Fragile X-associated tremor/ataxia syndrome (FXTAS), caused by the FMR1 premutation allele, is associated with brain degeneration, yet the mechanisms behind this neurodegeneration still need to be elucidated. Apoε polymorphism has been widely implicated in brain aging in cognitively healthy individuals and brain deterioration in Alzheimer's disease. This study aimed to examine the interaction of Apoε genotypes, FXTAS clinical symptoms, FMR1 molecular measures, and age, towards brain pathophysiology and cognitive functions. This longitudinal study includes MRI data collected from 205 male premutation carriers with and without FXTAS clinical symptoms and compared to 86 healthy male controls aged 40-85 years. The investigation includes FXTAS-related brain volumes, IQ, self-control behaviors, FMR1 molecular measures, and Apoε genotypes. In carriers with FXTAS, the presence of the Apoε2 allele showed a possible association with more favorable neuroimaging markers, such as reduced white matter hyperintensities, and lower incidence of the middle cerebellar peduncle sign, patterns that were not observed in carriers without FXTAS. Specifically, the presence of Apoε2 allele exhibited a potential protective effect on brain degeneration, and cognitive functions among FXTAS patients; on the contrary, the Apoε4 allele was associated with a worsening of brain volume and brain degeneration in carriers with no FXTAS symptoms. The identification of Apoε genotypes in FMR1 premutation carriers before any clinical symptoms of FXTAS are observed may improve symptomatic management leading to better outcomes for these individuals.

Background and objectives 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. The inferior cerebellar peduncles (ICP) contain fibers related to proprioception and vestibular functions (such as the rostral and posterior spinocerebellar tracts and the juxta restiform body), which are clinically associated with cerebellar gait ataxia, a major clinical criterion for FXTAS diagnosis. However, the ICP hyperintensity has yet to be studied in FXTAS.Methods We evaluated 588 MRI scans (mean 2.05 visits/participant) from 202 male premutation carriers (164 with FXTAS and 38 without FXTAS at last visits) and 85 controls. Two radiologists, independently, rated as absent or present the signal of the right and left ICP in T2-Fluid-attenuated inversion recovery (FLAIR) scans. Mixed-effects models were used for statistical analysis adjusting for age.Results Only carriers with FXTAS revealed ICP hyperintensities at last visits. Furthermore, ICP hyperintensity was associated with brain atrophy, increased white matter disease, the MCP sign, FXTAS stage, abnormal gait, lower cognitive functioning and faster age-related increase in anxiety and depression scores. Finally, carriers with ICP hyperintensities had significantly higher CGG repeat length than carriers without ICP hyperintensities.Discussion This study describes ICP hyperintensity as a new potential radiological finding in FXTAS, suggests involvement of the vestibulo-cerebellar, rostral, and posterior spinocerebellar tracts, and the vestibular system in FXTAS physiopathology, and reinforces the association of CGG expansion in the range of brain changes seen in FXTAS.

Fragile X Syndrome (FXS), an X-linked genetic condition, is associated with a wide range of phenotypic manifestations, namely intellectual disability (ID), autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and atypical behaviors. Individuals with FXS present robust electrophysiological (EEG) alterations, notably on signal complexity and power spectral density (PSD) resting state measures. To which extent they are associated to specific behavioral phenotypes in the FXS population remains to be comprehensively addressed. This study aimed to investigate the relations between resting state EEG markers and the most frequently observed symptoms in FXS. EEG and behavioral data from 41 individuals with FXS aged between 7 and 34 years old were collected, and correlational approaches were used to analyze the associations between EEG markers and symptomatology. We observed positive associations between complexity in higher scales and non-verbal intelligence quotient (NVIQ). Reduced alpha power, a robust biomarker in FXS, was associated with more social avoidance, a hallmark in FXS. Decreased high gamma power was linked to hyperactive symptoms. Our results suggest powerful relations between known biomarkers and core symptoms in FXS, highlighting that EEG biomarkers correspond to symptom severity which further supports their potential as objective, translational treatment outcome measures.

The NIH Toolbox Cognition Battery (NIHTB-CB) assesses crystallized verbal skills,and shows strong psychometric properties and sensitivity to developmental change in intellectual and developmental disabilities. However, whether gains in NIHTB-CB Crystallized Cognition reflect improvements in broader verbal abilities is unclear, and this has implications for clinical interpretation of the measure in the context of treatment studies. Two-hundred sixty-three participants completed NIHTB-CB Crystalized Cognition subtests (Picture Vocabulary, Oral Reading Recognition) and Stanford-Binet 5th ed. subtests (Verbal Knowledge, Verbal Fluid Reasoning) at baseline and at two-year follow-up. Bivariate latent change score models examined whether changes in Crystalized Cognition were related to changes in broader verbal skills. Changes in Crystalized Cognition were significantly related to changes in Verbal Knowledge (β = 7.92, p = .009) and Verbal Fluid Reasoning (β = 4.91, p = .018). Higher baseline Crystalized Cognition predicted greater improvement in these verbal domains, while higher initial verbal scores also predicted more Crystalized Cognition growth. Change in the NIHTB-CB Crystalized Composite was significantly related to growth in verbal reasoning in children and young adults with IDD. This may indicate that the Crystalized Composite is a useful proxy for broader verbal skills, underscoring its clinical relevance.

OBJECTIVE:The objective of this study was to examine whether machine learning has the capacity to prospectively identify and predict the emergence of Fragile X-associated tremor/ataxia syndrome (FXTAS) among male fragile X premutation carriers (PCs). METHODS:We explored neuropsychological and motor evaluation metrics, brain magnetic resonance imaging (MRI), and health metrics in 103 male participants (72 PCs, mean = 60.4 years at enrollment) and 31 healthy controls (HCs; mean = 57.8 years at enrollment) across a total of 299 visits to identify optimal FXTAS risk markers. We compared different machine learning model and feature selection method combinations to identify the best features and models for (a) identifying patients with FXTAS and (b) for predicting which individuals were likely to later develop FXTAS in the study to date. Using an optimal set of features (including age, psychological symptoms, executive function and motor measures, IQ, body mass index (BMI), and structural brain measurements), we developed random forest binary classifiers for the 2 tasks. We split the dataset randomly into multiple different train and test splits and observed the average classification performance metrics across all the splits. RESULTS:The models showed promising ability to identify and pre-emptively predict the emergence of FXTAS and achieved a reasonable balance between precision and recall. Accumulation of body fat (BMI), executive function weaknesses, slower reaction time and dexterity, and mental health changes, are clinical factors that may significantly increase a carrier's risk. Structural brain MRI measurements significantly added to the predictive power of the models. INTERPRETATION:These results suggest that machine learning has the potential to inform prediction of risk for FXTAS early, enabling better planning, timely interventions, and provision of necessary care. ANN NEUROL 2026;100:36-47.

Snijders Blok-Campeau syndrome (SNIBCPS), a neurodevelopmental disorder first described in 2018, is caused by heterozygous pathogenic variants in CHD3. Its encoded protein plays a crucial role in the development of the nervous system of embryos. While phenotypic traits have been broadly defined, i.e., global neurodevelopmental delays such as intellectual disabilities and delayed speech acquisition, and physical features such as characteristic facial features and macrocephaly, the phenotypic spectrum has not been further assessed. We present the neurobehavioral profile of 38 individuals with variants in CHD3 and compare it to the ones of autism spectrum disorder (ASD) and Fragile X syndrome (FXS) cohorts. Profound clinical deficits were found in adaptive functioning, communication skills, and sensorimotor functioning in most SNIBCPS participants. Similarities between FXS and SNIBCPS cohorts were unveiled, characterized by diminished levels of global adaptive behavior and adaptive functioning in the social and communication domains. Nevertheless, despite profound challenges in global adaptive behavior in SNIBCPS, we reveal the social domain as showing the highest adaptive levels alongside minimal emotional/behavioral issues within the sample, suggesting relative strengths inherent to SNIBCPS. This study enriches the scarce SNIBCPS literature by delineating the neurobehavioral phenotypic spectrum of SNIBCPS and by innovating comparisons with clinically akin neurodevelopmental disorders.

Individuals with Fragile X syndrome (FXS) manifest clinical impairments in several domains. Previous research has shown that auditory evoked potentials (AEPs), measured using electroencephalogram (EEG), are altered in FXS, but the associations between these alterations and the symptoms observed in FXS have not been thoroughly investigated. The aim of this study was to compare AEP markers between individuals with FXS and neurotypical (NT) controls, with the main purpose of exploring how these markers are related to various clinical symptoms present in FXS. A passive auditory oddball paradigm was presented. P1, N1, P2, N2, P3 and mismatch negativity (MMN) amplitudes and latencies were compared between 41 children and adults with FXS and 46 age-matched NT controls. Amplitudes and latencies, as well as habituation and change detection effects were compared between the groups using mixed design ANOVAs. Pearson correlations were then performed to explore associations between AEP markers and symptoms in the FXS group. Our results showed that FXS participants had increased N1, P2 and MMN amplitudes and latencies, as well as lack of habituation and change detection effects compared to NT controls. Our correlational analyses revealed several associations between AEPs and phenotypic manifestations; notably, associations between exaggerated N1 and P2 amplitudes and more severe autistic and ADHD symptoms. These findings confirm that abnormalities of the N1 and P2 components are robust biomarkers of altered sensory processing in FXS and suggest that these alterations may present a dose–response relation to clinical impairments in FXS.

Objective: The current intense period of drug development for fragile X syndrome (FXS) and other neurodevelopmental disorders (NDDs) indications has highlighted the importance of behavioral outcome measures with strong psychometric properties and specifically content validity. The Aberrant Behavior Checklist-Community Edition (ABC-C), which has successfully been applied to autism spectrum disorder drug trials, has been revised for FXS (ABCFX) and is widely used for both clinical and research purposes. Despite its strong psychometric validation, the ABCFX and its parent measure have not been subjected to qualitative content validity evaluations. The present study intended to fill this gap. Methods: Using two surveys administered sequentially and developed with guidance and review from the Food and Drug Administration (FDA), we asked 10 clinicians experienced in FXS and related NDDs to determine the adequacy of the ABCFX for assessing its behavioral constructs, its relevance to FXS, and its potential for detecting response to interventions. Various descriptive statistic parameters and ad hoc metrics were used to analyze categorical and Likert-like scale responses. Results: Experts considered that most items and all six ABCFX subscales indeed evaluated their explicit or implicit behavioral constructs. However, item and subscale specificity were relatively low (∼25%-30%). Relevance of items of the Hyperactivity subscale was relatively high while low for many items of the Socially Unresponsive/Lethargic subscale. These items were also considered of low responsiveness potential. Irritability, Hyperactivity, Stereotypy, and Social Avoidance were the subscales with the strongest profiles, although the experts estimated that Stereotypy items may not be that responsive to treatment. A novel Anxiety construct, representing mainly recently reported observable behaviors, contributed mainly by Irritability items, emerged as a potential measure. Conclusions: The present study demonstrated the overall adequacy of the ABCFX for its behavioral constructs, its relevance to FXS, and its potential for detecting response to treatment. It also showed that anxiety, a distinctive feature of FXS and other genetic NDDs, can also be measured by the ABCFX. These findings can help with the implementation and interpretation of the ABCFX, as well as with potential improvements to the measure in FXS and other NDDs.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder caused by the premutation (55–200 CGG repeats) in the fragile X messenger ribonucleoprotein-1 (FMR1) gene. An open question is: In what sequential order do FXTAS symptoms typically appear, and how does that sequence vary among patients and between males and females? We applied the ordinal-outcomes version of the Subtype and Stage Inference algorithm (‘Ordinal SuStaIn’) to identify the sequential events of clinical and brain MRI changes in cross-sectional data collected during baseline visits from a longitudinal cohort of FXTAS patients at Stages 0–5. We included 28 neurodegenerative symptoms collected from 253 premutation carriers (101 females and 152 males) and 44 controls (7 females and 37 males), aged 40–86 years old at entry, who participated in two longitudinal studies, with entry dates between 2008 and 2023. We found substantial differences in order of events depending on sex, and possibly in combination of sex and CGG repeats. The main finding is the predominance of the psychiatric co-morbidities that occur early in females (often before the onset of tremor and ataxia) compared to males. These findings suggest that the sequence of neuropsychiatric symptoms for FXTAS is different in females compared to males, particularly for early symptoms in disease development and progression. This could lead to sex-specific modifications of the FXTAS diagnostic stages.

OBJECTIVE:The objective of this study was to show the capacity of structural brain magnetic resonance imaging (MRI) measures to serve as monitoring biomarkers for Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS). METHODS:From 2 longitudinal studies of male FMR1 premutation carriers, 2 brain MRI scans were selected from each participant, collected within a period of 2 years (12 healthy controls, 17 carriers without FXTAS, and 51 carriers with FXTAS; all men, ages 40 to 80 years), along with clinical measurements and FMR1 cytosine-guanine-guanine (CGG) repeat numbers. Candidate MRI biomarkers included whole brain white matter hyperintensity (WMH) and cerebellar, brainstem, and whole brain volumes. RESULTS:In the FXTAS group, mixed-effects models demonstrated significant volume loss across an average interval of 1.32 years for the whole brain, cerebellum and brain stem volumes, and significant increases in WMH, with large magnitude effects for whole brain and WMH volumes. All MRI measures showed deterioration with advancing FXTAS stage, with the strongest pattern shown in WMH volume. CGG repeat number showed significant nonlinear associations with all 4 brain MRI metrics, with mid-range CGG repeat carriers evidencing the worst brain atrophy and WMHs. INTERPRETATION:Structural brain MRI measurements, especially those capturing white matter deterioration, are correlated with FMR1 premutation size of CGG repeat length and sensitive to FXTAS disease progression across a relatively short interval of less than 2 years, making them potentially suitable as surrogate end points for clinical trials. ANN NEUROL 2025;98:471-481.

Objective: The purpose of the present study was to assess the psychiatric manifestations of early to middle stages of fragile X-associated tremor-ataxia syndrome (FXTAS) and their relationship with executive function and FMR1 cytosine-guanine-guanine (CGG) repeat numbers across genders. Methods: Cross-sectional data from 100 participants (62 men, 38 women; mean +/- SD age=67.11 +/- 7.90 years) with FXTAS stage 1, 2, or 3 were analyzed, including demographic information, cognitive measures, psychiatric assessments (Symptom Checklist-90-Revised and Behavioral Dyscontrol Scale-II [BDS-II]), and CGG repeat number. Results: Participants with FXTAS stage 3 exhibited significantly worse psychiatric outcomes compared with participants with either stage 1 or 2, with distinct gender-related differences. Men showed differences in anxiety and hostility between stage 3 and combined stages 1 and 2, whereas women exhibited differences in anxiety, depression, interpersonal sensitivity, obsessive-compulsive symptoms, and somatization, as well as in the Global Severity Index, the Positive Symptom Distress Index, and the Positive Symptom Total. Among male participants, negative correlations were observed between BDS-II total scores and obsessive- compulsive symptoms, as well as between anxiety and CGG repeat number. Conclusions: These findings suggest that even at early FXTAS stages, patients have significant cognitive and other psychiatric symptoms, with notable gender-specific differences. This study underscores the clinical and prognostic relevance of comorbid psychiatric conditions in FXTAS, highlighting the need for early intervention and targeted support for individuals with relatively mild motor deficits.

Abstract Background Intellectual and developmental disabilities (IDDs) are associated with both cognitive challenges and difficulties in conceptual, social, and practical areas of living, commonly referred to as adaptive behavior (DSM–5). Although cross-sectional associations between intelligence or cognition and adaptive behavior have been reported in IDD populations, no study to date has examined whether developmental changes in cognition contribute to or track with changes in adaptive behavior. 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 in a large sample of children, adolescents and young adults with IDD. Methods Three groups were recruited, including those with fragile X syndrome, Down syndrome, and other/idiopathic intellectual disability. Eligible participants (n = 263) included those who were between 6 and 26 years (mage = 15.52, sd = 5.17) at Visit 1, and who had a diagnosis of, or suspected intellectual disability (ID), including borderline ID, with a mental age of at least 3.0 years. Participants were given cognitive and adaptive behavior assessments at two time points over a two year period (m = 2.45 years, range = 1.27 to 5.56 years). 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 Cognition, Crystallized Cognition, Total Cognition) 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 Crystallized and Total Composites) 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 changes 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 DLS 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 changes in cognition detected by the NIHTB-CB in IDD, and provides empirical support for the NIHTB-CB as a fit-for-purpose performance-based outcome measure for this population.

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.

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.

Estimating meaningful change thresholds (MCT) on clinical outcome assessments is an important consideration when evaluating treatments. In fragile X syndrome (FXS) research, there has been no consensus on how to define MCT’s on several commonly used outcome measures. The purpose of the current study was to determine clinically relevant MCT’s of caregiver-rated assessments using data from a phase 3 clinical trials of arbaclofen (Berry-Kravis et al., 2017). Data were collected as a part of previous phase 3, double-blind, placebo-controlled studies of arbaclofen in individuals with FXS (Berry-Kravis et al., 2017). The two studies enrolled age groups of 5–11-years (n = 159) and 12–50-years (n = 119). The current study examines meaningful within-patient change thresholds from baseline to treatment week 8 across several measures: ABC-CFXS; PSI; Vineland-II; and a Visual Analog Scale (VAS) of Anxiety and Disruptive Behaviors. MCT’s were established by using anchor-based methods, using the CGI-S and CGI-I as anchors. Examining the results of the anchor-based analyses and visual CDF plots, MCT’s were observed for the pediatric study for the ABC-CFXS subscales (with a range depending on use of CGI-S or CGI-I as anchor): Irritability: 11.1–14.8 points; Hyperactivity: 6.7–8.9 points; and Socially Unresponsive/Lethargic: 6.6–8.1 points; as well both VAS subscales: Anxiety: 28.3–36.2 mm; and Disruptive Behavior: 22.4–27.4 mm. Such thresholds were not observed for the Vineland-II and PSI subscales. Our analysis of MCT’s helps set the stage for interpreting clinical trial results in FXS. This may include use of relevant subscales of the ABC-CFXS and VAS as primary outcomes using the MCT’s for response definition. This work may help define future study inclusion criteria and enable future interpretation of treatment outcome results in the field.

In this study, the potential role and interaction of the APOε and KLOTHO genes on the penetrance of fragile X-associated tremor/ataxia syndrome (FXTAS) and on the IQ trajectory were investigated. FXTAS was diagnosed based on molecular, clinical and radiological criteria. Males with the premutation (PM) over 50 years, 165 with and 34 without an FXTAS diagnosis, were included in this study and were compared based on their APO (ε2-ε3-ε4) and KLOTHO variant (KL-VS) genotypes. The effect of APOε4 on FXTAS stage and on diagnosis did not differ significantly by KL-VS genotype with interaction effect p = 0.662 and p = 0.91, respectively. In the FXTAS individuals with an APOε2 allele, a marginal significance was observed towards a larger decline in verbal IQ (VIQ) in individuals with an APOε4 allele compared to those without an APOε4 allele (p = 0.071). In conclusion, our findings suggest that the APOε4 and KL-VS genotypes alone or through their interaction effect do not appear to predispose to either FXTAS diagnosis or stage in male carriers of the PM allele. A further study is needed to establish the trend of IQ decline in the FXTAS individuals who carry APOε4 with APOε2 compared to those without APOε4.