Intellectual Disability Disorder Research Articles

Intellectual disability and autism prevalence in Western Australia: impact of the NDIS

IntroductionEstimates of the prevalence of intellectual disability or autism spectrum disorder (ASD) may vary depending on the methodology, geographical location, and sources of ascertainment. The National Disability Insurance Scheme (NDIS) in Australia was introduced progressively from 2016 to provide individualized funding for eligible people with a significant and permanent disability.MethodsIts recent inclusion as a source of ascertainment in the population-based Intellectual Disability Exploring Answers (IDEA) database in Western Australia has allowed comparisons of the prevalence of intellectual disability and ASD before and after its introduction.ResultsPrevalence of intellectual disability in 2020 was 22.5 per 1,000 (/1,000) live births compared with previous estimates in 2010 of 17/1,000, and for ASD, the estimate was 20.7/1,000 in 2020 compared with 5.1 /1,000 in 2010. Whilst the prevalence of ASD in Aboriginal individuals was about two-thirds that of non-Aboriginals, there was an increased prevalence of ASD in Aboriginal children under 10 years compared with non-Aboriginal children.DiscussionThe concurrent relaxation of ASD diagnostic practice standards in Western Australia associated with the administration of access to the NDIS and the release of the National Guidelines empowering single diagnosticians to determine the appropriateness of engaging additional diagnosticians to form a multidisciplinary team on ASD diagnosis, appear to be important factors associated with the increase in ASD diagnoses both with and without intellectual disability.

Validity of the ESSENCE-Q neurodevelopmental screening tool in Japan.

To assess the validity of the Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations-Questionnaire (ESSENCE-Q), a simple screening tool for neurodevelopmental problems, in Japan. Parents/caregivers completed the 11-item ESSENCE-Q for 77 612 children aged 2 years 6 months included in a national birth cohort study. Information about neurodevelopmental disorders (NDDs: autism spectrum disorder; intellectual disability and/or developmental language disorder; motor delay/motor disorder) was collected at age 3 years. Each ESSENCE-Q item was scored on a binary (0,1) scale, with a total score range of 0 to 11. Total scores and individual items were compared across children with and without NDDs. NDDs were recorded in 854 children (1.1%). With a total ESSENCE-Q score cut-off of ≥3, receiver operating characteristic curve analysis showed an area under the curve of 0.91, with sensitivity 84.9%, specificity 84.8%, positive predictive value 5.9%, and negative predictive value 99.8%. The proportion of parental concerns at 2 years 6 months differed significantly by NDD status for communication (89.5% vs 14.2%) and general development (80.2% vs 7.4%). ESSENCE-Q total scores were moderately negatively correlated (-0.36, p < 0.001) with Japanese Ages and Stages Questionnaire scores. The parent/caregiver-completed ESSENCE-Q is useful as a tool for screening out children with neurotypical development at this early age. Further research into longer-term predictive validity will be possible as more NDD diagnoses are given as the children grow up.

CNKSR2 interactome analysis indicates its association with the centrosome/microtubule system

Abstract The protein connector enhancer of kinase suppressor of Ras 2 (CNKSR2), present in both the postsynaptic density and cytoplasm of neurons, is a scaffolding protein with several protein-binding domains. Variants of the CNKSR2 gene have been implicated in neurodevelopmental disorders, particularly intellectual disability, although the precise mechanism involved has not yet been fully understood. Research has demonstrated that CNKSR2 plays a role in facilitating the localization of postsynaptic density protein complexes to the membrane, thereby influencing synaptic signaling and the morphogenesis of dendritic spines. However, the function of CNKSR2 in the cytoplasm remains to be elucidated. In this study, we used immunoprecipitation and high-resolution liquid chromatography-mass spectrometry to identify the interactors of CNKSR2. Through a combination of bioinformatic analysis and cytological experiments, we found that the CNKSR2 interactors were significantly enriched in the proteome of the centrosome. We also showed that CNKSR2 interacted with the microtubule protein DYNC1H1 and with the centrosome marker CEP290. Subsequent colocalization analysis confirmed the centrosomal localization of CNKSR2. When we downregulated CNKSR2 expression in mouse neuroblastoma cells (Neuro 2A), we observed significant changes in the expression of numerous centrosomal genes. This manipulation also affected centrosome-related functions, including cell size and shape, cell proliferation, and motility. Furthermore, we found that CNKSR2 interactors were highly enriched in de novo variants associated with intellectual disability and autism spectrum disorder. Our findings establish a connection between CNKSR2 and the centrosome, and offer new insights into the underlying mechanisms of neurodevelopmental disorders.

Psychiatric exemptions at call-up and during military service: A comparative study

ABSTRACT Background: Military conscription is a legal obligation in many countries. Different psychiatric disorders may result in exemptions from compulsory military service. The study aimed to compare psychiatric diagnoses, and demographic and clinical characteristics of individuals exempted from conscription between the call-up and military service groups. Methods: The study analyzed exemption reports based on psychiatric evaluations conducted between 2016 and 2020 at a regional military hospital in Türkiye. Exemptions from conscription at the call-up stage and during military service were compared regarding sociodemographic characteristics, clinical information, and psychiatric diagnoses. Results: The study included 1225 exemption reports. The most common psychiatric diagnoses were intellectual disability and adjustment disorder. The exemption at the call-up group showed higher rates of psychiatric disability reports, intellectual disability, antisocial personality disorder, and depressive disorders. In contrast, the exemption during military service group had a higher history of substance use and prevalence of adjustment disorder. At the call-up, intellectual disability, antisocial personality disorder, and psychiatric medication predicted exemption. Adjustment disorder was the predictive factor for exemption during military service Conclusion: The study delineated crucial clinical and psychiatric distinctions among those exempted from conscription during call-up versus military service. Awareness of exemptions during military service can significantly contribute to improving the roll call examination during the call-up. The findings emphasize the need for targeted assessments and strategies for managing psychiatric disorders in the military context.

Heat and hospital admission via the emergency department for people with intellectual disability, autism, and mental disorders in South Korea: a nationwide, time-stratified, case-crossover study

Given the anticipated increase in ambient temperature due to climate change, the hazardous effects of heat on health have been extensively studied; however, its impact on people with intellectual disability, autism, and mental illness is largely unknown. We aimed to estimate the association between heat and hospitalisation through the emergency department (ED) among people with these mental disorders. In this nationwide study, we used data from the National Health Insurance Database (NHID) of the National Health Insurance Service, the single universal insurer in South Korea, the claims data for which is based on the ICD-10. We included individuals with identified intellectual disability, autism, and mental disorders (including schizophrenia, bipolar disorder, recurrent depressive disorder, schizoaffective disorder and persistent obsessive-compulsive disorder, Tourette's disorder, and narcolepsy) and we established two control groups of people without these disorders: one including 1 million systematically sampled individuals, and one matched to the cohort based on sex, age, and income group. Data on hospital admission via the ED were obtained from the NHID, including the primary cause of admission and corresponding medical costs, for the warm season (June-September) of the period 2006-2021. We used the Google Earth Engine with the ERA5-Land dataset to collect data on the daily mean temperature. We applied a time-stratified case-crossover design using a distributed lag non-linear model and performed a conditional logistic regression. The risk ratio was estimated as the odds ratio (OR) with calculated odds at the 99th percentile temperature compared with that at the local 75th percentile temperature. We did not include people with lived experience of mental illness in this study. Of the 456 946 people with intellectual disability, autism, or mental disorder in the NHID records, 99 845 were admitted to the ED, including 59 821 (59·9%) males and 40 024 (40·1%) females, and including 29 192 people with intellectual disability, 1428 people with autism, and 69 225 people with mental disorders. We were not able to collect data on ethnicity. The mean age at ED admission was 42·1 years (SD 17·9, range 0-102) for people with intellectual disability, 18·6 years (SD 10·4, range 1-72) for people with autism, and 50·8 years (SD 11·9, range 2-94) for people with mental disorders. The heat OR (odds at the 99th percentile vs 75th percentile of temperature) of ED admission was 1·23 (95% CI 1·11-1·36) for intellectual disability, 1·06 (0·68-1·63) for autism, and 1·20 (1·12-1·29) for mental disorders. People with intellectual disability, female individuals, people living in rural areas, or those with a low-income status were at increased risk of ED admission due to heat. The risk of ED admission due to genitourinary diseases was higher than that from other causes. Annual increase in medical costs attributable to heat among people with intellectual disability, autism, and mental disorders was US$ 224 970 per 100 000 person-years (95% empirical CI 139 784-305 770). People with intellectual disability, autism, and mental disorders should be included in groups considered at a high-risk for heat exposure, and heat adaptation policies should be implemented with consideration of these groups and their needs. The National Research Foundation of Korea, Korean Ministry of Environment, and Korean Ministry of Education. For the Korean translation of the abstract see Supplementary Materials section.

RNA-Seq data analysis reveals novel nonsense mutations in the NPR3 gene leading to the progression of intellectual disability disorder

Intellectual disability (ID) is a progressive disorder that affects around 1–3% of the world's population. The heterogeneity of intellectual disability makes it difficult to diagnose as a complete disease. Genetic factors and major mutations play a noticeable role in the development and progression of ID. There is a high need to explore novel variants that may lead to new insights into the progressive aspects of ID. In the current course of study, 31 samples of ID from different studies available on GEO (GSE77742, GSE74263, GSE90682, GSE98476, GSE108887, GSE145710, and PRJEB21964) datasets were taken for the study. These datasets were analyzed for differential gene expression and single nucleotide polymorphism (SNPs). The SNPs of high impact were compared with the differentially expressed genes. Comparison leads to the identification of the priority gene ie NPR3 gene. The identified priority gene further was evaluated for the effect of the mutation using a Mutation Taster. Structure comparison analysis of the wild and mutated proteins of the NPR3 gene was further carried out by UCSF Chimera. Structural analysis reveals the anomalies in protein expression affecting the regulations of the NPR3 gene. These findings identified a novel nonsense mutation (E222*) in the downregulated NPR3 gene that leads to anomalies in the regulation of its protein expression. This missense mutation reveals a major role in causing ID. Our study concludes that the decrease in the expression of the NPR3 gene causes delayed sensory, motor, and physiological functions of the human brain leading to neurodevelopmental delay that causes ID.

Purinergic Signalling Mediates Aberrant Excitability of Developing Neuronal Circuits in the Fmr1 Knockout Mouse Model.

Neuronal hyperexcitability within developing cortical circuits is a common characteristic of several heritable neurodevelopmental disorders, including Fragile X Syndrome (FXS), intellectual disability and autism spectrum disorders (ASD). While this aberrant circuitry is typically studied from a neuron-centric perspective, glial cells secrete soluble factors that regulate both neurite extension and synaptogenesis during development. The nucleotide-mediated purinergic signalling system is particularly instrumental in facilitating these effects. We recently reported that within a FXS animal model, theFmr1 KO mouse, the purinergic signalling system is upregulated in cortical astrocytes leading to altered secretion of synaptogenic and plasticity-related proteins. In this study, we examined whether elevated astrocyte purinergic signalling also impacts neuronal morphology and connectivity of Fmr1 KO cortical neurons. Here, we found that conditioned media from primary Fmr1 KO astrocytes was sufficient to enhance neurite extension and complexity of both wildtype and Fmr1 KO neurons to a similar degree as UTP-mediated outgrowth. Significantly enhanced firing was also observed in Fmr1 KO neuron-astrocyte co-cultures grown on microelectrode arrays but was associated with large deficits in firing synchrony. The selective P2Y2 purinergic receptor antagonist AR-C 118925XX effectively normalized much of the aberrant Fmr1 KO activity, designating P2Y2 as a potential therapeutic target in FXS. These results not only demonstrate the importance of astrocyte soluble factors in the development of neural circuitry, but also show that P2Y purinergic receptors play a distinct role in pathological FXS neuronal activity.

A novel framework for functional annotation of variants of uncertain significance in ID/ASD risk gene CC2D1A.

Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous with hundreds of identified risk genes, most affecting only a few patients. Novel missense variants in these genes are being discovered as clinical exome sequencing is now routinely integrated into diagnosis, yet most of them are annotated as variants of uncertain significance (VUS). VUSs are a major roadblock in using patient genetics to inform clinical action. We developed a framework to characterize VUSs in Coiled-coil and C2 domain containing 1A (CC2D1A), a gene causing autosomal recessive ID with comorbid ASD in 40% of cases. We analyzed seven VUSs (p.Pro319Leu, p.Ser327Leu, p.Gly441Val, p.Val449Met, p.Thr580Ile, p.Arg886His and p.Glu910Lys) from four cases of individuals with ID and ASD. Variants were cloned and overexpressed in HEK293 individually and in their respective heterozygous combination. CC2D1A is a signaling scaffold that positively regulates PKA-CREB signaling by repressing phosphodiesterase 4D (PDE4D) to prevent cAMP degradation. After testing multiple parameters including direct interaction between PDE4D and CC2D1A, cAMP levels and CREB activation, we found that the most sensitive readout was CREB transcriptional activity using a luciferase assay. Compared to WT CC2D1A, five VUSs (p.Pro319Leu, p.Gly441Val, p.Val449Met, p.Thr580Ile, and p.Arg886His) led to significantly blunted response to forskolin induced CREB activation. This luciferase assay approach can be scaled up to annotate ~150 CC2D1A VUSs that are currently listed in ClinVar. Since CREB activation is a common denominator for multiple ASD/ID genes, our paradigm can also be adapted for their VUSs.

Zmiz1 is a novel regulator of brain development associated with autism and intellectual disability.

Neurodevelopmental disorders (NDDs) are a class of pathologies arising from perturbations in brain circuit formation and maturation with complex etiological triggers often classified as environmental and genetic. Neuropsychiatric conditions such as autism spectrum disorders (ASD), intellectual disability (ID), and attention deficit hyperactivity disorders (ADHD) are common NDDs characterized by their hereditary underpinnings and inherent heterogeneity. Genetic risk factors for NDDs are increasingly being identified in non-coding regions and proteins bound to them, including transcriptional regulators and chromatin remodelers. Importantly, de novo mutations are emerging as important contributors to NDDs and neuropsychiatric disorders. Recently, de novo mutations in transcriptional co-factor Zmiz1 or its regulatory regions have been identified in unrelated patients with syndromic ID and ASD. However, the role of Zmiz1 in brain development is unknown. Here, using publicly available databases and a Zmiz1 mutant mouse model, we reveal that Zmiz1 is highly expressed during embryonic brain development in mice and humans, and though broadly expressed across the brain, Zmiz1 is enriched in areas prominently impacted in ID and ASD such as cortex, hippocampus, and cerebellum. We investigated the relationship between Zmiz1 structure and pathogenicity of protein variants, the epigenetic marks associated with Zmiz1 regulation, and protein interactions and signaling pathways regulated by Zmiz1. Our analysis reveals that Zmiz1 regulates multiple developmental processes, including neurogenesis, neuron connectivity, and synaptic signaling. This work paves the way for future studies on the functions of Zmiz1 and highlights the importance of combining analysis of mouse models and human data.

Shared and divergent mental health characteristics of ADNP-, CHD8- and DYRK1A-related neurodevelopmental conditions

BackgroundNeurodevelopmental conditions such as intellectual disability (ID) and autism spectrum disorder (ASD) can stem from a broad array of inherited and de novo genetic differences, with marked physiological and behavioral impacts. We currently know little about the psychiatric phenotypes of rare genetic variants associated with ASD, despite heightened risk of psychiatric concerns in ASD more broadly. Understanding behavioral features of these variants can identify shared versus specific phenotypes across gene groups, facilitate mechanistic models, and provide prognostic insights to inform clinical practice. In this paper, we evaluate behavioral features within three gene groups associated with ID and ASD – ADNP, CHD8, and DYRK1A – with two aims: (1) characterize phenotypes across behavioral domains of anxiety, depression, ADHD, and challenging behavior; and (2) understand whether age and early developmental milestones are associated with later mental health outcomes.MethodsPhenotypic data were obtained for youth with disruptive variants in ADNP, CHD8, or DYRK1A (N = 65, mean age = 8.7 years, 40% female) within a long-running, genetics-first study. Standardized caregiver-report measures of mental health features (anxiety, depression, attention-deficit/hyperactivity, oppositional behavior) and developmental history were extracted and analyzed for effects of gene group, age, and early developmental milestones on mental health features.ResultsPatterns of mental health features varied by group, with anxiety most prominent for CHD8, oppositional features overrepresented among ADNP, and attentional and depressive features most prominent for DYRK1A. For the full sample, age was positively associated with anxiety features, such that elevations in anxiety relative to same-age and same-sex peers may worsen with increasing age. Predictive utility of early developmental milestones was limited, with evidence of early language delays predicting greater difficulties across behavioral domains only for the CHD8 group.ConclusionsDespite shared associations with autism and intellectual disability, disruptive variants in ADNP, CHD8, and DYRK1A may yield variable psychiatric phenotypes among children and adolescents. With replication in larger samples over time, efforts such as these may contribute to improved clinical care for affected children and adolescents, allow for earlier identification of emerging mental health difficulties, and promote early intervention to alleviate concerns and improve quality of life.

The burden for clinical services of persons with an intellectual disability or mental disorder convicted of criminal offences: A birth cohort study of 14,605 persons followed to age 64

Background Intellectual disability (ID), schizophrenia spectrum disorder (SSD), bipolar disorder (BD), substance use disorder (SUD), and other mental disorders (OMDs) are associated with increased risks of criminality relative to sex-matched individuals without these conditions (NOIDMD). To resource psychiatric, addiction, and social services so as to provide effective treatments, further information is needed about the size of sub-groups convicted of crimes, recidivism, timing of offending, antecedents, and correlates. Stigma of persons with mental disorders could potentially be dramatically reduced if violence was prevented. Methods A birth cohort of 14,605 persons was followed to age 64 using data from Swedish national health, criminal, and social registers. Results Percentages of group members convicted of violence differed significantly: males NOIDMD, 7.3%, ID 29.2%, SSD 38.6%, BD 30.7%; SUD 44.0%, and OMD 19.3%; females NOIDMD 0.8%, ID 7.7%, SSD 11.2%, BD 2.4%, SD 17.0%, and OMD 2.1%. Violent recidivism was high. Most violent offenders in the diagnostic groups were also convicted of non-violent crimes. Prior to first diagnosis, convictions (violent or non-violent) had been acquired by over 90% of the male offenders and two-thirds of the female offenders. Physical victimization, adult comorbid SUD, childhood conduct problems, and adolescent substance misuse were each associated with increased risks of offending. Conclusion Sub-groups of cohort members with ID or mental disorders were convicted of violent and non-violent crimes to age 64 suggesting the need for treatment of primary disorders and for antisocial/aggressive behavior. Many patients engaging in violence could be identified at first contact with clinical services.

Allelic heterogeneity and abnormal vesicle recycling in PLAA-related neurodevelopmental disorders.

The human PLAA gene encodes Phospholipase-A2-Activating-Protein (PLAA) involved in trafficking of membrane proteins. Through its PUL domain (PLAP, Ufd3p, and Lub1p), PLAA interacts with p97/VCP modulating synaptic vesicles recycling. Although few families carrying biallelic PLAA variants were reported with progressive neurodegeneration, consequences of monoallelic PLAA variants have not been elucidated. Using exome or genome sequencing we identified PLAA de-novo missense variants, affecting conserved residues within the PUL domain, in children affected with neurodevelopmental disorders (NDDs), including psychomotor regression, intellectual disability (ID) and autism spectrum disorders (ASDs). Computational and in-vitro studies of the identified variants revealed abnormal chain arrangements at C-terminal and reduced PLAA-p97/VCP interaction, respectively. These findings expand both allelic and phenotypic heterogeneity associated to PLAA-related neurological disorders, highlighting perturbed vesicle recycling as a potential disease mechanism in NDDs due to genetic defects of PLAA.

The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b Δ ARID allele that lacks demethylase activity. Kdm5b Δ ARID/ Δ ARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice. A number of other learning-associated genes were also significantly dysregulated in the Kdm5b Δ ARID/ Δ ARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms.

Autophagy dysregulation via the USP20-ULK1 axis in the HERC2-related neurodevelopmental disorder

Sequence variants in the HERC2 gene are associated with a significant reduction in HERC2 protein levels and cause a neurodevelopmental disorder known as the HERC2-related disorder, which shares clinical features with Angelman syndrome, including global developmental delay, intellectual disability, autism, and movement disorders. Remarkably, the HERC2 gene is commonly deleted in individuals with Angelman syndrome, suggesting a potential contribution of HERC2 to the pathophysiology of this disease. Given the known critical role of autophagy in brain development and its implication in neurodevelopmental diseases, we undertook different experimental approaches to monitor autophagy in fibroblasts derived from individuals affected by the HERC2-related disorder. Our findings reveal alterations in the levels of the autophagy-related protein LC3. Furthermore, experiments with lysosomal inhibitors provide confirmation of an upregulation of the autophagy pathway in these patient-derived cells. Mechanistically, we corroborate an interaction between HERC2 and the deubiquitylating enzyme USP20; and demonstrate that HERC2 deficiency leads to increased USP20 protein levels. Notably, USP20 upregulation correlates with enhanced stability of the autophagy initiating kinase ULK1, highlighting the role of HERC2 as an autophagy regulator factor through the USP20-ULK1 axis. Moreover, we show that p38 acts as a modulator of this pathway, since p38 activation disrupts HERC2-USP20 interaction, leading to increased USP20 and LC3-II protein levels. Together, these findings uncover a previously unknown role for HERC2 in autophagy regulation and provide insights into the pathomolecular mechanisms underlying the HERC2-related disorder and Angelman syndrome.

Novel Splice Site Pathogenic Variant in STXBP1 Gene in a Child with Intellectual Disability, Epilepsy, and Autism Spectrum Disorder: A Case Report

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Pathogenic variants in the &lt;i&gt;STXBP1&lt;/i&gt; gene are associated to a large spectrum of severe early onset developmental and epileptic encephalopathies (OMIM #612164). They were also identified in various other neurodevelopmental disorders. This gene encodes for the syntaxin-binding protein 1, a member of the SEC-1 family of membrane-transport proteins that modulate the presynaptic vesicular fusion by interacting with soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). However, the physiopathology of &lt;i&gt;STXBP1&lt;/i&gt; pathogenic variants is not yet fully understood. &lt;b&gt;&lt;i&gt;Case Presentation:&lt;/i&gt;&lt;/b&gt; Herein, we report a patient presenting intellectual disability, early onset seizures, and autism. Clinical exome sequencing identified a novel monoallelic splice pathogenic variant &lt;i&gt;STXBP1&lt;/i&gt;(NM_001032221.6):c.38–2A&amp;gt;G. &lt;b&gt;&lt;i&gt;Discussion:&lt;/i&gt;&lt;/b&gt; Splice-site pathogenic variants in the &lt;i&gt;STXBP1&lt;/i&gt; gene are mostly associated with West syndrome, early onset epilepsy and encephalopathy, and Ohtahara syndrome. Our findings extend clinical and molecular spectrum of &lt;i&gt;STXBP1&lt;/i&gt; gene variants by reporting the first splice-site variant associated with autism along with early onset epilepsy and, and intellectual disability in a patient.

Domain-specific phenotypes in LINS1-related disorder-A Chinese family with the Q92X variant and literature review.

LINS1 is the human homolog of the Drosophila segment polarity gene that encodes an essential regulator of the wingless/Wnt signaling. By 2011, only seven pedigrees (16 patients) with eight causative variants in LINS1 gene have been reported. These cases mainly presented with infancy-/child-onset neurodevelopmental disorders, facial dysmorphia, and other clinical features, and a wide spectrum of clinically distinct phenotypes were also manifested. In our study, two brothers in a family were admitted and diagnosed with child-onset movement disorders, slight intellectual disability, psychological symptoms, eye problems, urinary and bowel dysfunction, mitral value prolapse, and Q-T prolongation. By exome sequencing, we identified a nonsense homozygous pathogenic variant (LINS1: c.274C > T (p.Q92X)), which had been reported in a case diagnosed with intellectual disability and psychiatric disorders (such as schizophrenia and anxiety). Compared with this case, the clinical features of our cases were distinct. In particular, our cases displayed unusual features of heart and blood system. Furthermore, the genotype-phenotype relationship analysis suggested that distinct phenotypes presented in cases carrying variants in different domains of the LINS1 gene. In conclusions, our findings suggest the high clinical variations in the LINS1 variants-related disorders. Moreover, the Q92X might be a recurrent variant in Hans of Southern China.

Globus Pallidus Lesion With Iron Deposition and Dopaminergic Denervation in a Patient With a Pathogenic SLC6A1 Variant: A Case Report.

SLC6A1-related disorders encompass heterogeneous neuropsychiatric manifestations through GABAergic dysregulation, without any specific abnormalities on brain MRI, nor evidence of dopaminergic cell loss on I123-FP-β-CIT SPECT. We report here a case of globus pallidus lesions and dopaminergic denervation in a patient with a pathogenic SLC6A1 variant. A 26-year-old female patient with intellectual disability, behavioral, and psychiatric disorders treated by neuroleptics for many years developed a parkinsonian syndrome associated with mild hand dystonia and chorea. A 3T brain MRI and I123-FP-β-CIT SPECT were performed. MRI of the brain found bilateral pallidal lesions consistent with neurodegeneration with iron accumulation. The I123-FP-β-CIT SPECT showed bilateral striatal presynaptic dopaminergic denervation. Whole-genome sequencing revealed a pathogenic SLC6A1 de novo variant. No additional variant was found in any of the genes responsible for Neurodegeneration with Brain Iron Accumulation (NBIA). This is a description of dopaminergic denervation and globus pallidus lesions with iron accumulation related to a SLC6A1 pathogenic variant. These findings expand the phenotype of SLC6A1-related disorder and suggest that it could be considered as a differential diagnosis of NBIA.

Autism Severity and its Relationship to Disability.

Autism severity is currently defined and measured based exclusively on the severity levels of the two core symptom domains: social-communication and restricted or repetitive patterns of behaviors and interests. Autistic individuals, however, are often diagnosed with other medical, developmental, and psychological co-occurring conditions. These additional challenges such as intellectual disability, limited expressive and/or receptive language, and anxiety disorders, can have a tremendous impact on the day-to-day lives of autistic individuals, for both their adaptive functioning as well as their sense of wellbeing. Furthermore, the initial presentation of core symptoms and their likelihood of changing over time are influenced by the presence of such co-occurring conditions. In order to truly understand how a person's autism impacts their life, both core symptoms as well as other challenges should be considered. This approach was recently taken by The Lancet Commission on the future of care and clinical research in autism, which proposed the term "profound autism" for a subgroup of individuals presenting with high core symptom severity, co-occurring intellectual disability, and little or no language, who require extensive long-term care. Considering other individual factors such as daily living skills, specific support needs and environmental resources would also enhance the evaluation of disability in autistic individuals. As currently employed in the assessment of intellectual disability, a multidimensional approach to autism could provide a more comprehensive system for classification of impairment. At present, however, there is no formal way to designate the combined effect of these different aspects of autism on a person's life. A comprehensive outlook that acknowledges impairments, capabilities, co-occurring conditions, and environmental factors would be useful for identifying subgroups of individuals as well as for determining individual needs and strengths in clinical assessments. Lay Summary: The severity of a person's autism is currently defined based on the severity of their core autism symptoms: impaired social-communication and the presence of restricted or repetitive patterns of behaviors and interests. But autistic people often face additional challenges such as intellectual disability, epilepsy, and anxiety disorder, that considerably impact their everyday life, wellbeing, and the need for support. A more complete view of autism severity, one that includes core symptoms as well as additional challenges, could help identify meaningful sub-groups of autistic individuals and could be useful in clinical care. Appeared originally in Autism Res 2023; 16:685-696.

Exploring dual diagnosis: Examining professional’s knowledge, attitudes, and training on intellectual disability and psychiatric disorder

People with Intellectual Disabilities (ID) and a Psychiatric Disorder (PD) are referred to as having a dual diagnosis (DD). Mental health (MH) professionals must possess the necessary skills and a positive outlook to care for people with DD adequately. Through appropriate instruction, these goals are achievable. ID and mental problems co-occurring are referred to as a DD, presenting complicated issues for those with ID and those with mental illnesses that work with them. To better understand the gaps and prospects for advancement in this area, this research set out to investigate the attitudes, knowledge, and training on ID and PD of professionals in relation to DD. This study on professional caregivers' attitudes, knowledge, and training about people with DD, ID, and PD supports extensive training programs to fill in knowledge gaps, encourage positive attitudes, and improve abilities while working with this group. For experts to give patients with DD the best service feasible, their attitudes, knowledge, and training must all be enhanced. The purpose of developing this approach was to discover manuscripts that have been published in English after the year 1995. By locating relevant literature within the required timeline and language, this method attempted to make sure that the articles chosen fit the parameters and goals of the study or research that was carried out. This study selected and examined six papers on knowledge, attitudes, and training on ID and PD in the area of DD. The outcome of this study underlines the need to provide practitioners in the DD sector with chances for training and practice to increase their knowledge, competence, and attitudes. Recommendations are offered in light of this evaluation for enhancing guidance opportunities and carrying out additional studies.

De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor

N-methyl-d-aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout the central nervous system. Genetic variants in GRIN genes encoding NMDAR subunits are associated with a spectrum of neurological disorders. The M3 transmembrane helices of the NMDAR couple directly to the agonist-binding domains and form a helical bundle crossing in the closed receptors that occludes the pore. The M3 functions as a transduction element whose conformational change couples ligand binding to opening of an ion conducting pore. In this study, we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix. These de novo variants were identified in children with neurological and neuropsychiatric disorders including epilepsy, developmental delay, intellectual disability, hypotonia and attention deficit hyperactivity disorder. All 48 variants in M3 for which comprehensive testing was completed produce a gain-of-function (28/48) compared to loss-of-function (9/48); 11 variants had an indeterminant phenotype. This supports the idea that a key structural feature of the M3 gate exists to stabilize the closed state so that agonist binding can drive channel opening. Given that most M3 variants enhance channel gating, we assessed the potency of FDA-approved NMDAR channel blockers on these variant receptors. These data provide new insight into the structure–function relationship of the NMDAR gate, and suggest that variants within the M3 transmembrane helix produce a gain-of-function.