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Community Mental Health Journal Aug 2023People with intellectual and developmental disabilities (IDD) have higher incidences of mental health conditions and behavioral support needs than people without IDD but...
People with intellectual and developmental disabilities (IDD) have higher incidences of mental health conditions and behavioral support needs than people without IDD but may not receive needed care from community providers. We examined rates of co-occurring conditions in a representative sample of adults with IDD who use state funded services in Virginia. Using data from two datasets, we identified four categories of mental health and behavioral conditions. We used these categories to examine differences in individual- and system-level factors in people with and without co-occurring conditions. We found high rates of co-occurring conditions in our sample. We found important disability factors and system-level characteristics that were associated with having a diagnosed mental health condition or behavioral support needs. Differing patterns of diagnosis and treatment for co-occurring conditions suggests more work needs to be done to support people with IDD and co-occurring mental health conditions living in the community.
Topics: Adult; Humans; Child; Developmental Disabilities; Intellectual Disability; Mental Health; Virginia
PubMed: 36739327
DOI: 10.1007/s10597-023-01091-4 -
BJOG : An International Journal of... Dec 2023To investigate whether mild neonatal hypoxic ischaemic encephalopathy (HIE) in term born infants is associated with cerebral palsy, epilepsy, mental retardation and...
OBJECTIVE
To investigate whether mild neonatal hypoxic ischaemic encephalopathy (HIE) in term born infants is associated with cerebral palsy, epilepsy, mental retardation and death up to 6 years of age.
DESIGN
Population-based cohort study.
SETTING
Sweden, 2009-2015.
POPULATION
Live term born infants without congenital malformations or chromosomal abnormalities (n = 505 075).
METHODS
Birth and health data were retrieved from Swedish national health and quality registers. Mild HIE was identified by diagnosis in either the Swedish Medical Birth Register or the Swedish Neonatal Quality Register. Cox proportional hazards regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs).
MAIN OUTCOME MEASURES
A composite of the outcomes cerebral palsy, epilepsy, mental retardation and death up to 6 years of age.
RESULTS
Median follow-up time was 3.3 years after birth. Of 414 infants diagnosed with mild HIE, 17 were classified according to the composite outcome and incidence rates were 12.6 and 2.9 per 1000 child-years in infants with and without HIE respectively. Infants with mild HIE was four times as likely to be diagnosed with the composite outcome (HR 4.42, 95% CI 2.75-7.12) compared with infants without HIE. When analysed separately, associations were found with cerebral palsy (HR 21.50, 95% CI 9.59-48.19) and death (HR 19.10, 95% CI 7.90-46.21). HRs remained essentially unchanged after adjustment for covariates.
CONCLUSIONS
Mild neonatal HIE was associated with neurological morbidity and mortality in childhood. Challenges include identifying infants who may develop morbidity and how to prevent adverse outcomes.
Topics: Infant, Newborn; Infant; Humans; Hypoxia-Ischemia, Brain; Cerebral Palsy; Cohort Studies; Intellectual Disability; Epilepsy
PubMed: 37199188
DOI: 10.1111/1471-0528.17533 -
Emerging Topics in Life Sciences Dec 2023Neurodevelopmental disorders (NDDs) encompass a diverse group of disorders characterised by impaired cognitive abilities and developmental challenges. Short tandem... (Review)
Review
Neurodevelopmental disorders (NDDs) encompass a diverse group of disorders characterised by impaired cognitive abilities and developmental challenges. Short tandem repeats (STRs), repetitive DNA sequences found throughout the human genome, have emerged as potential contributors to NDDs. Specifically, the CGG trinucleotide repeat has been implicated in a wide range of NDDs, including Fragile X Syndrome (FXS), the most common inherited form of intellectual disability and autism. This review focuses on CGG STR expansions associated with NDDs and their impact on gene expression through repeat expansion-mediated epigenetic silencing. We explore the molecular mechanisms underlying CGG-repeat expansion and the resulting epigenetic modifications, such as DNA hypermethylation and gene silencing. Additionally, we discuss the involvement of other CGG STRs in neurodevelopmental diseases. Several examples, including FMR1, AFF2, AFF3, XYLT1, FRA10AC1, CBL, and DIP2B, highlight the complex relationship between CGG STR expansions and NDDs. Furthermore, recent advancements in this field are highlighted, shedding light on potential future research directions. Understanding the role of STRs, particularly CGG-repeats, in NDDs has the potential to uncover novel diagnostic and therapeutic strategies for these challenging disorders.
Topics: Humans; Trinucleotide Repeat Expansion; Fragile X Syndrome; Trinucleotide Repeats; DNA Methylation; Intellectual Disability; Fragile X Mental Retardation Protein; Nerve Tissue Proteins
PubMed: 37768318
DOI: 10.1042/ETLS20230021 -
ELife Oct 2023Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the SLC6A8 gene. The impaired creatine uptake in the brain results in intellectual...
Creatine transporter deficiency (CTD) is an X-linked disease caused by mutations in the SLC6A8 gene. The impaired creatine uptake in the brain results in intellectual disability, behavioral disorders, language delay, and seizures. In this work, we generated human brain organoids from induced pluripotent stem cells of healthy subjects and CTD patients. Brain organoids from CTD donors had reduced creatine uptake compared with those from healthy donors. The expression of neural progenitor cell markers SOX2 and PAX6 was reduced in CTD-derived organoids, while GSK3β, a key regulator of neurogenesis, was up-regulated. Shotgun proteomics combined with integrative bioinformatic and statistical analysis identified changes in the abundance of proteins associated with intellectual disability, epilepsy, and autism. Re-establishment of the expression of a functional SLC6A8 in CTD-derived organoids restored creatine uptake and normalized the expression of SOX2, GSK3β, and other key proteins associated with clinical features of CTD patients. Our brain organoid model opens new avenues for further characterizing the CTD pathophysiology and supports the concept that reinstating creatine levels in patients with CTD could result in therapeutic efficacy.
Topics: Humans; Intellectual Disability; Creatine; Glycogen Synthase Kinase 3 beta; Mental Retardation, X-Linked; Brain; Organoids
PubMed: 37830910
DOI: 10.7554/eLife.88459 -
Biochimica Et Biophysica Acta.... Jun 2024Developmental and epileptic encephalopathies (DEE) are a broad and varied group of disorders that affect the brain and are characterized by epilepsy and comorbid... (Review)
Review
Developmental and epileptic encephalopathies (DEE) are a broad and varied group of disorders that affect the brain and are characterized by epilepsy and comorbid intellectual disability (ID). These conditions have a broad spectrum of symptoms and can be caused by various underlying factors, including genetic mutations, infections, and other medical conditions. The exact cause of DEE remains largely unknown in the majority of cases. However, in around 25 % of patients, rare nonsynonymous coding variants in genes encoding ion channels, cell-surface receptors, and other neuronally expressed proteins are identified. This review focuses on a subgroup of DEE patients carrying variations in the gene encoding the Transient Receptor Potential Melastatin 3 (TRPM3) ion channel, where recent data indicate that gain-of-function of TRPM3 channel activity underlies a spectrum of dominant neurodevelopmental disorders.
Topics: Humans; TRPM Cation Channels; Neurodevelopmental Disorders; Epilepsy; Intellectual Disability; Animals; Mutation
PubMed: 38522727
DOI: 10.1016/j.bbamcr.2024.119709 -
Brain : a Journal of Neurology Aug 2023Pitt-Hopkins syndrome is an autism spectrum disorder caused by autosomal dominant mutations in the human transcription factor 4 gene (TCF4). One pathobiological process...
Pitt-Hopkins syndrome is an autism spectrum disorder caused by autosomal dominant mutations in the human transcription factor 4 gene (TCF4). One pathobiological process caused by murine Tcf4 mutation is a cell autonomous reduction in oligodendrocytes and myelination. In this study, we show that the promyelinating compounds, clemastine, sobetirome and Sob-AM2 are effective at restoring myelination defects in a Pitt-Hopkins syndrome mouse model. In vitro, clemastine treatment reduced excess oligodendrocyte precursor cells and normalized oligodendrocyte density. In vivo, 2-week intraperitoneal administration of clemastine also normalized oligodendrocyte precursor cell and oligodendrocyte density in the cortex of Tcf4 mutant mice and appeared to increase the number of axons undergoing myelination, as EM imaging of the corpus callosum showed a significant increase in the proportion of uncompacted myelin and an overall reduction in the g-ratio. Importantly, this treatment paradigm resulted in functional rescue by improving electrophysiology and behaviour. To confirm behavioural rescue was achieved via enhancing myelination, we show that treatment with the thyroid hormone receptor agonist sobetirome or its brain penetrating prodrug Sob-AM2, was also effective at normalizing oligodendrocyte precursor cell and oligodendrocyte densities and behaviour in the Pitt-Hopkins syndrome mouse model. Together, these results provide preclinical evidence that promyelinating therapies may be beneficial in Pitt-Hopkins syndrome and potentially other neurodevelopmental disorders characterized by dysmyelination.
Topics: Humans; Animals; Mice; Clemastine; Autism Spectrum Disorder; Pharmaceutical Preparations; Intellectual Disability
PubMed: 37068912
DOI: 10.1093/brain/awad057 -
Behavioral Sciences & the Law 2024Forensic psychiatrists and neuropsychiatrists are likely to encounter individuals with intellectual disability as they are over-represented in the judicial system. These...
Forensic psychiatrists and neuropsychiatrists are likely to encounter individuals with intellectual disability as they are over-represented in the judicial system. These individuals may have the full range of mental illnesses and comorbid conditions, including physical infirmity, sensory deficits, language impairment, and maladaptive behaviors. They are frequently disadvantaged in the judicial system due to lack of comprehension, lack of accommodations, and stigmatization. Decision making capacity may need to be assessed for health care, sexual autonomy, marriage, financial management, making a will, and need for guardianship. The usual approach to conducting an evaluation needs adaptation to fit the unique characteristics and circumstances of the individual with intellectual disability. The forensic consultant can assist attorneys, defendants, and victims in recommending accommodations and the expert witness can provide education to juries.
Topics: Humans; Intellectual Disability; Forensic Psychiatry; Mental Competency; Mental Disorders; Expert Testimony; Decision Making
PubMed: 38459744
DOI: 10.1002/bsl.2653 -
Autism Research : Official Journal of... Aug 2023Likely gene-disrupting (LGD) variants in DYRK1A are causative of DYRK1A syndrome and associated with autism spectrum disorder (ASD) and intellectual disability (ID)....
Likely gene-disrupting (LGD) variants in DYRK1A are causative of DYRK1A syndrome and associated with autism spectrum disorder (ASD) and intellectual disability (ID). While many individuals with DYRK1A syndrome are diagnosed with ASD, they may present with a unique profile of ASD traits. We present a comprehensive characterization of the ASD profile in children and young adults with LGDs in DYRK1A. Individuals with LGD variants in DYRK1A (n = 29) were compared to children who had ASD with no known genetic cause, either with low nonverbal IQ (n = 14) or average or above nonverbal IQ (n = 41). ASD was assessed using the ADOS-2, ADI-R, SRS-2, SCQ, and RBS-R. Quantitative score comparisons were conducted, as were qualitative analyses of clinicians' behavioral observations. Diagnosis of ASD was confirmed in 85% and ID was confirmed in 89% of participants with DYRK1A syndrome. Individuals with DYRK1A syndrome showed broadly similar social communication behaviors to children with idiopathic ASD and below-average nonverbal IQ, with specific challenges noted in social reciprocity and nonverbal communication. Children with DYRK1A syndrome also showed high rates of sensory-seeking behaviors. Phenotypic characterization of individuals with DYRK1A syndrome may provide additional information on mechanisms contributing to co-occurring ASD and ID and contribute to the identification of genetic predictors of specific ASD traits.
Topics: Humans; Autism Spectrum Disorder; Autistic Disorder; Intellectual Disability; Phenotype; Social Behavior; Dyrk Kinases
PubMed: 37497568
DOI: 10.1002/aur.2995 -
Genes Jul 2023The vacuolar H-ATPase is a multisubunit enzyme which plays an essential role in the acidification and functions of lysosomes, endosomes, and synaptic vesicles. Many...
The vacuolar H-ATPase is a multisubunit enzyme which plays an essential role in the acidification and functions of lysosomes, endosomes, and synaptic vesicles. Many genes encoding subunits of V-ATPases, namely and , have been associated with neurodevelopmental disorders and epilepsy. The autosomal dominant p.Arg506* variant can cause both congenital deafness with onychodystrophy, autosomal dominant (DDOD) and deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures syndromes (DOORS). Some but not all individuals with this truncating variant have intellectual disability and/or epilepsy, suggesting incomplete penetrance and/or variable expressivity. To further explore the impact of the p.Arg506* variant in neurodevelopment and epilepsy, we generated mutant mice and performed standardized phenotyping using the International Mouse Phenotyping Consortium (IMPC) pipeline. In addition, we assessed the EEG profile and seizure susceptibility of mice. Behavioral tests revealed that the mice present locomotor hyperactivity and show less anxiety-associated behaviors. Moreover, EEG analyses indicate that mutant mice have interictal epileptic activity and that both heterozygous (like patients) and homozygous mice have reduced seizure thresholds to pentylenetetrazol. Our results confirm that variants in can cause seizures and that the heterozygous mouse model is a valuable tool to further explore the pathophysiology and potential treatments for vacuolar ATPases-associated epilepsy and disorders.
Topics: Animals; Mice; Seizures; Causality; Adenosine Triphosphatases; Anxiety; Arthrogryposis; Intellectual Disability; Vacuolar Proton-Translocating ATPases
PubMed: 37628590
DOI: 10.3390/genes14081538 -
Biological Psychiatry Jan 202415q11.2 deletions and duplications have been linked to autism spectrum disorder, schizophrenia, and intellectual disability. Recent evidence suggests that dysfunctional...
BACKGROUND
15q11.2 deletions and duplications have been linked to autism spectrum disorder, schizophrenia, and intellectual disability. Recent evidence suggests that dysfunctional CYFIP1 (cytoplasmic FMR1 interacting protein 1) contributes to the clinical phenotypes observed in individuals with 15q11.2 deletion/duplication syndrome. CYFIP1 plays crucial roles in neuronal development and brain connectivity, promoting actin polymerization and regulating local protein synthesis. However, information about the impact of single nucleotide variants in CYFIP1 on neurodevelopmental disorders is limited.
METHODS
Here, we report a family with 2 probands exhibiting intellectual disability, autism spectrum disorder, spastic tetraparesis, and brain morphology defects and who carry biallelic missense point mutations in the CYFIP1 gene. We used skin fibroblasts from one of the probands, the parents, and typically developing individuals to investigate the effect of the variants on the functionality of CYFIP1. In addition, we generated Drosophila knockin mutants to address the effect of the variants in vivo and gain insight into the molecular mechanism that underlies the clinical phenotype.
RESULTS
Our study revealed that the 2 missense variants are in protein domains responsible for maintaining the interaction within the wave regulatory complex. Molecular and cellular analyses in skin fibroblasts from one proband showed deficits in actin polymerization. The fly model for these mutations exhibited abnormal brain morphology and F-actin loss and recapitulated the core behavioral symptoms, such as deficits in social interaction and motor coordination.
CONCLUSIONS
Our findings suggest that the 2 CYFIP1 variants contribute to the clinical phenotype in the probands that reflects deficits in actin-mediated brain development processes.
Topics: Humans; Intellectual Disability; Actins; Autism Spectrum Disorder; Polymerization; Adaptor Proteins, Signal Transducing; Fragile X Mental Retardation Protein
PubMed: 37704042
DOI: 10.1016/j.biopsych.2023.08.027