Search Results (248)

Fragile X syndrome (FXS) is the most common form of X-linked intellectual disability (ID). This study aimed to share 30 years of experience in diagnosing FXS and determine its frequency in Thailand. We retrospectively reviewed 1480 unrelated patients (1390 males and 90 females) with ID, developmental delay, or autism spectrum disorder, or individuals referred for FXS DNA testing at Songklanagarind Hospital, Thailand, over a 30-year period. The samples were analyzed using cytogenetic methods, PCR-based techniques, and/or Southern blot analysis. Full mutations (>200 CGG repeats) were identified in 100 males (7.2%) and three females (3.3%). An intermediate allele was detected in one male, while no premutation was found in the index cases. Two males were suspected to have FMR1 gene deletions. Twelve families underwent prenatal testing during this study. Most families undergoing prenatal FXS diagnosis involved mothers who were premutation carriers and had given birth to children affected by FXS. This study represents the largest series of molecular genetic FXS testing cases reported in Thailand. The frequency of FXS identified in different cohorts of Thai patients across various periods was approximately 7%. This study enhances public awareness of at-risk populations and highlights the importance of prenatal testing and genetic counseling for vulnerable families. Full article

Background/Objectives: Autism spectrum disorders (ASDs) are neurodevelopmental conditions with early onset of clinical manifestations. ASD etiology is highly heterogeneous, with genetic factors being strong determinants of the behavioral problems and neurodevelopmental deficits. Fragile X syndrome (FXS) (OMIM #300624), caused by the transcriptional silencing of the FMR1 gene, represents the most common monogenic cause of autism. Our study included 226 boys with a diagnosis of ASD, for a systematic screening of genetic and epigenetic defects in the FMR1 gene promoter in a Romanian pediatric cohort. Methods: The methods, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) and triplet-primed PCR (TP-PCR)/melt curve analysis (MCA), were chosen for their ability to detect the methylation anomalies (the former) as well as repeat expansions in the FMR1 promoter (the latter). Results: Both methods used in our screening generated concordant results, detecting FMR1 full mutation in 4 out of 226 patients (~1.8%). This yield is similar to data obtained in larger studies. Three out of four boys presented the typical clinical features, in correlation with genetic findings. Conclusions: The combined use of MS-MLPA and TP-PCR/MCA-based assay was, in our experience, useful to fully describe the genetic defects responsible for FXS. A significant variability of clinical presentations was observed in our small group of children with FXS, from mild to severe intellectual disability and from atypical to characteristic dysmorphic features, as well as various behavioral problems. Full article

Pathogenic variants in the MAP1B gene have been associated with neurological impairment, including intellectual disability, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder, brain malformations, cognitive hearing loss, short stature, and dysmorphic features. However, few cases with detailed clinical characterization have been reported. We describe a 12-year-old boy carrying a loss-of-function MAP1B variant, presenting with severe elimination disorders despite normal intelligence. He was referred to the genetics service due to persistent elimination issues, including daytime urinary incontinence, nocturnal enuresis, and fecal incontinence. He had normal motor and cognitive development, with an IQ of 99; however, he also presented with ADHD, short stature, microcephaly, and myopia. Brain MRI revealed bilaterial subependymal periventricular nodular heterotopia (PVNH). Audiometry showed normal bilateral hearing. Testing fragile X syndrome (FXS) and karyotype analyses yielded normal results. Whole exome sequencing (WES) revealed a nonsense pathogenic variant in MAP1B (c.895 C>T; p.Arg299*). No other family members showed a similar phenotype; however, a great-uncle and a great-aunt had a history of nocturnal enuresis until age 10. The patient’s deceased mother had short stature and psychiatric disorders, and a history of consanguinity was reported on the maternal side. This case broadens the phenotypic spectrum associated with MAP1B syndrome, suggesting that elimination disorder, frequently reported in FXS, should also be evaluated in MAP1B pathogenic variant carriers. In addition, the presence of short stature also appears to be part of the syndrome. Full article

The study’s aim was to evaluate electroretinographic (ERG) alterations in Fragile X syndrome (FXS), FMR1 premutation carriers, and controls, and to explore correlations with peripheral blood FMRP expression levels and behavioral outcomes. ERG recordings were obtained using a handheld device across three stimulus protocols in 43 premutation carriers, 39 individuals with FXS, and 23 controls. Peripheral blood FMRP expression levels were quantified using TR-FRET (Time-Resolved Fluorescence Resonance Energy Transfer). Correlations were assessed with cognitive and behavioral measures including IQ (Intelligence Quotient), ABC_FX (Aberrant Behavior Checklist for Fragile X Syndrome), SNAP-IV (Swanson, Nolan, and Pelham Teacher and Parent Rating Scale), SEQ (Sensory Experiences Questionnaire), ADAMS (Anxiety, Depression, and Mood Scale), and the Vineland III Adaptive Behavior Scale standard score. Significant group differences were observed in multiple ERG parameters, particularly in 2 Hz b-wave amplitude (p = 0.0081), 2 Hz b-wave time to peak (p = 0.0164), 28.3 Hz flash combined amplitude (p = 0.0139), 3.4 Hz red/blue flash b-wave amplitude (p = 0.0026), and PhNR amplitude (p = 0.0026), indicating both outer and inner retinal dysfunction in FXS and premutation groups. Despite high test–retest reliability for ERG (ICC range = 0.71–0.92) and FMRP (ICC = 0.70), no correlation was found between ERG metrics and FMRP or behavioral measures. However, FMRP levels strongly correlated with IQ (ρ = 0.69, p < 0.0001) and inversely with behavioral impairment [ABC_FX (ρ = −0.47, p = 0.0041), SNAP-IV (ρ = −0.48, p = 0.0039), SEQ (ρ = −0.43, p = 0.0146), and the Vineland III standard score (ρ = 0.56, p = 0.0019)]. ERG reveals distinct retinal functional abnormalities in FMR1-related conditions but does not correlate with peripheral FMRP expression levels, highlighting the need for multimodal biomarkers integrating radiological, physiological, behavioral, and molecular measures. Full article

Astrocytes, a subtype of glial cells, have multiple roles in regulating neuronal development and homeostasis. In addition to the typical mammalian astrocytes, in the primate cortex, interlaminar astrocytes are located in the superficial layer and project long processes traversing multiple layers of the cerebral cortex. Previously, we described a human stem cell based chimeric mouse model where interlaminar astrocytes develop. Here, we utilized this model to study the calcium signaling properties of interlaminar astrocytes. To determine how interlaminar astrocytes could contribute to neurodevelopmental disorders, we generated a chimeric mouse model for Fragile X syndrome (FXS). We report that FXS interlaminar astrocytes exhibit hyperexcitable calcium signaling and are associated with dendritic spines with increased turnover rate. Full article

Fragile X syndrome is characterized by the diminished expression of the fragile X messenger ribonucleoprotein (FMRP), a ubiquitously expressed RNA binding protein with numerous functions in cells. Our prior work found significant differences in physiological and behavioral outcomes as a function of FMRP levels and in response to diet in mice. Here, we assess protein biomarker levels as a function of FMRP levels, sex and matched casein and soy protein isolate-based purified ingredient diets in Fmr1^KO and littermate mice. Brain regions (cortex, hippocampus, and hypothalamus) and blood plasma were analyzed by RayBiotech’s Quantibody^® Mouse Cytokine Antibody Array 640 to quantitate the expression of 640 proteins. The main findings were the identification of numerous proteins that were differentially expressed in response to diet, sex and/or genotype. Of note, prolactin (PRL) levels in blood plasma were significantly elevated in Fmr1^KO female mice as a function of genotype and sex selectively with the AIN-93G/casein diet. Also, using a moderately stringent significance cutoff, growth differentiation factor 9 (GDF-9) in plasma from mice fed AIN-93G/soy was the only protein studied by Quantibody arrays that was differentially expressed between WT and Fmr1^KO male mice. When comparing the results from a pelleted infant formula study with AIN-93G-based diets, insulin-like growth factor binding protein 5 (IGFBP5) in plasma was the only protein differentially expressed as a function of soy in the diet. There was no overlap in statistically significant results when comparing tissue analyzed by mass spectrometry versus Quantibody arrays from mice maintained on AIN-93G-based diets. In conclusion, gene–diet interactions affect protein expression in Fmr1^KO and littermate mice and need to be considered in study design. Full article

Neurosteroids pregnenolone, progesterone, allopregnanolone, and dehydroepiandrosterone have been actively studied in the last years as candidates for the treatment of neurodegenerative diseases and postinjury rehabilitation. The neuroprotective mechanisms of these neurosteroids have been shown in clinical studies of depression, epilepsy, status epilepticus, traumatic brain injury, fragile X syndrome, and chemical neurotoxicity. However, only the allopregnanolone analogs brexanolone and zuranolone have been recently approved by the FDA for the treatment of depression. The aim of this review was to evaluate whether the endogenous neurosteroids can be used in clinical practice as neuroprotectors. Neurosteroids are multitarget compounds with strong anti-inflammatory, immunomodulatory, and cytoprotective action; they stimulate the synthesis and release of BDNF and increase remyelination and regeneration. In addition to nuclear and membrane steroid hormone receptors, such as PR, mPR, PGRMC1,2, ER, AR, CAR, and PXR, they can bind to GABAA receptors, NMDA receptors, Sigma-1 and -2 receptors (σ1-R/σ2-R). Among these, mPRs, PGRMC1,2, sigma receptors, and mitochondrial proteins attract comprehensive attention because of strong binding with the P4 and DHEA, but subsequent signaling is poorly studied. Other plasma membrane and mitochondrial proteins are involved in the rapid nongenomic neuroprotective action of neurosteroids. P-glycoprotein, BCL-2 proteins, and the components of the mitochondrial permeability transition pore (mPTP) play a significant role in the defense against the injuries of the brain and the peripheral nervous system. The role of these proteins in the molecular mechanisms of action in neuroprotection and neuroinflammation has not yet been clearly established. The aspects of their participation in these pathological processes are discussed. New formulations, such as lipophilic emulsions, nanogels, and microneedle array patches, are attractive strategies to overcome the low bioavailability of these neurosteroids for the amelioration and treatment of various nervous disorders. Full article

Background/Objectives: The clinical utility of reproductive carrier screening varies based on the genes tested, variant reporting policies, and the screened patient population. This study aims to evaluate the outcomes of carrier screening among reproductive couples undergoing testing in a routine clinical setting. Methods: A total of 1595 couples, primarily referred by reproductive endocrinology and infertility specialists, underwent couple-based carrier screening across 390 genes. Carrier states were assessed on a couple basis and reported only if a couple were at risk of having affected offspring. At-risk conditions were classified by severity, as well as their likelihood of clinical impact based on the specific variants detected in each at-risk couple. Secondary findings with potential personal utility were also evaluated. Results: Among the screened couples, 4.2% were at risk of having a child with a genetic condition. When limited to high-clinical-impact results, the at-risk couple rate decreased to 1.0%, with 44% of these cases involving CFTR, SMN1, or FMR1. Secondary findings were identified in 1.7% of individuals. Conclusions: Carrier screening for only CFTR, SMN1, and FMR1 will miss more than half of at-risk couples, underscoring the importance of broader carrier screening. Specific variants and their combinations can influence the predicted clinical impact of at-risk conditions, marking a key advantage of couple-based reporting. Secondary findings were common, highlighting the importance of discussing these potential findings during pre-test counselling. Full article

Kleefstra syndrome (KS) is a rare neurodevelopmental disorder associated with disruptions in the EHMT1 gene, often leading to intellectual disability, autism spectrum behaviors and epilepsy. The electroencephalogram (EEG) serves as a non-invasive tool to explore brain function in KS; yet, systematic characterizations of EEG features remain extremely limited. This review synthesizes current evidence on EEG findings in KS, highlighting the high prevalence of nonspecific abnormalities and seizures, but the absence of a consistent electrophysiological biomarker. Given the growing role of machine learning (ML) in extracting patterns from EEG data in related disorders—such as Angelman, Rett and Fragile X syndromes—this review explores how similar approaches could be adapted for KS. Despite promising perspectives, a lack of large-scale, publicly available EEG datasets hinders the application of ML methodologies in KS research. Future directions are proposed to address these gaps, including standardized EEG data collection, adoption of quantitative EEG analyses and integration of ML techniques adapted for small datasets. This multidisciplinary strategy holds potential for improving early diagnosis, monitoring and personalized interventions in Kleefstra syndrome. Full article

The Fragile X Mental Retardation 1 (FMR1) gene is well-known for its role in Fragile X syndrome, a neurodevelopmental disorder, but emerging evidence suggests its involvement in regulating cellular metabolism, with implications for cancer biology. FMR1 encodes the Fragile X mental retardation protein (FMRP), an RNA-binding protein that controls various cellular processes, including translation, synaptic plasticity, and RNA metabolism. Recent studies have uncovered novel links between FMR1, metabolic regulation, and tumorigenesis. This review discusses the role of FMR1 in cellular metabolism and its potential involvement in cancer, focusing on glycolysis, mitochondrial metabolism, lipid metabolism, immune cell metabolism, and tumor immune evasion, and as a potential target to enhance immunotherapy, and highlights future research directions to elucidate its mechanistic roles in cancer. Full article

Background: To date, it remains unclear which oral doses and preparation forms of melatonin should be recommended for children and adolescents with non-organic sleep disorders and autism spectrum disorder (ASD). We reviewed the current state of knowledge on this topic based on randomised placebo-controlled trials (RCTs) and diagnosis-related blood melatonin concentrations available in this age group. Method: Two investigators independently searched PubMed, PsycINFO, MEDLINE, and Cochrane CENTRAL on 1 March 2025 for the keywords “melatonin”, “autism”, and “randomised” in titles and abstracts in all languages, including an evaluation of the references of the reviews, systematic reviews, and meta-analyses published up to that date, some of which were based on searches in numerous databases. Based on this, additional in-depth searches were carried out in PubMed for pharmacokinetic, physiological, and pathophysiological data on melatonin in children and adolescents, with a special focus on ASD. Results: To date, five RCTs on non-organic sleep disorders in children and adolescents with the sole diagnosis of ASD or with subgroup analyses in the presence of several initial diagnoses such as ADHD, epilepsy, Smith–Magenis, or Fragile X syndrome are available. In these studies, rapid-release, non-delayed preparations were administered orally. In one of these studies, the clinical efficacy of a combination preparation with a sustained-release and a non-released active substance component was tested. Pharmacokinetic data with multiple determinations of melatonin concentrations in the blood are only available for children with ASD in the form of a case series (N = 9). Discussion: RCTs comparing the efficacy of delayed melatonin preparations with non-delayed rapid-release oral preparations are not yet available. Physiological data and clinical effects documented in five RCTs indicate that non-delayed melatonin preparations with an initial rapid onset of action are effective for non-organic sleep disorders in children and adolescents with ASD. Conclusions: From a clinical, pharmacokinetic, and physiological point of view, the RCTs available to date and the data on melatonin concentrations in the blood of children with ASD, measured several times over 24 h, suggest that a low oral melatonin dose and a non-delayed preparation with rapid onset should be started in children and adolescents with non-organic sleep disorders in ASD, if sleep hygiene advice and psychotherapeutic interventions have not demonstrated sufficient effects. Full article

Genetic studies have identified numerous candidate genes for neurodevelopmental disorders associated with intellectual disability (ID) and autism spectrum disorders (ASD). Some genetic anomalies are very rare or challenging to detect, making it essential to validate the presence of gene mutations or copy number variations in additional patients with similar clinical phenotypes. Background/Objectives: Case reports play a crucial role in this process by validating rare variants in phenotypically matched patients, shedding light on novel candidate genes linked to these disorders. Methods: Patients with ID and ASD underwent neurological examinations, brain magnetic resonance imaging (MRI), sleep and wake electroencephalogram (EEG), neuropsychological evaluations, and laboratory tests including molecular analysis for fragile-X syndrome and array comparative genomic hybridization (aCGH). Results: We observed a patient with ID and ASD who carried a microdeletion in Xq22.1 that affects only exon 1 and intron 1 of the Nuclear RNA Export Factor 5 (NXF5) gene. The patient’s phenotypic features overlap with those of the only four previously reported cases of variations involving the same gene. Conclusions: Our findings suggest that NXF5 may play a role in neurodevelopmental disorders and should be considered in the spectrum of X-linked ID associated with ASD. Full article

The cerebellar peduncles (CPs) contain essential pathways connecting the cerebellum and other regions of the central nervous system, yet their role is often overlooked in daily medical practice. Individuals with the FMR1 premutation are at risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative disorder. The major clinical and radiological signs of FXTAS are cerebellar gait ataxia, intention tremor, and T2-weighted MRI hyperintensity of the middle cerebellar peduncle (MCP sign). Over the years, metabolic and structural abnormalities have also been described in the CPs of FMR1 premutation carriers, with some being associated with CGG repeat length and FMR1 mRNA levels. Evidence seems to associate the clinical disfunction observed in FXTAS with MCP abnormalities. However, other tracts within the different CPs may also contribute to the symptoms observed in FXTAS. By integrating imaging and pathological data, this review looks to enhance the understanding of the functional anatomy of the CPs and their involvement in different pathological entities, with special interest in premutation carriers and FXTAS. This review, therefore, aims to provide accessible knowledge on the subject of the CPs and their functional anatomy through detailed diagrams, offering a clearer understanding of their role in FMR1 premutation. Full article

The excitation/inhibition (E/I) balance is a critical feature of neural circuits, which is crucial for maintaining optimal brain function by ensuring network stability and preventing neural hyperexcitability. The hippocampus exhibits the particularly interesting characteristics of having different functions and E/I profiles between its dorsal and ventral segments. Furthermore, the hippocampus is particularly vulnerable to epilepsy and implicated in Fragile X Syndrome (FXS), disorders associated with heightened E/I balance and possible deficits in GABA-mediated inhibition. In epilepsy, the ventral hippocampus shows heightened susceptibility to seizures, while in FXS, recent evidence suggests differential alterations in excitability and inhibition between dorsal and ventral regions. This article explores the mechanisms underlying E/I balance regulation, focusing on the hippocampus in epilepsy and FXS, and emphasizing the possible mechanisms that may confer homeostatic flexibility to the ventral hippocampus in maintaining E/I balance. Notably, the ventral hippocampus in adult FXS models shows enhanced GABAergic inhibition, resistance to epileptiform activity, and physiological network pattern (sharp wave-ripples, SWRs), potentially representing a homeostatic adaptation. In contrast, the dorsal hippocampus in these FXS models is more vulnerable to aberrant discharges and displays altered SWRs. These findings highlight the complex, region-specific nature of E/I balance disruptions in neurological disorders and suggest that the ventral hippocampus may possess unique compensatory mechanisms. Specifically, it is proposed that the ventral hippocampus, the brain region most prone to hyperexcitability, may have unique adaptive capabilities at the cellular and network levels that maintain the E/I balance within a normal range to prevent the transition to hyperexcitability and preserve normal function. Investigating the mechanisms underlying these compensatory responses in the ventral hippocampus and their developmental trajectories may offer novel insights into strategies for mitigating E/I imbalances in epilepsy, FXS, and potentially other neuropsychiatric and neurodevelopmental disorders. Full article

The Fragile X mental retardation type 1 gene (FMR1) contains a CGG triplet cluster of varied length (30 repeats on average) located in its 5′ UTR. In its premutated state (54–200 repeats), FMR1 contributes to the pathogenesis of premature ovarian insufficiency (POI). Its gray zone alleles (41–54 repeats) are supposed to impair the ovarian function as well. In the case of a CGG repeat length > 200, Fragile X syndrome occurs. Post-transcriptional expression of FMR1 is regulated by microRNAs. Although miR-323a-3p overexpression suppresses FMR1 in various tissues, this relationship has not been evaluated in the human ovary. Additionally, this microRNA targets SMADs, which are suggested regulators of ovarian cell proliferation, growth, and function. This study investigated how FMR1 allele lengths with CGG repeat numbers n < 55 (normal and gray zone genotypes) relate to miR-323a-3p expression and how they may impact associated SMAD expression in human granulosa cells. COV434 cells and patient-derived GCs were used to evaluate FMR1, miR-323a-3p, and BMP/SMAD-pathway member expression levels. Briefly, miR-323a-3p was significantly upregulated in GCs of the gray zone group compared to the normal allele group (p < 0.0001), while the FMR1 level did not vary. Furthermore, the gray zone group showed a significant upregulation of BMPR2, SMAD1, SMAD4, and SMAD9. In contrast, the miR-323a-3p transfection of COV434 cells significantly downregulated SMAD3, SMAD4, SMAD5, and SMAD9, while the FMR1 and SMAD1 levels remained stable. Our findings highlight a CGG repeat number-dependent upregulation of miR-323a-3p and an alteration of the BMP/SMAD pathway, suggesting that these changes happen and contribute to impaired ovarian function independently. Full article