Cause Of Intellectual Disability Research Articles

Phenotypic analysis of multielectrode array EEG biomarkers in developing and adult male Fmr1 KO mice

Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability with symptoms that include increased anxiety and social and sensory processing deficits. Recent electroencephalographic (EEG) studies in humans with FXS have identified neural oscillation deficits that include increased resting state gamma power, increased amplitude of auditory evoked potentials, and reduced phase locking of sound-evoked gamma oscillations. Similar EEG phenotypes are present in mouse models of FXS, but very little is known about the development of such abnormal responses. In the current study, we employed a 30-channel mouse multielectrode array (MEA) system to record and analyze resting and stimulus-evoked EEG signals in male P21 and P91 WT and Fmr1 KO mice. This led to several novel findings. First, P91, but not P21, Fmr1 KO mice have significantly increased resting EEG power in the low- and high-gamma frequency bands. Second, both P21 and P91 Fmr1 KO mice have markedly attenuated inter-trial phase coherence (ITPC) to spectrotemporally dynamic auditory stimuli as well as to 40 Hz and 80 Hz auditory steady-state response (ASSR) stimuli. This suggests abnormal temporal processing from early development that may lead to abnormal speech and language function in FXS. Third, we found hemispheric asymmetry of fast temporal processing in the mouse auditory cortex in WT but not Fmr1 KO mice. Together, these findings define a set of EEG phenotypes in young and adult mice that can serve as translational targets for genetic and pharmacological manipulation in phenotypic rescue studies.

Parent perspectives following newborn screening resulting in diagnoses of fragile X syndrome or fragile X premutation

BackgroundFragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Early Check, a voluntary newborn screening study, screened 18,833 newborns for FXS over ∼3 years. Exploring parental attitudes and perspectives can provide insight to the potential future acceptability of public health screening. Methods and proceduresMothers of infants who received a screen positive result for FXS (n = 6) or fragile X premutation (FXPM; n = 18) were interviewed about their perceptions and experiences. Outcomes and resultsMothers of children with FXS described utility in receiving information about their child, particularly to monitor for potential developmental issues and intervene early; overall mothers did not regret participating. Mothers reported various reactions to receiving the FXS or FXPM results including (1) stress and worry; (2) guilt; (3) sadness and disappointment; (4) neutrality, relief, and acceptance; and (5) confusion and uncertainty. Conclusions and implicationsDespite initial reactions such as sadness, stress, and worry, mothers found value in learning of their child’s presymptomatic diagnosis of FXS, particularly the anticipated long-term benefits of early diagnosis to their child’s health and wellbeing. Our results indicate that professionals returning positive newborn screening results should anticipate and prepare for reactions such as parental shock, guilt, sadness, and uncertainty. Genetic counseling and psychosocial support are critical to supporting families.

[Inequalities in time to diagnosis of Down Syndrome in Bolivia].

Down Syndrome is the most common genetic condition and a leading cause of intellectual disability. Individuals in rural areas, particularly those with disabilities, often face disparities in healthcare access. Analyzing clinical records of patients diagnosed with Down Syndrome between 2013 and 2022 by the Institute of Genetics at the Universidad Mayor de San Andrés in La Paz, Bolivia, this study examined the time to diagnosis for 250 patients with Down Syndrome. The findings revealed that patients from rural areas with Down Syndrome take an average of five months to receive a diagnosis, compared to two months in urban areas (p<0.001). No significant differences were found in the time to diagnosis based on gender. However, a higher proportion of males from rural areas was observed (p=0.03). The results suggest that individuals in rural areas face challenges in receiving a timely diagnosis. On the other hand, women may not be brought to cities for proper diagnosis and treatment due to gender biases in certain communities. The importance of improving access to early diagnosis and treatment in rural areas is emphasized.

Variation of FMRP Expression in Peripheral Blood Mononuclear Cells from Individuals with Fragile X Syndrome.

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.

Developmental associations between motor and communication outcomes in Fragile X syndrome: Variation in the context of co-occurring autism.

Fragile X syndrome (FXS), the leading heritable cause of intellectual disability, has a co-occurrence rate of autism spectrum disorder (ASD) estimated at ~60%. Children with FXS experience delayed achievement and slower development of key motor abilities, which happens to an even greater extent for children with both FXS and ASD. A multitude of studies have demonstrated that motor abilities are foundational skills related to later communication outcomes in neurotypical development, as well as in the context of ASD. However, these associations remain unexamined in FXS, or FXS + ASD. In this study, we aimed to determine the associations between early motor skills and their rate of development on communication outcomes in FXS. Furthermore, we investigated whether these associations varied in the context of co-occurring FXS + ASD. Results revealed within-FXS variation in the context of co-occurring ASD between some aspects of motor development and communication outcomes, yet within-FXS consistency between others. Findings provide evidence for variability in developmental processes and outcomes in FXS in the context of co-occurring ASD and offer implications for intervention.

INVESTIGATING THE LANGUAGE DEVELOPMENT OF INDIVIDUALS WITH DOWN SYNDROME, AND HIGHLIGHTING THE IMPORTANCE OF SPEECH THERAPY

Down syndrome is the most common viable numerical chromosomal abnormality, affecting one in every 600 births. It is the most common cause of intellectual disability due to genetic factors. Nearly all individuals with this syndrome have an extra copy of the 21st, leading to cognitive and physical disabilities. Down syndrome can be detected through prenatal screening and is classified into three categories: trisomy 21, mosaicism, and translocation. The main aim of this study is to investigate the linguistic characteristics of people with Down syndrome and demonstrate the value of speech therapy. Statistical analysis shows that the linguistic development of individuals with Down syndrome differs in every subsection from normal development. There are deficiencies not only in their linguistic development (i.e., phonology, morphology, syntax, and pragmatics) but also in many cognitive categories (e.g., memory). Furthermore, this study confirmed the value of speech therapy through personalized intervention. However, we found that the speech therapists who participated in this survey did not have the appropriate expertise. Their knowledge of Down syndrome was good, but they needed a deeper understanding of the syndrome.&lt;p&gt; &lt;/p&gt;&lt;p&gt;&lt;strong&gt; Article visualizations:&lt;/strong&gt;&lt;/p&gt;&lt;p&gt;&lt;img src="/-counters-/edu/0748/a.php" alt="Hit counter" /&gt;&lt;/p&gt;

Challenges in developing therapies in fragile X syndrome: how the FXLEARN trial can guide research.

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and the single-gene cause of autism, is caused by decreased expression of the fragile X messenger ribonucleoprotein protein (FMRP), a ribosomal-associated RNA-binding protein involved in translational repression. Extensive preclinical work in several FXS animal models supported the therapeutic potential of decreasing metabotropic glutamate receptor (mGluR) signaling to correct translation of proteins related to synaptic plasticity; however, multiple clinical trials failed to show conclusive evidence of efficacy. In this issue of the JCI, Berry-Kravis and colleagues conducted the FXLEARN clinical trial to address experimental design concerns from previous trials. Unfortunately, despite treatment of young children with combined pharmacological and learning interventions for a prolonged period, no efficacy of blocking mGluR activity was observed. Future systematic evaluation of potential therapeutic approaches should evaluate consistency between human and animal pathophysiological mechanisms, utilize innovative clinical trial design from FXLEARN, and incorporate translatable biomarkers.

The lncRNA Snhg11, a new candidate contributing to neurogenesis, plasticity, and memory deficits in Down syndrome.

Down syndrome (DS) stands as the prevalent genetic cause of intellectual disability, yet comprehensive understanding of its cellular and molecular underpinnings remains limited. In this study, we explore the cellular landscape of the hippocampus in a DS mouse model, the Ts65Dn, through single-nuclei transcriptional profiling. Our findings demonstrate that trisomy manifests as a highly specific modification of the transcriptome within distinct cell types. Remarkably, we observed a significant shift in the transcriptomic profile of granule cells in the dentate gyrus (DG) associated with trisomy. We identified the downregulation of a specific small nucleolar RNA host gene, Snhg11, as the primary driver behind this observed shift in the trisomic DG. Notably, reduced levels of Snhg11 in this region were also observed in a distinct DS mouse model, the Dp(16)1Yey, as well as in human postmortem brain tissue, indicating its relevance in Down syndrome. To elucidate the function of this long non-coding RNA (lncRNA), we knocked down Snhg11 in the DG of wild-type mice. Intriguingly, this intervention alone was sufficient to impair synaptic plasticity and adult neurogenesis, resembling the cognitive phenotypes associated with trisomy in the hippocampus. Our study uncovers the functional role of Snhg11 in the DG and underscores the significance of this lncRNA in intellectual disability. Furthermore, our findings highlight the importance of DG in the memory deficits observed in Down syndrome.

Measurement of synaptic density in Down syndrome using PET imaging: a pilot study

Down syndrome (DS) is the most prevalent genetic cause of intellectual disability, resulting from trisomy 21. Recently, positron emission tomography (PET) imaging has been used to image synapses in vivo. The motivation for this pilot study was to investigate whether synaptic density in low functioning adults with DS can be evaluated using the PET radiotracer [11C]UCB-J. Data were acquired from low functioning adults with DS (n = 4) and older neurotypical (NT) adults (n = 37). Motion during the scans required the use of a 10-minute acquisition window for the calculation of synaptic density using SUVR50–60,CS which was determined to be a suitable approximation for specific binding in this analysis using dynamic data from the NT group. Of the regions analyzed a large effect was observed when comparing DS and NT hippocampus and cerebral cortex synaptic density as well as hippocampus and cerebellum volumes. In this pilot study, PET imaging of [11C]UCB-J was successfully completed and synaptic density measured in low functioning DS adults. This work provides the basis for studies where synaptic density may be compared between larger groups of NT adults and adults with DS who have varying degrees of baseline cognitive status.

A systematic review and meta-analysis of serum lipid concentrations in people with Down syndrome.

Down syndrome (DS) is the most prevalent chromosomal disorder, being the leading cause of intellectual disability. The increased life expectancy of individuals with DS has led to a shift in the incidence of non-communicable chronic diseases, resulting in new concerns, particularly cardiovascular disease (CVD) and Alzheimer's disease. This study aimed to analyse the blood lipid profile of a large DS cohort to establish a baseline for evaluating health risk parameters. A comprehensive literature search was conducted on PubMed and Virtual Health Library databases to identify original articles published before July 2022. Selected studies were included in the meta-analysis. Fifteen studies reporting serum lipid levels in individuals with DS were incorporated into the analysis. The meta-analysis used the means and standard deviations extracted from the selected studies. The analysis encompassed 671 participants in the DS group and 898 euploid controls. The results indicated significant differences in total cholesterol [C] (mean difference [MD]: -3.34; CI: 95%: -4.94 to -1.73; P<0.0001), HDL-C (MD: -3.39; CI: 95%: -6.72 to -0.06; P=0.05) and triglycerides (MD: 21.48; CI: 95%: 9.32 to 33.65; P=0.0005) levels between individuals with DS and their control counterparts. Individuals with DS have less favourable blood lipid concentrations than their controls, particularly HDL-C, triglycerides, and total-C, even when grouped by age. These findings underscore the importance of closer monitoring of lipid profiles in people with DS and the necessity for specific cut-offs for this population, considering the risk for ischemic heart and Alzheimer's diseases.

Analysis of the centre of pressure in bipedal stance among individuals with and without intellectual disabilities, individuals with Down syndrome and dancers with Down syndrome.

Individuals with intellectual disabilities (IDs) often present deficiencies in motor, balance and postural control. On the other hand, the practice of physical activity and dance usually reduces these deficiencies. Therefore, in this study, we aimed to compare the control of the centre of pressure (COP) in people with Down syndrome (DS) or other causes of ID in relation to people without disabilities and to observe the influence of vision and the practice of dance. This cross-sectional study analyses the COP in a static standing position with open and closed eyes in four study groups. A total of 273 people were recruited (80 adults without ID, 46adults with DS, 120 adults with other causes of ID and 27 dancers with DS). A greater area of oscillation and path of the COP was observed in the participants with ID compared with the participants without ID, especially in the sway area of the COP. The oscillation speed of the COP was also higher. When analysing the displacement of the COP, anteroposterior and mediolateral components, there were also differences, except when comparing the group of dancers with DS with respect to the group without ID. The visual condition only influenced the group of participants without disabilities. The results of our study show that there is a less efficient static postural control in people with ID, as greater displacements were observed in the COP of the participants with ID. The differences in some specific variables that analyse the displacement of the COP were smaller when comparing the group of dancers with DS and the individuals without ID.

Systemic lupus erythematosus and Down syndrome: a case report and literature review

Introduction: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can involve any organ system, and may lead to significant morbidity and even mortality. Down syndrome (DS) is the most frequent genetic cause of intellectual disabilities, typically caused by the presence of an extra chromosome 21. Case presentation: A 47-year-old Syrian female of DS who complained of low-grade fever, oral aphthae, fatigue, and arthralgia three months before presentation. Although the patient was diagnosed with phenotypically and gynogenically DS, a milder mosaic type was identified. She appeared fatigued with a blood pressure 110/70 mmHg, pulse 104/min, temp 100 F, having oral ulcers, tenderness of joints on palpation, haemoglobin 9.4 g/dl, white blood cells 10.9/mm3, platelets 87 000×109/cm with C-reactive protein of 2,3 mg/dl, and an erythrocyte sedimentation rate of 68. Urea 33 mg/dl with creatinine 0.9. The rest of the tests were unremarkable. Urine analysis was normal. Discussion: The prevalence of SLE in DS in the literature was found only in five cases, with different presentations, in the last 36 years. In our case the patient presented with mild lupus manifestations and responded well to steroids and hydroxychloroquine. Also, In our case, an onset of SLE in an old DS (DS female patient), whereas SLE is more frequent in childbirth-aged women, in addition to that DS patients had a short life expectancy. Conclusions: DS is associated with a predisposition to developing connective tissue disorders, especially in young females. unfortunately, patients were not diagnosed in all five cases until later with a flare because of the cognitive defect.

Bisphenol F affects neurodevelopmental gene expression, mushroom body development, and behavior in Drosophila melanogaster

Bisphenol F (BPF) is a potential neurotoxicant used as a replacement for bisphenol A (BPA) in polycarbonate plastics and epoxy resins. We investigated the neurodevelopmental impacts of BPF exposure using Drosophila melanogaster as a model. Our transcriptomic analysis indicated that developmental exposure to BPF caused the downregulation of neurodevelopmentally relevant genes, including those associated with synapse formation and neuronal projection. To investigate the functional outcome of BPF exposure, we evaluated neurodevelopmental impacts across two genetic strains of Drosophila— w1118 (control) and the Fragile X Syndrome (FXS) model—by examining both behavioral and neuronal phenotypes. We found that BPF exposure in w1118 Drosophila caused hypoactive larval locomotor activity, decreased time spent grooming by adults, reduced courtship activity, and increased the severity but not frequency of β-lobe midline crossing defects by axons in the mushroom body. In contrast, although BPF reduced peristaltic contractions in FXS larvae, it had no impact on other larval locomotor phenotypes, grooming activity, or courtship activity. Strikingly, BPF exposure reduced both the severity and frequency of β-lobe midline crossing defects in the mushroom body of FXS flies, a phenotype previously observed in FXS flies exposed to BPA. This data indicates that BPF can affect neurodevelopment and its impacts vary depending on genetic background. Further, BPF may elicit a gene-environment interaction with Drosophila fragile X messenger ribonucleoprotein 1 (dFmr1)—the ortholog of human FMR1, which causes fragile X syndrome and is the most common monogenetic cause of intellectual disability and autism spectrum disorder.

Attitudes of medical professionals toward fragile X carrier screening and genetic counseling in China.

Fragile X syndrome is the most common inherited cause of intellectual disability. Considering China's low prevalence, distinct healthcare system, middle-income economic status, and unique culture, China cannot simply replicate the screening systems in European and American countries. In this study, we investigated the attitudes of 450 Chinese medical professionals who received fragile X training on fragile X carrier screening and genetic counseling. Before the training, 57.6% of the respondents were unfamiliar with FXS. After the training, 7.3% of participants are unable to fully master the knowledge. Furthermore, 71.8% believe that the absence of phenotypes during the reproductive age and the availability of simple and feasible testing methods are prerequisites for screening. The presence of the phenotype would still require screening. Regarding the target population, over 90% of the participants support fragile X carrier screening in high-risk pregnant women. As for influencing factors, they consider cost as the most influential factor in pregnant women's decision to undergo screening. The acceptable price range for screening is determined to be ￥200-1000 ($30-150). In terms of the issues and challenges of screening, most medical professionals support the need for genetic counseling for intermediate alleles and 55-60 repeat premutation results. Additionally, some respondents believe that informing patients' family members of positive screening results is necessary. It is also recognized that positive results may lead to anxiety for patients. The findings of this study will provide valuable information for the establishment of fragile X carrier screening system, particularly for low-prevalence or middle-income countries.

The first case of intellectual disability caused by novel compound heterozygosity for NUDT2 variants

NUDT2 is an enzyme important for maintaining the intracellular level of the diadenosine tetraphosphate (Ap4A). Bi-allelic loss of function variants in NUDT2 has recently been reported as a rare cause of intellectual disability (ID). Herein, we describe a Chinese girl with ID, attention deficit hyperactivity disorder (ADHD), and motor delays with abnormal walking posture and difficulty climbing stairs, who bears compound heterozygous variants c.34 C > T (p.R12*) and c.194T > G (p.I65R) in NUDT2. Homozygous variants c.34 C > T (p.R12*) or c.186del (p.A63Qfs*3) in NUDT2 were previously reported to cause ID. This is the first patient with ID due to compound heterozygous variants in NUDT2 and p.I65R is a novel missense variant. This study enriched the genotype and phenotype of NUDT2-related ID and supported the critical developmental involvement of NUDT2.

EF1α-associated protein complexes affect dendritic spine plasticity by regulating microglial phagocytosis in Fmr1 knock-out mice.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. There is no specific treatment for FXS due to the lack of therapeutic targets. We report here that Elongation Factor 1α (EF1α) forms a complex with two other proteins: Tripartite motif-containing protein 3 (TRIM3) and Murine double minute (Mdm2). Both EF1α-Mdm2 and EF1α-TRIM3 protein complexes are increased in the brain of Fmr1 knockout mice as a result of FMRP deficiency, which releases the normal translational suppression of EF1α mRNA and increases EF1α protein levels. Increased EF1α-Mdm2 complex decreases PSD-95 ubiquitination (Ub-PSD-95) and Ub-PSD-95-C1q interaction. The elevated level of TRIM3-EF1α complex is associated with decreased TRIM3-Complement Component 3 (C3) complex that inhibits the activation of C3. Both protein complexes thereby contribute to a reduction in microglia-mediated phagocytosis and dendritic spine pruning. Finally, we created a peptide that disrupts both protein complexes and restores dendritic spine plasticity and behavioural deficits in Fmr1 knockout mice. The EF1α-Mdm2 and EF1α-TRIM3 complexes could thus be new therapeutic targets for FXS.

Astrocytes in fragile X syndrome.

Astrocytes have an important role in neuronal maturation and synapse function in the brain. The interplay between astrocytes and neurons is found to be altered in many neurodevelopmental disorders, including fragile X syndrome (FXS) that is the most common inherited cause of intellectual disability and autism spectrum disorder. Transcriptional, functional, and metabolic alterations in Fmr1 knockout mouse astrocytes, human FXS stem cell-derived astrocytes as well as in in vivo models suggest autonomous effects of astrocytes in the neurobiology of FXS. Abnormalities associated with FXS astrocytes include differentiation of central nervous system cell populations, maturation and regulation of synapses, and synaptic glutamate balance. Recently, FXS-specific changes were found more widely in astrocyte functioning, such as regulation of inflammatory pathways and maintenance of lipid homeostasis. Changes of FXS astrocytes impact the brain homeostasis and function both during development and in the adult brain and offer opportunities for novel types of approaches for intervention.

Facial Classification for Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a mental condition that affects people’s learning, communication, and expression in their daily lives. ASD usually makes it difficult to socialize and communicate with others, and also sometimes shows repetition of certain behaviors. ASD can be a cause of intellectual disability. ASD is a big challenge in neural development, specially in children. It is very important that it is identified at an early stage for timely guidance and intervention. This research identifies the application of deep learning and vision transformer (ViT) models for classification of facial images of autistic and non-autistic children. ViT models are powerful deep learning models used for image classification tasks. This model applies transformer architectures to analyze input image patches and connect the information to achieve global-level information. By employing these techniques, this study aims to contribute toward early ASD detection. ViT models are showing good results in identifying facial features associated with ASD, leading toward early diagnostics. Results show the ViT model’s capability in distinguishing the faces of autistic and non-autistic children.

Suggestion of creatine as a new neurotransmitter by approaches ranging from chemical analysis and biochemistry to electrophysiology

The discovery of a new neurotransmitter, especially one in the central nervous system, is both important and difficult. We have been searching for new neurotransmitters for 12 y. We detected creatine (Cr) in synaptic vesicles (SVs) at a level lower than glutamate and gamma-aminobutyric acid but higher than acetylcholine and 5-hydroxytryptamine. SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in Slc6a8 and Agat mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP-dependent manner. Our biochemical, chemical, genetic, and electrophysiological results are consistent with the possibility of Cr as a neurotransmitter, though not yet reaching the level of proof for the now classic transmitters. Our novel approach to discover neurotransmitters is to begin with analysis of contents in SVs before defining their function and physiology.

Suggestion of creatine as a new neurotransmitter by approaches ranging from chemical analysis and biochemistry to electrophysiology.

The discovery of a new neurotransmitter, especially one in the central nervous system, is both important and difficult. We have been searching for new neurotransmitters for 12 y. We detected creatine (Cr) in synaptic vesicles (SVs) at a level lower than glutamate and gamma-aminobutyric acid but higher than acetylcholine and 5-hydroxytryptamine. SV Cr was reduced in mice lacking either arginine:glycine amidinotransferase (a Cr synthetase) or SLC6A8, a Cr transporter with mutations among the most common causes of intellectual disability in men. Calcium-dependent release of Cr was detected after stimulation in brain slices. Cr release was reduced in Slc6a8 and Agat mutants. Cr inhibited neocortical pyramidal neurons. SLC6A8 was necessary for Cr uptake into synaptosomes. Cr was found by us to be taken up into SVs in an ATP-dependent manner. Our biochemical, chemical, genetic, and electrophysiological results are consistent with the possibility of Cr as a neurotransmitter, though not yet reaching the level of proof for the now classic transmitters. Our novel approach to discover neurotransmitters is to begin with analysis of contents in SVs before defining their function and physiology.