Psychiatric and Cognitive Features in Italian Women With the FMR1 Premutation: A Comprehensive Assessment Using SCID-5 and Standardized Cognitive Measures.

Study question What cell type is specific for the expression of FMRpolyG of FMR1 premutation (PM) in peripheral mononuclear blood cells (PMBC) and how can this impact female fertility? Summary answer The expression of FMRpolyG is significantly higher in T cells from peripheral blood mononuclear cells (PBMCs) of FMR1 PM carriers. What is known already Fragile X-associated primary ovarian insufficiency (FXPOI) is characterized by oligo/amenorrhea and hypergondotropic hypogonadism and is caused by expansion of the CGG-repeat in the 5'UTR of FMR1. Autoimmunity is highly associated with POI and in FMR1-PM activated inflammatory state and immune response have been discovered. RAN-translation dependent on variable CGG-repeat length is thought to cause FXPOI due to production of the polyglycine-containing-FMR1-protein, FMRpolyG. Colocalization of ubiquitin and FMRpolyG was recently demonstrated in ovarian stromal and mural granulosa cells from FMR1 PM carriers. Our previous data have also shown that FMRpolyG is aggregated in ubiquitin-positive inclusions in PBMCs from PM carriers. Study design, size, duration PBMCs and granulosa cells (GCs) from women with PM (5) and women without PM (10) (controls) were examined by immunofluorescence staining (IF) for the presence of inclusions positive for ubiquitin and FMRpolyG. Cell lysis and protein extraction samples were subjected to Western blot analysis (WB) to detect FMRP and FMRpolyG. Flow cytometric analyzes (FACs) were performed to determine cell type-specific expression of FMRpolyG. Participants/materials, setting, methods PBMCs were isolated from peripheral blood using Ficoll-Paque. PBMCs were fixed, IF stained for FMRpolyG and ubiquitin, and analyzed by fluorescence microscopy. WB was used to detect the expression of FMRP, FMRpolyG in extracted protein from lymphocytes and GCs. PBMCs were surface stained with CD3, CD14 and CD19 antibodies and later intracellular stained with FMRpolyG and ubiquitin for FACs analysis. Main results and the role of chance FMRpolyG aggregates were detected as ubiquitin-positive inclusions in PBMCs from PM carriers, whereas only weak signal without inclusions was detected in controls. We detected FMRpolyG as a 15- to 25-kDa protein in PBMCs from two FMR1 PM carriers with 124 and 81 CGG repeats, a PM range that is supposed to carry the highest risk to develop FXPOI within all PM carriers. Using FACs, we found that the expression levels of FMRpolyG were significantly higher in the FMR1 PM carriers than in the group without PM (3.5-fold, p = 0.03). Both FMR1 PM and non-PM groups showed normal distribution of T cells (58.38% ± 11.54 and 58.72% ± 6.16, respectively). However, FMRpolyG fluorescence intensity was 28.98-fold higher (p = 0.01) in the T cells of FMR1 PM carriers than in those of women without PM. FMRpolyG expression levels of B cells (CD19+) and monocytes (CD14+) were comparable in both groups. Of note, the ubiquitin-positive cells of FMR1 PM carriers had significantly higher expression levels of FMRpolyG than those of non-PM carriers (17.84-fold, p < 0.0001). Limitations, reasons for caution More patients are needed to support the present results. Further studies on the possible consequences of these FMRpolyG-positive inclusions in PM carriers are also advisable. Wider implications of the findings We found for the first time FMRpolyG aggregates in the peripheral blood of PM-carriers and a significant increase in FMRpolyG expression in T cells from PM-carriers. These results suggest that FMRpolyG may have a toxic potential and play an immunological role in ovarian damage, finally triggering the development of FXPOI. Trial registration number RE 3647/1-1 and /1-2

Changes in the fragile X mental retardation 1 gene (FMR1) have been associated with specific phenotypes, most specifically those of fragile X syndrome (FXS), fragile X tremor/ataxia syndrome (FXTAS), and fragile X primary ovarian insufficiency (FXPOI). Evidence of increased risk for additional medical, psychiatric, and cognitive features and conditions is now known to exist for individuals with a premutation, although some features have been more thoroughly studied than others. This review highlights the literature on medical, reproductive, cognitive, and psychiatric features, primarily in females, that have been suggested to be associated with changes in the FMR1 gene. Based on this review, each feature is evaluated with regard to the strength of evidence of association with the premutation. Areas of need for additional focused research and possible intervention strategies are suggested.

The FMR1 gene in its premutation (PM) state has been linked to a range of clinical and subclinical phenotypes among FMR1 PM carriers, including some subclinical traits associated with autism spectrum disorder (ASD). This study attempted to further characterize the phenotypic profile associated with the FMR1 PM by studying a battery of assessments examining clinical-behavioral traits, social-cognitive, and executive abilities in women carrying the FMR1 PM, and associations with FMR1-related variability. Participants included 152 female FMR1 PM carriers and 75 female controls who were similar in age and IQ, and screened for neuromotor impairments or signs of fragile X-associated tremor/ataxia syndrome. The phenotypic battery included assessments of ASD-related personality and language (i.e., pragmatic) traits, symptoms of anxiety and depression, four different social-cognitive tasks that tapped the ability to read internal states and emotions based on different cues (e.g., facial expressions, biological motion, and complex social scenes), and a measure of executive function. Results revealed a complex phenotypic profile among the PM carrier group, where subtle differences were observed in pragmatic language, executive function, and social-cognitive tasks that involved evaluating basic emotions and trustworthiness. The PM carrier group also showed elevated rates of ASD-related personality traits. In contrast, PM carriers performed similarly to controls on social-cognitive tasks that involved reliance on faces and biological motion. The PM group did not differ from controls on self-reported depression or anxiety symptoms. Using latent profile analysis, we observed three distinct subgroups of PM carriers who varied considerably in their performance across tasks. Among PM carriers, CGG repeat length was a significant predictor of pragmatic language violations. Results suggest a nuanced phenotypic profile characterized by subtle differences in select clinical-behavioral, social-cognitive, and executive abilities associated with the FMR1 PM in women.

FMR1 premutation (PM) carriers are at increased risk of ovarian impairment resulting in diminished ovarian response (DOR) to exogenous follicle-stimulating hormone (FSH) stimulation. Expanded CGG repeat transcript and RAN-associated protein (FMRpolyG) have been shown to accumulate in cellular aggregates and sequester proteins, thus impairing their function. Sam68 is a multifunctional RNA-binding protein highly expressed in the gonads involved in FSH receptor (FSHR) transcript maturation during FSH-dependent follicular development. The present study examined a possible pathophysiological explanation for DOR to exogenous FSH stimulation in FMR1 PM carriers. We used both a human granulosa cell (GC) line model and human GCs from FMR1 PM carriers to evaluate whether Sam68 is sequestered with expanded CGG repeat transcript. We show that Sam68 is sequestered in GCs, most likely by interaction with the expanded CGG repeat transcript. The sequestration may lead to reduced levels of free Sam68 available for FHSR precursor transcript processing, causing dysregulation of FSHR transcript maturation, and a consequent decrease in FSHR protein levels. Sam68 sequestration may underlie the diminished ovarian response to FSH stimulation in FMR1 PM carriers.

The FMR1 premutation (PM) is relatively common in the general population. Evidence suggests that PM carriers may exhibit subtle differences in specific cognitive and language abilities. This study examined potential mechanisms underlying such differences through the study of gaze and language coordination during a language processing task (rapid automatized naming; RAN) among female carriers of the FMR1 PM. RAN taps a complex set of underlying neuropsychological mechanisms, with breakdowns implicating processing disruptions in fundamental skills that support higher order language and executive functions, making RAN (and analysis of gaze/language coordination during RAN) a potentially powerful paradigm for revealing the phenotypic expression of the FMR1 PM. Forty-eight PM carriers and 56 controls completed RAN on an eye tracker, where they serially named arrays of numbers, letters, colors, and objects. Findings revealed a pattern of inefficient language processing in the PM group, including a greater number of eye fixations (namely, visual regressions) and reduced eye-voice span (i.e., the eyes’ lead over the voice) relative to controls. Differences were driven by performance in the latter half of the RAN arrays, when working memory and processing load are the greatest, implicating executive skills. RAN deficits were associated with broader social-communicative difficulties among PM carriers, and with FMR1-related molecular genetic variation (higher CGG repeat length, lower activation ratio, and increased levels of the fragile X mental retardation protein; FMRP). Findings contribute to an understanding of the neurocognitive profile of PM carriers and indicate specific gene-behavior associations that implicate the role of the FMR1 gene in language-related processes.

Atypical visual attention patterns have been observed among carriers of the fragile X mental retardation gene (FMR1) premutation (PM), with some similarities to visual attention patterns observed in autism spectrum disorder (ASD) and among clinically unaffected relatives of individuals with ASD. Patterns of visual attention could constitute biomarkers that can help to inform the neurocognitive profile of the PM, and that potentially span diagnostic boundaries. This study examined patterns of eye movement across an array of fixation measurements from three distinct eye-tracking tasks in order to investigate potentially overlapping profiles of visual attention among PM carriers, ASD parents, and parent controls. Logistic regression analyses were conducted to examine whether variables constituting a PM-specific looking profile were able to effectively predict group membership. Participants included 65PM female carriers, 188 ASD parents, and 84 parent controls. Analyses of fixations across the eye-tracking tasks, and their corresponding areas of interest, revealed a distinct visual attention pattern in carriers of the FMR1 PM, characterized by increased fixations on the mouth when viewing faces, more intense focus on bodies in socially complex scenes, and decreased fixations on salient characters and faces while narrating a wordless picture book. This set of variables was able to successfully differentiate individuals with the PM from controls (Sensitivity = 0.76, Specificity = 0.85, Accuracy = 0.77) as well as from ASD parents (Sensitivity = 0.70, Specificity = 0.80, Accuracy = 0.72), but did not show a strong distinction between ASD parents and controls (Accuracy = 0.62), indicating that this set of variables comprises a profile that is unique to PM carriers. Regarding predictive power, fixations toward the mouth when viewing faces was able to differentiate PM carriers from both ASD parents and controls, whereas fixations toward other social stimuli did not differentiate PM carriers from ASD parents, highlighting some overlap in visual attention patterns that could point toward shared neurobiological mechanisms. Results demonstrate a profile of visual attention that appears strongly associated with the FMR1 PM in women, and may constitute a meaningful biomarker.

Probability of major depression diagnostic classification based on the SCID, CIDI and MINI diagnostic interviews controlling for Hospital Anxiety and Depression Scale – Depression subscale scores: An individual participant data meta-analysis of 73 primary studies

Neurobiological basis for cognitive development and psychiatric conditions remains unexplored in children with the FMR1 premutation (PM). Knock-in mouse models of PM revealed defects in embryonic cortical development that may affect cortical folding. Cortical-folding complexity quantified using local gyrification index (LGI) was examined in 61 children (age 8–12 years, 19/14 male/female PM carriers, 15/13 male/female controls). Whole-brain vertex-wise analysis of LGI was performed for group comparisons and correlations with IQ. Individuals with aberrant gyrification in 68 cortical areas were identified using Z-scores of LGI (hyper: Z ≥ 2.58, hypo: Z ≤ − 2.58). Significant group-by-sex-by-age interaction in LGI was detected in right inferior temporal and fusiform cortices, which correlated negatively with CGG repeat length in the PM carriers. Sixteen PM boys (hyper/hypo: 7/9) and 10 PM girls (hyper/hypo: 2/5, 3 both) displayed aberrant LGI in 1–17 regions/person while 2 control boys (hyper/hypo: 0/2) and 2 control girls (hyper/hypo: 1/1) met the same criteria in only 1 region/person. LGI in the precuneus and cingulate cortices correlated positively with IQ scores in PM and control boys while negatively in PM girls and no significant correlation in control girls. These findings reveal aberrant gyrification, which may underlie cognitive performance in children with the PM.

PurposeWomen of reproductive age who carry fragile X premutation (PM) alleles have 56 to 200 CGG repeats in the 5′-untranslated region of FMR1 gene are at increased risk for producing children with intellectual disabilities (ID) or autism spectrum disorders (ASD) due to expansion of PM alleles to full mutation alleles (> 200 repeats) during maternal transmission.MethodsIn present study fragile X PM carrier screening was performed in total 808 women who were consulting primary health care centers for preconception care in Khyber Pakhtunkhwa region of Pakistan between April, 2018 and December, 2020. Polymerase chain reaction (PCR) was performed for detection of PM carrier women and the CGG repeats number was confirmed by Southern blotting and capillary electrophoresis.ResultsThe prevalence rate for PM carriers among preconception women was found to be 0.7% that was contributed by 0.5% women in risk group (RG1) with family history of ID and 0.2% in risk group 2 (RG2) with family history of ASD. PM carrier women had at least one affected child or sibling. In addition, the preconception women with FMR1 PM alleles were found to be at increased risk for primary ovary insufficiency (RG1: P = 0.0265, RG2: P = 0.0389), postpartum depression (RG1: P = 0.0240, RG2: P = 0.0501) and neuropsychiatric disorders (RG1: P = 0.0389, RG2: P = 0.0432).ConclusionsCurrent study provides first evidence of fragile X PM carrier screening in Pakistani preconception women in primary care consultation. Findings of current study may help to improve preconception care and to reduce burden of fragile X associated disorders in our population.

Summary The utility of Raven's Standard Progressive Matrices (RPM) as a measure of intelligence (IQ) was studied. RPM was administered to 380 Vocational Rehabilitation applicants and correlated with selected variables and IQ measures. The results indicate that use of RPM 1948 British norms on U. S. Vocational Rehabilitation and general populations is a viable procedure where there is no need for IQ accuracy over 120. RPM did show a ceiling of about IQ 120. Construct validity was reinforced by correlations of RPM with other standard IQ measures. RPM shows the same race effect as is found regularly—the white mean is higher than the black mean—and is related to number of years education.

BackgroundConsistent with the contemporary literature that psychosis constructs are best represented as continuous syndromes, this study aims to determine if dimensional psychosis measures outperform traditional categorical measures, thereby improving detection of symptom severity. The Rorschach Performance Assessment System (R-PAS) contains meta-analytically supported internationally normed scales for assessing disordered thinking and reality testing that have been replicated in many countries. Given the literature trend of utilizing a dimensional approach when assessing psychosis, a dimensional R-PAS scale for assessing disordered thinking was recently developed. Therefore, it is important to determine if this new measure outperforms the traditional measure. We also attempt to replicate recent research by deconstructing the key components of psychosis (e.g., disorganized thinking, hallucinations, and negative symptoms) and evaluating the validity of the R-PAS measures designed to assess these constructs.MethodsOur study uses an archival clinical sample of 70 male inpatients with schizophrenia, schizoaffective, and major depressive disorder (Mean age = 41.9, Range 20 to 63) that were collected as part of an IRB-approved research project. Two trained diagnosticians independently interviewed the patients using the Structured Clinical Interview for DSM (SCID) and blindly assigned diagnoses as well as Brief Psychiatric Rating Scale (BPRS) ratings. Interrater reliability of their ratings using ICCs will be computed. The Rorschach was administered and relevant R-PAS variables were scored by trained research assistants. The new R-PAS dimensional measure of disorganized thinking (SPCT) will be coded by the first author, and a subset of protocols will be blindly coded by the third author. Interrater reliability will be computed for all variables.ResultsFirst, we will conduct correlational analyses to test the relationship between clinician ratings of disorganized thinking (on the BPRS Conceptual Disorganization and relevant SCID criteria) and the traditional measure of disorganized thinking on R-PAS (WSumCog). We will then use hierarchical regression analyses to determine whether the new dimensionalized measure of disorganized thinking (SPCT) provides incremental prediction of the clinician ratings of disorganized thinking on the BPRS and SCID-P over the traditional R-PAS measure (WSumCog). To replicate previous research, we will test the relationship between negative symptom ratings (on the BPRS and SCID) and R-PAS measures of behavioral, perceptual, and emotional task engagement (Complexity & FQ-%). Further, we anticipate that clinician ratings of delusions (on the BPRS and the SCID) will correlate with R-PAS measures of inaccurate understanding of human intention and action (M-) and illogical thinking (SPCT Illogical Thinking subscale). Lastly, we use correlational analyses to test the relationship between clinician ratings of hallucinations (on the BPRS and SCID) and an R-PAS measure of visual misperceptions (FQ-%).DiscussionImplications of this research provide additional validation for assessing key components of psychosis with a standardized internationally normed measure. Psychosis components (e.g., poor reality testing) limit the accuracy of patients’ self-reported symptoms and inflate rates of misdiagnosis; these R-PAS measures provide a framework for clinicians to behaviorally assess symptoms on a continuum ranging from nonclinical to severe psychosis-level disturbance. This research will aid in more accurate symptom assessment, thereby improving prognosis and treatment planning.

Fragile X-associated tremor/ataxia syndrome (FXTAS) affects motor and coordination pathways and is linked to swallowing and choking difficulties, which can lead to aspiration pneumonia, a leading cause of death in late-stage FXTAS. Despite their severity, these issues are under-investigated. This study examined their association with FXTAS stages and potential as markers of disease progression in FMR1 premutation (PM) carriers. A secondary analysis of Genotype-Phenotype cohort data (2017–2025, MIND Institute, UC Davis) examined swallowing/choking problems, FXTAS stage, neuroimaging, and psychological distress (Symptom Checklist-90-Revised; SCL-90-R). Associations between independent and dependent variables were tested using Generalized Estimating Equation (GEE) regression due to their correlated data. The study included 169 PM carriers (mean age 65 ± 10.9 years; 54% male), with approximately 35% reporting swallowing/choking difficulties. After adjusting for age and sex, individuals in the severe stage of FXTAS (stage 4–5) had a significantly higher risk of swallowing/choking problems compared to those without FXTAS (adjusted odds ratio [aOR] = 4.17; 95%CI = 1.28–13.58). PM carriers with swallowing/choking problems showed a significantly increased association with magnetic resonance imaging (MRI) findings of moderate to severe abnormalities in several brain regions, including cerebral atrophy (aOR = 2.69, p = 0.027), cerebellar atrophy (aOR = 3.34, p = 0.013), cerebellar white matter hyperintensity (aOR = 3.33, p = 0.012), and pons white matter hyperintensity (aOR = 3.93, p = 0.035). Swallowing/choking problems are common in FXTAS, particularly in later stages, and may represent an important clinical marker of disease progression. These patients should be referred to speech-language pathologists for evaluation and treatment. Such interventions could reduce morbidity-mortality associated with these problems.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-25959-5.

Evidence suggests that carriers of FMR1 mutations (e.g., fragile X syndrome and the FMR1 premutation) may demonstrate specific phenotypic patterns shared with autism (AU), particularly in the domain of pragmatic language, which involves the use of language in social contexts. Such evidence may implicate FMR1, a high-confidence gene associated with AU, in components of the AU phenotype. Prosody (i.e., using intonation and rhythm in speech to express meaning) is a pragmatic feature widely impacted in AU. Prosodic differences have also been observed in unaffected relatives of autistic individuals and in those with fragile X syndrome, although prosody has not been extensively studied among FMR1 premutation carriers. This study investigated how FMR1 variability may specifically influence prosody by examining the prosodic characteristics and related neural processing of prosodic features in women carrying the FMR1 premutation (PM). In Study 1, acoustic measures of prosody (i.e., in intonation and rhythm) were examined in speech samples elicited from a semi-structured narrative task. Study 2 examined the neural frequency following response (FFR) as an index of speech prosodic processing. Findings revealed differences in the production of intonation and rhythm in PM carriers relative to controls, with patterns that parallel differences identified in parents of autistic individuals. No differences in neural processing of prosodic cues were found. Post hoc analyses further revealed associations between speech rhythm and FMR1 variation (number of CGG repeats) among PM carriers. Together, the results suggest that FMR1 may play a role in speech prosodic phenotypes, at least in speech production, contributing to a deeper understanding of AU-related speech and language phenotypes among FMR1 mutation carriers.

IntroductionThe volume of the striatal structures has been associated with disease progression in individuals with Huntington's disease (HD) from North America, Europe, and Australia. However, it is not known whether the gray matter (GM) volume in the striatum is also sensitive in differentiating vulnerability from disease manifestation in HD families from a South‐American region known to have high incidence of the disease. In addition, the association of enlarged brain perivascular spaces (PVS) with cognitive, behavioral, and motor symptoms of HD is unknown.Materials and MethodsWe have analyzed neuroimaging indicators of global atrophy, PVS burden, and GM tissue volume in the basal ganglia and thalami, in relation to behavioral, motor, and cognitive scores, in 15 HD patients with overt disease manifestation and 14 first‐degree relatives not genetically tested, which represent a vulnerable group, from the region of Magdalena, Colombia.ResultsPoor fluid intelligence as per the Raven's Standard Progressive Matrices was associated with global brain atrophy (p = 0.002) and PVS burden (p ≤ 0.02) in HD patients, where the GM volume in all subcortical structures, with the exception of the right globus pallidus, was associated with motor or cognitive scores. Only the GM volume in the right putamen was associated with envy and MOCA scores (p = 0.008 and 0.015 respectively) in first‐degree relatives.ConclusionStriatal GM volume, global brain atrophy and PVS burden may serve as differential indicators of disease manifestation in HD. The Raven's Standard Progressive Matrices could be a cognitive test worth to consider in the differentiation of vulnerability versus overt disease in HD.

Objective: Psychometric properties of Raven's Standard Progressive Matrices in a Portuguese community sample were investigated. Method: The sample consists of 522 people (250 men and 272 women), aged between 12 and 95 years. All participants completed an informed consent form and a battery of neuropsychological tests, including Raven's Standard Progressive Matrices (RSPM), Rey 15-Item Memory Test, Zung Self-Rating Anxiety Scale, and Rey Complex Figure Test. Results: The average in RSPM was 41.18 (SD = 12.03). The results showed that all sociodemographic variables (age, sex, education, profession, regions, and place of residence) significantly influenced RSPM scores. The reliability and temporal stability of RSPM were adequate. Conclusions: This study suggests that RSPM is an instrument with potential for use among the Portuguese population.