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Psychiatria Danubina Dec 2023Within the domain of intellectual disability, evidence suggests a potential association with changes in the developmental pathways governing the maturation of...
BACKGROUND
Within the domain of intellectual disability, evidence suggests a potential association with changes in the developmental pathways governing the maturation of interhemispheric communication mechanisms.
SUBJECTS AND METHOD
Through this study, our objective was to identify potential anomalies in interhemispheric transfer among individuals with Down syndrome (DS). Specifically, we investigated whether a significant difference exists in interhemispheric communication efficiency between DS and control participants of similar chronological age. For our analysis, 11 participants with DS and 13 from the control group were evaluated. A fingertip cross-localization test was used to quantify the efficiency of interhemispheric information transfer.
RESULTS
The data revealed a significantly reduced efficiency of interhemispheric communication in participants diagnosed with DS compared to the control group.
CONCLUSIONS
These findings suggest a potential dysfunction in the corpus callosum of DS individuals. It is plausible to suggest that this functional disconnection might influence the development of cognitive anomalies.
Topics: Humans; Down Syndrome; Functional Laterality; Corpus Callosum; Intellectual Disability; Communication
PubMed: 37994063
DOI: No ID Found -
European Journal of Medical Genetics Aug 2023Jansen de Vries syndrome (JDVS, OMIM: 617450) is a rare neurodevelopmental disorder associated with hypotonia, behavioral features, high threshold to pain, short... (Review)
Review
Jansen de Vries syndrome (JDVS, OMIM: 617450) is a rare neurodevelopmental disorder associated with hypotonia, behavioral features, high threshold to pain, short stature, ophthalmological abnormalities, dysmorphism and occasionally a structural cardiac condition. It is caused by truncating variants of the last and penultimate exons of PPM1D. So far, 21 patients with JVDS have been reported in the literature. Here, we describe four novel cases of JVDS and review the current literature. Notably, our patients 1, 3 and 4 do not have intellectual disability albeit they have significant developmental difficulties. Thus, the phenotype may span from a classic intellectual disability syndrome to a milder neurodevelopmental disorder. Interestingly, two of our patients have received successful growth hormone treatment. Considering the phenotype of all the known JDVS patients, a cardiological consultation is recommended, as at least 7/25 patients showed a structural cardiac defect. Episodic fever and vomiting may associate with hypoglycemia and may even mimic a metabolic disorder. We also report the first JDVS patient with a mosaic gene defect and a mild neurodevelopmental phenotype.
Topics: Humans; Intellectual Disability; Abnormalities, Multiple; Mutation; Neurodevelopmental Disorders; Phenotype
PubMed: 37385405
DOI: 10.1016/j.ejmg.2023.104807 -
European Journal of Human Genetics :... Dec 2023Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15...
Börjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked intellectual disability syndrome caused by variants in the PHF6 gene. We ascertained 19 individuals from 15 families with likely pathogenic or pathogenic PHF6 variants (11 males and 8 females). One family had previously been reported. Six variants were novel. We analysed the clinical and genetic findings in our series and compared them with reported BFLS patients. Affected males had classic features of BFLS including intellectual disability, distinctive facies, large ears, gynaecomastia, hypogonadism and truncal obesity. Carrier female relatives of affected males were unaffected or had only mild symptoms. The phenotype of affected females with de novo variants overlapped with the males but included linear skin hyperpigmentation and a higher frequency of dental, retinal and cortical brain anomalies. Complications observed in our series included keloid scarring, digital fibromas, absent vaginal orifice, neuropathy, umbilical hernias, and talipes. Our analysis highlighted sex-specific differences in PHF6 variant types and locations. Affected males often have missense variants or small in-frame deletions while affected females tend to have truncating variants or large deletions/duplications. Missense variants were found in a minority of affected females and clustered in the highly constrained PHD2 domain of PHF6. We propose recommendations for the evaluation and management of BFLS patients. These results further delineate and extend the genetic and phenotypic spectrum of BFLS.
Topics: Male; Humans; Female; Intellectual Disability; Mental Retardation, X-Linked; Hypogonadism; Obesity
PubMed: 37704779
DOI: 10.1038/s41431-023-01447-0 -
The Journal of Gene Medicine Jan 2024Intellectual disability (ID) can be associated with different syndromes such as Rubinstein-Taybi syndrome (RSTS) and can also be related to conditions such as metabolic...
BACKGROUND
Intellectual disability (ID) can be associated with different syndromes such as Rubinstein-Taybi syndrome (RSTS) and can also be related to conditions such as metabolic encephalomyopathic crises, recurrent,with rhabdomyolysis, cardiac arrhythmias and neurodegeneration. Rare congenital RSTS1 (OMIM 180849) is characterized by mental and growth retardation, significant and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms, and an elevated risk of malignancies. Microdeletions and point mutations in the CREB-binding protein (CREBBP) gene, located at 16p13.3, have been reported to cause RSTS. By contrast, TANGO2-related metabolic encephalopathy and arrhythmia (TRMEA) is a rare metabolic condition that causes repeated metabolic crises, hypoglycemia, lactic acidosis, rhabdomyolysis, arrhythmias and encephalopathy with cognitive decline. Clinicians need more clinical and genetic evidence to detect and comprehend the phenotypic spectrum of this disorder.
METHODS
Exome sequencing was used to identify the disease-causing variants in two affected families A and B from District Kohat and District Karak, Khyber Pakhtunkhwa. Affected individuals from both families presented symptoms of ID, developmental delay and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing.
RESULTS
In the present study, two families (A and B) exhibiting various forms of IDs were enrolled. In Family A, exome sequencing revealed a novel missense variant (NM 004380.3: c.4571A>G; NP_004371.2: p.Lys1524Arg) in the CREBBP gene, whereas, in Family B, a splice site variant (NM 152906.7: c.605 + 1G>A) in the TANGO2 gene was identified. Sanger sequencing of both variants confirmed their segregation with ID in both families. The in silico tools verified the aberrant changes in the CREBBP protein structure. Wild-type and mutant CREBBP protein structures were superimposed and conformational changes were observed likely altering the protein function.
CONCLUSIONS
RSTS and TRMEA are exceedingly rare disorders for which specific clinical characteristics have been clearly established, but more investigations are underway and required. Multicenter studies are needed to increase our understanding of the clinical phenotypes, mainly showing the genotype-phenotype associations.
Topics: Humans; CREB-Binding Protein; Intellectual Disability; Mutation; Mutation, Missense; Phenotype; Rhabdomyolysis; Rubinstein-Taybi Syndrome
PubMed: 37721116
DOI: 10.1002/jgm.3591 -
Epidemiology and Psychiatric Sciences Nov 2023To estimate the self-reported and parent-reported mental well-being of adolescents (aged 14 and 17) with/without intellectual disability in a sample of young people...
AIMS
To estimate the self-reported and parent-reported mental well-being of adolescents (aged 14 and 17) with/without intellectual disability in a sample of young people representative of the UK population.
METHODS
Secondary analysis of data collected in Waves 6 and 7 of the UK's . The analytic sample consisted of 10,838 adolescent respondents at age 14 (361 with intellectual disability and 10,477 without) and 9,408 adolescent respondents at age 17 (292 with intellectual disability and 9,116 without).
RESULTS
Parental reports of adolescent problems on the Strengths and Difficulties Questionnaire (SDQ) indicated that adolescents with intellectual disability at ages 14 and 17 were more likely to have problems than those without intellectual disability across all SDQ domains. Adolescent self-report data at age 17 indicated that adolescents with intellectual disability were more likely to (self)-report that they had problems than those without intellectual disability on all but one SDQ domain. The magnitude of relative inequality between those with and without intellectual disability was consistently lower for self-report than parental report. On indicators of depression, mental well-being, self-harm, positive mental health, happiness and general psychological distress at ages 14 and 17, we found no self-reported group differences between adolescents with and without intellectual disability.
CONCLUSIONS
Further research is needed to understand: (1) why the magnitude of mental health inequalities between those with and without intellectual disability on the SDQ may be dependent on the identity of the informant; and (2) whether such differences are also apparent for other measures of mental health or well-being.
Topics: Humans; Adolescent; Mental Health; Cohort Studies; Intellectual Disability; Self Report; United Kingdom; Surveys and Questionnaires; Mental Disorders
PubMed: 38031716
DOI: 10.1017/S204579602300080X -
Journal of Neurodevelopmental Disorders Apr 2024Neurodevelopmental conditions such as intellectual disability (ID) and autism spectrum disorder (ASD) can stem from a broad array of inherited and de novo genetic...
BACKGROUND
Neurodevelopmental 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.
METHODS
Phenotypic 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.
RESULTS
Patterns 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.
CONCLUSIONS
Despite 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.
Topics: Adolescent; Child; Female; Humans; Male; Autism Spectrum Disorder; DNA-Binding Proteins; Homeodomain Proteins; Intellectual Disability; Mental Health; Nerve Tissue Proteins; Neurodevelopmental Disorders; Quality of Life; Transcription Factors
PubMed: 38622540
DOI: 10.1186/s11689-024-09532-1 -
Alzheimer's Research & Therapy Jul 2023People with intellectual disability (ID) without Down syndrome (DS) are presumed to be at higher risk of developing dementia due to their lower baseline cognitive...
BACKGROUND
People with intellectual disability (ID) without Down syndrome (DS) are presumed to be at higher risk of developing dementia due to their lower baseline cognitive reserve. We aimed to determine the prevalence of dementia in people with ID without DS and to identify risk factors of dementia.
METHODS
This was a cross-sectional survey and multicenter study in Japan. Adults with ID without DS residing in the facilities were included. Caregivers of all participants were interviewed by medical specialists, and participants suspected of having cognitive decline were examined directly. ICD-10 criteria for dementia, DC-LD criteria for dementia, and DSM-5 criteria for neurocognitive disorders were used to diagnose dementia. The severity of ID, educational history, and comorbidities were compared by dividing the groups into those with and without dementia.
RESULTS
A total of 1831 participants were included; 118/1831 (6.44%) were diagnosed with dementia. The prevalence of dementia for each age group was 8.8%, 60-64 years; 9.0%, 65-69 years; 19.6%, 70-74 years; and 19.4%, 75-79 years. Age, severity of ID, duration of education, hypertension, depression, stroke, and traumatic brain injury were significantly associated with the presence of dementia.
CONCLUSIONS
Although the prevalence of dementia in people with ID without DS was found to be higher at a younger age than in the general population, the results of this study suggested that adequate education, prevention of head trauma and stroke, and treatments of hypertension and depression may reduce the risk of dementia. These may be potentially important modifiable risk factors for the prevention of dementia in these people.
Topics: Adult; Humans; Middle Aged; Intellectual Disability; Dementia; Prevalence; Cross-Sectional Studies; Down Syndrome; Risk Factors; Stroke; Hypertension
PubMed: 37464412
DOI: 10.1186/s13195-023-01270-1 -
Orphanet Journal of Rare Diseases Feb 2024Parents of individuals with rare neurodevelopmental conditions and intellectual disabilities (ID) are vulnerable to mental health difficulties, which vary between...
BACKGROUND
Parents of individuals with rare neurodevelopmental conditions and intellectual disabilities (ID) are vulnerable to mental health difficulties, which vary between parents and within parents over time. The underlying cause of a child's condition can influence parents' mental health, via uncertain pathways and within unknown time-windows.
RESULTS
We analysed baseline data from the IMAGINE-ID cohort, comprising 2655 parents of children and young people with ID of known genetic origin. First, we conducted a factor analysis of the SDQ Impact scale to isolate specific pathways from genetic aetiology to parents' mental health. This suggested a two-factor structure for the SDQ Impact scale, with a "home & distress" dimension and a "participation" dimension. Second, we tested via structural equation modelling (SEM) whether genetic diagnosis affects Impact and mental health directly, or indirectly via children's characteristics. This analysis identified an indirect pathway linking genetic aetiology to parents' mental health, serially through child characteristics (physical disabilities, emotional and behavioural difficulties) and Impact: home & distress. Third, we conducted moderation analysis to explore the influence of time elapsed since genetic diagnosis. This showed that the serial mediation model was moderated by time since diagnosis, with strongest mediating effects among recently diagnosed cases.
CONCLUSIONS
There are multiple steps on the pathway from ID-associated genetic diagnoses to parents' mental health. Pathway links are strongest within 5 years of receiving a genetic diagnosis, highlighting opportunities for better post-diagnostic support. Recognition and enhanced support for children's physical and behavioural needs might reduce impact on family life, ameliorating parents' vulnerabilities to mental health difficulties.
Topics: Child; Humans; Adolescent; Mental Health; Parents; Intellectual Disability
PubMed: 38360654
DOI: 10.1186/s13023-024-03076-2 -
ELife Jul 2023Human mutations in the gene encoding the solute carrier (SLC) 6A17 caused intellectual disability (ID). The physiological role of and pathogenesis of -based-ID were...
Human mutations in the gene encoding the solute carrier (SLC) 6A17 caused intellectual disability (ID). The physiological role of and pathogenesis of -based-ID were both unclear. Here, we report learning deficits in knockout and point mutant mice. Biochemistry, proteomic, and electron microscopy (EM) support SLC6A17 protein localization in synaptic vesicles (SVs). Chemical analysis of SVs by liquid chromatography coupled to mass spectrometry (LC-MS) revealed glutamine (Gln) in SVs containing SLC6A17. Virally mediated overexpression of SLC6A17 increased Gln in SVs. Either genetic or virally mediated targeting of reduced Gln in SVs. One ID mutation caused SLC6A17 mislocalization while the other caused defective Gln transport. Multidisciplinary approaches with seven types of genetically modified mice have shown Gln as an endogenous substrate of SLC6A17, uncovered Gln as a new molecule in SVs, established the necessary and sufficient roles of SLC6A17 in Gln transport into SVs, and suggested SV Gln decrease as the key pathogenetic mechanism in human ID.
Topics: Animals; Mice; Glutamine; Intellectual Disability; Mutation; Proteomics; Synaptic Vesicles
PubMed: 37440432
DOI: 10.7554/eLife.86972 -
American Journal of Community Psychology Dec 2023People living with physical, sensory, intellectual, and/or developmental disabilities experience complex social, environmental, political, and cultural challenges along... (Review)
Review
People living with physical, sensory, intellectual, and/or developmental disabilities experience complex social, environmental, political, and cultural challenges along with stigma and marginalization in education, employment, and community life. These multiple and complex barriers often hinder their full and effective participation in society. In this reflection, we curated articles on physical, sensory, intellectual, and/or developmental disabilities published in the American Journal of Community Psychology from 1973 to 2022. We reviewed titles and abstracts to identify themes that grouped manuscripts in relevant community psychology core concepts and values. From our analysis, five themes emerged: (a) promoting empowerment and advocacy; (b) promoting organizations and settings that support people with disabilities; (c) including people with disabilities in knowledge production; (d) promoting social justice in disability research, and (e) promoting support networks of families of people with disabilities. We conclude this reflection with a discussion of recommendations for future research, practice, and a call to action.
Topics: Humans; Disabled Persons; Social Justice; Employment; Intellectual Disability
PubMed: 37853910
DOI: 10.1002/ajcp.12710