Mitochondrial dysfunction in brain tissues and Extracellular Vesicles Fragile X-associated tremor/ataxia syndrome.

OBJECTIVE: Mitochondrial impairments have been implicated in the pathogenesis of Fragile X-associated tremor/ataxia syndrome (FXTAS) based on analysis of mitochondria in peripheral tissues and cultured cells. We sought to assess whether mitochondrial abnormalities present in postmortem brain tissues of patients with FXTAS are also present in plasma neuron-derived extracellular vesicles (NDEVs) from living carriers of fragile X messenger ribonucleoprotein1 (FMR1) gene premutations at an early asymptomatic stage of the disease continuum. METHODS: We utilized postmortem frozen cerebellar and frontal cortex samples from a cohort of eight patients with FXTAS and nine controls and measured the quantity and activity of the mitochondrial proteins complex IV and complex V. In addition, we evaluated the same measures in isolated plasma NDEVs by selective immunoaffinity capture targeting L1CAM from a separate cohort of eight FMR1 premutation carriers and four age-matched controls. RESULTS: Lower complex IV and V quantity and activity were observed in the cerebellum of FXTAS patients compared to controls, without any differences in total mitochondrial content. No patient-control differences were observed in the frontal cortex. In NDEVs, FMR1 premutation carriers compared to controls had lower activity of Complex IV and Complex V, but higher Complex V quantity. INTERPRETATION: Quantitative and functional abnormalities in mitochondrial electron transport chain complexes IV and V seen in the cerebellum of patients with FXTAS are also manifest in plasma NDEVs of FMR1 premutation carriers. Plasma NDEVs may provide further insights into mitochondrial pathologies in this syndrome and could potentially lead to the development of biomarkers for predicting symptomatic FXTAS among premutation carriers and disease monitoring.

Enlarged perivascular spaces and their association with motor, cognition, MRI markers and cerebrovascular risk factors in male fragile X premutation carriers.

FMR1 premutation carriers (55-200 CGG repeats) are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a neurodegenerative disorder associated with motor and cognitive impairment. Bilateral hyperintensities of the middle cerebellar peduncles (MCP sign) are the major radiological hallmarks of FXTAS. In the general population, enlarged perivascular spaces (PVS) are biomarkers of small vessel disease and glymphatic dysfunction and are associated with cognitive decline. Our aim was to determine if premutation carriers show higher ratings of PVS than controls and whether enlarged PVS are associated with motor and cognitive impairment, MRI features of neurodegeneration, cerebrovascular risk factors and CGG repeat length. We evaluated 655 MRIs (1-10 visits/participant) from 229 carriers (164 with FXTAS and 65 without FXTAS) and 133 controls. PVS in the basal ganglia (BG-EPVS), centrum semiovale, and midbrain were evaluated with a semiquantitative scale. Mixed-effects models were used for statistical analysis adjusting for age. In carriers with FXTAS, we revealed that (1) BG-PVS ratings were higher than those of controls and carriers without FXTAS; (2) BG-PVS severity was associated with brain atrophy, white matter hyperintensities, enlarged ventricles, FXTAS stage and abnormal gait; (3) age-related increase in BG-PVS was associated with cognitive dysfunction; and (4) PVS ratings of all three regions showed robust associations with CGG repeat length and were higher in carriers with the MCP sign than carriers without the sign. This study demonstrates clinical relevance of PVS in FXTAS especially in the basal ganglia region and suggests microangiopathy and dysfunctional cerebrospinal fluid circulation in FXTAS physiopathology.

Navigating the outcome maze: a scoping review of outcomes and instruments in clinical trials in genetic neurodevelopmental disorders and intellectual disability.

Background: Individuals with genetic neurodevelopmental disorders (GNDs) or intellectual disability (ID) are often affected by complex neuropsychiatric comorbidities. Targeted treatments are increasingly available, but due to the heterogeneity of these patient populations, choosing a key outcome and corresponding outcome measurement instrument remains challenging. Objectives: The aim of this scoping review was to describe the research on outcomes and instruments used in clinical trials in GNDs and ID. Eligibility criteria: Clinical trials in individuals with GNDs and ID for any intervention over the past 10 years were included in the review. Sources of evidence: MEDLINE, PsycINFO, and Cochrane CENTRAL were searched. Titles and abstracts were independently screened for eligibility with a subsample of 10% double-screening for interrater reliability. Data from full texts were independently reviewed. Discrepancies were discussed until consensus was reached. Charting methods: Information was recorded on patient populations, interventions, designs, outcomes, measurement instruments, and type of reporter when applicable. Qualitative and descriptive analyses were performed. Results: We included 312 studies reporting 91 different outcomes, with cognitive function most frequently measured (28%). Various outcome measurement instruments (n = 457) were used, with 288 in only a single clinical trial. There were 18 genetic condition-specific instruments and 16 measures were designed ad-hoc for one particular trial. Types of report included proxy-report (39%), self-report (22%), clinician-report (16%), observer-report (6%), self-assisted report (1%), or unknown (16%). Conclusion: This scoping review of current practice reveals a myriad of outcomes and outcome measurement instruments for clinical trials in GNDs and ID. This complicates generalization, evidence synthesis, and evaluation. It underlines the need for consensus on suitability, validity, and relevancy of instruments, ultimately resulting in a core outcome set. A series of steps is proposed to move from the myriad of measures to a more unified approach.

Navigating the maze of outcome measures in rare disorders Treatments for genetic neurodevelopmental disorders and intellectual disability are increasingly available. However, it is hard to find appropriate instruments to measure whether these treatments are working. This hampers research and means some patients might not get the treatment they need. This scoping review provides an overview of investigated outcomes in this group, and with which instruments these are measured. It reveals that many different and overlapping outcomes are measured, complicating gathering, combining, and comparing of evidence. This scoping review underlines the need for harmonization and consensus on suitability, validity, and relevancy. Steps are proposed to move from the maze of outcome measures to a unified approach. Also, we provided recommendations for researchers to measure what matters to affected individuals and patient-centered care.

Developmental Associations between Cognition and Adaptive Behavior in Intellectual and Developmental Disability.

Background: Intellectual and developmental disabilities (IDDs) are associated with both cognitive challenges and difficulties in conceptual, social, and practical areas of living (DSM-5). Individuals with IDD often present with an intellectual disability in addition to a developmental disability such as autism or Down syndrome. Those with IDD may present with deficits in intellectual functioning as well as adaptive functioning that interfere with independence and living skills. The present study sought to examine associations of longitudinal developmental change in domains of cognition (NIH Toolbox Cognition Battery, NIHTB-CB) and adaptive behavior domains (Vineland Adaptive Behavior Scales-3; VABS-3) including Socialization, Communication, and Daily Living Skills (DLS) over a two-year period. Methods: Eligible participants for this multisite longitudinal study included those who were between 6 and 26 years at Visit 1, and who had a diagnosis of, or suspected intellectual disability (ID), including borderline ID. Three groups were recruited, including those with fragile X syndrome, Down syndrome, and other/idiopathic intellectual disability. In order to examine the association of developmental change between cognitive and adaptive behavior domains, bivariate latent change score (BLCS) models were fit to compare change in the three cognitive domains measured by the NIHTB-CB (Fluid, Crystallized, Composite) and the three adaptive behavior domains measured by the VABS-3 (Communication, DLS, and Socialization). Results: Over a two-year period, change in cognition (both Crystalized and Composite) was significantly and positively associated with change in daily living skills. Also, baseline cognition level predicted growth in adaptive behavior, however baseline adaptive behavior did not predict growth in cognition in any model. Conclusions: The present study demonstrated that developmental improvements in cognition and adaptive behavior are associated in children and young adults with IDD, indicating the potential for cross-domain effects of intervention. Notably, improvements in Daily Living Skills on the VABS-3 emerged as a primary area of adaptive behavior that positively related to improvements in cognition. This work provides evidence for the clinical, "real life" meaningfulness of the NIHTB-CB in IDD, and important empirical support for the NIHTB-CB as a fit-for-purpose performance-based outcome measure for this population.

FMR1 Carriers Report Executive Function Changes Prior to Fragile X-Associated Tremor/Ataxia Syndrome: A Longitudinal Study.

BACKGROUND: Men with fragile X-associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross-sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies has made it difficult to address this hypothesis. OBJECTIVE: To determine whether executive function deterioration experienced by premutation carriers (PC) in daily life precedes and predicts FXTAS. METHODS: This study included 66 FMR1 PC ranging from 40 to 78 years (mean, 59.5) and 31 well-matched healthy controls (HC) ages 40 to 75 (mean, 57.7) at baseline. Eighty-four participants returned for 2 to 5 follow up visits over a duration of 1 to 9 years (mean, 4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was completed by participants and their spouses/partners at each visit. RESULTS: Longitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self-initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, increased self-report executive function problems at baseline significantly predicted later development of FXTAS. CONCLUSIONS: Executive function changes experienced by male PC represent a prodrome of the later movement disorder. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

iBehavior-a preliminary proof of concept study of a smartphone-based tool for the assessment of behavior change in neurodevelopmental disabilities.

Purpose: The purpose of the present study was to describe the content and function of iBehavior, a smartphone-based caregiver-report electronic ecological momentary assessment (eEMA) tool developed to assess and track behavior change in people with intellectual and developmental disabilities (IDDs), and to examine its preliminary validity. Methods: Ten parents of children (ages of 5-17 years) with IDDs (n = 7 with fragile X syndrome; n = 3 with Down syndrome) rated their child's behavior (aggression and irritability, avoidant and fearful behavior, restricted and repetitive behavior and interests, and social initiation) using iBehavior once daily for 14 days. At the conclusion of the 14-day observation period, parents completed traditional rating scales as validation measures, as well as a user feedback survey. Results: Across the 140 possible observations, 8 were skipped, leading to a 94% response rate over 10 participants' observation periods. Participants also completed 100% of items for each of their logged observations. Parent ratings using iBehavior showed emerging evidence of convergent validity among domains with traditional rating scales including the Behavior Rating Inventory of Executive Function 2 (BRIEF-2), and Aberrant Behavior Checklist-Community (ABC-C). iBehavior was feasible in the sample, and parent feedback indicated high overall satisfaction. Conclusion: Results of the present pilot study indicate successful implementation and preliminary feasibility and validity of an eEMA tool for use as a behavioral outcome measure in IDDs.

Blood Proteome Profiling Reveals Biomarkers and Pathway Alterations in Fragile X PM at Risk for Developing FXTAS.

Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is a neurodegenerative disorder associated with the FMR1 premutation. Currently, it is not possible to determine when and if individual premutation carriers will develop FXTAS. Thus, with the aim to identify biomarkers for early diagnosis, development, and progression of FXTAS, along with associated dysregulated pathways, we performed blood proteomic profiling of premutation carriers (PM) who, as part of an ongoing longitudinal study, emerged into two distinct groups: those who developed symptoms of FXTAS (converters, CON) over time (at subsequent visits) and those who did not (non-converters, NCON). We compared these groups to age-matched healthy controls (HC). We assessed CGG repeat allele size by Southern blot and PCR analysis. The proteomic profile was obtained by liquid chromatography mass spectrometry (LC-MS/MS). We identified several significantly differentiated proteins between HC and the PM groups at Visit 1 (V1), Visit 2 (V2), and between the visits. We further reported the dysregulated protein pathways, including sphingolipid and amino acid metabolism. Our findings are in agreement with previous studies showing that pathways involved in mitochondrial bioenergetics, as observed in other neurodegenerative disorders, are significantly altered and appear to contribute to the development of FXTAS. Lastly, we compared the blood proteome of the PM who developed FXTAS over time with the CSF proteome of the FXTAS patients recently reported and found eight significantly differentially expressed proteins in common. To our knowledge, this is the first report of longitudinal proteomic profiling and the identification of unique biomarkers and dysregulated protein pathways in FXTAS.

Insight and Recommendations for Fragile X-Premutation-Associated Conditions from the Fifth International Conference on FMR1 Premutation.

The premutation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene is characterized by an expansion of the CGG trinucleotide repeats (55 to 200 CGGs) in the 5' untranslated region and increased levels of FMR1 mRNA. Molecular mechanisms leading to fragile X-premutation-associated conditions (FXPAC) include cotranscriptional R-loop formations, FMR1 mRNA toxicity through both RNA gelation into nuclear foci and sequestration of various CGG-repeat-binding proteins, and the repeat-associated non-AUG (RAN)-initiated translation of potentially toxic proteins. Such molecular mechanisms contribute to subsequent consequences, including mitochondrial dysfunction and neuronal death. Clinically, premutation carriers may exhibit a wide range of symptoms and phenotypes. Any of the problems associated with the premutation can appropriately be called FXPAC. Fragile X-associated tremor/ataxia syndrome (FXTAS), fragile X-associated primary ovarian insufficiency (FXPOI), and fragile X-associated neuropsychiatric disorders (FXAND) can fall under FXPAC. Understanding the molecular and clinical aspects of the premutation of the FMR1 gene is crucial for the accurate diagnosis, genetic counseling, and appropriate management of affected individuals and families. This paper summarizes all the known problems associated with the premutation and documents the presentations and discussions that occurred at the International Premutation Conference, which took place in New Zealand in 2023.

A Longitudinal Study of Executive Function in Daily Life in Male Fragile X Premutation Carriers and Association with FXTAS Conversion.

Background: Men with fragile X-associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross-sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies have made it difficult to address this hypothesis. Methods: This study included 66 FMR1 premutation carriers (PC) ranging from 40-78 years (Mean=59.5) and 31 well-matched healthy controls (HC) ages 40-75 (Mean 57.7) at baseline. Eighty-four participants returned for 2-5 follow up visits over a duration of 1 to 9 years (Mean=4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was completed by participants and their spouses/partners at each visit. Results: Longitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self-initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, BRIEF-A executive function problems at baseline significantly predicted later development of FXTAS. Conclusions: These findings suggest that executive function changes represent a prodrome of the later movement disorder.

Adaptive, behavioral, and cognitive outcomes in individuals with fragile X syndrome with varying autism severity.

This study aimed to determine the association between severity of autism spectrum disorder (ASD) and cognitive, behavioral, and molecular measures in individuals with fragile X syndrome (FXS). Study inclusion criteria included individuals with FXS and (1) age 6-40 years, (2) full-scale IQ < 84, and (3) language ≥3-word phrases. ASD symptom severity was determined by Autism Diagnostic Observation Schedule-2 (ADOS-2). Other measures identified non-verbal IQ, adaptive skills, and aberrant behaviors. Molecular measures included blood FMR1 and CYFIP1 mRNA levels, FMRP and MMP9 levels. Analysis of variance (ANOVA) and Spearman's correlations were used to compare ASD severity groups. Data from 54 individuals was included with no/mild (N = 7), moderate (N = 18), and severe (N = 29) ASD. Individuals with high ASD severity had lower adaptive behavior scores (47.48 ± 17.49) than the no/mild group (69.00 ± 20.45, p = 0.0366); they also had more challenging behaviors, lethargy, and stereotypic behaviors. CYFIP1 mRNA expression levels positively correlated with the ADOS-2 comparison score(r2  = 0.33, p = 0.0349), with no significant correlations with other molecular markers. In conclusion, autism symptom severity is associated with more adverse cognitive and adaptive skills and specific behaviors in FXS, whereas CYFIP1 mRNA expression levels may be a potential biomarker for severity of ASD in FXS.

Deviation scores: An innovative approach to interpreting cognitive test results for individuals with intellectual disabilities.

BACKGROUND: Students with Intellectual Disability undergo frequent cognitive testing. Testing with this population is limited by insensitivity to relative strengths and weaknesses due to floor effects. AIM: The study explored the utility of deviation scores via four case studies as a supplement to educational decision-making. METHODS: Four students with Intellectual Disability completed cognitive testing. Deviation scores were calculated using age dependent raw z-score transformations to determine deviation from the standardization sample norms. RESULTS: The application of deviation scores highlighted true relative strengths and weaknesses for students with Intellectual Disability rather than documenting previously known deficits. The four cases studies illustrated where deviation scores could, or could not, add value above and beyond traditional scoring. DISCUSSION: Deviation scores can supplement placement and service decisions for students. Practical and psychometric considerations are reviewed. CONCLUSION: The findings highlight the usefulness of deviation scores in providing meaningful information to school- and clinic-based practitioners.

Effects of AFQ056 on language learning in fragile X syndrome.

BACKGROUNDFXLEARN, the first-ever large multisite trial of effects of disease-targeted pharmacotherapy on learning, was designed to explore a paradigm for measuring effects of mechanism-targeted treatment in fragile X syndrome (FXS). In FXLEARN, the effects of metabotropic glutamate receptor type 5 (mGluR5) negative allosteric modulator (NAM) AFQ056 on language learning were evaluated in 3- to 6-year-old children with FXS, expected to have more learning plasticity than adults, for whom prior trials of mGluR5 NAMs have failed.METHODSAfter a 4-month single-blind placebo lead-in, participants were randomized 1:1 to AFQ056 or placebo, with 2 months of dose optimization to the maximum tolerated dose, then 6 months of treatment during which a language-learning intervention was implemented for both groups. The primary outcome was a centrally scored videotaped communication measure, the Weighted Communication Scale (WCS). Secondary outcomes were objective performance-based and parent-reported cognitive and language measures.RESULTSFXLEARN enrolled 110 participants, randomized 99, and had 91 who completed the placebo-controlled period. Although both groups made language progress and there were no safety issues, the change in WCS score during the placebo-controlled period was not significantly different between the AFQ056 and placebo-treated groups, nor were there any significant between-group differences in change in any secondary measures.CONCLUSIONDespite the large body of evidence supporting use of mGluR5 NAMs in animal models of FXS, this study suggests that this mechanism of action does not translate into benefit for the human FXS population and that better strategies are needed to determine which mechanisms will translate from preclinical models to humans in genetic neurodevelopmental disorders.TRIAL REGISTRATIONClincalTrials.gov NCT02920892.FUNDING SOURCESNeuroNEXT network NIH grants U01NS096767, U24NS107200, U24NS107209, U01NS077323, U24NS107183, U24NS107168, U24NS107128, U24NS107199, U24NS107198, U24NS107166, U10NS077368, U01NS077366, U24NS107205, U01NS077179, and U01NS077352; NIH grant P50HD103526; and Novartis IIT grant AFQ056X2201T for provision of AFQ056.

Intercorrelation of Molecular Biomarkers and Clinical Phenotype Measures in Fragile X Syndrome.

This study contributes to a greater understanding of the utility of molecular biomarkers to identify clinical phenotypes of fragile X syndrome (FXS). Correlations of baseline clinical trial data (molecular measures-FMR1 mRNA, CYFIP1 mRNA, MMP9 and FMRP protein expression levels, nonverbal IQ, body mass index and weight, language level, NIH Toolbox, adaptive behavior rating, autism, and other mental health correlates) of 59 participants with FXS ages of 6-32 years are reported. FMR1 mRNA expression levels correlated positively with adaptive functioning levels, expressive language, and specific NIH Toolbox measures. The findings of a positive correlation of MMP-9 levels with obesity, CYFIP1 mRNA with mood and autistic symptoms, and FMR1 mRNA expression level with better cognitive, language, and adaptive functions indicate potential biomarkers for specific FXS phenotypes. These may be potential markers for future clinical trials for targeted treatments of FXS.

iBehavior - A Smartphone-Based Ecological Momentary Assessment Tool for the Assessment of Behavior Change in Neurodevelopmental Disorders.

The purpose of the present study was to describe the content and function of iBehavior, a smartphone-based caregiver-report electronic ecological momentary assessment (eEMA) tool developed to assess and track behavior change in people with intellectual and developmental disabilities (IDDs), and to examine its preliminary validity. Ten parents of children (ages of 5-17 years) with IDDs (n = 7 with fragile X syndrome; n = 3 with Down syndrome) rated their child's behavior (aggression and irritability, avoidant and fearful behavior, restricted and repetitive behavior and interests, and social initiation) using iBehavior once daily for 14 days. At the conclusion of the 14-day observation period, parents completed traditional rating scales as validation measures, as well as a user feedback survey. Parent ratings using iBehavior showed emerging evidence of convergent validity among domains with traditional rating scales including the Behavior Rating Inventory of Executive Function 2 (BRIEF-2), Aberrant Behavior Checklist - Community (ABC-C), and Conners 3. iBehavior was feasible in our sample, and parent feedback indicated high overall satisfaction. Results of the present pilot study indicate successful implementation and preliminary feasibility and validity of an eEMA tool for use as a behavioral outcome measure in IDDs.

The comparison of expressed emotion of parents of individuals with fragile X syndrome to other intellectual disabilities.

BACKGROUND: Parenting children and young adults with intellectual disabilities, including individuals with fragile X syndrome and Down syndrome, is challenging, joyful, and complicated. Exploring how parents talk about their children, and the quality of the parent/child relationship can provide insight into the home environment and interactional patterns of the family. METHOD: Expressed emotion (EE) is a measurement of a family's emotional climate based on a parent or caregiver's report of warmth, emotional overinvolvement, hostility, and criticism. The purpose of this study was to describe EE for a sample of parents of individuals with intellectual disabilities and to determine any differences in EE amongst individuals within subgroups. Based on previous research about fragile X syndrome and family systems, we hypothesized that there would be significant differences between the disability groups (higher EE in families with children/young adults with fragile X syndrome). RESULTS: Results showed relatively high proportions of EE across groups of individuals with intellectual disabilities, however, there were no significant differences between the subgroups. Null findings suggest that differences in EE may not relate directly to a child's specific genetic condition. Rather, increased EE in caregiver populations may simply reflect well-documented stressors related to stigma, caregiver burden, and limited community supports. Critical statements were infrequent, however, over half of the participants reported dissatisfaction with their situation, and many were categorized as having emotional overinvolvement, as measured by frequent statements of intense worry and self-sacrifice. CONCLUSION: Findings point to potential utility in family-level interventions focused on providing structured caregiver therapy to manage excessive worry and grief related to a diagnosis of intellectual disability, and respite care to encourage caregiver independence and pursuit of personal care.

Sensitivity of the NIH Toolbox to Detect Cognitive Change in Individuals With Intellectual and Developmental Disability.

BACKGROUND AND OBJECTIVE: Individuals with intellectual disability (ID) experience protracted cognitive development compared with typical youth. Sensitive measurement of cognitive change in this population is a critical need for clinical trials and other intervention studies, but well-validated outcome measures are scarce. This study's aim was to evaluate the sensitivity of the NIH Toolbox Cognition Battery (NIHTB-CB) to detect developmental changes in groups with ID-fragile X syndrome (FXS), Down syndrome (DS), and other ID (OID)-and to provide further support for its use as an outcome measure for treatment trials. METHODS: We administered the NIHTB-CB and a reference standard cross-validation measure (Stanford-Binet Intelligence Scales, Fifth Edition [SB5]) to 256 individuals with FXS, DS, and OID (ages 6-27 years). After 2 years of development, we retested 197 individuals. Group developmental changes in each cognitive domain of the NIHTB-CB and SB5 were assessed using latent change score models, and 2-year growth was evaluated at 3 age points (10, 16, and 22 years). RESULTS: Overall, effect sizes of growth measured by the NIHTB-CB tests were comparable with or exceeded those of the SB5. The NIHTB-CB showed significant gains in almost all domains in OID at younger ages (10 years), with continued gains at 16 years and stability in early adulthood (22 years). The FXS group showed delayed gains in attention and inhibitory control compared with OID. The DS group had delayed gains in receptive vocabulary compared with OID. Unlike the other groups, DS had significant growth in early adulthood in 2 domains (working memory and attention/inhibitory control). Notably, each group's pattern of NIHTB-CB growth across development corresponded to their respective pattern of SB5 growth. DISCUSSION: The NIHTB-CB is sensitive to developmental changes in individuals with ID. Comparison with levels and timing of growth on the cross-validation measure shows that the NIHTB-CB has potential to identify meaningful trajectories across cognitive domains and ID etiologies. Sensitivity to change within the context of treatment studies and delineation of clinically meaningful changes in NIHTB-CB scores, linked to daily functioning, must be established in future research to evaluate the battery more completely as a key outcome measure.

Tophaceous gout of the nose in a male FMR1 premutation carrier.

Premutation alleles with 55-200 CGG repeats in FMR1 can lead to fragile X-associated tremor/ataxia syndrome (FXTAS). In this case study, we report uncontrolled gout in a 68-year-old male with FXTAS with multiple sites of involvement including a rare gouty tophus in the nasal region.

Fragile X-associated tremor ataxia syndrome rating scale: Revision and content validity using a mixed method approach.

Background: The original Fragile X-associated Tremor Ataxia Syndrome Rating Scale (FXTAS-RS) contained 61 items, some requiring modifications to better meet recommendations for patient-focused rating scale development. Purpose: Provide initial validation of a revised version of the FXTAS-RS for motor signs. Method: We conducted a two-phase mixed-method approach. In Phase 1, revision, we implemented a Delphi technique identifying pertinent domains/subdomains and developing items through expert consensus. In Phase 2, content validation, we conducted cognitive pretesting assessing comprehensibility, comprehensiveness, and relevance of items to FXTAS motor signs. Results: After five rounds of Delphi panel and two rounds of cognitive pretesting, the revised version of the FXTAS-RS was established with 18 items covering five domains and 13 subdomains of motor signs. Cognitive pretesting revealed adequate content validity for the assessment of FXTAS motor signs. Conclusion: The revised FXTAS-RS has been successfully validated for content and it is now ready for large-scale field validation.

Observable Symptoms of Anxiety in Individuals with Fragile X Syndrome: Parent and Caregiver Perspectives.

Caregiver reports, clinical observations, and diagnostic assessments indicate that most individuals with fragile X syndrome experience high levels of chronic anxiety. However, anxiety is a challenging endpoint for outcome measurement in FXS because most individuals cannot reliably report internal emotional or body states. A comprehensive survey of the presence, frequency, and duration of anxiety-related symptoms and questions to elicit open-ended responses was completed by caregivers of 456 individuals with FXS, ages 2-81 years (87 female, 369 male) and 24 female and 2 male FXS self-advocates ages 15-66 years. Caregivers reported classic behavioral indicators of anxiety, such as avoidance, irritability, motor agitation, and physiological symptoms, as well as behavioral features in FXS such as repetitive behavior, aggression, and self-injury. Self-advocate accounts largely paralleled caregiver data. Factor analyses yielded four factors: (1) increased irritability, aggression, and self-injury; (2) increased physical movement, nervous activity, and restlessness; (3) physical and physiological features of anxiety; and (4) internalizing and gastrointestinal symptoms. Caregivers are capable of observing and reporting behaviors that are valid indicators of anxious states that are usually reported in self-report standardized assessments. These results support the development of an anxiety measure for FXS that minimizes problems with rater inference.

Working Memory Training in Youth With Autism, Fragile X, and Intellectual Disability: A Pilot Study.

This pilot study sought to identify potential markers of improvement from pre-post treatment in response to computerized working memory (WM) training for youth (ages 8-18) with autism spectrum disorder (ASD) and comorbid intellectual disability (ID) in a single arm, pre-post design. Participants included 26 children with ASD and 18 with comorbid ASD and fragile X syndrome (ASD+FXS). Analyses were adjusted for age and IQ. The ASD group demonstrated greater improvement on WM training relative to the ASD+FXS group. Participants improved on WM and far transfer outcomes, however, there were no significant group differences in improvement except for repetitive behavior. Higher hyperactivity/impulsivity ratings predicted lower performance on visuospatial WM. Findings suggest cognitive training may be beneficial for youth with ASD and ID, warranting further exploration.