Search Results (1,532)

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition often associated with genetic syndromes. Structural variants on the long arm of chromosome 15 (15q) are recurrently implicated in syndromic ASD, yet their phenotypic spectrum remains insufficiently characterized in diverse populations. We retrospectively analyzed clinical and molecular data from three patients with ASD treated at a Brazilian public reference center who also presented neurological and systemic comorbidities. Genetic investigations included G-banded karyotyping, chromosomal microarray analysis (CMA), methylation assays, and multiplex ligation-dependent probe amplification (MLPA) when indicated. Variants were classified according to ACMG guidelines and correlated with individual phenotypes. Case 1 showed an 8.4 Mb triplication at 15q11.2–q13.1 encompassing SNRPN, UBE3A, and GABRB3, which are associated with epilepsy, delayed neuropsychomotor development, and dysmorphic traits. Case 2 presented a 418 kb duplication at 15q13.3 involving CHRNA7 and OTUD7A, a variant of uncertain significance correlated with intellectual disability, speech apraxia, and self-injurious behavior. Case 3 demonstrated extensive loss of heterozygosity at 15q11.2–q13.1 and 15q21.3–q26.2, which is compatible with maternal uniparental disomy and Prader–Willi syndrome, manifesting hypotonia, seizures, and global delay. These findings underscore the potential involvement of the 15q region in syndromic ASD and related neurological comorbidities, highlighting the diverse pathogenic mechanisms and the importance of comprehensive genomic profiling for diagnosis, counseling, and individualized care. Full article

People with moderate to severe intellectual disabilities (M/S ID) and behaviour that challenges are still almost exclusively encountered and understood within a highly specialized professional care system context. They are almost invisible in the societal mainstream, where a wider variety of perspectives on (everyday) manners, encounters, relationships and life applies. These (and other) exclusionary dynamics render everyday relations with residents with M/S ID whose behaviours challenge still largely dependent on the interpretative frameworks and actions of professionals. Professionals are trained and socialized within highly specialized professional care system contexts, despite a growing scientific and professional awareness that behaviour that challenges is a multifaceted and contextual phenomenon. In this paper, we report on a pioneering initiative (titled Project WAVE) which aimed to cultivate a fresh and comprehensive approach to behaviours that challenge within stagnant care practices. Our goal was to foster an innovative collaborative paradigm by facilitating an extensive and enduring exchange between “insiders”—professionals of specialized care system contexts—and “outsider-researchers”—individuals socialized through alternative avenues. We present our epistemological and methodological approach, the data collection process (a multiple case-informed community of practice), and the most important lessons learned. Full article

N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate channels that play a pivotal role in brain development and the regulation of learning and memory processes. De novo pathogenic variants in four genes encoding NMDA receptor subunits (GRIN1, GRIN2A, GRIN2B, and GRIN2D) have been implicated in a broad spectrum of neurodevelopmental disorders, including developmental delay, intellectual disability, autism spectrum disorders, epilepsy, and movement disorders. Mutations in the GRIN1 and GRIN2B genes, which encode the GluN1 and GluN2B subunits, respectively, are strongly associated with malformations of cortical development, including diffuse dysgyria, bilateral polymicrogyria, hippocampal dysplasia, corpus callosum hypoplasia, and other findings such as ventricular enlargement and basal ganglia abnormalities. Conversely, GRIN2A mutations are associated with heterogeneous and less specific neuroimaging patterns. We reviewed the existing literature on the neuroradiological features associated with GRIN gene mutations, also providing pictorial representations from our patient cohort. The analysis revealed a more consistent association of malformations of cortical development with GRIN1 and GRIN2B variants, likely reflecting the critical role of these genes in neuronal migration and proper development of cortical structures. In comparison, GRIN2A mutations are associated with milder brain abnormalities. An integrated assessment of neuroimaging patterns and GRIN gene variants provides valuable insights for differential diagnosis and supports targeted genetic screening in patients presenting with epileptic encephalopathy, global developmental delay, and autism spectrum disorders. Full article

Brain pathophysiology in Down syndrome (DS), the most common genetic cause of intellectual disability, has traditionally been considered a consequence of neuronal dysfunction. However, although it is well documented that astrocytes play a critical role in brain homeostasis, synaptic regulation, and neuronal support, and their malfunction has been associated with the onset and progression of different neurological disorders, only a few studies have addressed whether astrocyte dysfunction can contribute to the DS pathophysiology. Astrocytes are increased in number and size, and show increased levels of expression of astroglial markers like S100β and GFAP. In this study, we detected a region-specific increase in astrocyte population in CA1 and, to a lesser extent, in the dentate gyrus. Single-nucleus transcriptomic profiling identified markers associated with reactive astroglia, synaptic transmission, and neuroinflammation in trisomic astrocytes. Functional analysis revealed abnormal Ca²⁺ oscillations in trisomic astrocytes and impaired astrocyte-to-neuron communication in CA1, the most affected subregion, leading to astrocyte-mediated excitatory synaptic depression. Our findings demonstrate that astrocytes play an active and critical role in the pathophysiology of DS, not only as reactive responders to neuronal injury but as key contributors to the disease process itself. This astrocytic dysfunction presents a region-specific distribution within the hippocampus, suggesting localized vulnerability and complex glial involvement in DS-related neuropathology. Full article

Background/Objectives: Alterations in immunoinflammatory activation may constitute a pathogenetic mechanism in neurodevelopmental disorders (NDDs). Blood cell count (CBC) parameters and hematological inflammatory indices (neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, platelet-to-lymphocyte ratio) are now assuming a greater role as potential biomarkers for NDDs. Methods: In this retrospective observational study, we gathered data on 135 medication-free individuals aged 6 to 17 years: 90 with NDDs (34 with autism spectrum disorder (ASD), 29 with attention-deficit/hyperactivity disorder, 14 with intellectual disability, and 13 with tic disorder) and 45 typically developed controls. The variables analyzed were compared using analysis of variance including Bonferroni posthoc testing for pairwise comparisons Significance was defined as p < 0.05. Results: The analysis of variance revealed statistical significance for all evaluated CBC parameters, as well as for the lymphocyte-to-monocyte ratio. Notably, subjects with ASD exhibited increased values of neutrophils, lymphocytes, monocytes, and eosinophils compared to both typically developing subjects and other NDDs. The lymphocyte-to-monocyte ratio was found to be lower in the tic disorder group compared to typically developing subjects. The elevated lymphocyte and monocyte levels in ASD subjects might reflect chronic low-grade inflammation. Conclusions: Consistent with the evidence in literature, statistically significant differences between the NDD group and typically developed subjects in the CBC parameters were found. The principal limitations of this investigation are the restricted sample size and the exclusion of specific NDD subtypes. Future research is needed to evaluate CBC parameters and inflammatory indices in a broader spectrum of NDDs to better understand the immunoinflammatory response specific to each disorder. Full article

Neurodevelopmental disorders (NDDs), including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), intellectual disability (ID), and tic disorders, comprise a range of conditions that originate in early childhood and impact cognitive, behavioral, and social functioning. Despite their clinical heterogeneity, they often share common molecular and neurobiological framework. This narrative review aims to examine the role of neurotrophins—particularly the brain-derived neurotrophic factor, nerve growth factor, and related molecules—in the pathophysiology of NDDs, and to explore their potential as biomarkers and therapeutic targets. A comprehensive literature search was conducted using PubMed, Scopus, and Web of Science, including both clinical and preclinical studies. Neurotrophins are critically involved in brain development, influencing neurogenesis, synaptic plasticity, and neuronal survival. Dysregulation in their signaling pathways has been associated with core features of ASD and ADHD and may modulate cognitive outcomes in ID. Emerging evidence also supports a role for neuroimmune interactions and neurotrophic dysfunction in tic disorders. However, findings across studies remain inconsistent due to methodological variability and limited longitudinal data. Future research should aim for standardized methodologies and stratified, longitudinal designs to clarify their role across developmental stages and clinical phenotypes. Full article

The IQSEC2 protein is a guanine nucleotide exchange factor for Arf6. Pathogenic variants in the X-linked IQSEC2 gene are associated with drug-resistant epilepsy, severe intellectual disability, and autism. The vast majority of disease-causing variants introduce premature termination codons into the IQSEC2 gene, resulting in little or no IQSEC2 protein being produced. Approximately 20% of cases are missense variants in the seven functional domains of the IQSEC2 protein. We sought to determine whether an adeno-associated virus (AAV) containing the IQSEC2 gene could rescue abnormal phenotypes in mice in two different Iqsec2 mouse models with premature Iqsec2 termination codons resulting in a knockout of the Iqsec2 gene expression and in mice with an A350V Iqsec2 missense mutation. In the Iqsec2 knockout mice, the AAV significantly improved growth, corrected behavioral abnormalities, and normalized the seizure threshold. Behavioral abnormalities were partially rescued in A350V mice, which expression studies suggest may have been due to the feedback inhibition of the endogenous Iqsec2 allele by viral IQSEC2. We propose that the success in the Iqsec2 knockout mice warrants a proof-of-concept study for gene replacement therapy in boys with IQSEC2 premature termination variants. Full article

Objective: We aimed to investigate the relationship between camouflaging and lifetime depression among autistic people, along with the role of sex in this relationship. Methods: Sixty-five autistic subjects with no intellectual or language disability (34 females, 31 males), presenting to an outpatient service for the treatment of concurrent mental disorders, were administered module A of the Structured Clinical Interview for DSM-5 Disorders, the Autism Spectrum Quotient (AQ), and the Camouflaging Autistic Traits Questionnaire (CAT-Q). Results: No differences were found in CAT-Q total or domain scores across sexes. Subjects with lifetime depression reported significantly higher scores than those without for all CAT-Q scores, with depressed women often reporting the highest scores among the groups. The difference between depressed and non-depressed women was significant for all but the CAT-Q assimilation score. The CAT-Q total score significantly predicted lifetime depression (B = 0.053, p = 0.003) when controlling for age, sex, and the AQ total score. Conclusions: Our study expands the extant knowledge about the role of camouflaging in the mental wellbeing of autistic people by showing a correlation between camouflaging and depressive disorders throughout the lifetime among both males and females. Full article

Background/Objectives: This study explores the adaptation and implementation of a positive psychological intervention based on the Emotional Styles model to improve well-being and reduce stress in employees with and without intellectual disabilities (IDs). Methods: A longitudinal intervention was conducted in a social foundation with 45 participants (12 with ID). The program, based on Davidson’s six emotional dimensions, included six weekly sessions adapted through Easy Read strategies and COVID-19 adjustments. Data were collected at pre-test, post-test, and six-month follow-up using the Emotional Styles Questionnaire, PERMA Profiler, and UWES-3. Results: Significant improvements were found in outlook, resilience, engagement, relationships, and reduction in negative emotions, with stronger effects for non-ID participants, although context sensibility improved in the ID group. High satisfaction (93% very satisfied) confirmed the program’s acceptability. Conclusions: The adapted intervention effectively enhances emotional well-being in heterogeneous workplaces, supporting inclusive positive psychology practices. Full article

Background: CRELD1 encodes a cell adhesion molecule initially implicated in atrioventricular septal defects (AVSDs). More recently, biallelic CRELD1 variants have been associated with syndromic and non-syndromic neurodevelopmental disorders (NDDs). Methods: We describe three individuals from unrelated families with compound heterozygous CRELD1 variants, identified through exome sequencing. Clinical and genetic data were reviewed to delineate shared and divergent features. Results: All three patients presented with developmental delay, intellectual disability, seizures, hypotonia, and dysmorphic facial features. Patient 1 and patient 2 carried a recurrent variant combination previously reported in five individuals, while Patient 3 harboured the recurrent frameshift p.(Gln320Argfs*25) variant in trans with a novel missense variant. The milder clinical course of patient 3 highlights phenotypic heterogeneity. Notably, none of the patients had cardiac anomalies or immunological abnormalities, further expanding the clinical spectrum associated with CRELD1. Conclusion: Our findings reinforce genotype–phenotype correlations and provide additional evidence that biallelic CRELD1 variants underlie a distinct autosomal recessive neurodevelopmental disorder, broadening both the phenotypic and genetic spectrum of this emerging syndrome. Full article

Odontophobia, defined as the intense and persistent fear of dentists or dental care, is a widely underestimated, yet clinically significant, barrier to oral health. It affects individuals across all age groups, from children to the elderly, and is particularly prevalent among those with intellectual or developmental disabilities. Odontophobia is a multifactorial condition influenced by psychological, sensory, cognitive, and sociocultural factors. Left unaddressed, it contributes to poor oral health outcomes, avoidant behavior, and broader health disparities. This perspective paper explores the clinical manifestations and principles of management of odontophobia across populations and different age groups, highlighting the limitations of pharmacological sedation, especially when used in isolation. Instead, evidence supports the use of cognitive behavioral strategies, desensitization protocols, sensory-adaptive environments, and communication-based approaches, such as the “tell-show-do” method. Innovative technologies, including virtual reality, offer additional promise. This paper also addresses critical gaps in the research, the paucity of tailored interventions for vulnerable groups, and both ethical and legal complexities surrounding consent, autonomy, and equitable access. Ultimately, managing odontophobia requires a shift toward “person-centered” and “trauma-informed” dental care, supported by interdisciplinary collaboration, inclusive infrastructure, and policy-level commitment to reduce fear-based disparities in oral health. Full article

Rafiq syndrome (RAFQS) is a rare autosomal recessive disorder that is classified as a type II congenital disorder of glycosylation (CDG-II), and caused by MAN1B1 gene mutation. To date, 24 pathogenic MAN1B1 mutations have been reported in association with MAN1B1-CDG. However, the underlying pathogenic mechanisms remain poorly understood. In this study, we recruited a consanguineous family from Pakistan with multiple affected individuals exhibiting mild facial dysmorphism, developmental delay, and intellectual disability. Utilizing exome sequencing and homozygosity mapping, we identified a novel MAN1B1 mutation (c.772_775del) that co-segregated with RAFQS in this family. Analysis of public single-cell transcriptomic data revealed that MAN1B1 is predominantly expressed in dorsal progenitors and intermediate excitatory neurons during human brain development. Knockdown of Man1b1 in primarily cultured mouse excitatory neurons disrupted axon growth, dendrite formation, and spine maturation, and could not be rescued by truncated variants identified in the family. Furthermore, in utero, electroporation experiments revealed that Man1b1 knockdown in the murine cortex impaired neural stem cells’ proliferation and differentiation, as well as cortical neuron migration. Collectively, these findings elucidate a critical role for MAN1B1 in the etiology of RAFQS and demonstrate that loss-of-function mutation in MAN1B1 disrupt neuro-developmental processes, providing mechanistic insights into the pathogenesis of this disorder. Full article

Cytomegalovirus (CMV) represents the most prevalent cause of congenital viral infection in newborns and the leading non-genetic etiology of sensorineural hearing loss (SNHL) in children. Notably, only 10–15% of congenitally infected infants possibly present with classic clinical symptoms at birth, including Small for gestational age, Microcephaly, Petechiae or purpura, Blueberry muffin rash, Jaundice, Hepatomegaly, Splenomegaly and abnormal neurologic signs. In contrast, approximately 90% of infected neonates exhibit no apparent symptoms initially. Current research predominantly focuses on symptomatic cases due to their severe acute presentations and high rates of long-term sequelae (40–60%), including SNHL and neurodevelopmental impairments. However, significant controversy persists regarding the management of asymptomatic infants. Emerging evidence reveals that 8–15% of asymptomatic carriers develop Late-onset Hearing Loss (LOHL) beyond the neonatal period. Additionally, 5–10% may manifest neurodevelopmental abnormalities including mild intellectual disability, learning difficulties, or motor coordination disorders. Crucially, given the substantial population of asymptomatic cCMV cases, these delayed complications account for 30–40% of all cCMV-related long-term morbidity, underscoring their considerable public health impact. This review synthesizes current evidence and controversies regarding cCMV-related SNHL in asymptomatic or mildly symptomatic children, with a focus on screening, diagnostic classification, and antiviral management gaps, to heighten clinical awareness of this underrecognized cause of hearing loss. Full article

The Montessori method was originally developed from an examination of children with cognitive disabilities. Numerous studies have explored the application of Montessori principles with typically developing children and adolescents across different educational settings. However, despite its original interest in children with cognitive disabilities, there has been a limited number of systematic reviews specifically addressing its impact on these children. We conducted a systematic review of quantitative research based on a search of the literature on the effects of the Montessori educational approach in teaching academic and non-academic skills to children and young people with intellectual disabilities (IDs) and autism. A search was conducted of seven bibliographic databases: Embase, PubMed/MEDLINE, PsycINFO, Cochrane Library, Ebscohost, Proquest, and Scopus, until 31 October 2024. We identified 7165 reports, 3 of which meet the inclusion criteria for the review. The selected studies reported improvements in the areas investigated, including motor skills, perceptual abilities, cognitive development, and self-care, confirming the effectiveness of the Montessori methodology. Although there are few experimental studies available, these findings provide valuable operational insights. They suggest that we can return to the roots of the method, which was originally designed for children with mental disorders. An experimental approach to this time-honored method could enhance its application in neurodevelopmental disorders, maximizing autonomy and inclusion while improving the quality of life for individuals with disabilities. Full article

Time perception, especially duration estimation, plays a crucial role in the organization of behavior across development. Despite its importance, the cognitive mechanisms underlying impaired duration estimation remain insufficiently explored. Recently, the role of cognitive functions, such as executive functions, has been demonstrated in duration estimation. In the present study, the duration estimation, inhibition, shifting, and processing speed performances of participants with idiopathic mild intellectual disability (MID) without associated disorders (N = 79), aged between 10 and 20 years, were compared with those of typical participants (N = 81). The results show that the individuals with MID had difficulties in all cognitive functions (with the exception of one shifting task). Moreover, our results highlight—for the first time—the role of inhibition abilities and processing speed not only in the increase in duration estimation abilities with age, but also in the deficits observed in MID. To conclude, deficits in duration estimation in MID are due to an impairment of other cognitive functions. Full article