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Brain Sciences Jan 2019Executive function (EF) supports goal-directed behavior and includes key aspects such as working memory, inhibitory control, cognitive flexibility, attention, processing... (Review)
Review
Executive function (EF) supports goal-directed behavior and includes key aspects such as working memory, inhibitory control, cognitive flexibility, attention, processing speed, and planning. Fragile X syndrome (FXS) is the leading inherited monogenic cause of intellectual disability and is phenotypically characterized by EF deficits beyond what is expected given general cognitive impairments. Yet, a systematic review of behavioral studies using performance-based measures is needed to provide a summary of EF deficits across domains in males and females with FXS, discuss clinical and biological correlates of these EF deficits, identify critical limitations in available research, and offer suggestions for future studies in this area. Ultimately, this review aims to advance our understanding of the underlying pathophysiological mechanisms contributing to EF in FXS and to inform the development of outcome measures of EF and identification of new treatment targets in FXS.
PubMed: 30654486
DOI: 10.3390/brainsci9010015 -
Genes Jan 2022Fragile X syndrome (FXS) causes intellectual disability and is the known leading cause of autism. Common problems in FXS include behavior and social problems. Along with... (Review)
Review
Fragile X syndrome (FXS) causes intellectual disability and is the known leading cause of autism. Common problems in FXS include behavior and social problems. Along with syndromic characteristics and autism comorbidity, environmental factors might influence these difficulties. This systematic review focuses on the last 20 years of studies concerning behavior and social problems in FXS, considering environmental and personal variables that might influence both problems. Three databases were reviewed, leading to fifty-one studies meeting the inclusion criteria. Attention deficit hyperactivity disorder (ADHD) problems remain the greatest behavior problems, with behavioral problems and social competence being stable during the 20 years. Some developmental trajectories might have changed due to higher methodological control, such as aggressive behavior and attention problems. The socialization trajectory from childhood to adolescence remains unclear. Comorbidity with autism in individuals with FXS increased behavior problems and worsened social competence profiles. At the same time, comparisons between individuals with comorbid FXS and autism and individuals with autism might help define the comorbid phenotype. Environmental factors and parental characteristics influenced behavior problems and social competence. Higher methodological control is needed in studies including autism symptomatology and parental characteristics. More studies comparing autism in FXS with idiopathic autism are needed to discern differences between conditions.
Topics: Autistic Disorder; Child; Fragile X Syndrome; Humans; Intellectual Disability; Problem Behavior; Social Skills
PubMed: 35205326
DOI: 10.3390/genes13020280 -
Journal of Neurodevelopmental Disorders Jul 2021Whilst up to 60% of males with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD), the prevalence and nature of ASD in females with FXS remains... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Whilst up to 60% of males with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD), the prevalence and nature of ASD in females with FXS remains unclear.
METHOD
A systematic literature search identified papers reporting ASD prevalence and/or symptomatology in females with FXS.
RESULTS AND CONCLUSION
Meta-analysis suggested that rates of ASD for females with FXS are reliably higher than for females in the general population (a random effects model estimated weighted average prevalence at 14%, 95% CI 13-18%). Whilst papers highlighted a number of social and repetitive difficulties for females with FXS, characteristic profiles of impairment are not clear. Possible associations between ASD traits and IQ, and between ASD and levels of fragile X mental retardation protein, are suggested, but data are equivocal.
Topics: Autism Spectrum Disorder; Female; Fragile X Syndrome; Humans; Male; Prevalence
PubMed: 34294028
DOI: 10.1186/s11689-021-09362-5 -
BMC Neurology Oct 2009Fragile X syndrome (FXS) is considered the most common cause of inherited mental retardation. Affected people have mental impairment that can include Attention Deficit... (Review)
Review
BACKGROUND
Fragile X syndrome (FXS) is considered the most common cause of inherited mental retardation. Affected people have mental impairment that can include Attention Deficit and/or Hyperactivity Disorder (ADHD), autism disorder, and speech and behavioural disorders. Several pharmacological interventions have been proposed to treat those impairments.
METHODS
Systematic review of the literature and summary of the evidence from clinical controlled trials that compared at least one pharmacological treatment with placebo or other treatment in individuals with diagnosis of FXS syndrome and assessed the efficacy and/or safety of the treatments. Studies were identified by a search of PubMed, EMBASE and the Cochrane Databases using the terms fragile X and treatment. Risk of bias of the studies was assessed by using the Cochrane Collaboration criteria.
RESULTS
The search identified 276 potential articles and 14 studies satisfied inclusion criteria. Of these, 10 studies on folic acid (9 with crossover design, only 1 of them with good methodological quality and low risk of bias) did not find in general significant improvements. A small sample size trial assessed dextroamphetamine and methylphenidate in patients with an additional diagnosis of ADHD and found some improvements in those taking methylphenidate, but the length of follow-up was too short. Two studies on L-acetylcarnitine, showed positive effects and no side effects in patients with an additional diagnosis of ADHD. Finally, one study on patients with an additional diagnosis of autism assessed ampakine compound CX516 and found no significant differences between treatment and placebo. Regarding safety, none of the studies that assessed that area found relevant side effects, but the number of patients included was too small to detect side effects with low incidence.
CONCLUSION
Currently there is no robust evidence to support recommendations on pharmacological treatments in patients with FXS in general or in those with an additional diagnosis of ADHD or autism.
Topics: Acetylcarnitine; Dioxoles; Folic Acid; Fragile X Syndrome; Humans; Methylphenidate; Piperidines; Treatment Outcome
PubMed: 19822023
DOI: 10.1186/1471-2377-9-53 -
Genetics in Medicine : Official Journal... Jul 2010To conduct a systematic review of literature regarding population-based screening for fragile X syndrome in newborns and women of reproductive age, either before or... (Review)
Review
PURPOSE
To conduct a systematic review of literature regarding population-based screening for fragile X syndrome in newborns and women of reproductive age, either before or during pregnancy.
METHODS
Seven electronic databases were searched for English language studies published between January 1991 and November 2009. Data extraction was performed for all included studies. Results were synthesized using a narrative approach.
RESULTS
One article that examined offering newborn screening for fragile X syndrome and 10 that examined the offer of fragile X syndrome screening to women of reproductive age were identified. Two of these articles also addressed psychosocial aspects of population screening for fragile X syndrome such as attitudes to screening and experiences of screening, and a further nine addressed these issues alone. Studies exploring psychosocial issues demonstrated challenges for counseling arising from a lack of awareness or personal experience with fragile X syndrome in the general population.
CONCLUSIONS
Targeted counseling and educational strategies will be essential to support women from the general population. It is crucial that future studies offering screening for fragile X syndrome explore a range of psychosocial aspects in addition to looking at uptake of testing and mutation frequency.
Topics: Female; Fragile X Syndrome; Genetic Testing; Humans; Infant, Newborn; Neonatal Screening; Pregnancy; Prenatal Diagnosis
PubMed: 20548240
DOI: 10.1097/GIM.0b013e3181e38fb6 -
Neuroscience and Biobehavioral Reviews Aug 2022Predictive models are essential for advancing knowledge of brain disorders. High variation in study outcomes hampers progress. To address the validity of predictive... (Meta-Analysis)
Meta-Analysis Review
Predictive models are essential for advancing knowledge of brain disorders. High variation in study outcomes hampers progress. To address the validity of predictive models, we performed a systematic review and meta-analysis on behavioural phenotypes of the knock-out rodent model for Fragile X syndrome according to the PRISMA reporting guidelines. In addition, factors accountable for the heterogeneity between findings were analyzed. The knock-out model showed good translational validity and replicability for hyperactivity, cognitive and seizure phenotypes. Despite low replicability, translational validity was also found for social behaviour and sensory sensitivity, but not for attention, aggression and cognitive flexibility. Anxiety, acoustic startle and prepulse inhibition phenotypes, despite low replicability, were opposite to patient symptomatology. Subgroup analyses for experimental factors moderately explain the low replicability, these analyses were hindered by under-reporting of methodologies and environmental conditions. Together, the model has translational validity for most clinical phenotypes, but caution must be taken due to low effect sizes and high inter-study variability. These findings should be considered in view of other rodent models in preclinical research.
Topics: Animal Experimentation; Animals; Disease Models, Animal; Fragile X Mental Retardation Protein; Fragile X Syndrome; Mice; Mice, Knockout; Rodentia
PubMed: 35690123
DOI: 10.1016/j.neubiorev.2022.104722 -
Pediatrics Jun 2017The 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... (Review)
Review
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), 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.
CONCLUSIONS
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.
Topics: Adult; Caregivers; Child; Cross-Sectional Studies; DNA Mutational Analysis; Delivery of Health Care; Developmental Disabilities; Diagnosis, Differential; Female; Fragile X Mental Retardation Protein; Fragile X Syndrome; Genetic Testing; Humans; Language Development Disorders; Male; Parenting; Phenotype; Prognosis; Public Health; Social Adjustment; Trinucleotide Repeats
PubMed: 28814537
DOI: 10.1542/peds.2016-1159C -
Ontario Health Technology Assessment... 2023We conducted a health technology assessment to evaluate the safety, effectiveness, and cost-effectiveness of carrier screening programs for cystic fibrosis (CF), fragile...
BACKGROUND
We conducted a health technology assessment to evaluate the safety, effectiveness, and cost-effectiveness of carrier screening programs for cystic fibrosis (CF), fragile X syndrome (FXS), hemoglobinopathies and thalassemia, and spinal muscular atrophy (SMA) in people who are considering a pregnancy or who are pregnant. We also evaluated the budget impact of publicly funding carrier screening programs, and patient preferences and values.
METHODS
We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Cochrane Risk of Bias tool and the Risk of Bias Assessment tool for Non-randomized Studies (RoBANS), and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search and conducted cost-effectiveness analyses comparing preconception or prenatal carrier screening programs to no screening. We considered four carrier screening strategies: 1) universal screening with standard panels; 2) universal screening with a hypothetical expanded panel; 3) risk-based screening with standard panels; and 4) risk-based screening with a hypothetical expanded panel. We also estimated the 5-year budget impact of publicly funding preconception or prenatal carrier screening programs for the given conditions in Ontario. To contextualize the potential value of carrier screening, we spoke with 22 people who had sought out carrier screening.
RESULTS
We included 107 studies in the clinical evidence review. Carrier screening for CF, hemoglobinopathies and thalassemia, FXS, and SMA likely results in the identification of couples with an increased chance of having an affected pregnancy (GRADE: Moderate). Screening likely impacts reproductive decision-making (GRADE: Moderate) and may result in lower anxiety among pregnant people, although the evidence is uncertain (GRADE: Very low).We included 21 studies in the economic evidence review, but none of the study findings were directly applicable to the Ontario context. Our cost-effectiveness analyses showed that in the short term, preconception or prenatal carrier screening programs identified more at-risk pregnancies (i.e., couples that tested positive) and provided more reproductive choice options compared with no screening, but were associated with higher costs. While all screening strategies had similar values for health outcomes, when comparing all strategies together, universal screening with standard panels was the most cost-effective strategy for both preconception and prenatal periods. The incremental cost-effectiveness ratios (ICERs) of universal screening with standard panels compared with no screening in the preconception period were $29,106 per additional at-risk pregnancy detected and $367,731 per affected birth averted; the corresponding ICERs in the prenatal period were about $29,759 per additional at-risk pregnancy detected and $431,807 per affected birth averted.We estimated that publicly funding a universal carrier screening program in the preconception period over the next 5 years would require between $208 million and $491 million. Publicly funding a risk-based screening program in the preconception period over the next 5 years would require between $1.3 million and $2.7 million. Publicly funding a universal carrier screening program in the prenatal period over the next 5 years would require between $128 million and $305 million. Publicly funding a risk-based screening program in the prenatal period over the next 5 years would require between $0.8 million and $1.7 million. Accounting for treatment costs of the screened health conditions resulted in a decrease in the budget impact of universally provided carrier screening programs or cost savings for risk-based programs.Participants value the perceived potential positive impact of carrier screening programs such as medical benefits from early detection and treatment, information for reproductive decision-making, and the social benefit of awareness and preparation. There was a strong preference expressed for thorough, timely, unbiased information to allow for informed reproductive decision-making.
CONCLUSIONS
Carrier screening for CF, FXS, hemoglobinopathies and thalassemia, and SMA is effective at identifying at-risk couples, and test results may impact preconception and reproductive decision-making.The cost-effectiveness and budget impact of carrier screening programs are uncertain for Ontario. Over the short term, carrier screening programs are associated with higher costs, and also higher chances of detecting at-risk pregnancies compared with no screening. The 5-year budget impact of publicly funding universal carrier screening programs is larger than that of risk-based programs. However, accounting for treatment costs of the screened health conditions results in a decrease in the total additional costs for universal carrier screening programs or in cost savings for risk-based programs.The people we spoke with who had sought out carrier screening valued the potential medical benefits of early detection and treatment, particularly the support and preparation for having a child with a potential genetic condition.
Topics: Child; Female; Humans; Pregnancy; Cystic Fibrosis; Fragile X Syndrome; Hemoglobinopathies; Muscular Atrophy, Spinal; Technology Assessment, Biomedical; Thalassemia
PubMed: 37637488
DOI: No ID Found -
The Cochrane Database of Systematic... May 2015People with fragile X syndrome (FXS) have an intellectual dysfunction that can range from very mild to severe. Symptoms can include speech and language delays and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
People with fragile X syndrome (FXS) have an intellectual dysfunction that can range from very mild to severe. Symptoms can include speech and language delays and behavioural difficulties such as aggression or self injurious behaviours, emotional lability, and anxiety-related problems (for example obsessive-compulsive symptoms and perseverative behaviours). In some cases, affected people may have an additional diagnosis of attention deficit hyperactivity disorder or an autism spectrum disorder.
OBJECTIVES
To review the efficacy and safety of L-acetylcarnitine in improving the psychological, intellectual, and social performance of people with FXS.
SEARCH METHODS
In May 2015 we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PsycINFO, Web of Science, and two other databases. We also searched three trials registers, four theses databases, and the reference lists of relevant studies and reviews.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that assessed the efficacy of L-acetylcarnitine, at any dose, in people of any age diagnosed with FXS compared with placebo.
DATA COLLECTION AND ANALYSIS
For each trial, two review authors independently extracted data on the children included and interventions compared, and assessed the risk of bias of the studies across the following domains: randomisation sequence generation, allocation concealment, blinding (of participants, personnel, and outcome assessors), incomplete outcome data, selective outcome reporting, and other potential sources of bias.
MAIN RESULTS
We found only two RCTs that compared oral L-acetylcarnitine (LAC) with oral placebo in children with FXS. The studies included a total of 83 participants, all of them male, who were treated and followed for one year. The age of participants at the start of treatment ranged from 6 to 13 years, with a mean age of 9 years. Neither study provided information on randomisation, allocation concealment procedures, or blinding of outcome assessment, and we received no responses from the authors we emailed for clarification. We therefore rated studies as being at unclear risk of bias on these domains. We judged both studies to be at low risk of bias for blinding of participants and personnel, incomplete outcome data, and selective reporting, but to be at high risk of other bias, as at least one study was funded by a drug company, and in both studies people working for the company were part of the research team.We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to rate the quality of the available evidence. Overall, the quality of the evidence was low due to the imprecision of results and high risk of other bias.Regarding the primary outcome of psychological and learning capabilities, both studies assessed the effect of interventions on children's verbal and non-verbal intellectual functioning using the Wechsler Intelligence Scale for Children - Revised. The authors did not provide detailed data on those results but said that they found no important differences between treatment and placebo.Both studies evaluated the impact of the treatment on hyperactive behaviour using the Conners' Abbreviated Parent-Teacher Questionnaire. In one study, teachers' assessments of the children found no clear evidence of a difference (mean difference (MD) 0.50, 95% confidence interval (CI) -5.08 to 6.08, n = 51; low-quality evidence). The other study stated that there were no differences between treated and untreated participants, but did not provide detailed data for inclusion in the meta-analysis.Parents' assessments favoured LAC in one study (MD -0.57, 95% CI -0.94 to -0.19, n = 17; low-quality evidence), but not in the other (MD -2.80, 95% CI -7.61 to 2.01, n = 51; low-quality evidence), though changes were not large enough to be considered clinically relevant.Regarding social skills, one study reported no clear evidence of a difference in Vineland Adaptive Behavior composite scores (MD 8.20, 95% CI -0.02 to 16.42, n = 51; low-quality evidence), yet results in the socialisation domain favoured LAC (MD 11.30, 95% CI 2.52 to 20.08, n = 51; low-quality evidence).Both studies assessed the safety of the active treatment and recorded no side effects. Neither of the included studies assessed the secondary outcome of caregiver burden.
AUTHORS' CONCLUSIONS
Low-quality evidence from two small trials showed that when compared to placebo, LAC may not improve intellectual functioning or hyperactive behaviour in children with FXS.
Topics: Acetylcarnitine; Administration, Oral; Adolescent; Attention Deficit Disorder with Hyperactivity; Child; Fragile X Syndrome; Humans; Male; Randomized Controlled Trials as Topic; Vitamin B Complex
PubMed: 25985235
DOI: 10.1002/14651858.CD010012.pub2 -
Revista de Neurologia Oct 2022Nearly 60% of those diagnosed with fragile X syndrome show comorbidity with autism. Thus, there are similarities and differences between both conditions that lead to...
INTRODUCTION
Nearly 60% of those diagnosed with fragile X syndrome show comorbidity with autism. Thus, there are similarities and differences between both conditions that lead to very different clinical manifestations. However, an early differential diagnosis may help professionals to detect deficits and enhance strengths to apply the best suitable intervention. The purpose of this scoping review was to provide a comprehensive overview of the relation and the differences between autism and fragile X syndrome to orientate diagnosis and intervention.
MATERIALS AND METHODS
The research for articles was carried out in PsycInfo, Medline, SCOPUS and Web of Science, including scientific articles published from 2010 to 2020 and children aged 0-6 years. The scoping review followed the PRISMA-ScR criteria.
RESULTS
22 studies were selected. Results were reviewed in terms of structural and morphological changes and cognitive, communicative, social-emotional and sensory-motor skills.
CONCLUSIONS
Different growing cerebral patterns are observed in both conditions. Besides, there are early signs from the different developmental areas studied that show comorbidity or allow early differentiation. However, attentional function or repetitive mannerisms, among others, need further research.
Topics: Autism Spectrum Disorder; Autistic Disorder; Child; Diagnosis, Differential; Fragile X Syndrome; Humans; Motor Skills
PubMed: 36218252
DOI: 10.33588/rn.7508.2022074