Un análisis integrado entre la calidad de vida y las necesidades de apoyo de personas adultas con discapacidad intelectual en Chile / An integrated analysis between the quality of life and the support needs of adults with intellectual disabilities in Chile

El paradigma de apoyos y el de calidad de vida se han transformado en guías fundamentales para los avances en el ámbito de la discapacidad intelectual (DI). Con base en una muestra de 93 personas adultas con DI, se analiza, desde un enfoque cuantitativo no experimental, la relación entre la calidad de vida y las necesidades de apoyo, aplicando la escala INICO-FEAPS y la escala de Intensidad de Apoyos (SIS) para cada constructo. Los principales resultados evidencian que existe una relación fuerte e indirecta entre calidad de vida y necesidades de apoyos, y también la relevancia de analizar dichos resultados desde variables como grado de discapacidad, sexo o nivel socioeconómico. La discusión permite inferir la necesidad de discutir nuevas estrategias en torno a categorías como el grado de discapacidad, la autodeterminación e inclusión social, como elementos facilitadores de la calidad de vida y apoyos desde un enfoque integral que contribuya al desarrollo de estrategias de programas sociales para la población con DI. (AU)

The support paradigm and the quality of life paradigm have become fundamental guides for progress in the field of Intellectual Disability (ID). Based on a sample of 93 adults with ID, the relationship between Quality of Life and Support Needs is analyzed from a non-experimental quantitative approach, applying the INICO-FEAPS scale and the SIS Support Intensity scale for each construct. The main results show that there is a strong and indirect relationship between quality of life and support needs, and the relevance of analyzing these results from variables such as the degree of disability, sex or socioeconomic level. The discussion allows us to infer the need to discuss new strategies around categories such as the degree of disability, self-determination and social inclusion, as facilitating elements of quality of life and supporting a comprehensive approach that contributes to the development of social program strategies for the population with ID. (AU)

Beneficios y limitaciones de la planificación centrada en la persona en el campo de la discapacidad intelectual y del desarrollo: una revisión sistemática según las directrices de PRISMA / Benefits and limitations of person-centered planning in the field of intellectual and developmental disabilities: a systematic review according to PRISMA guidelines

La metodología de Planificación Centrada en la Persona (PCP) cada vez tiene mayor impacto en España. Comenzando desde las distintas legislaciones que regulan la atención a este colectivo en las diferentes autonomías y terminando en los centros que proveen este servicio. No obstante, existe escasa literatura internacional de estudios empíricos a grandes escalas que sitúen este enfoque metodológico en una posición relevante que garantice la eficacia de la PCP. El objetivo principal de este estudio es conocer el estado del uso de la metodología de PCP a través de estudios avalados empíricamente que sostengan tanto beneficios como limitaciones durante los últimos 10 años (2012-2022). Para ello, se ha realizado una revisión sistemática desde las directrices de PRISMA (2020), que incluye un total de 31 artículos. Como conclusión, se han descubierto más beneficios que limitaciones entre las que destacan las ventajas en su uso para las personas con discapacidad intelectual y del desarrollo y las mejoras de aspectos relacionados con la autodeterminación. No obstante, las limitaciones prevalecen por la falta de apoyos y recursos adecuados de las organizaciones para responder a una planificación centrada en la persona y la necesidad de formación de las personas implicadas en la elaboración de la PCP, lo que genera la incógnita de si se están realizando buenas prácticas en el uso de dicha metodología. (AU)

The methodology of Person Centered Planning (PCP) is having an increasing impact in Spain. Starting from the different legislations that regulate the attention to this group in the different autonomous regions and ending in the centers that provide this service. However, there is little international literature on large-scale empirical studies that place this methodological approach in a relevant position to guarantee the efficacy of PCP. The main objective of this study is to know the status of the use of PCP methodology through empirically supported studies that sustain both benefits and limitations during the last 10 years (2012-2022). For this purpose, a systematic review has been conducted since the PRISMA guidelines (2020), including a total of 31 articles. As a conclusion, more benefits than limitations have been found, among which the advantages in its use for people with intellectual and developmental disabilities and improvements in aspects related to self-determination stand out. However, limitations prevail due to the lack of adequate support and resources from organizations to respond to person-centered planning and the need for training of the people involved in the development of the PCP, which raises the question of whether good practices are being carried out in the use of this methodology. (AU)

Un análisis integrado entre la calidad de vida y las necesidades de apoyo de personas adultas con discapacidad intelectual en Chile / An integrated analysis between the quality of life and the support needs of adults with intellectual disabilities in Chile

El paradigma de apoyos y el de calidad de vida se han transformado en guías fundamentales para los avances en el ámbito de la discapacidad intelectual (DI). Con base en una muestra de 93 personas adultas con DI, se analiza, desde un enfoque cuantitativo no experimental, la relación entre la calidad de vida y las necesidades de apoyo, aplicando la escala INICO-FEAPS y la escala de Intensidad de Apoyos (SIS) para cada constructo. Los principales resultados evidencian que existe una relación fuerte e indirecta entre calidad de vida y necesidades de apoyos, y también la relevancia de analizar dichos resultados desde variables como grado de discapacidad, sexo o nivel socioeconómico. La discusión permite inferir la necesidad de discutir nuevas estrategias en torno a categorías como el grado de discapacidad, la autodeterminación e inclusión social, como elementos facilitadores de la calidad de vida y apoyos desde un enfoque integral que contribuya al desarrollo de estrategias de programas sociales para la población con DI. (AU)

The support paradigm and the quality of life paradigm have become fundamental guides for progress in the field of Intellectual Disability (ID). Based on a sample of 93 adults with ID, the relationship between Quality of Life and Support Needs is analyzed from a non-experimental quantitative approach, applying the INICO-FEAPS scale and the SIS Support Intensity scale for each construct. The main results show that there is a strong and indirect relationship between quality of life and support needs, and the relevance of analyzing these results from variables such as the degree of disability, sex or socioeconomic level. The discussion allows us to infer the need to discuss new strategies around categories such as the degree of disability, self-determination and social inclusion, as facilitating elements of quality of life and supporting a comprehensive approach that contributes to the development of social program strategies for the population with ID. (AU)

Beneficios y limitaciones de la planificación centrada en la persona en el campo de la discapacidad intelectual y del desarrollo: una revisión sistemática según las directrices de PRISMA / Benefits and limitations of person-centered planning in the field of intellectual and developmental disabilities: a systematic review according to PRISMA guidelines

La metodología de Planificación Centrada en la Persona (PCP) cada vez tiene mayor impacto en España. Comenzando desde las distintas legislaciones que regulan la atención a este colectivo en las diferentes autonomías y terminando en los centros que proveen este servicio. No obstante, existe escasa literatura internacional de estudios empíricos a grandes escalas que sitúen este enfoque metodológico en una posición relevante que garantice la eficacia de la PCP. El objetivo principal de este estudio es conocer el estado del uso de la metodología de PCP a través de estudios avalados empíricamente que sostengan tanto beneficios como limitaciones durante los últimos 10 años (2012-2022). Para ello, se ha realizado una revisión sistemática desde las directrices de PRISMA (2020), que incluye un total de 31 artículos. Como conclusión, se han descubierto más beneficios que limitaciones entre las que destacan las ventajas en su uso para las personas con discapacidad intelectual y del desarrollo y las mejoras de aspectos relacionados con la autodeterminación. No obstante, las limitaciones prevalecen por la falta de apoyos y recursos adecuados de las organizaciones para responder a una planificación centrada en la persona y la necesidad de formación de las personas implicadas en la elaboración de la PCP, lo que genera la incógnita de si se están realizando buenas prácticas en el uso de dicha metodología. (AU)

The methodology of Person Centered Planning (PCP) is having an increasing impact in Spain. Starting from the different legislations that regulate the attention to this group in the different autonomous regions and ending in the centers that provide this service. However, there is little international literature on large-scale empirical studies that place this methodological approach in a relevant position to guarantee the efficacy of PCP. The main objective of this study is to know the status of the use of PCP methodology through empirically supported studies that sustain both benefits and limitations during the last 10 years (2012-2022). For this purpose, a systematic review has been conducted since the PRISMA guidelines (2020), including a total of 31 articles. As a conclusion, more benefits than limitations have been found, among which the advantages in its use for people with intellectual and developmental disabilities and improvements in aspects related to self-determination stand out. However, limitations prevail due to the lack of adequate support and resources from organizations to respond to person-centered planning and the need for training of the people involved in the development of the PCP, which raises the question of whether good practices are being carried out in the use of this methodology. (AU)

Consolidating the Role of Mutated ATP2B2 in Neurodevelopmental and Cerebellar Pathologies.

Plasma membrane calcium ATPases (PMCAs) encoded by ATP2B genes have been implicated in Mendelian diseases with ataxia, dystonia, and intellectual disability. Work to date has shown that ATP2B2 (encoding PMCA2) is required for synaptic function and Purkinje-cell integrity in the cerebellum. A recent case series has linked ATP2B2 to a novel entity, characterized by neurodevelopmental and movement phenotypes, in only seven individuals. We called for collaboration to collect five unpublished families affected by the new rare ATP2B2-related condition. Exome-/genome sequencing-identified genotypes included four likely pathogenic/pathogenic heterozygous de novo missense variants and one dominantly inherited end-truncating frameshift allele. The six affected individuals shared features with the described patients including developmental delay, cognitive disturbances, epilepsy, autistic traits, and motor disorders. Striking cerebellar atrophy was observed in one affected individual. In association with hearing loss and movement abnormalities, we report a recurrent p.(Glu457Lys) substitution, previously documented in a neurologically impaired ATP2B2 mouse mutant. Our study further delineates the mutational spectrum and presentation of a human syndrome caused by ATP2B2 variants, confirming the importance of PMCA2 in neurotypical and cerebellar development.

Specific phobias in children with moderate to severe intellectual disabilities: SPIRIT, an adaptation and feasibility study.

Background: There is a lack of interventions for specific phobia in children and adolescents with moderate to severe intellectual disabilities. Objectives: The objectives were to: (a) develop an intervention for specific phobia, together with an intervention fidelity checklist and logic model, and evaluate candidate outcome measures, together with parents/carers and clinicians; (b) describe treatment as usual; (c) model the intervention to determine the acceptability and feasibility for all stakeholders, judge the appropriateness of outcome measures, explore recruitment pathways, and examine the feasibility and acceptability of consent and associated processes; and (d) describe factors that facilitate or challenge the intervention. Design: Phase 1a: using consensus methods, an Intervention Development Group was established who met to develop the intervention, review candidate outcome measures and contribute to the development of the intervention fidelity checklists and logic model. Phase 1b: a national online survey was conducted with parents and professionals to describe treatment as usual. Phase 2: a single-group non-randomised feasibility study was designed to model the intervention and to test intervention feasibility and acceptability, outcome measures and aspects of the research process. Setting: Phase 2: participants were recruited from National Health Service community child learning disabilities teams and special schools in England. Treatment was delivered in the child learning disabilities teams. Participants: Children aged 5-15 years with moderate to severe learning disability and specific phobia, and their parents/carers. Interventions: The SPIRIT intervention comprised two half-day workshops and eight support sessions plus treatment as usual. Main outcomes: The feasibility and acceptability of the intervention and research processes, recruitment, outcome measure completion rates and acceptability, and intervention adherence. Parents completed all of the outcome measures, with very low rates of missing data. The recruitment of sites and participants was impacted by the COVID-19 pandemic. Results: The intervention was successfully developed and modelled with 15 participants with moderate to severe learning disabilities and their parents. The intervention was judged to be feasible and acceptable by parents/carers and therapists. Parents/carers and therapists suggested minor intervention revisions. Limitations: Randomisation was not modelled within this feasibility study, although the majority of parents and therapists indicated that this would be acceptable. Conclusions: The SPIRIT intervention and associated study processes were judged to be feasible and acceptable. The intervention requires minor revisions. Future work: The SPIRIT intervention should be tested further within a clinical trial. Study registration: Current Controlled Trials ISRCTN34766613. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: NIHR130177) and is published in full in Health Technology Assessment; Vol. 28, No. 64. See the NIHR Funding and Awards website for further award information.

This study was about children and adolescents who have moderate to severe learning disabilities and specific phobia. This study had two parts. In the first part, we worked with parents of young people with learning disabilities and therapists to develop a treatment for specific phobia in children and adolescents with moderate to severe learning disabilities. We also collected information about what treatment young people were currently getting. To do this, we conducted a national (United Kingdom) survey of parents/carers who have a child with a learning disability and a phobia, along with a survey of health professionals who work with children with learning disabilities. Together with parents and therapists, we developed a treatment for specific phobia in children and adolescents with moderate to severe learning disabilities. We collected information about what treatments young people received for specific phobia and found that many do not receive any treatment for their specific phobia. In the second part, we wanted to find out whether the treatment was acceptable to parents and therapists. To do this, we tried out the treatment with 15 children and adolescents. We had difficulties getting people involved in the study due to the COVID-19 pandemic. We got enough people involved to help us to work out whether the treatment was acceptable to parents and therapists. We interviewed parents and therapists to find out how they felt about the treatment and being part of the study. We also talked to therapists to ask them what they thought about the treatment. Parents told us that they liked being involved in the study and found the treatment helped them to help their children. Parents and therapists suggested some changes to the treatment to help improve it in the future. It was recommended that a larger study should be completed.

Clinical, developmental and serotonemia phenotyping of a sample of 70 Italian patients with Phelan-McDermid Syndrome.

BACKGROUND: Phelan-McDermid syndrome (PMS) is caused by monoallelic loss or inactivation at the SHANK3 gene, located in human chr 22q13.33, and is often associated with Autism Spectrum Disorder (ASD). OBJECTIVES: To assess the clinical and developmental phenotype in a novel sample of PMS patients, including for the first time auxometric trajectories and serotonin blood levels. METHODS: 70 Italian PMS patients were clinically characterized by parental report, direct medical observation, and a thorough medical and psychodiagnostic protocol. Serotonin levels were measured in platelet-rich plasma by HPLC. RESULTS: Our sample includes 59 (84.3%) cases with chr. 22q13 terminal deletion, 5 (7.1%) disruptive SHANK3 mutations, and 6 (8.6%) ring chromosome 22. Intellectual disability was present in 69 (98.6%) cases, motor coordination disorder in 65 (92.9%), ASD in 20 (28.6%), and lifetime bipolar disorder in 12 (17.1%). Prenatal and postnatal complications were frequent (22.9%-48.6%). Expressive and receptive language were absent in 49 (70.0%) and 19 (27.1%) cases, respectively. Decreased pain sensitivity was reported in 56 (80.0%), hyperactivity in 49 (80.3%), abnormal sleep in 45 (64.3%), congenital dysmorphisms in 35 (58.3%), chronic stool abnormalities and especially constipation in 29 (41.4%). Parents reported noticing behavioral abnormalities during early childhood immediately after an infective episode in 34 (48.6%) patients. Brain MRI anomalies were observed in 53 (79.1%), EEG abnormalities in 16 (23.5%), kidney and upper urinary tract malformations in 18 (28.1%). Two novel phenotypes emerged: (a) a subgroup of 12/44 (27.3%) PMS patients displays smaller head size at enrollment (mean age 11.8 yrs) compared to their first year of neonatal life, documenting a deceleration of head growth (p < 0.001); (b) serotonin blood levels are significantly lower in 21 PMS patients compared to their 21 unaffected siblings (P < 0.05), and to 432 idiopathic ASD cases (p < 0.001). CONCLUSIONS: We replicate and extend the description of many phenotypic characteristics present in PMS, and report two novel features: (1) growth trajectories are variable and head growth appears to slow down during childhood in some PMS patients; (2) serotonin blood levels are decreased in PMS, and not increased as frequently occurs in ASD. Further investigations of these novel features are under way.

Identification of a Novel Frameshift variant of the ATRX gene: a Case Report and Review of the genotype-phenotype relationship.

BACKGROUND: X-linked intellectual disability-hypotonic facies syndrome-1 (MRXHF1) and Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome are caused by pathogenic variant in the ATRX gene, a member of the switch/sucrose non-fermentable (SWI-SNF) protein family that exhibits chromatin remodeling activity. These syndromes show a wide spectrum of clinical manifestations, such as distinctive dysmorphic features, mild-to-profound intellectual disability, motor development delay, seizures, urogenital abnormalities, and gastrointestinal disorders. CASE PRESENTATION AND LITERATURE REVIEW: A 3-year-old boy from a Chinese non-consanguineous family was diagnosed with MRXHF1 by whole-exome sequencing. Comprehensive family history information was obtained. The Medline database was searched until 1st Aug 2023 for articles related to ATRX pathogenic variant. Data on gene/protein mutations and clinical symptoms were extracted. The proband showed intellectual disability, motor development delay, typical facial abnormalities, urogenital defect, behavior problems, and optical nerve dysplasia. A novel frameshift mutation c.399_400dup, (p.Leu134Cysfs*2) in the ATRX gene was the primary cause, which occurs right before the ATRXDNMT3-DNMT3L (ADD) domain of ATRX protein. Missense mutation is the most common variation type. The ADD and helicase-like domains are the most frequently affected domains. Epilepsy, congenital heart disease, urogenital defect, acoustic defect, and optical defect are more prevalent in patients with frameshift mutations compared to those with missense mutations. There are more urogenital defects with C-terminal frameshift mutations than with N-terminal frameshift mutations. CONCLUSION: We described a novel frameshift mutation in the ATRX gene in a patient with MRXHF1 syndrome and summarized the genotype-phenotype relationship of ATRX pathogenic variant by variation type and affected protein domain. The regulatory mechanism underlying ATRX variant requires comprehensive analysis in future studies.

Novel loss-of-function variants in WDR26 cause Skraban-Deardorff syndrome in two Chinese patients.

Introduction: Mutations in the protein WD repeat structural domain 26 (WDR26, MIM 617424) have been identified as the cause of autosomal dominant Skraban-Deardorff syndrome, a rare genetic disorder characterized by intellectual disability (ID), developmental delay (DD), hypotonia, epilepsy, infant feeding difficulties, gait abnormalities and distinctive facial features. The objective of this study is to investigate the genetic factors that may contribute to the development of Skraban-Deardorff syndrome in affected individuals. Methods: In this study, we used whole-exome sequencing (WES) to analyze pathogenic and likely pathogenic variants in two unrelated Chinese patients with DD and ID. We confirmed the origin of the variants by conducting Sanger sequencing and classified them according to ACMG/AMP guidelines. Results: Here, two novel de novo variants (c.1797delC(p.His599fs*11) and c.1414C>T(p.Gln472*)) in the WDR26 gene have been identified in two Chinese patients with Skraban-Deardorff syndrome. These patients exhibit a range of symptoms, including varying degrees of ID, DD, speech delay, an abnormal wide-foot and/or stiff-legged gait, facial dysmorphism, behavioural abnormalities, with or without seizures. Conclusions: In this study, We report two unrelated Chinese patients with Skraban-Deardorff syndrome caused by novel de novo pathogenic variants of the WDR26 gene. These patients showed a clinical phenotype similar to that of patients with the WDR26 variant. Compared to reported cases with WDR26 pathogenic variants, patient 2 presented a novel complication of severe behavioural problems, including hyperactivity, social anxiety, self-mutilation, impulsivity and violent behaviour. This research broadens the range of genetic and clinical features of Skraban-Deardorff syndrome. In addition, the symptoms may become more pronounced as the patient ages. Furthermore, our report highlights the clinical diversity of Skraban-Deardorff syndrome. The findings may assist healthcare professionals in providing more accurate genetic testing and counselling to affected families and improving the overall management of the condition.

Case report: A novel FBXW7 gene variant causes global developmental delay.

Objective: To investigate a case of neurodevelopmental disorder caused by mutation of FBXW7. Methods: Clinical data were collected from the patient, trio-WES (whole-exome sequencing) was performed on the patient and his parents (trio), and the results were verified by Sanger sequencing. RESULTS: The patient was a 2-year and 1-month old male who presented with facial dysmorphism (prominent forehead, ocular hypertelorism, and low nasal bridge), global developmental delay, language impairment, hypertonia, labial hemangioma, hydrocele, and overgrowth. The trio-WES confirmed that the child had a pathogenic de novo FBXW7 gene variant, c.1612C>T (p.G1n538*), a heretofore unreported locus. Conclusion: This case of developmental delay, hypotonia, and impaired language (OMIM: #620012) related to a mutation in FBXW7, is a rare genetic disorder, newly identified in recent years, and seldom reported. The presence of hypertonia, labial hemangioma, and hydrocele in this child suggests significant phenotypic heterogeneity of the disease, and the discovery of new mutant loci enriches the spectrum of pathogenic variants of the disease.

The effect of motor dual-task training on gait and mobility performances in children with intellectual disabilities.

The study investigated the impact of motor dual-task training on gait and mobility in children with intellectual disabilities. Performance was assessed using the Timed Up and Go Test (TUGT) and the 10-Meter Walking Test (TMWT) before and after an 8-week training period, with participants divided into a Trained Group (n=12) and a Control Group (n=14). Results indicated that, across both groups and regardless of session, TUGT and TMWT scores were significantly higher (p < 0.001) in the motor dual-task condition compared to the single-task condition. Post-training, TUGT scores significantly decreased (p < 0.05) in the single-task condition. The Trained Group showed significant improvements in second motor-task performance on both TUGT (p < 0.05) and TMWT (p < 0.001) under dual-task conditions, while the Control Group showed no change. The study demonstrated the effectiveness of motor dual-task training in enhancing mobility in children with intellectual disabilities.

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

Introduction: Pathogenic variants in the STXBP1 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 STXBP1 pathogenic variants is not yet fully understood. Case Presentation: Herein, we report a patient presenting intellectual disability, early onset seizures, and autism. Clinical exome sequencing identified a novel monoallelic splice pathogenic variant STXBP1(NM_001032221.6):c.38-2A>G. Discussion: Splice-site pathogenic variants in the STXBP1 gene are mostly associated with West syndrome, early onset epilepsy and encephalopathy, and Ohtahara syndrome. Our findings extend clinical and molecular spectrum of STXBP1 gene variants by reporting the first splice-site variant associated with autism along with early onset epilepsy and, and intellectual disability in a patient.

Ubiquitin ligase signalling networks shape presynaptic development, function and disease.

Ubiquitin ligases are important regulators of nervous system development, function and disease. To date, numerous ubiquitin ligases have been discovered that regulate presynaptic biology. Here, we discuss recent findings on presynaptic ubiquitin ligases that include members from the three major ubiquitin ligase classes: RING, RBR and HECT. Several themes emerge based on findings across a range of model systems. A cadre of ubiquitin ligases is required presynaptically to orchestrate development and transmission at synapses. Multiple ubiquitin ligases deploy both enzymatic and non-enzymatic mechanisms, and act as hubs for signalling networks at the synapse. Both excitatory and inhibitory presynaptic terminals are influenced by ligase activity. Finally, there are several neurodevelopmental disorders and neurodegenerative diseases associated with presynaptic ubiquitin ligases. These findings highlight the growing prominence and biomedical relevance of the presynaptic ubiquitin ligase network.

A systematic review of attachment interventions for people with intellectual disability and their caregivers.

OBJECTIVE: The current mixed-methods systematic review evaluated available literature to find out which attachment-based interventions have been implemented for people with intellectual disability and whether they are efficacious and acceptable. METHODS: Five databases were searched (in July 2023 and April 2024), using terms related to intellectual disability and attachment-based interventions. The search yielded 793 papers; 15 papers (13 studies) met inclusion criteria. Relevant data was extracted from each study. Paper quality was appraised using the Mixed Methods Appraisal Tool. Findings were synthesised in an integrative review. RESULTS: Of the included studies, 7 had people with intellectual disability as participants and 6 had their caregivers. Interventions included education, psychotherapy, technology assisted therapy, video interaction guidance/feedback and circle of security. Research methods varied. CONCLUSIONS: Evidence for efficacy and acceptability of interventions was mixed but promising. Most studies had limited generalisability. Therefore, further research is required. Pre-registration with PROSPERO [351287].

Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy.

BACKGROUND: ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype. METHODS: We collected patients with duplications encompassing ARID1A and ARID1B duplications. RESULTS: 16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1-1.2 Mb(1-44 genes) for ARID1A and 0.9-10.3 Mb(2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation re-analysis, resulting in the reclassification of two ARID1A and two ARID1B duplications as pathogenic. CONCLUSION: Our findings reveal that ARID1B duplications manifest a clinical phenotype and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole gene duplication rather than haploinsufficiency.

Clozapine for persons with neurodevelopmental disorders: a systematic review and expert recommendations for clinical practice.

INTRODUCTION: We aimed to synthesize the information on the risks and benefits of clozapine prescription for resistant challenging behavior in persons with neurodevelopmental disorders. METHODS: Articles were identified with MEDLINE, Web of Sciences, and PsycINFO search from inception through January 2024. The review was restricted to persons with intellectual disability (ID) and/or autism spectrum disorder (ASD) without comorbid psychotic or affective disorder. Data were synthesized narratively. RESULTS: We identified 24 articles (13 case reports, eight chart studies, two controlled studies, one pharmaco-epidemiological study) including 296 patients with ID (n = 222) or ASD (n = 74) (10% aged ≤ 18 years). After clozapine initiation, a decreased frequency of challenging behavior persisting over time was reported in most participants included in clinical studies, and a significant reduction in the number of admissions in the population-based two-year mirror-image study. Adverse drug reactions were those commonly observed with clozapine, i.e. constipation, sedation, and weight gain. CONCLUSIONS: Since only four participants were included in the controlled studies, the benefits of clozapine in neurodevelopmental disorders are supported by a body of evidence exclusively drawn from observational studies. Further studies are required to clarify the indications of clozapine with respect to the unmet need induced by resistant challenging behavior. REGISTRATION: PROSPERO database registration number CRD42024522343.

CTNND2 moderates the pace of synaptic maturation and links human evolution to synaptic neoteny.

Human-specific genes are potential drivers of brain evolution. Among them, SRGAP2C has contributed to the emergence of features characterizing human cortical synapses, including their extended period of maturation. SRGAP2C inhibits its ancestral copy, the postsynaptic protein SRGAP2A, but the synaptic molecular pathways differentially regulated in humans by SRGAP2 proteins remain largely unknown. Here, we identify CTNND2, a protein implicated in severe intellectual disability (ID) in Cri-du-Chat syndrome, as a major partner of SRGAP2. We demonstrate that CTNND2 slows synaptic maturation and promotes neuronal integrity. During postnatal development, CTNND2 moderates neuronal excitation and excitability. In adults, it supports synapse maintenance. While CTNND2 deficiency is deleterious and results in synaptic loss of SYNGAP1, another major ID-associated protein, the human-specific protein SRGAP2C, enhances CTNND2 synaptic accumulation in human neurons. Our findings suggest that CTNND2 regulation by SRGAP2C contributes to synaptic neoteny in humans and link human-specific and ID genes at the synapse.

The risk of type 2-diabetes among persons with intellectual disability: a Danish population-based matched cohort study.

BACKGROUND: Previous research shows that obesity, unhealthy eating, physical inactivity and a high use of psychotropic medications are prevalent among persons with intellectual disability (ID), which might increase the risk of type 2-diabetes (T2DM). This study aims to investigate: (1) whether persons with ID have an increased risk of T2DM compared with an age- and sex-matched reference group and (2) differences in T2DM risk by sex, birth year, ID inclusion diagnosis and ID severity. METHODS: This study is a nationwide cohort study, including 65 293 persons with ID and 659 723 persons in an age- and sex-matched reference group without ID. Incidence rates for T2DM were calculated and Cox proportional regression models were used to estimate adjusted hazard ratios (aHRs) for the association between ID and T2DM. Follow-up began from the 1 January 1977 (when T2DM data were available), participants' 22nd birthday or from the date the participants immigrated to Denmark, whichever came last and continued until the onset of T2DM, emigration, death or end of follow-up (31 December 2021), whichever came first. RESULTS: Persons with ID had more than double risk of T2DM compared with the reference group [aHR = 2.15, 95% confidence interval (CI): 2.09-2.20]. The strongest associations were found among women, persons born between 1980 and 1999 and among persons with mild ID. CONCLUSIONS: Persons with ID have an increased risk of T2DM. This knowledge is important in relation to the development and prioritising of preventive initiatives among persons with ID in the healthcare sector. Future research should focus on the underlying mechanisms that can explain the possible association between ID and T2DM as it allows a more targeted prevention strategy.

Cicchetti's organizational-developmental perspective of Down syndrome: Contributions to the emergence of developmental psychopathology and the study of persons with neurodevelopmental conditions.

Dante Cicchetti's earliest work, his studies of social-emotional development in infants and children with Down syndrome, set the stage for the emergence of the larger field of developmental psychopathology. By applying basic developmental principles, methodologies, and questions to the study of persons with Down syndrome, Dante took on the challenge of searching for patterns in atypical development. In doing so, he extended traditional developmental theory and introduced a more "liberal" approach that both continues to guide developmentally based research with persons with neurodevelopmental conditions (NDCs), including Down syndrome. We highlight five themes from Dante's work: (1) appreciating the importance of developmental level; (2) prioritizing the organization of development; (3) examining whether developmental factors work similarly in those with known genetic conditions; (4) rethinking narratives about ways of being; and (5) examining the influence of multiple levels of the environment on the individual's functioning. We highlight ways that these essential lessons anticipated present-day research with persons with a variety of NDCs, including Down syndrome, other genetic syndromes associated with intellectual disability, and autism. We conclude with visions to the future for research with these populations as well as for the field of developmental psychopathology more generally.

Social Workers' Experiences of Working With Support Workers in Services for Adults With Intellectual Disabilities in Hong Kong.

BACKGROUND: Services for adults with intellectual disabilities in Hong Kong have a hierarchical staffing structure. Professional social workers, who performed as mid-level employees, work with frontline support workers to deliver services to clients. METHODS: This qualitative study explored social workers' experiences of working with support workers through in-depth interviews with 13 participants. FINDINGS: The study revealed that social workers perceived a significant variation between themselves and support workers in terms of working motivation, values and attitudes towards clients with intellectual disabilities. Despite the hierarchical relationships, social workers and support workers share the power of service decision-making. Social workers used firm and gentle approaches to facilitate changes in practices to uphold service values. These findings were compared with Western literature on this topic, indicating similarities and differences. CONCLUSION: The organisations need to facilitate an effective collaboration between social workers and support workers to enhance the quality of services for adults with intellectual disabilities in Hong Kong.