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Fragile X syndrome (FXS) is a genetic condition caused by the inheritance of alleles with >200 CGG repeats in the 5 UTR of the fragile X messenger ribonucleoprotein 1 (FMR1) gene. These full mutation (FM) alleles are associated with DNA methylation and gene silencing, which result in intellectual disabilities, developmental delays, and social and behavioral issues. Mosaicism for both the size of the CGG repeat tract and the extent of its methylation is commonly observed in individuals with the FM. Mosaicism has also been reported in carriers of premutation (PM) alleles, which have 55-200 CGG repeats. PM alleles confer risk for the fragile X premutation-associated conditions (FXPAC), including FXTAS, FXPOI, and FXAND, conditions thought to be due to the toxic consequences of transcripts containing large CGG-tracts. Unmethylated FM (UFM) alleles are transcriptionally and translationally active. Thus, they produce transcripts with toxic effects. These transcripts do produce some FMRP, the encoded product of the FMR1 gene, albeit with reduced translational efficiency. As a result, mosaicism can result in a complex clinical presentation. Here, we review the concept of mosaicism in both FXS and in PM carriers, including its potential clinical significance.

PURPOSE: Fragile X syndrome (FXS) is a neurodevelopmental disorder, caused by an CGG repeat expansion (FM, > 200 CGG) in the fragile X messenger ribonucleoprotein 1 (FMR1) gene. Female carriers of a premutation (PM; 55-200 CGG) can transmit the PM allele, which, depending on the CGG allele size, can expand to an allele in the FM range in the offspring. METHODS: Carrier screening for FMR1 PM is not available in Thailand. This study aimed to investigate the prevalence of PM carriers among Thai reproductive women at the tertiary hospital. A total of 1250 females participated in this study; ages ranged from 20 to 45 years, mean of 30 years (S.D. = 6.27). RESULTS: Two carriers of a premutation allele, with 32,62 and 32,69 CGG repeats respectively, were identified. This corresponds to 1 in 600 women or 0.17% of the population. Further, three women carrying a gray zone allele (45-54 CGG repeats) were identified (29,51; 29,49; and 30,47 CGG repeats) which equals to 1:400 women or 0.25% of the population. No FM case was detected. CONCLUSIONS: This study heightens the importance of PM carrier screening of women of reproductive age, particularly for the higher risk of developing fragile X-associated primary ovarian insufficiency (FXPOI). Early identification of PM carrier status enhances family planning and fecundity alternatives and improves reproductive health outcomes leading to a better life.

BackgroundPremutation alleles of the FMR1 X-linked gene containing CGG repeat expansions ranging from 55 to 200 are associated with diverse late-onset neurological involvements, including most severe disorder termed Fragile X-associated Tremor/Ataxia Syndrome (FXTAS). It is intriguing that at least one-third of male, and a much lower than predicted from the X-linkage proportion of female carriers are free of this syndrome. This suggests the existence of secondary genetic factors modifying the risk of neurological involvements in these carriers. Considering the occasional presence of parkinsonian features in FXTAS, we explored the possibility that the Parkinson's Disease Polygenic Risk Score (PD PRS) is related to the occurrence of FXTAS or less severe neurological involvements, in premutation carriers.MethodsThe Genome-wide SNP genotyping and clinical data on neurological status were obtained from 250 unrelated affected and non-affected male and female adult carriers of the premutation. The medians for the Parkinson's Disease Polygenic Risk Score (PD PRS) were compared between the groups of asymptomatic and neurologically affected carriers, and the association of PD PRS with neurological involvement in context with the other known risk factors was explored by fitting univariate and multiple logistic regression models.ResultsThere was a significant difference between the medians from the asymptomatic versus neurologically affected (FXTAS+) groups (p = 0.009). The FXTAS+ status was significantly associated with age at testing (p

BACKGROUND: Fragile X syndrome (FXS) and autism spectrum disorder (ASD) are neurodevelopmental conditions that often have a substantial impact on daily functioning and quality of life. FXS is the most common cause of inherited intellectual disability (ID) and the most common monogenetic cause of ASD. Previous literature has shown that electrophysiological activity measured by electroencephalogram (EEG) during resting state is perturbated in FXS and ASD. However, whether electrophysiological profiles of participants with FXS and ASD are similar remains unclear. The aim of this study was to compare EEG alterations found in these two clinical populations presenting varying degrees of cognitive and behavioral impairments. METHODS: Resting state EEG signal complexity, alpha peak frequency (APF) and power spectral density (PSD) were compared between 47 participants with FXS (aged between 5-20), 49 participants with ASD (aged between 6-17), and 52 neurotypical (NT) controls with a similar age distribution using MANCOVAs with age as covariate when appropriate. MANCOVAs controlling for age, when appropriate, and nonverbal intelligence quotient (NVIQ) score were subsequently performed to determine the impact of cognitive functioning on EEG alterations. RESULTS: Our results showed that FXS participants manifested decreased signal complexity and APF compared to ASD participants and NT controls, as well as altered power in the theta, alpha and low gamma frequency bands. ASD participants showed exaggerated beta power compared to FXS participants and NT controls, as well as enhanced low and high gamma power compared to NT controls. However, ASD participants did not manifest altered signal complexity or APF. Furthermore, when controlling for NVIQ, results of decreased complexity in higher scales and lower APF in FXS participants compared to NT controls and ASD participants were not replicated. CONCLUSIONS: These findings suggest that signal complexity and APF might reflect cognitive functioning, while altered power in the low gamma frequency band might be associated with neurodevelopmental conditions, particularly FXS and ASD.

Multiple myeloma is a treatable, but currently incurable, hematological malignancy of plasma cells characterized by diverse and complex tumor genetics for which precision medicine approaches to treatment are lacking. The Multiple Myeloma Research Foundations Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile study ( NCT01454297 ) is a longitudinal, observational clinical study of newly diagnosed patients with multiple myeloma (n = 1,143) where tumor samples are characterized using whole-genome sequencing, whole-exome sequencing and RNA sequencing at diagnosis and progression, and clinical data are collected every 3 months. Analyses of the baseline cohort identified genes that are the target of recurrent gain-of-function and loss-of-function events. Consensus clustering identified 8 and 12 unique copy number and expression subtypes of myeloma, respectively, identifying high-risk genetic subtypes and elucidating many of the molecular underpinnings of these unique biological groups. Analysis of serial samples showed that 25.5% of patients transition to a high-risk expression subtype at progression. We observed robust expression of immunotherapy targets in this subtype, suggesting a potential therapeutic option.

BACKGROUND: Premutations in the Fragile X Messenger Ribonucleoprotein 1 (FMR1) gene, defined as between 55 and 200 CGGs, have been implicated in fragile X-associated primary ovarian insufficiency (FXPOI). Only 20% of female premutation carriers develop early ovulatory dysfunction, the reason for this incomplete penetrance is unknown. This study validated the mathematical model in premutation alleles, after assigning each allele a score representing allelic complexity. Subsequently, allelic scores were used to investigate the impact of allele complexity on age at amenorrhea for 58 premutation cases (116 alleles) previously published. METHODS: The allelic score was determined using a formula previously described by our group. The impact of each allelic score on age at amenorrhea was analyzed using Pearsons test and a contour plot generated to visualize the effect. RESULTS: Correlation of allelic score revealed two distinct complexity behaviors in premutation alleles. No significant correlation was observed between the allelic score of premutation alleles and age at amenorrhea. The same lack of significant correlation was observed regarding normal-sized alleles, despite a nearly significant trend. CONCLUSIONS: Our results suggest that the use of allelic scores combination have the potential to explain female infertility, namely the development of FXPOI, or ovarian dysfunction, despite the lack of correlation with age at amenorrhea. Such a finding is of great clinical significance for early identification of females at risk of ovulatory dysfunction, enhancement of fertility preservation techniques, and increasing the probability for a successful pregnancy in females with premutations. Additional investigation is necessary to validate this hypothesis.

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.

Electrification to reduce or eliminate greenhouse gas emissions is essential to mitigate climate change. However, a substantial portion of our manufacturing and transportation infrastructure will be difficult to electrify and/or will continue to use carbon as a key component, including areas in aviation, heavy-duty and marine transportation, and the chemical industry. In this Roadmap, we explore how multidisciplinary approaches will enable us to close the carbon cycle and create a circular economy by defossilizing these difficult-to-electrify areas and those that will continue to need carbon. We discuss two approaches for this: developing carbon alternatives and improving our ability to reuse carbon, enabled by separations. Furthermore, we posit that co-design and use-driven fundamental science are essential to reach aggressive greenhouse gas reduction targets.

This case series plus review seeks to describe the clinical characteristics and pathophysiology of VM among individuals with the fragile X premutation. We also seek to discuss treatment and future steps in addressing VM in this population.

To compare pregnancy outcomes after laparoscopic radiofrequency ablation and myomectomy.The ULTRA (Uterine Leiomyoma Treatment With Radiofrequency Ablation) study is an ongoing multicenter prospective cohort study with longitudinal follow-up up to 5 years comparing outcomes of radiofrequency ablation with myomectomy in premenopausal women older than age 21 years with symptomatic uterine leiomyomas. Participants were queried every 6 months after surgery to assess the incidence of pregnancy and pregnancy outcomes.Among 539 women enrolled in ULTRA, a total of 37 participants (mean age at first pregnancy 35.0±4.7 years) conceived 43 times as of March 2023 (22 radiofrequency ablation, 21 myomectomy). The average length of follow-up time after all procedures was 2.5±1.0 years. The baseline miscarriage rate in the study population was 33.3%. In participants who underwent radiofrequency ablation, 9 of 22 pregnancies (40.9%, 95% CI, 20.3-61.5%) ended in first-trimester miscarriage, 11 resulted in live births (50.0%, 95% CI, 29.1-70.9%), one resulted fetal death at 30 weeks of gestation, and one resulted in uterine rupture during miscarriage treatment with misoprostol 10 weeks after radiofrequency ablation. Among the live births in the radiofrequency ablation group, 45.5% were by vaginal delivery. In the myomectomy group, 9 of 21 pregnancies (42.9%, 95% CI, 21.7-64.0%) ended in first-trimester miscarriage and 12 resulted in live births (57.1%, 95% CI, 36.0-78.3%). There were no significant differences in the likelihood of live birth or miscarriage between the study groups.Full-term pregnancy and vaginal delivery are achievable after radiofrequency ablation of leiomyomas. However, in this interim analysis, the miscarriage rate in both radiofrequency ablation and myomectomy groups was higher than expected for women in this age group. Long-term data collection in the ongoing ULTRA study aims to further understand pregnancy outcomes after radiofrequency ablation compared with myomectomy.ClinicalTrials.gov, NCT0210094.

BACKGROUND: FXLEARN, 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.

INTRODUCTION: The chromosome 22q11.2 deletion syndrome (22q11.2DS) is characterized by a well-defined microdeletion and is associated with a wide range of brain-related phenotypes including schizophrenia spectrum disorders (SCZ), autism spectrum disorders (ASD), anxiety disorders and attention deficit disorders (ADHD). The typically deleted region in 22q11.2DS contains multiple genes which haploinsufficiency has the potential of altering the protein and the metabolic profiles. OBJECTIVES: Alteration in metabolic processes and downstream protein pathways during the early brain development may help to explain the increased prevalence of the observed neurodevelopmental phenotypes in 22q11.2DS. However, relatively little is known about the correlation of dysregulated protein/metabolite expression and neurobehavioral impairments in individuals who developed them over time. METHODS: In this study, we performed untargeted metabolic and proteomic analysis in plasma samples derived from 30 subjects including 16 participants with 22q11.2DS and 14 healthy controls (TD) enrolled in a longitudinal study, aiming to identify a metabolic and protein signature informing about the underlying mechanisms involved in disease development and progression. The metabolic and proteomic profiles were also compared between the participants with 22q11.2DS with and without various comorbidities, such as medical involvement, psychiatric conditions, and autism spectrum disorder (ASD) to detect potential changes among multiple specimens, collected overtime, with the aim to understand the basic underlying mechanisms involved in disease development and progression. RESULTS: We observed a large number of statistically significant differences in metabolites between the two groups. Among them, the levels of taurine and arachidonic acid were significantly lower in 22q11.2DS compared to the TD group. In addition, we identified 16 proteins that showed significant changes in expression levels (adjusted P

Self-assembly of colloidal nanocrystals (NCs) into superlattices (SLs) is an appealing strategy to design hierarchically organized materials with promising functionalities. Mechanistic studies are still needed to uncover the design principles for SL self-assembly, but such studies have been difficult to perform due to the fast time and short length scales of NC systems. To address this challenge, we developed an apparatus to directly measure the evolving phases in situ and in real time of an electrostatically stabilized Au NC solution before, during, and after it is quenched to form SLs using small-angle X-ray scattering. By developing a quantitative model, we fit the time-dependent scattering patterns to obtain the phase diagram of the system and the kinetics of the colloidal and SL phases as a function of varying quench conditions. The extracted phase diagram is consistent with particles whose interactions are short in range relative to their diameter. We find the degree of SL order is primarily determined by fast (subsecond) initial nucleation and growth kinetics, while coarsening at later times depends nonmonotonically on the driving force for self-assembly. We validate these results by direct comparison with simulations and use them to suggest dynamic design principles to optimize the crystallinity within a finite time window. The combination of this measurement methodology, quantitative analysis, and simulation should be generalizable to elucidate and better control the microscopic self-assembly pathways of a wide range of bottom-up assembled systems and architectures.

BackgroundFragile X syndrome, with an approximate incidence rate of 1 in 4000 males to 1 in 8000 females, is the most prevalent genetic cause of heritable intellectual disability and the most common monogenic cause of autism spectrum disorder. The full mutation of the Fragile X Messenger Ribonucleoprotein-1 gene, characterized by an expansion of CGG trinucleotide repeats (>200 CGG repeats), leads to fragile X syndrome. Currently, there are no targeted treatments available for fragile X syndrome. In a recent large multi-site trial, FXLEARN, the effects of the mGluR5 negative allosteric modulator, AFQ056 (mavoglurant), were investigated, but did not show a significant impact of AFQ056 on language development in children with fragile X syndrome aged 3-6 years.ObjectivesThe current analyses from biospecimens collected in the FXLEARN study aimed to determine whether AFQ056 affects the level of potential biomarkers associated with Akt/mTOR and matrix metalloproteinase 9 signaling in young individuals with fragile X syndrome. Previous research has indicated that these biomarkers play crucial roles in the pathophysiology of fragile X syndrome.DesignA double-blind placebo-controlled parallel-group flexible-dose forced titration design.MethodsBlood samples for biomarkers were collected during the FXLEARN at baseline and subsequent visits (1- and 8-month visits). Biomarker analyses included fragile X messenger ribonucleoprotein-1 genotyping by Southern blot and PCR approaches, fragile X messenger ribonucleoprotein-1 mRNA levels determined by PCR, matrix metalloproteinase 9 levels' detection using a magnetic bead panel, and targets of the Akt/mTOR signaling pathway with their phosphorylation levels detected.ResultsThis research revealed that administering AFQ056 does not affect the expression levels of the investigated blood biomarkers in young children with fragile X syndrome.ConclusionOur findings of the lack of association between clinical improvement and biomarkers' levels in the treatment group are in line with the lack of benefit observed in the FXLEARN study. These findings indicate that AFQ056 does not provide benefits as assessed by primary or secondary endpoints.RegistrationClincalTrials.gov NCT02920892.

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.

IntroductionMetformin has been used as a targeted treatment to potentially improve cognition and slow the typical IQ decline that occurs during development among individuals with fragile X syndrome (FXS). In this follow-up study, we are following the trajectory of IQ and adaptive behavior changes over 1 to 3 years in individuals with FXS who are clinically treated with metformin in an open label trial.MethodIndividuals with FXS ages 6 to 25 years (mean 13.15 ± 5.50) and nonverbal IQ mean 57.69 (±15.46) were treated for 1-3 years (1.88 ± 0.63). They all had a baseline IQ test using the Leiter-III non-verbal cognitive assessment and the Vineland-III adaptive behavior assessment before the start of metformin. Repeat Leiter-III and Vineland-III were completed after at least 1 year of metformin (500-1,000 mg/dose given twice a day).ResultThere were no significant changes in non-verbal IQ or in the adaptive behavior measurements at FDR

BACKGROUND: There is evidence for a significant excess of kinetic upper limb tremor in non-FXTAS female FMR1 premutation carriers. The present study explores the possibility that this tremor is associated with various other features reminiscent of those occurring in syndromic FXTAS. SAMPLE/METHODS: This study analyzed the data from an Australian cohort of 48 asymptomatic premutation women. We utilized spiral drawings from CRST, representing action tremor; the CRST total tremor; and ICARS- kinetic tremors/cerebellar ataxia scales. Cognitive tests (involving executive functioning) included SDMT, TMT, two subtests of the WAIS-III: MR and Similarities. Spearman Rank correlations assessed the relationships between the above measures, and the Chi-square tested hypothesis about the association between the white matter hyperintensities (wmhs) in the splenium of corpus callosum assessed from MR images and spiral drawings scores. RESULTS: The spiral drawing scores were significantly correlated with all three non-verbal cognitive test scores, and with the CRST scores; the latter correlated with all four cognitive test measures. Similarities (verbal) scores correlated with CRST, ICARS, and with the remaining cognitive scores. Ordered spiral scores categories were significantly associated with the degree of splenium involvement. CONCLUSION: This study showed that, in non-FXTAS premutation female carriers, sub-symptomatic forms of kinetic tremor were associated with a broader motor, and cognitive (especially executive) dysfunction.

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability (ID) and single gene cause of autism. Although most patients with FXS and the full mutation (FM) have complete methylation of the fragile X messenger ribonucleoprotein 1 (FMR1) gene, some have mosaicism in methylation and/or CGG repeat size, and few have completely unmethylated FM alleles. Those with a complete lack of methylation are rare, with little literature about the cognitive and behavioral phenotypes of these individuals. A review of past literature was conducted regarding individuals with unmethylated and mosaic FMR1 FM. We report three patients with an unmethylated FM FMR1 alleles without any behavioral or cognitive deficits. This is an unusual presentation for men with FM as most patients with an unmethylated FM and no behavioral phenotypes do not receive fragile X DNA testing or a diagnosis of FXS. Our cases showed that mosaic males with unmethylated FMR1 FM alleles may lack behavioral phenotypes due to the presence of smaller alleles producing the FMR1 protein (FMRP). However, these individuals could be at a higher risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS) due to the increased expression of mRNA, similar to those who only have a premutation.

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and autism spectrum disorder. The syndrome is often caused by greatly reduced or absent protein expression from the fragile X messenger ribonucleoprotein 1 (FMR1) gene due to expansion of a 5'-non-coding trinucleotide (CGG) element beyond 200 repeats (full mutation). To better understand the complex relationships among FMR1 allelotype, methylation status, mRNA expression, and FMR1 protein (FMRP) levels, FMRP was quantified in peripheral blood mononuclear cells for a large cohort of FXS (n = 154) and control (n = 139) individuals using time-resolved fluorescence resonance energy transfer. Considerable size and methylation mosaicism were observed among individuals with FXS, with FMRP detected only in the presence of such mosaicism. No sample with a minimum allele size greater than 273 CGG repeats had significant levels of FMRP. Additionally, an association was observed between FMR1 mRNA and FMRP levels in FXS samples, predominantly driven by those with the lowest FMRP values. This study underscores the complexity of FMR1 allelotypes and FMRP expression and prompts a reevaluation of FXS therapies aimed at reactivating large full mutation alleles that are likely not capable of producing sufficient FMRP to improve cognitive function.

BackgroundVestibular migraine (VM) is one of the most common causes of recurrent vertigo and presents with a history of spontaneous or positional vertigo with a history of migraine headaches. While research has identified a high prevalence of migraine headaches and vestibular deficits among fragile X premutation carriers, there has been no discussion about VM within this population.ObjectiveThis case series and review seeks to describe the clinical characteristics and pathophysiology of VM among individuals with the fragile X premutation. We also seek to discuss treatment and future steps in addressing VM in this population.MethodsA review of the literature regarding vestibular migraine and presentation of migraine headaches and vestibular deficits among premutation carriers was performed. A detailed clinical history of migraine headaches and vertigo was obtained from three patients with the fragile X premutation seen by the senior author (RJH).ResultsAll three cases first developed symptoms of migraine headaches earlier in life, with the development of VM near menopause. Two of the three cases developed progressive balance issues following the development of VM. All three cases found that their VM episodes were improved or resolved with pharmacological and/or lifestyle interventions.ConclusionsIt is important to recognize VM among premutation carriers because beneficial treatments are available. Future studies are needed regarding the prevalence of VM and the relationship to subsequent FXTAS. The pathophysiology of VM remains uncertain but possibilities include mitochondrial abnormalities, cranial nerve VIII toxicity secondary to neurotoxic protein accumulation, and calcitonin gene-related peptide (CGRP) signaling dysfunction due to altered levels of fragile X messenger ribonucleoprotein (FMRP).

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

Since the middle of the last century, and especially in the contemporary era, dominated by the image, the power of a historical fact is not only political, social and archival, but also cinematographic: from its very beginnings, cinema possesses a strong capacity for rewriting that can produce a historical consciousness superior to that of any other text. Examining the specific case of the Spanish Civil War up to the collapse of the Franco dictatorship, the essay offers a reflection on the process of historical re-appropriation conducted in Spain through cinema. The cinema is not merely a summary of history’s events, but offers the possibility of establishing a historical-aesthetic relationship with the spectator that is functional to the understanding of one’s individuality connected to the processes of collective memorisation.

This study explores the intersection role of students' epistemic beliefs and gender in argumentative essay writing. In total, 148 undergraduate students from a Dutch university followed an argumentation module, filled out the epistemic beliefs survey, and wrote an argumentative essay. Results showed that students' beliefs about the Internet-specific justification of knowledge did not influence essay performance. On the other hand, beliefs about the nature of scientific knowledge influenced their argumentative essay writing. Overall, there were no gender differences in argumentative essay writing. However, female students outperformed male students in taking a position on the topic. The interaction effects of beliefs about the Internet-specific justification of knowledge and gender in argumentation performance were neutral. There was, however, an intersection effect of students' epistemic beliefs about the nature of scientific knowledge and their gender in argumentation performance. We discuss these results and provide suggestions for future research.

In the light of urgent global sustainability challenges, vocational education is searching for new approaches that are more just and future proof. At least a part of the answer seems to lie in so-called collaborative learning arrangements where students together with societal actors explore sustainability-related challenges. The amount of this kind of arrangements in which vocational education participates increases. Empirical studies on what actually goes on in the collaborative arrangements are rather scarce. This study addresses the theory-practice gap by applying a participatory design. The study unveils that deeply seated educational and socio-cultural routines like the student as learner, alienation from issues, a bias towards cognitive knowing and 'solving' problems seem to limit the possibilities for more genuine collaboration to emerge. The study also found that by intervening with creative and reflexive methods, space for transformative learning can unfold that allows engagement with existential questions like 'what is it what I really got to do here?'. The opening up of these spaces was accompanied by longings to go beyond the rosy narratives of collaborative learning arrangements and to have more attention for the persistent embeddedness of educational routines in the societal issues around us. Vocational education "as" society. What happens if we progress towards vocational education for sustainable futures with more modesty and introspection?

In response to challenges emerging in society, universities are searching for ways to innovate their courses through novel institutional educational policies and practices. Those efforts, however, are often not informed by knowledge about course innovation characteristics university-wide, and are often not supported by processes of reflection questioning the 'who', 'how' and 'for what' of course innovations. This study applied the multifaceted analytical Course Innovation Framework (CIF) in order to explore characteristics of a large set of intended course innovations in a higher education institution in the Netherlands. The application of the CIF enabled a descriptive analysis of multiple characteristics of the intended course innovations. This analysis unveiled university-wide course innovation trends, upon which university stakeholders reflected in order to responsibly guide and transform policy and practices. The study findings show how the application of the CIF helps to gather situated knowledge on university-wide innovation trends, and how reflection on these trends empowers stakeholders to deliberate the culture and values of educational innovation they wish to promote within their institution.

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.

Fragile X syndrome (FXS) presents with autism spectrum disorder (ASD), intellectual disability, developmental delay, seizures, hypotonia during infancy, joint laxity, behavioral issues, and characteristic facial features. The predominant mechanism is due to CGG trinucleotide repeat expansion of more than 200 repeats in the 5′UTR (untranslated region) of FMR1 (Fragile X Messenger Ribonucleoprotein 1) causing promoter methylation and transcriptional silencing. However, not all patients presenting with the characteristic phenotype and point/frameshift mutations with deletions in FMR1 have been described in the literature. It is believed that < 1% of cases are caused by point mutations. Genetic and functional testing of point mutations in FXS has yielded insights on KH domain RNA-binding properties of FMRP (Fragile X Messenger Ribonucleoprotein Protein) and nuclear export of the protein. Here, we report a c.1599_1601del p.Arg534del novel mutation in FMR1 with homozygous C677T MTHFR polymorphism in a 12-year-old boy. He presents with unique phenotype of FXS with ASD, developmental delay, nonverbal learning disorder (NVLD), overall IQ in the 5th percentile with above average verbal IQ (66th percentile), difficulties with quantitative reasoning, dyspraxia, below average visual-spatial skills (2nd percentile), difficulty with social pragmatics and social understanding, and executive dysfunction. He has a strong aptitude for music and exceptional aural skills. Identification of novel variants has helped in understanding functional aspects of FMRP. In addition, it aids families in genetic counseling and in administering therapies for children with FXS who present with atypical features.

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.

BackgroundFragile X syndrome (FXS) and fetal alcohol syndrome disorders are both common causes of intellectual disability in children. When both conditions are present in the same individual, the resultant phenotype may make identification of clinical issues and management challenging.Case presentationIn this case report, we present a case of triplets who had significant in utero alcohol exposure; 2 of whom also have FXS and the other not having the fragile X mutation. The siblings with FXS have subtle differences in the physical phenotype compared with the other one, who has prominent features of partial fetal alcohol syndrome instead. However, all 3 siblings have intellectual impairment (although this is more severe in the 2 with FXS), meet diagnostic criteria for autism spectrum disorder, and present with severe behavioral challenges. The clinical presentation of the 2 siblings with FXS is much more severe as compared to a child with FXS alone, and this is likely due to the additive effect of in utero alcohol exposure and environmental factors. We discuss the combination of these 2 pathologies and how this can affect the overall clinical presentation.ConclusionIn the management of children with FXS, evaluation for other risk factors that can have neurobehavioral sequelae is important, and these can affect clinical presentation and prognosis.