database collects clinician- and parent-reported data on individuals diagnosed with FXS, focused on those who a...

Intractable & Rare Diseases Research

Reymundo Lozano

BackgroundFragile X syndrome (FXS) is a common cause of intellectual disability and autism spectrum disorder (ASD) usually associated with a CGG expansion, termed full mutation (FM: CGG ≥ 200), increased DNA methylation of theFMR1promoter and silencing of the gene. Mosaicism for presence of cells with either methylated FM or smaller unmethylated pre-mutation (PM: CGG 55–199) alleles in the same individual have been associated with better cognitive functioning. This study compares age- and sex-matched FM-only and PM/FM mosaic individuals on intellectual functioning, ASD features and maladaptive behaviours.MethodsThis study comprised a large international cohort of 126 male and female participants with FXS (aged 1.15 to 43.17 years) separated into FM-only and PM/FM mosaic groups (90 males, 77.8% FM-only; 36 females, 77.8% FM-only). Intellectual functioning was assessed with age appropriate developmental or intelligence tests. The Autism Diagnostic Observation Schedule-2nd Edition was ...

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Research Gaps in Fragile X Syndrome: An Updated Literature Review to Inform Clinical and Public Health Practice

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Source: J Dev Behav Pediatr. 44(1):e56-e65
Alternative Title: J Dev Behav Pediatr
Personal Author: Raspa, Melissa ; Wheeler, Anne ; Okoniewski, Katherine C. ; Edwards, Anne ; Scott, Samantha Raspa, Melissa ; Wheeler, Anne ; Okoniewski, Katherine C. ; Edwards, Anne ; Scott, Samantha Less -
Description: Objective The phenotypic impact of fragile X syndrome (FXS) has been well-documented since the discovery of the FMR1 gene 30 years ago. However, gaps remain in clinical and public health research. The purpose of this literature review was to determine the extent to which these gaps have been addressed and identify targeted areas of future research. Methods We conducted an electronic search of several scientific databases using a variety of key words. The search focused on five areas identified as research gaps by an earlier review: (1) diagnosis, (2) phenotypic presentation, (3) familial impact, (4) interventions and treatments, and (5) lifespan perspectives. Inclusion criteria included publication between 2014 and 2020, focus on human subjects, and publication in English. A total of 480 articles were identified, 365 were reviewed, and 112 are summarized in this review. Results Results are organized into the following categories: (1) FXS phenotype and subtypes (FXS subtypes, medical profile, cognitive/developmental profile, social and behavioral profile); (2) Needs of adults; (3) Public health needs (clinical diagnosis and newborn screening, healthcare needs and access); (4) Treatment (treatment priorities, pharmacological treatments, behavioral and educational interventions); (5) Families (economic burden, mother-child relationship). Conclusion Despite the progress in many areas of FXS research, work remains to address gaps in clinical and public health knowledge. We pose three main areas of focused research, including early detection and diagnosis, determinants of health, and development and implementation of targeted interventions. More ▼ -->
Keywords: [+] Adult Clinical Phenotype Delivery Of Health Care Evidence Gaps Family Needs Fragile X Syndrome Humans Infant, Newborn Phenotype Public Health Needs Public Health Practice Treatment
Pubmed ID: 36219479
Pubmed Central ID: PMC9770151
Document Type: Journal Article
Funding: HHSD2002013M53964B/CC/CDC HHSUnited States/ ; HHSD2002013M53964B/ImCDC/Intramural CDC HHSUnited States/ HHSD2002013M53964B/CC/CDC HHSUnited States/ ; HHSD2002013M53964B/ImCDC/Intramural CDC HHSUnited States/ Less -
Collection(s): CDC Public Access
Main Document Checksum: [+] urn:sha256:7947fa01195b09006dcc1467b9ffffcae82ecf3f50a2b2b43e3e4f0c806e4cec
Download URL: https://stacks.cdc.gov/view/cdc/123017/cdc_123017_DS1.pdf

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Intractable Rare Dis Res
v.5(3); 2016 Aug

Fragile X syndrome: A review of clinical management

Reymundo lozano.

1 Medical Investigation of Neurodevelopmental Disorders MIND Institute, UC Davis, CA, USA

2 Department of Pediatrics, UC Davis, Sacramento, CA, USA

Atoosa Azarang

Tanaporn wilaisakditipakorn, randi j hagerman.

The fragile X mental retardation 1 gene, which codes for the fragile X mental retardation 1 protein, usually has 5 to 40 CGG repeats in the 5′ untranslated promoter. The full mutation is the almost always the cause of fragile X syndrome (FXS). The prevalence of FXS is about 1 in 4,000 to 1 in 7,000 in the general population although the prevalence varies in different regions of the world. FXS is the most common inherited cause of intellectual disability and autism. The understanding of the neurobiology of FXS has led to many targeted treatments, but none have cured this disorder. The treatment of the medical problems and associated behaviors remain the most useful intervention for children with FXS. In this review, we focus on the non-pharmacological and pharmacological management of medical and behavioral problems associated with FXS as well as current recommendations for follow-up and surveillance.

1. Introduction

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability (ID) and the most common monogenetic cause of autism (ASD) that is known. FXS was initially described in 1969 by Lubs and colleagues ( 1 ) and the first fragile X-linked pattern of inheritance was reported by Martin and Bell in 1949 ( 2 , 3 ). In FXS there is a mutation in the Fragile X Mental Retardation 1 ( FMR1 ) gene which involves an expansion of more than 200 CGG repeats. Individuals in the normal population have approximately 5 to 40 CGG repeats within FMR1 and individuals who are carriers for FXS (premutation) have 55 to 200 CGG repeats ( 4 – 6 ). The molecular basis of FXS is characterized by the CGG full mutation and methylation of the cytosine bases, which leads to silencing of transcription and deficiency or absence of the encoded protein, Fragile X mental retardation protein (FMRP). FMRP is a major protein regulator of the translation of many mRNAs involved in synaptic plasticity ( 7 ). Therefore, in FXS the lack of FMRP causes significant intellectual deficits. Usually, expansions occur between generations when passed on by a female with the premutation into a full mutation in the offspring ( 8 ). Women, who are known carriers of the FMR1 gene mutation, can obtain prenatal diagnosis including chorionic villus sampling (CVS) and/or amniocentesis studies as recommended by the American College of Obstetricians and Gynecologist ( 9 ). Preimplantation diagnostic services and in vitro fertilization are also available ( 10 – 12 ). Individuals with FXS present with a wide range of learning disabilities ranging from normal functioning to borderline cognition or mild to severe ID. The average Intelligence Quotient (IQ) of males with the full mutation is 40 ( 13 ). Intellectual and developmental disability occurs in 85% of males and 25% of females. Furthermore, FXS also accounts for approximately 2 to 5% of all individuals diagnosed with ASD. In FXS about 60% of males have ASD ( 14 ). Physical manifestations are subtle in infants and young boys. These include: midface hypoplasia with sunken eyes, arched palate, macroorchidism, and large cupped ears among others ( Figure 1 ).

An external file that holds a picture, illustration, etc.
Object name is irdr-5-9-g001.jpg

Young boy with fragile X syndrome and his Go Talk device. Note prominent ears with cupping of the pinnae. The participant's family provided informed consent for the use of this picture.

Medical problems associated with FXS include mitral valve prolapse, otitis media, seizures, strabismus, joint laxity, sleep disturbances, and gastrointestinal problems. In this review, we provided a summary of the prevalence and clinical management of medical problems associated with FXS other than ID and ASD ( Table 1 ).

FXCRC: Fragile X Clinical and Research Consortium Study; FXS: Fragile X syndrome.

2. Fragile X syndrome associated medical problems

2.1. after birth problems.

Boys with FXS are slightly larger than average in weight at birth. The mean birth weight from earlier studies ranges from 3,490 gms. to 4,046 gms. in white male infants ( 15 ). The mean birth weight of boys with the FXS was in the 70 th percentile, they also had a higher birth weight than their siblings when this was corrected for gestational age and sex ( 16 ). The mean birth weight in FXS was increased and the average linear growth was also above the mean for typically developed boys with the greatest increase after the second year of life. In contrast, the weight measurements were on average below the mean until two years of age. It is suggested that in FXS there is a disturbance of early infantile growth ( 17 ); however, the overall proportion of infants with low birth weight was similar to that in the general population ( 18 ). After birth, the head circumference tends to rise above the 50 th percentile and continues to be larger than those without FXS. Jacobs c noted that in six of nine affected men, the head circumference was greater than the 90 th percentile ( 18 ), but other studies have shown that the mean head circumference ( 19 – 21 ) and the mean birth length are not different of those of control population ( 21 ). Hagerman and colleagues found no difference in the height, weight or head circumference of girls with FXS compared with those without the full mutation ( 22 ).

Some studies reported that the height of males with FXS is greater than the 50 th percentile and height curves for FXS were higher at nearly every point in the prepubertal section of the curves, but height was lower at postpubertal ages ( 23 , 24 ). A subset of children with FXS can be misdiagnosed as having Sotos syndrome or Prader-Willi syndrome ( 25 ). The Prader-Willi phenotype (PWP) can be observed in FXS and it consists of extreme obesity, hyperphagia, lack of satiation after meals, small genitalia, delayed puberty, sometimes short stature and stubby hands and feet ( 26 – 28 ). Sotos-like syndrome was reported in 1986 in two boys with FXS featuring large size at birth, unusual length, large head circumference and minor facial abnormality ( 29 ).

Structural longitudinal magnetic resonance imaging (MRI) study of preschoolers with FXS observed generalized brain overgrowth compared to controls, evident at age two and maintained across ages 4–5 ( 30 ). The molecular biology of FXS suggests a possible mechanism for brain growth patterns. Harlow and colleagues have demonstrated that FMRP inhibits the generation of progenitor neurons from glia cells but enhances the glial cell number in mouse cerebral cortex, suggesting that the lack of FMRP, as seen in FXS might result in an increased proliferation of progenitor glial cells and subsequent cerebral cortical overgrowth ( 31 ). The presence of early brain differences in young children with FXS points to aberrant early brain development in this condition ( 31 ).

FMRP also regulates the phosphatase and tensin homolog ( PTEN ) gene translation that in turn regulates growth. The results of genetic and regression analysis showed that in both boys and girls, total pubertal height gain is impaired, whereas the rate of growth during the preadolescent period is increased, compared with the growth rate of subjects without FXS. The study demonstrates the linear effect of progressively reduced levels of FMRP on a number of physical measurements ( 32 ). This effect is predictably less strong in females than in the males because of the presence of the second unaffected X chromosome. The inverse relationship of height and limb length with FMRP deficit supports a possible role of hypothalamic dysfunction in growth disturbances in FXS that may be more severe in those with the PWP ( 33 ). This dysfunction may cause a premature increase in the pulsating secretion of high doses of estrogen, thus leading to earlier epiphyseal maturation ( 34 ). The hypothesis of premature activation of the hypothalamic-pituitary-gonadal axis may explain the cause of growth impairment in FXS and occasional precocious puberty in females with FXS, a few cases have been reported ( 35 , 36 ).

2.2. Otitis media (OM)

OM is one of the most frequent medical problems associated with FXS. Even when children with FXS have a high pain threshold and may not specifically complain about ear pain, 85% of children with FXS have at least one diagnosed episode of OM ( 37 ). An ear examination is warranted for any change of behavior and sleep patterns as well other symptoms including fever, vomiting, and headache. Children with FXS commonly develop OM complications including decreased hearing acutely and at least one-fourth develop acute sinusitis. Furthermore, OM recurs in about 50% of children with FXS recurrent 5 years of age ( 37 ). There is not data reported about the rates of chronic otitis. Recurrent otitis media may cause conductive hearing deficits and exacerbate the cognitive, language, and behavior problems that exist in this syndrome ( 38 ); therefore, the treatment of OM should be aggressive. The American Academy of Pediatrics initial recommendation for uncomplicated OM is an observation period for children 6 months to 2 years with unilateral OM without otorrhea and for children older than 2 years with bilateral OM without otorrhea; however, we recommend to consider skipping the observation period and using antibiotic therapy in children with FXS ( 39 ). The craniofacial changes in FXS including a long face and collapsible Eustachian tubes predispose children to OM infections. Signs of slight redness, mobility impairments and abnormal positioning of tympanic membrane (TM) such as retraction or bulging, should be carefully assessed. Initial antibiotic therapy for 10 days includes a high dose of amoxicillin (80–90 mg/kg per day in 2–3 divided doses). If not improvement after 48–72 hour, Amoxicillin-clavulanate (same dose of amoxicillin + 6.4 mg/kg per day of clavulanate (amoxicillin to clavulanate ratio, 14:1) in 2 divided doses) or Ceftriaxone (50 mg IM or IV for 3 day) are recommended. A low threshold for early tympanostomy tube placement and antibiotic prophylaxis (amoxicillin low dose) is also advised. The potential adverse effects of antibiotics, principally allergic reaction and gastrointestinal tract consequences, such as diarrhea are important considerations for tympanostomy tubes over prophylaxis.

Clinicians should stress the recommendations of pneumococcal conjugate and influenza vaccine to all children, according to the schedule of the Advisory Committee on Immunization Practices, American Academy of Pediatrics (AAP), and American Academy of Family Physicians (AAFP). Multiple studies provide evidence that breastfeeding for at least 4 to 6 months reduces episodes of OM and recurrent OM ( 40 – 43 ). Eliminating passive exposure to tobacco smoke could also reduce the incidence of OM in infancy. In addition, bottles and pacifiers have been also associated with OM ( 44 – 49 ). Finally, Xylitol syrup, chemically a pentitol or 5-carbon polyol sugar alcohol, has shown a statistically significant reduction (25%) in the risk of occurrence of OM among healthy children ( 50 ).

2.3. Seizures

Seizure prevalence studies in FXS have shown discordant results; a study conducted in neurology clinics reported a broad prevalence range of 14% to 44%, while studies that focus on FXS patients in community hospitals or FXS clinics reported lower ranges of 12–18% ( 51 – 53 ). Typically, males have a higher prevalence when compare to females. In the national survey of caregivers of individuals with FXS, from 1,394 individuals, 14% of males and 6% of females were reported to have seizure ( 54 , 55 ). Studies in the Fmr1 knockout (KO) mouse shows immature dendritic connections, increased number of long and thin spines which point to the deficiency in the normal selection or pruning of the synaptic contacts that occurs in neuronal development ( 56 , 57 ). These results demonstrate that FMRP is important in the maturation of adult dendritic spine morphology ( 58 ). Immature dendritic connections can predispose the KO mouse to audiogenic seizures, although deficits in gamma amino butyric acid (GABA) inhibition are also related to the seizures in FXS ( 59 , 60 ). Similar abnormal dendritic formations are also observed in the brain of humans with FXS and may explain the higher frequency of seizures. In addition to structural changes, the absence or deficiency of FMRP leads to increased neuronal excitability and susceptibility to seizure ( 61 ). Other studies hypothesize that the pathophysiology of seizures in those with FXS can be related to the imbalance of the excitatory and inhibitory neurotransmitter systems ( 60 , 61 ).

It is important to consider that many children with FXS have abnormal electroencephalogram (EEG) without overt seizures ( 62 , 63 ). In those with overt seizures, all types of seizures can occur. Some studies have shown a predominance of generalized seizures ( 64 ), secondary generalized seizure and status epilepticus seizure ( 64 ). Seizures in FXS may also resemble benign focal epilepsy in childhood with centro-temporal spikes ( 65 , 66 ). In general, complex partial seizures are the major type of seizure in FXS. The observed seizures are – typically- not severe and mostly limited to childhood ( 66 ); however, the presence of seizures at an early age appears to be associated with developmental and behavioral morbidity that can impact brain function. Remarkably, those patients with FXS and seizures are more likely to have ASD ( 67 ). The current practice is to educate parents and follow-up patients closely for any possible episodes of seizure: starring spells, unexplained behavior, atypical facial gestures, vomiting at night, regression of development, language or behavior changes, as well as, significant sleep disturbance. If seizures are suspected, then it is recommended to obtain an EEG in both the waking and sleeping states ( 68 ). It is also important to tell families to avoid soy formulas in young children with FXS because of the recent report of soy formula intake increasing the prevalence of seizures in those with ASD and FXS ( 69 ).

Seizures are usually easily managed on monotherapy with anticonvulsants. Historically, most individuals with FXS have experienced good control with carbamazepine or valproic acid, with fairly limited adverse effects ( 69 ). Carbamazepine stabilizes the inactivated state of voltage-gate sodium channels. Its action leaves the affected neuronal cells less excitable. Carbamazepine has also α1, β2, and γ2 subunits containing GABA receptor agonist actions. Carbamazepine-gene testing, pharmacogenomics or pharmacogenetics, to look for the human leukocyte antigen B 1502 (HLA-B*1502), the variant may determine whether carbamazepine could be an effective treatment or whether side effects may develop. The United States Food and Drug Administration (FDA) recommends that patients with Asian ancestry should be tested for the HLA-B*1502 gene variant before treatment. Testing individuals of other ancestries is not typically performed ( 70 – 72 ). The carbamazepine label contains warning for blood dyscrasia and common side effects are drowsiness, dizziness, headaches and migraines, motor coordination impairment, nausea, vomiting, and/or constipation. Carbamazepine has also the advantage that can be used as a mood stabilizer at a typical dosage ( 73 ). The valproic acid mechanism of action is not fully understood, but the reduction of phosphatidylinositol (3,4,5)-trisphosphate (PIP3), as well as, the blockade of voltage-dependent sodium channels may protect against seizures; the increased brain levels of GABA may contribute to its mood stabilizer properties as well as its antiepileptic mechanism of action. The most common adverse effects of valproic acid are digestive complaints (diarrhea, nausea, vomiting and indigestion), vision problems (double vision or lazy eye), hormonal disturbances (increased testosterone production in females and menstrual irregularities), hair loss, memory problems, weight gain, infections, low platelet count, dizziness, drowsiness, tremor and headache ( 74 , 75 ). The FDA recommends patient testing on the Valproate (VP) drug label to avoid prescribing the drug to individuals with urea cycle disorders, the information is lacking about what type of genetic testing and how it should be carried out. Newer studies correlating genotype-phenotype associations with the clinical response will be helpful to increase drug efficacy and to reduce drug-related toxicity ( 76 ).

For those who failed carbamazepine or valproic acid, lamotrigine can be used as a fairly effective second line. Phenytoin has the adverse effects of gum hypertrophy and can interfere with dental hygiene. Phenobarbital and gabapentin also should be avoided because they exacerbate behavioral problems including hyperactivity ( 76 ). Drug-specific blood level testing, liver function studies, electrolytes, complete blood count (CBC) and general health monitoring should be considered for any child taking anticonvulsant medications ( 76 ).

2.4. Mitral valve prolapse

Mitral Valve Prolapse (MVP, floppy mitral valve) is a valvular heart condition that is characterized by the displacement of an abnormally thickened mitral valve leaflet into the left atrium during systole ( 77 ). The prevalence of MVP in the general population is estimated at 2–3% ( 77 ); however, MVP is observed in 7% of autopsies in the United States ( 78 ). Studies of individuals with FXS have shown that MVP occurs in approximately 50% of males and 20% females with echocardiogram confirmation ( 79 , 80 ). However, a recent Fragile X Clinical Research Center (FXCRC) database study using only clinical reports showed a prevalence of only 0.8%. Perhaps this relates to the fact that MVP is more common in adults than children and often cannot be diagnosed by just auscultation. Careful cardiac auscultation is recommended during every annual physical examination and if a systolic murmur or the classical MVP murmur is detected (a mid-systolic click, followed by a late systolic murmur heard best at the apex), then it is recommended to request a cardiology evaluation which should include an echocardiogram ( 81 ). Individuals with MVP, particularly those without symptoms, often require no treatment ( 82 ). Those rare cases of MVP and symptoms of arrhythmias or dysautonomia may benefit from beta-blockers. Individuals with MVP are at higher risk of infective endocarditis, approximately three- to eightfold the risk of the general population ( 82 ). Before 2007, the American Heart Association recommended prophylaxis for dental surgery and other invasive procedures that could introduce bacteria into the blood stream. Thereafter, the association determined that individuals with MVP should not receive prophylaxis routinely; prophylaxis for dental procedures should be recommended only for patients with underlying cardiac conditions associated with the highest risk of adverse outcome from infective endocarditis ( 83 ).

Surveillance cardiac evaluations are necessary for those with moderate MVP, in order to evaluate the degree of regurgitation. In very rare instances when MVP is associated with severe mitral regurgitation, mitral valve repair or surgical replacement may be necessary. In the general population, MVP is observed in individuals who tend to have low body mass index (BMI), it is unknown if MVP in FXS is associated with lower BMI. Abnormal elastin fibers have been detected in the cardiac valves and in the skin of individuals with FXS so MVP is thought to be related to the connective tissue problems seen in FXS and are related to abnormalities of the elastin fibers ( 84 ). Dilation of the aortic root is also seen in many individuals with FXS in both childhood and adulthood and this is also associated with abnormal elastin fibers ( 35 , 58 ); Typically, this is not progressive nor have significant aneurisms been reported. In summary, MVP carries a very low risk of complications, but in rare severe cases complications may include mitral regurgitation, infective endocarditis and congestive heart failure. Further, larger longitudinal studies that described the prevalence and MVP and its complications are necessary.

2.5. Gastrointestinal problems

The frequency of gastro intestinal (GI) problems in FXS remains to be determined, but initial and current studies showed a similar proportion (prevalence ∼11%) of children suffering from diarrhea and gastro-esophageal reflux disease (GERD) ( 85 , 86 ). Interestingly GI problems have been described to be quite common in other connective tissue disorders, such as Ehlers-Danlos syndrome (EDS) and Marfan syndrome; such problems include GERD, irritable bowel syndrome, and diarrhea ( 87 – 90 ). Even more intriguing is the association of the premutation and irritable bowel syndrome and the fact that developmental disorders and autism are usually associated with constipation rather than diarrhea as observed in FXS ( 91 ). General recommendations should be provided and medication management, such as, thickening agents, antacids, histamine-2 (H-2) blockers and proton-pump inhibitors, should be prescribed if necessary. Individuals with FXS have higher pain threshold which along with the communication deficits can mask the frequency of abdominal pain and other gastrointestinal symptoms. Surveillance on height and weight are appropriate to determine a failure to thrive (FTT) and referral to gastroenterologist specialist and nutritionist are recommended in the presence of FTT or poor weight gain. It is likely that the frequent loose stools in FXS are related to autonomic dysregulation including sympathetic hyperarousal and chronic anxiety ( 92 ).

Sleep problems are very common in the general population and even more common in young children with FXS. There are many issues that disturb normal sleeping patterns such as problems falling asleep, frequent nighttime awakenings, waking up too early, and parasomnias. In children with FXS the prevalence of sleep problems was reported to be 26–47% ( 93 , 94 ) which is higher than the prevalence observed in typical children (10–25%) ( 95 , 96 ). A recent study showed that the prevalence did not have gender or demographic differences and that the severity of sleep disturbance in FXS children was more pronounced when compared to typically developing children. The most frequent problems reported were difficulty falling asleep and frequent nighttime awakening ( 97 ). In addition, altered sleep patterns and dysregulated melatonin profiles have been observed in adolescents with FXS as well as greater variability in total sleep time, difficulty in sleep maintenance, and significantly greater nocturnal melatonin production in the boys with FXS ( 98 ). Children with FXS are at a higher risk for sleep problems at very young age (∼3 years of age) and the sleep problems may not resolve with age. Therefore; it is recommended that a careful history of sleep habits must be included in every clinical visit ( 99 ), starting at a young age and continue throughout their life. The physician may simply ask the parents if they have any concerns about their child's sleep or if their child takes more than 30 minutes to fall asleep at bedtime. Standardized parent questionnaires, such as the Child's Sleep Habit's Questionnaire or a two-week sleep diary are good tools to assess sleep problems ( 99 ).

Treatment of sleep problems in FXS includes behavioral interventions and medications. Behavioral intervention should include bedtime routines, positive reinforcement, effective instructions and parental support. An example is "extinction" (removing reinforcement to reduce a behavior) which can effectively reduce the falling to sleep period and increase overall sleep time. The medications used to treat this medical problem include melatonin and if needed, clonidine ( 99 ). Melatonin can effectively improve total night sleep duration, sleep latency time, and sleep-onset time ( 100 ). A study in the Fmr1 KO mouse showed that the therapeutic effects of melatonin may be due to its antioxidant effects and ability to normalize synaptic connections ( 101 , 102 ). Other studies of antioxidants in the KO mouse include alpha-tocopherol (vitamin E) and N-acetyl-cysteine (NAC) ( 103 ) and omega-3 therapy ( 104 ) with improvement in the maturity of dendritic spines and enhanced Brain Derived Neurotropic Factor (BDNF) levels in the hippocampus respectively. However, these antioxidants have not been studied for improvement in sleep in FXS. Melatonin should be given 1 hour before bedtime. The dose recommended for children with FXS ranges 0.5–5 mg. It is recommended to start with the lowest dose of 0.5 mg then adjust the dose with the response ( 105 , 106 ). No significant adverse effects of melatonin have been reported in those with FXS although in some patients it can cause agitation ( 106 , 107 ). Another study reported increased seizures in children with neurologic disabilities treated with melatonin but this has not been seen in FXS ( 108 ). Clonidine is alpha-agonist with off-labeled use for insomnia in the pediatric population. It is also used to treat attention deficit hyperactive disorder (ADHD) symptoms because it can decrease motor activity ( 109 ). Clonidine has an overall calming effect for the treatment of ADHD in FXS, but clonidine can cause significant sedation at higher doses so it is helpful for facilitating sleep. Dangerous side effects can occur in overdose so its use must be carefully monitored. The clonidine patch or catapres transdermal therapeutic system (Catapres-TTS1, 2 and 3) should not be used in young children who might pull it off and eat it because this leads to a significant overdose. Clonidine should not be used in the patients with a history of cardiovascular disease or depression ( 109 ).

2.7. Obstructive sleep apnea

Obstructive sleep apnea (OSA) is characterized by repeat brief episodes of airflow obstruction in the oral-nasal airway that occurs during sleep ( 110 ). These episodes of complete airflow cessation (apnea) or partial airflow obstruction (hypopnea) result in both frequent and transient reduction of brain oxygen levels ( 111 ). It occurs more often during rapid eye movement (REM) sleep and is rarely proceed by body movements ( 112 ). The prevalence of OSA among normal children is about 0.8% to 2.8% ( 113 ); however, it can be higher among children with neurodevelopment problems including FXS ( 114 , 115 ). OSA-related symptoms included loud snoring, apnea, awakening with gasping breaths, enuresis and daytime sleepiness ( 116 , 117 ). OSA in children is associated with concentration deficits, reduce learning ability, lower cognitive function, and school difficulties. Vigilance impairments and neuropsychological deficits are among the main symptoms seen in OSA ( 118 ). Some studies suggest that vigilance impairment is attributed mostly to nocturnal hypoxemia ( 118 ). In addition to cognitive issues, a large number of studies found that OSA is associated with medical problems such as cardiac tissue changes as well as systolic and diastolic blood pressure changes. Previous reports suggest that children with OSA and hypertrophied tonsils tend to aspirate oropharyngeal secretion which can lead to pneumonia ( 119 ). The association of GERD with OSA has been documented previously, possible due to higher esophageal negative pressure which is generated by increased respiratory efforts ( 120 ). Studies suggest that in typically developing children, early diagnosis, and treatment of pediatric OSA may improve the child's long-term cognitive, social potential and school performance. The standard diagnostic procedure for establishing the presence of OSA is the overnight polysomnography (PSG) ( 120 ). Although overnight PSG can be very effective in diagnosing OSA, for some patients the test is labor-intensive. The management of OSA has three main aspects. The first step is drug therapy, which may alleviate adenoidal and tonsillar hypertrophy. The second is drainage of nasal secretions, and the third step is surgery. Adenoidectomy with or without tonsillectomy is the primary treatments for OSA and it is usually very effective for those with FXS ( 121 ). Continuous positive airway pressure (CPAP) is a feasible therapeutic intervention in children with neurodevelopment deficits including FXS, although it is reported that patients have a low compliance to this therapy ( 121 ).

2.8. Strabismus

Strabismus is one of the phenotypic characteristics in FXS and it is an abnormality of the ocular motility and deviation of the eyes away from binocular vision. Strabismus is better defined as exotropia, esotropia, hypotropia, and hypertropia which describe the orientation of the eyes. Exotropia is the most common type of strabismus found in FXS and it is thought to be caused by an asymmetrical tone of the extraocular muscles ( 122 ). Early studies reported the prevalence of strabismus in FXS ranging from 28 to 57% ( 123 – 125 ), however later studies found that the prevalence was only 4.4–8% ( 126 , 127 ) and a recent FXCRC study reported a prevalence of 17.5%. The initial higher rates are thought to be related to selection bias in the earlier studies. Nevertheless, the prevalence was significantly higher than the prevalence in typical children (2.6% vs . 4%) ( 128 , 129 ).

It is crucial to detect strabismus early in life because if left untreated strabismus may progress to amblyopia, a permanent decrease in visual acuity due to the disuse of the abnormal eye during visual development. Tests used to detect the strabismus are; corneal light reflex, cover/uncover test and simultaneous red reflex test. Once strabismus is detected, the child should be referred to a pediatric ophthalmologist for further evaluation and management. It is recommended that every child with FXS have a comprehensive ophthalmologic examination by age 4 or sooner if an abnormality is detected ( 130 ). The treatment of strabismus should improve vision impairment and alignment abnormalities. The vision impairment leading to amblyopia can be treated by occluding the preferred eye and correcting the refractive errors of the affected eye with eyeglasses. The ocular alignment can be corrected by visual training exercises, but surgery is needed in many cases ( 131 ).

2.9. Tic disorder

Tics disorders are generally classified according to the age of onset, duration, and severity of symptoms and the presence of vocal and/or motor tics ( 132 ). The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) lists three types of tic disorders: Tourette syndrome (TS), chronic motor or vocal tic disorder, and provisional (transient) tic disorder ( 133 ). The prevalence of transient tic disorders in children aged 13–14 years is from 3–15% and chronic motor tics ranges from 2–5% ( 134 – 136 ); however, tic disorders may be more frequent than the prevalence reported because many patients with tics do not seek medical attention ( 136 ).

The prevalence of tics in FXS differs among studies. Tics were reported in 16% of 152 people with FXS in a cohort study in the United States. Tic disorders are characterized by involuntary or semi-voluntary, sudden, brief and rapid, recurrent, repetitive, non-rhythmic, unpredictable, meaningless and stereotyped motor movements, such as, eye blinking, shoulder shrugging and throat clearing or sounds produced by moving air through the nose, mouth or throat (phonic or vocal tics) including swearing and complex expressions ( 136 ). Tics are not constant and appear in the background of normal motor activity, except for extremely severe cases ( 137 ). Tics disorders appear before 18 years of age and occur before taking stimulant medications in those FXS, however, tics may be unmasked or worsened by stimulants. An important step in the approach to the patient with tics is to rule out secondary causes of tics disorders. Drugs including stimulants, antidepressants, antihistamine and antiepileptic's may cause tics; tics disappear with the interruption of these medications ( 137 ). Treatment is not always necessary and only severe cases should be treated preferably with monotherapy at low doses ( 138 , 139 ). Usually clonidine or guanfacine use in FXS is effective for tics in FXS; however, most of the time tics are not severe and do not need medication treatment. Aripiprazole or risperidone may sometimes be helpful to treat tics in FXS ( 139 ).

2.10. Other Problems

Toileting issues are one of the most challenging problems for patients and their families. The problems include bowel and bladder control, washing and wiping abilities, and inclination to be toilet trained. Nearly half (48.8%) ( 140 ) of children with FXS had toileting problems and the time they were toilet-trained was delayed compared to the normal population. A study of functional skills of individuals with FXS showed that the majority of females with FXS could demonstrate toileting skills by age 11 to 15 years, while males by age 15 to 20 ( 141 ).

We must take into consideration that toilet training is a challenging task for parents even in typically developed children. The guidelines for toilet training for children with FXS are not different from those of typical children. The most important step is to start the training when the child is ready; the appropriate time to initiate the training should be based on developmental and behavioral milestones achievements rather than chronological age ( 142 ). Physicians should initiate conversations about this issue with the parents at a young age (∼1 year of age), it is also important to discuss with the family how to assess the child's readiness for toilet training in order to avoid maladaptive behaviors among other psychological problems associated with failed toileting training. Special concerns for children with FXS may be due to their increased anxiety, slow learning skills, sensory sensitivity and defensiveness ( 142 ). The steps for toilet training are deciding what words to use, picking a potty-chair, helping the child recognize signs of needing to use the potty-chair, making trips to the potty-chair as a routine, and encouraging the use of the potty-chair ( 143 ). Positive reinforcement, extinction, and a star-chart can be used as strategies in the training. During the training accidents should be expected, the parents should address these events lightly and avoid upsetting comments and negative reinforcement. Punishment and scolding will only make the training harder and may increase the time needed for toilet training. Creating a routine pattern and patience are keys to success in the training.

Other common problems in children with FXS mentioned by caregivers and physicians are sensory processing and integration issues. Sensory processing and integration have major roles in human development ( 144 ). Individuals with FXS have an enhanced sympathetic response to sensory stimuli ( 145 ), and the feel of a potty-chair. The sensation of evacuation is often anxiety provoking to children with FXS such that they may avoid these stimuli.

The sensory process has two important components which are sensory discrimination and sensory modulation. Sensory discrimination is the process in which sensory stimuli are distinguished, given their meaning and use. Problems with sensory discrimination can cause poor recognition and interpretation of sensory stimuli, which in turn may result in difficulties in sensory-motor skill development, such as, brushing teeth, climbing or riding a bike, being a picky eater, etc. Sensory modulation is how the sensory stimuli are used and responded to. Problems with this process can cause hyper-response, over-activity, poor attention and poor coping. The most common sensory modulation difficulty reported in FXS is hyperarousal. Examples of the processing problem are difficulty tolerating bright lights and loud noises, crowded places overstimulation, difficulty making good eye contact, and trouble tolerating certain clothes. These problems are related to a lack of normal habituation to a sensory stimulus seen in both electrodermal studies ( 145 ) and even on Functional Magnetic Resonance Imaging (fMRI) studies to recurrent direct or indirect eye contact ( 146 ).

To attain full assessment and treatment plans, a team approach is needed. The team usually includes occupational therapists, physical therapists, speech therapists, educators, psychologists, and physicians. The team can be adjusted for each individual's problems. There are many tools that have been proven useful and reliable for assessing an individual's condition such as the Sensory Profile questionnaire, the Sensory Processing Measure questionnaire, the Movement Assessment Battery for Children, the Quick Neurological Screening Test and the Berg Balance Scale ( 146 ). It is recommended that children with FXS should receive routine assessments from occupational therapists and receive occupational therapy at least twice a week during early development ( 66 ). The treatments are individualized for each patient's medical problem.

3. Discussion

Clinicians need to know that those with FXS are at risk for a wide range of medical problems other than ID, ADHD, and ASD that are so common in FXS. The diagnosis and treatment of the medical problems in FXS are described here and the treatment of behavioral problems are described elsewhere including the use of targeted treatments to reverse the cognitive and behavioral problems ( 147 , 148 ). Many of the medical problems in FXS, such as OM, MVP, GERD, hernias, joint dislocation, and flat feet are related to the connective tissue problems inherent in the syndrome. These connective tissue problems are related to the lack of FMRP on the structure of the elastin fibrils in the skin, heart, vessels and organs ( 149 ). These changes also relate to the soft and velvet like skin seen in FXS. Improvements in the looseness of connective tissue in FXS have been reported with the use of minocycline, a targeted treatment that lowers Matrix Metallopeptidase 9 (MMP9) levels. In FXS minocycline has been shown to be efficacious for behavior in children. Minocycline has also been used to treat aortic aneurisms because of the effects of pulling together connective tissue in cardiology studies so it may be helpful for dilated aortas in FXS, although this is rarely a problem. Most of these problems are treated symptomatically as described above and the response is usually good to such treatment ( Table 1 ). It is likely that the most severe medical problem in FXS, seizures, will also improve with targeted treatments, although the response to standard anticonvulsants is good as described above. The key to this treatment is early and aggressive intervention because ongoing seizures will further exacerbate ID and ASD severity. The future looks bright for not only reversing the cognitive and behavioral problems but also many of the medical problems of FXS with targeted treatments ( 150 ).

Acknowledgements

This work was supported by the NIH diversity supplement for the NICHD (HD036071), and also supported by grants from the National Fragile X Foundation and IDDRC (MIND Institute Intellectual and Developmental Disability) grant U54 HD 0791250.

Conflict of Interest:

Dr. Randi J Hagerman has received funding from Novartis, Roche, Alcobra and Neuren for carrying out treatment studies in fragile X syndrome, autism and Down syndrome. She has also consulted with Roche/Genentech and Novartis for treatment studies in fragile X syndrome.

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Public Health Literature Review of Fragile X Syndrome
The purpose of this systematic literature review is to describe what is known about fragile X syndrome (FXS) and to identify research gaps. The results can be used to help inform future public health research and provide pediatricians with up-to-date information about the implications of the condition for individuals and their families.
Public Health Literature Review of Fragile X Syndrome
PMC5621610. 10.1542/peds.2016-1159C. The purpose of this systematic literature review is to describe what is known about fragile X syndrome (FXS) and to identify research gaps. The results can be used to help inform future public health research and provide pediatricians with up-to-date information about the implications of the condition for ...
Public Health Literature Review of Fragile X Syndrome
The purpose of this systematic literature review is to describe what is known about fragile X syndrome (FXS) and to identify research gaps. The results can be used to help inform future public health research and provide pediatricians with up-to-date information about the implications of the condition for individuals and their families.METHODS:.
Research Gaps in Fragile X Syndrome: An Updated Literature Review to
The phenotypic impact of fragile X syndrome (FXS) has been well-documented since the discovery of the fragile X messenger ribonucleoprotein 1 gene 30 years ago. However, gaps remain in clinical and public health research. The purpose of this literature ...
Public Health Literature Review of Fragile X Syndrome
OBJECTIVES: The purpose of this systematic literature review is to describe what is known about fragile X syndrome (FXS) and to identify research gaps. The results can be used to help inform future public health research and provide pediatricians with up-to-date information about the implications of the condition for individuals and their families.
Public Health Literature Review of Fragile X Syndrome
OBJECTIVES The purpose of this systematic literature review is to describe what is known about fragile X syndrome (FXS) and to identify research gaps. The results can be used to help inform future public health research and provide pediatricians with up-to-date information about the implications of the condition for individuals and their families.
Public Health Literature Review of Fragile X Syndrome
The phenotypic impact of FXS has been welldocumented since the discovery of the FMR1 gene 30 years ago, including our own public health literature review that summarized research between 1991 and ...
Epidemiology of fragile X syndrome: a systematic review and meta
Abstract. Prevalence estimates for fragile X syndrome vary considerably. This systematic review and meta-analysis was conducted to provide an accurate prevalence estimate for this disorder using primary publications in PubMed, Embase, and the Cochrane library. Data were pooled using Bayesian fixed-effects and random-effects models.
PDF Research Gaps in Fragile X Syndrome: An Updated Literature Review to
Research Gaps in Fragile X Syndrome: An Updated Literature Review to Inform Clinical and Public Health Practice Melissa Raspa, PhD1,*, Anne Wheeler, ... gene 30 years ago, including our own public health literature review which summarized research between 1991 and 20141. The goal of the previous review was to identify what was
Research Gaps in Fragile X Syndrome: An Updated Literature Review to
Research Gaps in Fragile X Syndrome: An Updated Literature Review to Inform Clinical and Public Health Practice. ... The initial public health literature review identified several gaps regarding the impact on families of individuals with FXS given the complex nature of the FMR1 gene expansions. Families of individuals with FXS are unique; in ...
Research Gaps in Fragile X Syndrome: An Updated Literature Review to
Objective: The phenotypic impact of fragile X syndrome (FXS) has been well-documented since the discovery of the fragile X messenger ribonucleoprotein 1 gene 30 years ago. However, gaps remain in clinical and public health research. The purpose of this literature review was to determine the extent to which these gaps have been addressed and identify targeted areas of future research.
Research Gaps in Fragile X Syndrome: An Updated Literature Review to
Despite the progress in many areas of FXS research, work remains to address gaps in clinical and public health knowledge, including early detection and diagnosis, determinants of health, and development and implementation of targeted interventions. ABSTRACT: Objective: The phenotypic impact of fragile X syndrome (FXS) has been well-documented since the discovery of the fragile X messenger ...
Research gaps in fragile x syndrome: An updated literature review to
OBJECTIVE: The phenotypic impact of fragile X syndrome (FXS) has been well-documented since the discovery of the fragile X messenger ribonucleoprotein 1 gene 30 years ago. However, gaps remain in clinical and public health research.
The Future of Fragile X Syndrome: CDC Stakeholder Meeting Summary
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. ... Raspa M, Wheeler A, Riley C. Public health literature review of ...
Research Gaps in Fragile X Syndrome: An Updated Literature Review to
(J Dev Behav Pediatr 44:e56 - e65, 2023) Index terms: fragile X syndrome, clinical phenotype, public health needs, treatment, family needs. F ragile X syndrome (FXS) is t he lea din g know n sin ...
Public Health Literature Review of Fragile X Syndrome
The purpose of this systematic literature review is to describe what is known about fragile X syndrome (FXS) and to identify research gaps. The results can be used to help inform future public health research and provide pediatricians with up-to-date information about the implications of the condition for individuals and their families.
Fragile X Syndrome
Fragile X syndrome (FXS), also known as Martin-Bell syndrome in the past, is a non-Mendelian trinucleotide repeat disorder. FXS is the most prevalent inherited cause of mild-to-severe intellectual disability and the most common monogenic cause of autism spectrum disorder.[1][2] It accounts for about one-half of cases of X-linked intellectual disability and is the most common cause of mental ...
PDF HHS Public Access Anne C. Wheeler, PhD , and Catharine Riley, PhD, MPH
Public Health Literature Review of Fragile X Syndrome Melissa Raspa, PhDa, Anne C. Wheeler, PhDa, and Catharine Riley, PhD, MPHb aRTI International, Research Triangle Park, North Carolina bNational Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia Abstract OBJECTIVES—The purpose of this systematic literature review is to ...
Research Gaps in Fragile X Syndrome: An Updated Literature R ...
The results from the systemic review are organized based on the research gaps identified in the previous literature review. Fragile X Syndrome Phenotype and Subtypes ... The initial public health literature review identified several gaps regarding the impact on families of individuals with FXS given the complex nature of the FMR1 gene ...
Public Health Literature Review of Fragile X Syndrome
The Committee on Genetics public health and clinical importance interventions and treatment topic published a clinical report on the in FXS guided the systematic search combined either "fragile comprehensive genetic evaluation of literature review: (1) epidemiology, X syndrome," or "fragile X," with children with general development (2 ...
Research Gaps in Fragile X Syndrome: An Updated Literature Review to
Objective The phenotypic impact of fragile X syndrome (FXS) has been well-documented since the discovery of the FMR1 gene 30 years ago. However, gaps remain in clinical and public health research. The purpose of this literature review was to determine the extent to which these gaps have been addressed and identify targeted areas of future research.
Fragile X syndrome
Fragile X syndrome is one of the most common genetic causes of learning disability. ... RCGP (2020a) Syndrome specific medical health check guide - Fragile X syndrome (FXS). Available ... Song FJ, Barton P, Sleightholme V, et al.(2003) Screening for fragile X syndrome: A literature review and modelling study. Health Technology Assessment 7(16 ...
Fragile X syndrome: A review of clinical management
Summary. The fragile X mental retardation 1 gene, which codes for the fragile X mental retardation 1 protein, usually has 5 to 40 CGG repeats in the 5′ untranslated promoter. The full mutation is the almost always the cause of fragile X syndrome (FXS). The prevalence of FXS is about 1 in 4,000 to 1 in 7,000 in the general population although ...

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Cognitive Development and Academic Skills

Language Development

Prelinguistic

Functional Skills

Transition to Adulthood

Cooccurring Psychiatric Diagnoses

Other Behavioral Problems

Physical Features

Other Medical and Health Problems

Physiologic Features

Behavioral Interventions

Cognitive/Educational Interventions

Allied Health Services

Pharmacologic Treatments

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Aggression and Mood Symptoms

Next Generation Treatments

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Developmental Profile

Language Development

Prelinguistic

Functional Skills

Transition to Adulthood

Social-Emotional Profile

Other Behavioral Problems

Medical Profile

Other Medical and Health Problems

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Cognitive/Educational Interventions

Allied Health Services

Pharmacologic Treatments

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Language Skills Influence Transition Planning in Adolescents With Fragile X Syndrome.

Cognition, academic achievement, and adaptive behavior in school-aged girls with fragile X syndrome.

Brain Mitochondrial Bioenergetics in Genetic Neurodevelopmental Disorders: Focus on Down, Rett and Fragile X Syndromes.

Vector enabled CRISPR gene editing - A revolutionary strategy for targeting the diversity of brain pathologies.

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