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Brain development may be influenced by both genetic and environmental factors, with potential consequences that may last through the lifespan. Alterations during neurogenesis are linked to neurodevelopmental cognitive disorders. Many neurotransmitters and their systems play a vital role in brain development, as most are present prior to synaptogenesis, and they are involved in the aetiology of many neurodevelopmental disorders. For instance, dopamine (DA) receptor expression begins at the early stages of development and matures at adolescence. The long maturation period suggests how important it is for the stabilisation and integration of neural circuits. DA and dopaminergic (DAergic) system perturbations have been implicated in the pathogenesis of several neurological and neuropsychiatric disorders. The DAergic system controls key cognitive and behavioural skills including emotional and motivated behaviour through DA as a neurotransmitter and through the DA neuron projections to major parts of the brain. In this review, we summarise the current understanding of the DAergic system's influence on neurodevelopment and its involvement in the aetiology and progression of major disorders of the developing brain including autism, schizophrenia, attention deficit hyperactivity disorder, down syndrome, and fragile X syndrome., Competing Interests: Declarations. Ethical Approval: Not applicable. Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Accessing peer support can be difficult for people with, or carers of people with, inherited intellectual disabilities. One way to improve access is to provide services online, yet few studies have explored people's experiences with online peer support programmes. We aimed to explore experiences with such programmes for communities affected by fragile X-associated conditions., Methods: Qualitative study involving individual semi-structured interviews with 16 people with, or carers of people with, a fragile X-associated condition (n = 4 adult premutation carriers; n = 12 parents/carers of children/adults), who participated in at least one of three online peer support programmes: educational webinars, Facebook discussion group and small peer group sessions via Zoom. Reflexive thematic analysis was used to develop themes., Results: Three overarching themes relating to experiences were as follows: (1) uncertainty and value of shared experiences, (2) support navigating healthcare, (3) advantages being online, but still a place for in-person events. Educational webinars were perceived to be a valuable source of information about fragile X-associated conditions although people had variable information needs. Facebook discussion groups enabled people to connect with others, although participants expressed some competing preferences for how the groups were organised. Zoom peer group sessions were perceived to help participants feel supported by others, but that consistency in organisation was important., Conclusions: Online peer support programmes were perceived to be beneficial, bridging informational gaps and facilitating social connection. However, participants believed there was still a place for in-person events, some felt educational webinars did not always meet their needs and some had privacy concerns., (© 2024 The Author(s). Journal of Intellectual Disability Research published by John Wiley & Sons and MENCAP.)

FMR1 (Fragile X messenger ribonucleoprotein 1), located on the X-chromosome, encodes the multi-functional FMR1 protein (FMRP), critical to brain development and function. Trinucleotide CGG repeat expansions at this locus cause a range of neurological disorders, collectively referred to as Fragile X-related conditions. The most well-known of these is Fragile X syndrome, a neurodevelopmental disorder associated with syndromic facial features, autism, intellectual disabilities, and seizures. However, CGG expansions of different sizes also confer a risk of neuropsychiatric and neurodegenerative disorders throughout the lifespan, through distinct molecular mechanisms. Although Fragile X syndrome is associated with downstream synaptic deficits and neuronal hyperexcitability, work in the past decade has demonstrated that both the causative FMR1 trinucleotide repeat expansion and FMRP itself play important roles in nuclear function and regulation, including non-canonical nucleic acid structure formation and chromatin dynamics. These effects are critical to cellular pathophysiology, although the full extent of their contribution to clinical phenotypes is only just emerging. Here, we present a focused review on some of the nuclear consequences of FMR1 /FMRP dysregulation, including parallels in other repeat expansion disorders, ranging from studies in model systems to human cells and tissues.

Lay Abstract: Autism is clinically defined by challenges with social language, including difficulties offering on-topic language in a conversation. Similar differences are also seen in genetically related conditions such as fragile X syndrome (FXS), and even among those carrying autism-related genes who do not have clinical diagnoses (e.g., the first-degree relatives of autistic individuals and carriers of the FMR1 premutation), which suggests there are genetic influences on social language related to the genes involved in autism. Characterization of social language is therefore important for informing potential intervention strategies and understanding the causes of communication challenges in autism. However, current tools for characterizing social language in both clinical and research settings are very time and labor intensive. In this study, we test an automized computational method that may address this problem. We used a type of artificial intelligence known as pre-trained language model to measure aspects of social language in autistic individuals and their parents, non-autistic comparison groups, and individuals with FXS and the FMR1 premutation. Findings suggest that these artificial intelligence approaches were able to identify differences in social language in autism, and to provide insight into the individuals' ability to keep a conversation on-topic. These findings also were associated with broader measures of participants' social communication ability. This study is one of the first to use artificial intelligence models to capture important differences in social language in autism and genetically related groups, demonstrating how artificial intelligence might be used to provide automatized, efficient, and objective tools for language characterization., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Developments in preconception and prenatal technologies have led to undeniable advances in how health-care providers screen and treat patients. Despite these advances, at any point errors can occur leading to misdiagnosis or a missed diagnosis. In some instances, the missed information can lead to the birth of a child with health issues where short of the error, the decision to avoid conception or terminate the pregnancy might have been made. When these lapses unfold, there exists the potential for a wrongful birth or wrongful life lawsuit to ensue. While these 2 actions are based on the same set of events, they are distinct legal claims with varying degrees of judicial permissibility. Global legal acceptability of wrongful birth and life lawsuits tends to resemble patterns in the United States. Analyzing prior wrongful birth and wrongful life claims can reveal common trends in events leading to these types of lawsuits, as well as an understanding of their potential outcomes. A familiarity with wrongful birth and wrongful life lawsuits demonstrates how these cases are unique from other forms of prenatal or birth injury tort lawsuits and can provide insights to common shortcomings in clinical practice. Applying these lessons to clinical practice highlights key approaches towards limiting the risk of certain errors leading to wrongful birth and wrongful life lawsuits, with the goal of health-care providers offering high quality health care., (Copyright © 2024 Elsevier Inc. All rights reserved.)

This study aims to understand the healthcare experiences of African American women with a fragile X premutation (PM). PM carriers are at risk for fragile X-associated conditions, including primary ovarian insufficiency (FXPOI) and neuropsychiatric disorders (FXAND). There is no racial/ethnic association with carrying a PM, but African American women historically experience barriers receiving quality healthcare in the USA. Obstacles to care may increase mental health conditions like anxiety and depression. Eight African American women with a PM were interviewed to explore disparities in receiving healthcare and to learn about psychosocial experiences during and after their diagnoses. Interviews were transcribed verbatim and independently coded by two researchers. A deductive-inductive approach was used, followed by thematic analysis to determine prominent themes. The average participant age was 52.3 ± 8.60 years, with a mean age at premutation diagnosis of 31 ± 5.95 years. Seven participants had children with FXS. Themes from interviews included healthcare experiences, family dynamics, and emotional/mental health after their diagnosis. Participants reported concerns about not being taken seriously by providers and mistrust of the medical institutions. Within families, participants reported denial, insensitivity, and isolation. Participants reported a high incidence of anxiety and depression. Both are symptoms of FXAND and stresses of systemic racism and sexism. The reported family dynamics around the news of a genetic diagnosis stand apart from other racial cohorts in fragile X research: interventions like family counseling sessions and inclusive support opportunities from national organizations could ease the impacts of a PM for African American women., Competing Interests: Declarations Competing Interest The authors declare that they have no known competing financial interests., (© 2023. The Author(s).)

Sensory processing abnormalities are a hallmark of autism spectrum disorder (ASD) and are included in its diagnostic criteria. Among these challenges, food neophobia has garnered attention due to its prevalence and potential impact on nutritional intake and health outcomes. This review describes the correlation between novel odor perception and feeding difficulties within the context of ASD. Moreover, this review underscores the role of odor processing in shaping feeding behaviors within the ASD population. It examines the psychophysics of odor perception in individuals with ASD and evaluates the behavioral and neurophysiological assessments conducted using novel odor stimuli in mouse models relevant to autism and wild-type mice. Additionally, we explore the mechanism on how odor novelty affects neuronal circuitry, shedding light on potential underlying mechanisms for the effect of odor novelty on ASD., (© 2024 The Author(s). Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)

Extensive evidence demonstrates that prenatal nutrition is crucial for adequate fetal development. Specifically, maternal choline intake plays a significant role in gene expression, epigenetics, and cell membrane formation. Preclinical models have shown that maternal dietary intake improves the development of the cerebral cortex and hippocampus. This review focuses on the role of prenatal choline intake and discusses its potential role in neurodevelopmental disorders especially since choline has emerged as a promising coadjutant to mitigate cognitive and developmental disorders. However, more evidence regarding timing, dosage, and molecular mechanisms is needed. In this review, we discuss the impact of prenatal choline availability, evidence from current models, and gaps to address in how choline may impact the symptomology and manifestation of Rett syndrome, fragile X syndrome, and Down syndrome. Our ultimate goal is to highlight the importance of choline for maternal health and its potential beneficial impact on neurodevelopmental disorders., Competing Interests: IT-G has had grant funding from Balchem, a company that makes choline for diet supplements and animal feed. EP, (PhD) is a Balchem postdoctoral fellow. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Mujica-Coopman, Paules and Trujillo-Gonzalez.)

Repeat expansion disorders (REDs) encompass over 50 inherited neurological disorders and are characterized by the expansion of short tandem nucleotide repeats beyond a specific repeat length. Particularly intriguing among these are multiple fragile X-associated disorders (FXds), which arise from an expansion of CGG repeats in the 5' untranslated region of the FMR1 gene. Despite arising from repeat expansions in the same gene, the clinical manifestations of FXds vary widely, encompassing developmental delays, parkinsonism, dementia, and an increased risk of infertility. FXds also exhibit molecular mechanisms observed in other REDs, that is, gene- and protein-loss-of-function and RNA- and protein-gain-of-function. The heterogeneity of phenotypes and pathomechanisms in FXds results from the different lengths of the CGG tract. As the number of repeats increases, the structures formed by RNA and DNA fragments containing CGG repeats change significantly, contributing to the diversity of FXd phenotypes and mechanisms. In this review, we discuss the role of RNA and DNA structures formed by expanded CGG repeats in driving FXd pathogenesis and how the genetic instability of CGG repeats is mediated by the complex interplay between transcription, DNA replication, and repair. We also discuss therapeutic strategies, including small molecules, antisense oligonucleotides, and CRISPR-Cas systems, that target toxic RNA and DNA involved in the development of FXds., (© 2024 The Author(s). WIREs RNA published by Wiley Periodicals LLC.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The etiological heterogeneity of depression poses a challenge for prevention and intervention efforts. One solution is to map unique etiological pathways for subgroups defined by a singular risk factor. A relevant population for this approach is women who carry the premutation of the fragile X messenger ribonucleoprotein 1 ( FMR 1) gene, who are at high risk for adult-onset depression. This study explores a candidate neurophysiological marker of depression risk: reduced reward sensitivity, indexed by the reward positivity (RewP). The RewP has been linked to depression risk in the general population, but is unexplored within FMR 1 premutation carriers. 16 women with the FMR 1 premutation and a matched control group completed a simple guessing task while the electroencephalogram was recorded. Among premutation carriers, RewP difference score (win versus loss) was reduced. These preliminary finding suggest that the FMR 1 premutation may confer increased risk for depression in part through abnormal neural sensitivity to rewards.

A diagnosis of the X-linked condition Fragile X syndrome (FXS) in a child commonly reveals the mother's carrier status. Previous research focused on the genetic counseling process for the child and maternal family, despite calls for more research on the support needs of fathers. This study explored experiences and support needs of fathers at least 1 year after their child's FXS diagnosis to understand barriers and enablers and optimize health outcomes for the family. In-depth interviews were conducted with 11 fathers recruited through the Australian Genetics of Learning Disability Service and the Fragile X Association. Deidentified transcripts were analyzed using thematic analysis guided by an inductive approach. Four themes emerged: (1) making life easier through understanding-yesterday and today, (2) the path to a new normal-today and tomorrow, (3) seeking information and support, and (4) what men want. Fathers reported diagnostic odysseys, postdiagnostic grief, and challenges adjusting. They highlighted difficulties in understanding their child's unique behaviors and needs, responding to their partner's psychological support needs, planning for their child's future, and navigating complex health and disability systems. Participants suggested health professionals facilitate father-to-father support and psychological counseling. These findings highlight the unmet needs of fathers and suggest that a strengths-based approach is critically important given the recognized mental health impact., (© 2023 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Altered function of peripheral sensory neurons is an emerging mechanism for symptoms of autism spectrum disorders. Visual sensitivities are common in autism, but whether differences in the retina might underlie these sensitivities is not well-understood. We explored retinal function in the Fmr1 knockout model of Fragile X syndrome, focusing on a specific type of retinal neuron, the "sustained On alpha" retinal ganglion cell. We found that these cells exhibit changes in dendritic structure and dampened responses to light in the Fmr1 knockout. We show that decreased light sensitivity is due to increased inhibitory input and reduced E-I balance. The change in E-I balance supports maintenance of circuit excitability similar to what has been observed in cortex. These results show that loss of Fmr1 in the mouse retina affects sensory function of one retinal neuron type. Our findings suggest that the retina may be relevant for understanding visual function in Fragile X syndrome., Competing Interests: Declaration of interests The authors have no conflicts of interest to declare.

Objective: Fragile X Syndrome (FXS) is a hereditary form of autism spectrum disorder. It is caused by a trinucleotide repeat expansion in the Fmr1 gene, leading to a loss of Fragile X Protein (FMRP) expression. The loss of FMRP causes auditory hypersensitivity: FXS patients display hyperacusis and the Fmr1- knock-out (KO) mouse model for FXS exhibits auditory seizures. FMRP is strongly expressed in the cochlear nucleus and other auditory brainstem nuclei. We hypothesize that the Fmr1-KO mouse has altered gene expression in the cochlear nucleus that may contribute to auditory hypersensitivity., Methods: RNA was isolated from cochlear nuclei of Fmr1-KO and WT mice. Using next-generation sequencing (RNA-seq), the transcriptomes of Fmr1-KO mice and WT mice (n = 3 each) were compared and analyzed using gene ontology programs., Results: We identified 270 unique, differentially expressed genes between Fmr1-KO and WT cochlear nuclei. Upregulated genes (67%) are enriched in those encoding secreted molecules. Downregulated genes (33%) are enriched in neuronal function, including synaptic pathways, some of which are ideal candidate genes that may contribute to hyperacusis., Conclusion: The loss of FMRP can affect the expression of genes in the cochlear nucleus that are important for neuronal signaling. One of these, Kcnab2, which encodes a subunit of the Shaker voltage-gated potassium channel, is expressed at an abnormally low level in the Fmr1-KO cochlear nucleus. Kcnab2 and other differentially expressed genes may represent pathways for the development of hyperacusis. Future studies will be aimed at investigating the effects of these altered genes on hyperacusis., Level of Evidence: N/A Laryngoscope, 134:1363-1371, 2024., (© 2023 The American Laryngological, Rhinological and Otological Society, Inc.)

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

Introduction: Fragile X messenger ribonucleoprotein (FMRP) is a protein involved in many neuronal processes in the nervous system including the modulation of synaptic transmission. The loss of FMRP produces the fragile X syndrome (FXS), a neurodevelopmental disorder affecting synaptic and neuronal function and producing cognitive impairments. However, the effects of FXS on short-term processing of synaptic inputs and neuronal outputs in the hippocampus have not yet been sufficiently clarified. Furthermore, it is not known whether dorsal and ventral hippocampi are affected similarly or not in FXS., Method: We used an Fmr1 knockout (KO) rat model of FXS and recordings of evoked field potentials from the CA1 field of transverse slices from both the dorsal and the ventral hippocampi of adult rats., Results: Following application of a frequency stimulation protocol consisting of a ten-pulse train and recordings of fEPSP, we found that the dorsal but not ventral KO hippocampus shows altered short-term synaptic plasticity. Furthermore, applying the frequency stimulation protocol and recordings of population spikes, both segments of the KO hippocampus display altered short-term neuronal dynamics., Conclusions: These data suggest that short-term processing of synaptic inputs is affected in the dorsal, not ventral, FXS hippocampus, while short-term processing of neuronal output is affected in both segments of the FXS hippocampus in a similar way. These FXS-associated changes may have significant impact on the functions of the dorsal and ventral hippocampi in individuals with FXS., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Cerebellar dysfunction has been linked to autism spectrum disorders (ASDs). Although cerebellar pathology has been observed in individuals with fragile X syndrome (FXS) and in mouse models of the disorder, a cerebellar functional contribution to ASD-relevant behaviors in FXS has yet to be fully characterized. In this study, we demonstrate a critical cerebellar role for Fmr1 (fragile X messenger ribonucleoprotein 1) in ASD-relevant behaviors. First, we identify reduced social behaviors, sensory hypersensitivity, and cerebellar dysfunction, with loss of cerebellar Fmr1. We then demonstrate that cerebellar-specific expression of Fmr1 is sufficient to impact social, sensory, cerebellar dysfunction, and cerebro-cortical hyperexcitability phenotypes observed in global Fmr1 mutants. Moreover, we demonstrate that targeting the ASD-implicated cerebellar region Crus1 ameliorates behaviors in both cerebellar-specific and global Fmr1 mutants. Together, these results demonstrate a critical role for the cerebellar contribution to FXS-related behaviors, with implications for future therapeutic strategies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder characterized by intellectual disability and is related to autism. FXS is caused by mutations of the fragile X messenger ribonucleoprotein 1 gene ( Fmr1 ) and is associated with alterations in neuronal network excitability in several brain areas including hippocampus. The loss of fragile X protein affects brain oscillations, however, the effects of FXS on hippocampal sharp wave-ripples (SWRs), an endogenous hippocampal pattern contributing to memory consolidation have not been sufficiently clarified. In addition, it is still not known whether dorsal and ventral hippocampus are similarly affected by FXS. We used a Fmr1 knock-out (KO) rat model of FXS and electrophysiological recordings from the CA1 area of adult rat hippocampal slices to assess spontaneous and evoked neural activity. We find that SWRs and associated multiunit activity are affected in the dorsal but not the ventral KO hippocampus, while complex spike bursts remain normal in both segments of the KO hippocampus. Local network excitability increases in the dorsal KO hippocampus. Furthermore, specifically in the ventral hippocampus of KO rats we found an increased effectiveness of inhibition in suppressing excitation and an upregulation of α1GABA A receptor subtype. These changes in the ventral KO hippocampus are accompanied by a striking reduction in its susceptibility to induced epileptiform activity. We propose that the neuronal network specifically in the ventral segment of the hippocampus is reorganized in adult Fmr1 -KO rats by means of balanced changes between excitability and inhibition to ensure normal generation of SWRs and preventing at the same time derailment of the neural activity toward hyperexcitability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Leontiadis, Trompoukis, Tsotsokou, Miliou, Felemegkas and Papatheodoropoulos.)

A common neurobiological mechanism in several neurodevelopmental disorders, including fragile X syndrome (FXS), is alterations in the balance between excitation and inhibition in the brain. It is thought that in the hippocampus, as in other brain regions, FXS is associated with increased excitability and reduced inhibition. However, it is still not known whether these changes apply to both the dorsal and ventral hippocampus, which appear to be differently involved in neurodegenerative disorders. Using a Fmr1 knock-out (KO) rat model of FXS, we found increased neuronal excitability in both the dorsal and ventral KO hippocampus and increased excitatory synaptic transmission in the dorsal hippocampus. Interestingly, synaptic inhibition is significantly increased in the ventral but not the dorsal KO hippocampus. Furthermore, the ventral KO hippocampus displays increased expression of the α1GABA A receptor subtype and a remarkably reduced rate of epileptiform discharges induced by magnesium-free medium. In contrast, the dorsal KO hippocampus displays an increased rate of epileptiform discharges and similar expression of α1GABA A receptors compared with the dorsal WT hippocampus. Blockade of α5GABA A receptors by L-655,708 did not affect epileptiform discharges in any genotype or hippocampal segment, and the expression of α5GABA A receptors did not differ between WT and KO hippocampus. These results suggest that the increased excitability of the dorsal KO hippocampus contributes to its heightened tendency to epileptiform discharges, while the increased phasic inhibition in the Fmr1-KO ventral hippocampus may represent a homeostatic mechanism that compensates for the increased excitability reducing its vulnerability to epileptic activity.

How nucleic acids interact with proteins, and how they affect protein folding, aggregation, and misfolding is a still-evolving area of research. Considerable effort is now focusing on a particular structure of RNA and DNA, G-quadruplexes, and their role in protein homeostasis and disease. In this state-of-the-art review, we track recent reports on how G-quadruplexes influence protein aggregation, proteolysis, phase separation, and protein misfolding diseases, and pose currently unanswered questions in the advance of this scientific field., (© 2022 Federation of European Biochemical Societies.)

Background: Men with fragile X-associated tremor/ataxia syndrome (FXTAS) often develop executive dysfunction, characterized by disinhibition, frontal dyscontrol of movement, and working memory and attention changes. Although cross-sectional studies have suggested that earlier executive function changes may precede FXTAS, the lack of longitudinal studies have made it difficult to address this hypothesis., Methods: This study included 66 FMR1 premutation carriers (PC) ranging from 40-78 years (Mean=59.5) and 31 well-matched healthy controls (HC) ages 40-75 (Mean 57.7) at baseline. Eighty-four participants returned for 2-5 follow up visits over a duration of 1 to 9 years (Mean=4.6); 28 of the PC developed FXTAS. The Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A) was completed by participants and their spouses/partners at each visit., Results: Longitudinal mixed model regression analyses showed a greater decline with age in PC compared to HC on the Metacognition Index (MI; self-initiation, working memory, organization, task monitoring). Conversion to FXTAS was associated with worsening MI and Behavioral Regulation Index (BRI; inhibition, flexibility, emotion modulation). For spouse/partner report, FXTAS conversion was associated with worsening MI. Finally, BRIEF-A executive function problems at baseline significantly predicted later development of FXTAS., Conclusions: These findings suggest that executive function changes represent a prodrome of the later movement disorder., Competing Interests: Conflicts of Interest: Dr. Hessl has received funding from the following, all of which is directed to UC Davis, in support of fragile X syndrome treatment programs, unrelated to this study, and he receives no personal funds and has no relevant financial interest in any of the commercial entities listed: Autifony, Ovid, Tetra, Healx, and Zynerba pharmaceutical companies to consult on outcome measures and clinical trial design. RJH has received funding from Zynerba and the Azrieli foundation for treatment studies in fragile X syndrome and unrelated to this study. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Neurodegeneration in Fragile X-associated tremor/ataxia syndrome (FXTAS) is caused by a CGG trinucleotide repeat expansion in the 5' UTR of FMR1. Expanded CGG repeat RNAs form stable secondary structures, which in turn support repeat-associated non-AUG (RAN) translation to produce toxic peptides. The parameters that impact RAN translation initiation efficiency are not well understood. Here we used a Drosophila melanogaster model of FXTAS to evaluate the role of the eIF4G family of eukaryotic translation initiation factors (EIF4G1, EIF4GII and EIF4G2/DAP5) in modulating RAN translation and CGG repeat-associated toxicity. DAP5 knockdown robustly suppressed CGG repeat-associated toxicity and inhibited RAN translation. Furthermore, knockdown of initiation factors that preferentially associate with DAP5 (such as EIF2β, EIF3F and EIF3G) also selectively suppressed CGG repeat-induced eye degeneration. In mammalian cellular reporter assays, DAP5 knockdown exhibited modest and cell-type specific effects on RAN translation. Taken together, these data support a role for DAP5 in CGG repeat associated toxicity possibly through modulation of RAN translation., Competing Interests: Declaration of Competing Interest The authors have no financial conflicts of interest associated with the work presented in this manuscript., (Published by Elsevier Inc.)

Understanding how the RNA-binding domains of a protein regulator are used to recognize its RNA targets is a key problem in RNA biology, but RNA-binding domains with very low affinity do not perform well in the methods currently available to characterize protein-RNA interactions. Here, we propose to use conservative mutations that enhance the affinity of RNA-binding domains to overcome this limitation. As a proof of principle, we have designed and validated an affinity-enhanced K-homology (KH) domain mutant of the fragile X syndrome protein FMRP, a key regulator of neuronal development, and used this mutant to determine the domain's sequence preference and to explain FMRP recognition of specific RNA motifs in the cell. Our results validate our concept and our nuclear magnetic resonance (NMR)-based workflow. While effective mutant design requires an understanding of the underlying principles of RNA recognition by the relevant domain type, we expect the method will be used effectively in many RNA-binding domains., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Introduction: Fragile X syndrome (FXS), resulting from a mutation in the Fmr1 gene, is the most common monogenic cause of autism and inherited intellectual disability. Fmr1 encodes the Fragile X Messenger Ribonucleoprotein (FMRP), and its absence leads to cognitive, emotional, and social deficits compatible with the nucleus accumbens (NAc) dysfunction. This structure is pivotal in social behavior control, consisting mainly of spiny projection neurons (SPNs), distinguished by dopamine D1 or D2 receptor expression, connectivity, and associated behavioral functions. This study aims to examine how FMRP absence differentially affects SPN cellular properties, which is crucial for categorizing FXS cellular endophenotypes., Methods: We utilized a novel Fmr1-/y :: Drd1a-tdTomato mouse model, which allows in-situ identification of SPN subtypes in FXS mice. Using RNA-sequencing, RNAScope and ex-vivo patch-clamp in adult male mice NAc, we comprehensively compared the intrinsic passive and active properties of SPN subtypes., Results: Fmr1 transcripts and their gene product, FMRP, were found in both SPNs subtypes, indicating potential cell-specific functions for Fmr1 . The study found that the distinguishing membrane properties and action potential kinetics typically separating D1- from D2-SPNs in wild-type mice were either reversed or abolished in Fmr1-/y :: Drd1a-tdTomato mice. Interestingly, multivariate analysis highlighted the compound effects of Fmr1 ablation by disclosing how the phenotypic traits distinguishing each cell type in wild-type mice were altered in FXS., Discussion: Our results suggest that the absence of FMRP disrupts the standard dichotomy characterizing NAc D1- and D2-SPNs, resulting in a homogenous phenotype. This shift in cellular properties could potentially underpin select aspects of the pathology observed in FXS. Therefore, understanding the nuanced effects of FMRP absence on SPN subtypes can offer valuable insights into the pathophysiology of FXS, opening avenues for potential therapeutic strategies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Giua, Lassalle, Makrini-Maleville, Valjent, Chavis and Manzoni.)

Fragile X syndrome is a neuro-developmental disease affecting intellectual abilities and social interactions. Drosophila melanogaster represents a consolidated model to study neuronal pathways underlying this syndrome, especially because the model recapitulates complex behavioural phenotypes. Drosophila Fragile X protein, or FMRP, is required for a normal neuronal structure and for correct synaptic differentiation in both the peripheral and central nervous systems, as well as for synaptic connectivity during development of the neuronal circuits. At the molecular level, FMRP has a crucial role in RNA homeostasis, including a role in transposon RNA regulation in the gonads of D. m. Transposons are repetitive sequences regulated at both the transcriptional and post-transcriptional levels to avoid genomic instability. De-regulation of transposons in the brain in response to chromatin relaxation has previously been related to neurodegenerative events in Drosophila models. Here, we demonstrate for the first time that FMRP is required for transposon silencing in larval and adult brains of Drosophila "loss of function" dFmr1 mutants. This study highlights that flies kept in isolation, defined as asocial conditions, experience activation of transposable elements. In all, these results suggest a role for transposons in the pathogenesis of certain neurological alterations in Fragile X as well as in abnormal social behaviors.

Objective: Carriers of Fragile X premutation may have associated medical comorbidities, such as Fragile X-associated tremor and ataxia (FXTAS) and Fragile X-associated premature ovarian insufficiency (FXPOI). We examined the Fragile X premutation effect on cognition, and we assumed that there is a direct correlation between the continuous spectrum of specific learning and attention deficits to the number of CGG repeats on the FMR1 gene., Methods: A total of 108 women were referred to our center due to a related Fragile X syndrome (FXS) patient, 79 women carried a premutation of 56-199 repeats, and 19 women carried a full mutation of more than 200 CGG repeats on FMR1 gene. Genetic results of CGG repeats, demographic information, structured questionnaires for ADHD, learning disabilities of language and mathematics, and independence level were analyzed in women carrying the FMR1 premutation and compared to the group carrying the full mutation. Women with FXS and FXTAS were excluded., Results: When analyzed as a continuum, there was a significant increase in the following complaints which were associated with a higher number of repeats: specific daily function skills such as driving a car, writing checks, disorientation in directions, and also specific learning difficulties such as spelling and math difficulties. Additionally, when tested as a categorical independent variable, we observe that women with the full mutation were more likely to have ADHD or other learning disability diagnoses in the past than during premutation (<200 CGG repetitions)., Conclusion: Specific learning and attention difficulties and resulting daily function difficulties correlate with an increased number of CGG repeats and are more likely to be associated as a common feature of premutation and full mutation in a female premutation carrier. Despite evidence of learning and attention difficulties, it is encouraging that most female carriers of the premutation and full mutation function well in most areas. Nevertheless, they face significant difficulties in specific areas of functioning such as driving, and confusion in times and schedules. Those daily function skills are mostly impacted by dyscalculia, right and left disorientation, and attention difficulties. This may aid to design specific interventions to address specific learning deficits in order to improve daily function skills and quality of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Gabis, Shaham, Attia, Kowal, David, Banet-Levi, Shefer, Gabis, Mula-Topf, Avrech Bar, Bart and Segal.)

Over a third of the human genome is comprised of repetitive sequences, including more than a million short tandem repeats (STRs). While studies of the pathologic consequences of repeat expansions that cause syndromic human diseases are extensive, the potential native functions of STRs are often ignored. Here, we summarize a growing body of research into the normal biological functions for repetitive elements across the genome, with a particular focus on the roles of STRs in regulating gene expression. We propose reconceptualizing the pathogenic consequences of repeat expansions as aberrancies in normal gene regulation. From this altered viewpoint, we predict that future work will reveal broader roles for STRs in neuronal function and as risk alleles for more common human neurological diseases., Competing Interests: SW No competing interests declared, PT Dr Todd served as a consultant to Denali Therapeutics and holds a shared patent on ASOs developed with Ionis Pharmaceuticals

Based on the inclusive and methodologically rigorous framework provided by Ed Zigler's developmental approach, we previously challenged what we called, 'the mysterious myth of attention deficit', the fallacy of attention as a universal deficit among persons with intellectual disability (ID). In this latest update, we conducted a systematic review of studies of essential components of attention among persons with ID published in the interim since the last iteration of the mysterious myth narrative was submitted for publication approximately a decade ago. We searched the databases PubMed and PsycINFO for English-language peer-reviewed studies published from 1 January 2011 through 5 February 2021. In keeping with the developmental approach, the two essential methodological criteria were that the groups of persons with ID were aetiologically homogeneous and that the comparisons with persons with average IQs (or with available norms) were based on an appropriate index of developmental level, or mental age. Stringent use of these criteria for inclusion served to control for bias in article selection. Articles were then categorised based on aetiological group studied and component of visual attention. Based on these criteria, 18 articles were selected for inclusion out of the 2837 that were identified. The included studies involved 547 participants: 201 participants with Down syndrome, 214 participants with Williams syndrome and 132 participants with fragile X syndrome. The findings from these articles call attention to the complexities and nuances in understanding attentional functioning across homogeneous aetiological groups and highlight that functioning must be considered in relation to aetiology; factors associated with the individual, such as developmental level, motivation, styles and biases; and factors associated with both the task, such as context, focus, social and emotional implications, and levels of environmental complexity., (© 2022 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.)

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication along with repetitive stereotypic behaviors. Currently, there are no specific biomarkers for diagnostic screening or treatments available for autistic patients. Numerous genetic disorders are associated with high prevalence of ASD, including tuberous sclerosis complex, phosphatase and tensin homolog, and fragile X syndrome. Preclinical investigations in animal models of these diseases have revealed irregularities in the PI3K/Akt/mTOR signaling pathway as well as ASD-related behavioral defects. Reversal of the downstream molecular irregularities, associated with mTOR hyperactivation, improved the behavioral deficits observed in the preclinical investigations. Plant bioactive molecules have shown beneficial pre-clinical evidence in ASD treatment by modulating the PI3K/Akt/mTOR pathway. In this review, we summarize the involvement of the PI3K/Akt/mTOR pathway as well as the genetic alterations of the pathway components and its critical impact on the development of the autism spectrum disorder. Mutations in negative regulators of mTORC1, such as TSC1, TSC2, and PTEN, result in ASD-like phenotypes through the disruption of the mTORC1-mediated signaling. We further discuss the various naturally occurring phytoconstituents that have been identified to be bioactive and modulate the pathway to prevent its disruption and contribute to beneficial therapeutic effects in ASD.

In fragile X syndrome (FX), the leading monogenic cause of autism, excessive neuronal protein synthesis is a core pathophysiology; however, an overall increase in protein expression is not observed. Here, we tested whether excessive protein synthesis drives a compensatory rise in protein degradation that is protective for FX mouse model (Fmr1 -/y ) neurons. Surprisingly, although we find a significant increase in protein degradation through ubiquitin proteasome system (UPS), this contributes to pathological changes. Normalizing proteasome activity with bortezomib corrects excessive hippocampal protein synthesis and hyperactivation of neurons in the inferior colliculus (IC) in response to auditory stimulation. Moreover, systemic administration of bortezomib significantly reduces the incidence and severity of audiogenic seizures (AGS) in the Fmr1 -/y mouse, as does genetic reduction of proteasome, specifically in the IC. Together, these results identify excessive activation of the UPS pathway in Fmr1 -/y neurons as a contributor to multiple phenotypes that can be targeted for therapeutic intervention., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: The fragile X premutation occurs when there are 55-200 CGG repeats in the 5' UTR of the FMR1 gene. An estimated 1 in 148 women carry a premutation, with 20-30% of these individuals at risk for fragile X-associated primary ovarian insufficiency (FXPOI). Diagnostic experiences of FXPOI have not previously been included in the literature, limiting insight on experiences surrounding the diagnosis. This study identifies barriers and facilitators to receiving a FXPOI diagnosis and follow-up care, which can inform care and possibly improve quality of life., Methods: We conducted qualitative interviews with 24 women with FXPOI exploring how FMR1 screening, physician education, and supportive care impacted their experience. Three subgroups were compared: women diagnosed through family history who have biological children, women diagnosed through family history who do not have biological children, and women diagnosed through symptoms of POI., Results: Themes from interviews included hopes for broader clinician awareness of FXPOI, clear guidelines for clinical treatment, and proper fertility workups to expand reproductive options prior to POI onset. Participants also spoke of difficulty finding centralized sources of care., Conclusions: Our results indicate a lack of optimal care of women with a premutation particularly with respect to FMR1 screening for molecular diagnosis, short- and long-term centralized treatment, and clinical and emotional support. The creation of a "FXPOI health navigator" could serve as a centralized resource for the premutation patient population, assisting in connection to optimal treatment and appropriate referrals, including genetic counseling, mental health resources, advocacy organizations, and better-informed physicians., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability in males and the most common single gene cause of autism. This X-linked disorder is caused by an expansion of a trinucleotide CGG repeat (> 200 base pairs) on the promotor region of the fragile X messenger ribonucleoprotein 1 gene (FMR1). This leads to the deficiency or absence of the encoded protein, fragile X messenger ribonucleoprotein 1 (FMRP). FMRP has a central role in the translation of mRNAs involved in synaptic connections and plasticity. Recent studies have demonstrated the benefit of therapeutics focused on reactivation of the FMR1 locus towards improving key clinical phenotypes via restoration of FMRP and ultimately disease modification. A key step in future studies directed towards this effort is the establishment of proof of concept (POC) for FMRP reactivation in individuals with FXS. For this, it is key to determine the feasibility of repeated collection of tissues or fluids to measure FMR1 mRNA and FMRP., Methods: Individuals, ages 3 to 22 years of age, with FXS and those who were typically developing participated in this single-site pilot clinical biomarker study. The repeated collection of hair follicles was compared with the collection of blood and buccal swabs for detection of FMR1 mRNA and FMRP and related molecules., Results: There were n = 15 participants, of whom 10 had a diagnosis of FXS (7.0 ± 3.56 years) and 5 were typically developing (8.2 ± 2.77 years). Absolute levels of FMRP and FMR1 mRNA were substantially higher in healthy participants compared to full mutation and mosaic FXS participants and lowest in the FXS boys. Measurement of FMR1 mRNA and FMRP levels by any method did not show any notable variation by collection location at home versus office across the various sample collection methodologies of hair follicle, blood sample, and buccal swab., Conclusion: Findings demonstrated that repeated sampling of hair follicles in individuals with FXS, in both, home, and office settings, is feasible, repeatable, and can be used for measurement of FMR1 mRNA and FMRP in longitudinal studies., (© 2022. The Author(s).)

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder caused by FMR1 premutation expansion of CGG repeats. FXTAS can be misdiagnosed with many neurodegenerative disorders manifesting with cerebellar ataxias owing to their overlapping clinical and radiological features. The frequency of the FMR1 premutation allele in Japan has not been fully determined. Herein, we aimed to determine the frequency of FMR1 premutation alleles in Japanese patients with undiagnosed cerebellar ataxia and multiple system atrophy, using repeat-primed PCR in 186 patients with adult onset of undiagnosed cerebellar ataxia and 668 patients with multiple system atrophy, to identify expanded CGG repeats as well as to detect AGG interruptions within the expanded alleles. The size of expansions was estimated using fragment length analysis of PCR products obtained by conventional PCR employing a pair of unique primers flanking the repeat sequence. We identified FMR1 premutation alleles in three male patients. One patient revealed 84 repeat units with one AGG interruption and another patient showed 103 repeat units. Both had presented with sporadic cerebellar ataxia, giving an estimated frequency of 3.7% among Japanese male patients with sporadic cerebellar ataxia with age at onset above 50 years. One patient with the clinical diagnosis of multiple system atrophy harbored 60 repeat units with four AGG interruptions. FMR1 intermediate alleles were observed in two males and one female among the multiple system atrophy patients. We found that genetic tests for FMR1 premutation should be considered in Japanese male patients with cerebellar ataxia with the age at onset above 50 years., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Our institution developed and continuously improved a Neurodevelopmental Reflex (NDR) algorithm to help physicians with genetic test ordering for neurodevelopmental disorders (NDDs). To assess its performance, we performed a retrospective study of 511 patients tested through NDR from 2018 to 2019. SNP Microarray identified pathogenic/likely pathogenic copy number variations in 27/511 cases (5.28%). Among the 484 patients tested for Fragile X FMR1 CGG repeats, a diagnosis (0.20%) was established for one male mosaic for a full mutation, a premutation, and a one-CGG allele. Within the 101 normocephalic female patients tested for MECP2, two patients were found to carry pathogenic variants (1.98%). This retrospective study suggested the NDR algorithm effectively established diagnoses for patients with NDDs with a yield of 5.87%., (© 2021. The Author(s).)

Fragile X Syndrome (FXS) is the most prevalent monogenic cause of Autism Spectrum Disorders (ASDs). Despite a common genetic etiology, the affected individuals display heterogenous metabolic abnormalities including hypocholesterolemia. Although changes in the metabolism of fatty acids (FAs) have been reported in various neuropsychiatric disorders, it has not been explored in humans with FXS. In this study, we investigated the FA profiles of two different groups: (1) an Argentinian group, including FXS individuals and age- and sex-matched controls, and (2) a French-Canadian group, including FXS individuals and their age- and sex-matched controls. Since phospholipid FAs are an indicator of medium-term diet and endogenous metabolism, we quantified the FA profile in plasma phospholipids using gas chromatography. Our results showed significantly lower levels in various plasma FAs including saturated, monosaturated, ω-6 polyunsaturated, and ω-3 polyunsaturated FAs in FXS individuals compared to the controls. A decrease in the EPA/ALA (eicosapentaenoic acid/alpha linoleic acid) ratio and an increase in the DPA/EPA (docosapentaenoic acid/eicosapentaenoic acid) ratio suggest an alteration associated with desaturase and elongase activity, respectively. We conclude that FXS individuals present an abnormal profile of FAs, specifically FAs belonging to the ω-3 family, that might open new avenues of treatment to improve core symptoms of the disorder.

Lay Abstract: Autism is the most common neurodevelopmental disorder in children worldwide. Genetic factors play an important role in the risk of developing autism. Determining the genetic cause of autism is key to understanding the biological processes that lead to the clinical manifestations of autism, and can inform the management and even prevention of this condition. Establishing genetic causes of autism requires collection of genetic data on a global scale. Limited research on genetic testing for individuals with autism is available from developing countries in low-resource regions. In this study, we explored the types of investigations ordered for Jordanian children with autism by their physicians. A representative sample of parents of children with autism in Jordan was questioned about the studies that their children received. We found that the recommended genetic testing was only performed in a small number of children with autism. In contrast, most children in the sample received non-genetic testing, which is not routinely recommended. We also explored the sociocultural factors that may influence the decision to perform genetic testing in this population. We discuss our findings in light of the data available from other developing and developed countries.

Short hairpin RNAs, or short hairpin RNAs (shRNAs), are a proven tool for gene knockdown and a promising therapeutic approach for suppression of disease-associated genes. The efficient preparation of shRNA-expressing vectors can sometimes become a bottleneck due to the complexity of shRNA hairpin sequence and structure, especially for repetitive or high GC-content targets. Here, we present improved shRNA cloning and validation methods that enabled efficient and rapid cloning of several shRNAs targeting disease-associated repeat expansions, including GGGGCC, CAG, CTG, CCTG, and CGG into modified pLKO.1 vectors. Improvements included shRNA insert design and preparation, recombination-based cloning, and sequencing-based validation that included Sanger and nanopore long-read sequencing. This improved method should enable practical, efficient cloning of nearly any shRNA sequence.

Sleep is critical for brain development and synaptic plasticity. In male wild-type mice, chronic sleep restriction during development results in long-lasting impairments in behavior including hypoactivity, decreased sociability, and increased repetitive behavior. Disordered sleep is characteristic of many neurodevelopmental disorders. Moreover, the severity of behavioral symptoms is correlated with the degree of disordered sleep. We hypothesized that chronic developmental sleep restriction in a mouse model of fragile X syndrome (FXS) would exacerbate behavioral phenotypes. To test our hypothesis, we sleep-restricted Fmr1 knockout (KO) mice for 3 h per day from P5 to P52 and subjected mice to behavioral tests beginning on P42. Contrary to our expectations, sleep restriction improved the hyperactivity and lack of preference for social novelty phenotypes in Fmr1 KO mice but had no measurable effect on repetitive activity. Sleep restriction also resulted in changes in regional distribution of myelin basic protein, suggesting effects on myelination. These findings have implications for the role of disrupted sleep in the severity of symptoms in FXS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Saré, Song, Levine, Lemons, Loutaev, Sheeler, Hildreth, Mfon and Smith.)

Many patients with fragile X syndrome (FXS) have sleep disturbances, and Fmr1 knockout (KO) mice (a model of FXS) have reduced sleep duration compared to wild type (WT). Sleep is important for brain development, and chronic sleep restriction during development has long-lasting behavioral effects in WT mice. We hypothesized that the sleep abnormalities in FXS may contribute to behavioral impairments and that increasing sleep duration might improve behavior. We treated adult male Fmr1 KO and WT mice subacutely with three different classes of hypnotics (DORA-22, ramelteon, and zolpidem) and caffeine, a methylxanthine stimulant, and we tested the effects of treatments on sleep duration and behavior. Behavior tests included activity response to a novel environment, anxiety-like behavior, and social behavior. As expected, all hypnotics increased, and caffeine decreased sleep duration in the circadian phase in which drugs were administered. Caffeine and DORA-22 treatment significantly reduced activity in the open field regardless of genotype. Other effects were not as apparent., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Saré, Lemons and Smith.)

Mice fed soy-based diets exhibit increased weight gain compared to mice fed casein-based diets, and the effects are more pronounced in a model of fragile X syndrome (FXS; Fmr1 KO ). FXS is a neurodevelopmental disability characterized by intellectual impairment, seizures, autistic behavior, anxiety, and obesity. Here, we analyzed body weight as a function of mouse age, diet, and genotype to determine the effect of diet (soy, casein, and grain-based) on weight gain. We also assessed plasma protein biomarker expression and behavior in response to diet. Juvenile Fmr1 KO mice fed a soy protein-based rodent chow throughout gestation and postnatal development exhibit increased weight gain compared to mice fed a casein-based purified ingredient diet or grain-based, low phytoestrogen chow. Adolescent and adult Fmr1 KO mice fed a soy-based infant formula diet exhibited increased weight gain compared to reference diets. Increased body mass was due to increased lean mass. Wild-type male mice fed soy-based infant formula exhibited increased learning in a passive avoidance paradigm, and Fmr1 KO male mice had a deficit in nest building. Thus, at the systems level, consumption of soy-based diets increases weight gain and affects behavior. At the molecular level, a soy-based infant formula diet was associated with altered expression of numerous plasma proteins, including the adipose hormone leptin and the β-amyloid degrading enzyme neprilysin. In conclusion, single-source, soy-based diets may contribute to the development of obesity and the exacerbation of neurological phenotypes in developmental disabilities, such as FXS.

Background and Aims: Women with primary ovarian insufficiency exhibit an unfavorable cardiovascular risk profile. A common cause for primary ovarian insufficiency is fragile X premutation (FXPC), and data on the cardiovascular risk factors in women with FXPC are scarce. We aimed to assess the prevalences of abnormal metabolic components among FXPC., Methods and Results: Clinical, anthropometric and laboratory data were collected from 71 women with FXPC and compared to 78 women referred for counseling in an in-vitro fertilization clinic (control group). The mean ± SD ages of the FXPC and control groups were 33.5 ± 5.6 and 36.2 ± 5.3 years, respectively (p = 0.003). In a logistic regression analysis, the FXPC group had increased risks for hyperglycemia, hypertriglyceridemia, central obesity and low high-density lipoprotein cholesterol, of 21.8-fold (95% CI 2.7-175, p = 0.004), 6.9-fold (95% CI 2.5-18.7, p < 0.0001), 3.1-fold (95% CI 1.4-6.9, p = 0.005) and 2.4-fold (95% CI 1.1-5.2, p = 0.03), compared to the control group. The FXPC group had 2.7-fold higher prevalence of two abnormal metabolic components; 19% met the full criteria of MetS, compared to 3% of the control group. Neither CGG repeats nor ovarian reserve markers were associated with metabolic risk., Conclusions: Carriers of fragile X premutation are at increased metabolic risk from early adulthood; waist circumference, glucose and lipid levels are particularly elevated. We recommend metabolic screening for all women with FMR1 premutation, to enable early interventions for prevention of long-term cardiovascular comorbidities., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest related to this work., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Although larger trinucleotide expansions give rise to a neurodevelopmental disorder called fragile X syndrome, fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a "premutation" (55-200 CGG repeats) in the FMR1 gene. FXTAS is one of the more common single-gene forms of late-onset ataxia and tremor that may have a more complex development in women, with atypical presentations. After a brief presentation of the atypical case of an Italian woman with FXTAS, who had several paroxysmal episodes suggestive of acute cerebellar and/or brainstem dysfunction, this article will revise the phenotype of FXTAS in women. Especially in females, FXTAS has a broad spectrum of symptoms, ranging from relatively severe diseases in mid-adulthood to mild cases beginning in later life. Female FXTAS and male FXTAS have a different symptomatic spectrum, and studies on the fragile X premutation should be conducted separately on women or men. Hopefully, a better understanding of the molecular processes involved in the polymorphic features of FXTAS will lead to more specific and effective therapies for this complex disorder.

Tremor, the most common movement disorder, may occur in isolation or may co-exist with a variety of other neurologic and movement disorders including parkinsonism, dystonia, and ataxia. When associated with Parkinson's disease, tremor may be present at rest or as an action tremor overlapping in phenomenology with essential tremor. Essential tremor may be associated not only with parkinsonism but other neurological disorders, suggesting the possibility of essential tremor subtypes. Besides Parkinson's disease, tremor can be an important feature of other parkinsonian disorders, such as atypical parkinsonism and drug-induced parkinsonism. In addition, tremor can be a prominent feature in patients with other movement disorders such as fragile X-associated tremor/ataxia syndrome, and Wilson's disease in which parkinsonian features may be present. This article is part of the Special Issue "Parkinsonism across the spectrum of movement disorders and beyond" edited by Joseph Jankovic, Daniel D. Truong and Matteo Bologna., (Copyright © 2021. Published by Elsevier B.V.)

Fragile X (FX) syndrome is one of the leading inherited causes of autism spectrum disorder (ASD). A majority of FX and ASD patients exhibit sensory hypersensitivity, including auditory hypersensitivity or hyperacusis, a condition in which everyday sounds are perceived as much louder than normal. Auditory processing deficits in FX and ASD also afford the opportunity to develop objective and quantifiable outcome measures that are likely to translate between humans and animal models due to the well-conserved nature of the auditory system and well-developed behavioral read-outs of sound perception. Therefore, in this study we characterized auditory hypersensitivity in a Fmr1 knockout (KO) transgenic rat model of FX using an operant conditioning task to assess sound detection thresholds and suprathreshold auditory reaction time-intensity (RT-I) functions, a reliable psychoacoustic measure of loudness growth, at a variety of stimulus frequencies, bandwidths, and durations. Male Fmr1 KO and littermate WT rats both learned the task at the same rate and exhibited normal hearing thresholds. However, Fmr1 KO rats had faster auditory RTs over a broad range of intensities and steeper RT-I slopes than WT controls, perceptual evidence of excessive loudness growth in Fmr1 KO rats. Furthermore, we found that Fmr1 KO animals exhibited abnormal perceptual integration of sound duration and bandwidth, with diminished temporal but enhanced spectral integration of sound intensity. Because temporal and spectral integration of sound stimuli were altered in opposite directions in Fmr1 KO rats, this suggests that abnormal RTs in these animals are evidence of aberrant auditory processing rather than generalized hyperactivity or altered motor responses. Together, these results are indicative of fundamental changes to low-level auditory processing in Fmr1 KO animals. Finally, we demonstrated that antagonism of metabotropic glutamate receptor 5 (mGlu5) selectively and dose-dependently restored normal loudness growth in Fmr1 KO rats, suggesting a pharmacologic approach for alleviating sensory hypersensitivity associated with FX. This study leverages the tractable nature of the auditory system and the unique behavioral advantages of rats to provide important insights into the nature of a centrally important yet understudied aspect of FX and ASD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Fragile X syndrome (FXS) is the leading monogenic form of intellectual disability and autism, with patients exhibiting numerous auditory-related phenotypes during their developmental period, including communication, language development, and auditory processing deficits. Despite FXS studies describing excitatory-inhibitory (E-I) imbalance in the auditory circuit and an impaired auditory critical period, evaluation of E-I circuitry maturation in the auditory cortex of FXS models remains limited. Here, we examined GABAA receptor (GABAAR)-mediated inhibitory synaptic transmission within the auditory cortex, characterizing normal intracortical circuit development patterns in wild-type (WT) mice and examining their dysregulation in developing Fmr1 knock-out (KO) mice. Electrophysiological recordings revealed gradual developmental shifts in WT L4-L2/3 connectivity, where circuit excitability significantly increased after critical period onset. KO mice exhibited accelerated developmental shifts related to aberrant GABAergic signaling. Specifically, Fmr1 KO L2/3 pyramidal neurons have enhanced developmental sensitivity to pharmacological GABAAR modulators, altered maturation of GABAAR voltage-dependent conductance, with additional presynaptic GABA release alterations. These differences are further accompanied by alterations in developmental long-term potentiation. Together, our results suggest that altered GABAergic signaling within developing Fmr1 KOs impairs the normal patterning of E-I circuit and synaptic plasticity maturation to contribute to the impaired auditory cortex critical period and functional auditory deficits in FXS., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

FMR1 (FMRP translational regulator 1) variants other than repeat expansion are known to cause disease phenotypes but can be overlooked if they are not accounted for in genetic testing strategies. We collected and reanalyzed the evidence for pathogenicity of FMR1 coding, noncoding, and copy number variants published to date. There is a spectrum of disease-causing FMR1 variation, with clinical and functional evidence supporting pathogenicity of five splicing, five missense, one in-frame deletion, one nonsense, and four frameshift variants. In addition, FMR1 deletions occur in both mosaic full mutation patients and as constitutional pathogenic alleles. De novo deletions arise not only from full mutation alleles but also alleles with normal-sized CGG repeats in several patients, suggesting that the CGG repeat region may be prone to genomic instability even in the absence of repeat expansion. We conclude that clinical tests for potentially FMR1 -related indications such as intellectual disability should include methods capable of detecting small coding, noncoding, and copy number variants.

GGGGCC (G 4 C 2 ) hexanucleotide repeat expansions in the endosomal trafficking gene C9orf72 are the most common genetic cause of ALS and frontotemporal dementia. Repeat-associated non-AUG (RAN) translation of this expansion through near-cognate initiation codon usage and internal ribosomal entry generates toxic proteins that accumulate in patients' brains and contribute to disease pathogenesis. The helicase protein DEAH-box helicase 36 (DHX36-G4R1) plays active roles in RNA and DNA G-quadruplex (G4) resolution in cells. As G 4 C 2 repeats are known to form G4 structures in vitro, we sought to determine the impact of manipulating DHX36 expression on repeat transcription and RAN translation. Using a series of luciferase reporter assays both in cells and in vitro, we found that DHX36 depletion suppresses RAN translation in a repeat length-dependent manner, whereas overexpression of DHX36 enhances RAN translation from G 4 C 2 reporter RNAs. Moreover, upregulation of RAN translation that is typically triggered by integrated stress response activation is prevented by loss of DHX36. These results suggest that DHX36 is active in regulating G 4 C 2 repeat translation, providing potential implications for therapeutic development in nucleotide repeat expansion disorders., Competing Interests: Conflict of interest P. K. T. served as a paid consultant for Denali Therapeutics, holds a joint patent with Ionis Therapeutics, and receives publishing royalties from UpToDate. None of these are directly relevant to his role on this article, and none of these organizations have any role in the conception, preparation, or editing of this article. All other authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)