Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure.

Domain Z7 of nuclear transcription factor ZNF711 has the consensus last metal-ligand H23 found in odd-numbered zinc-fingers of this protein replaced by a phenylalanine. Ever since the discovery of ZNF711 it has been thought that Z7 is probably non-functional because of the H23F substitution. The presence of H26 three positions downstream prompted us to examine if this histidine could substitute as the last metal ligand. The Z7 domain adopts a stable tertiary structure upon metal binding. The NMR structure of Zn2+-bound Z7 shows the classical ßßα-fold of CCHH zinc fingers. Mutagenesis and pH titration experiments indicate that H26 is not involved in metal binding and that Z7 has a tridentate metal-binding site comprised of only residues C3, C6, and H19. By contrast, an F23H mutation that introduces a histidine in the consensus position forms a tetradentate ligand. The structure of the WT Z7 is stable causing restricted ring-flipping of phenyalanines 10 and 23. Dynamics are increased with either the H26A or F23H substitutions and aromatic ring rotation is no longer hindered in the two mutants. The mutations have only small effects on the Kd values for Zn2+ and Co2+ and retain the high thermal stability of the WT domain above 80 °C. Like two previously reported designed zinc fingers with the last ligand replaced by water, the WT Z7 domain is catalytically active, hydrolyzing 4-nitophenyl acetate. We discuss the implications of naturally occurring tridentate zinc fingers for cancer mutations and drug targeting of notoriously undruggable transcription factors. Our findings that Z7 can fold with only a subset of three metal ligands suggests the recent view that most everything about protein structure can be predicted through homology modeling might be premature for at least the resilient and versatile zinc-finger motif.

X-linked intellectual developmental disorder with onset of neonatal heart failure: A case report and literature review.

X-linked intellectual developmental disorder is a rare X-linked genetic disease, manifested as heart disease, intellectual impairment, and developmental disorders. We report a male infant who presented with dyspnea after birth. Physical examination on admission revealed poor responsiveness, deep eye sockets, a small mandible, abnormalities of the outer ears, and reduced limb muscle tone. The child was moaning with shortness of breath and a positive three-concave sign without pulmonary rales. The heart sounds were weak with a grade 2/6 diastolic heart murmur. Echocardiography showed an enlarged heart with increased trabeculae in the left ventricular muscle wall. X-linked mental retardation syndrome type 34(MRXS34, OMIM# 300967) was diagnosed after exome sequencing showed a c.1131G > A hemizygous variant in the NONO gene. After timely therapy including respiratory support, cardiac glycosides, and diuresis, the child's condition improved and he was discharged at one month of age. A literature review showed that, to date, 22 live births with X-linked mental retardation have been reported. The NONO-related phenotype can be summarized as a neurological and cardiac developmental disorder, which may be accompanied by multisystem malformations. The present case enriches the knowledge of X-linked intellectual developmental syndromes.

Autosomal Dominant Intellectual Development Disorder-6 (MRD6) Without Seizures Linked to a De Novo Mutation in the grin2b Gene Revealed by Exome Sequencing: A Case Report of a Moroccan Child.

Autosomal dominant intellectual development disorder-6 (MRD6) arises from a grin2b gene mutation, inducing neurodevelopmental issues. The effects of MRD6 encompass cognitive disabilities, seizures, muscle tone decline, and autism-like traits. Its severity ranges from mild impairment to severe epilepsy. The disorder's rarity is emphasized by roughly 100 reported GRIN2B-related cases, spotlighting the gene's significance in brain development. We present the case of a three-year-old Moroccan boy who was referred to a neuropediatric department for a molecular diagnosis. Initial genetic testing yielded inconclusive results, and subsequent tests for Angelman syndrome and metabolic diseases showed no abnormalities. Given the complexity of the disorder, exome sequencing was employed to identify the underlying genetic cause. Exome sequencing identified a nonsense (STOP) mutation c.3912C>G (p.Tyr1304Ter) in the grin2b gene in the heterozygous state known to be present in MRD6 (Online Mendelian Inheritance in Man (OMIM) 613970). The family segregation study shows that this is a de novo variant, which is confirmed by Sanger sequencing. This variant has not been previously reported in the GnomAD database. Based on current scientific knowledge, the variant is considered pathogenic (PVS1, PS2, PM2, PP3, PP5) according to the criteria of the American College of Medical Genetics and Genomics (ACMG). The mutation in the grin2b gene (p.Tyr1304Ter) was predicted to be deleterious through bioinformatics analysis tools. This study highlights the crucial role of the grin2b gene in normal brain development and communication within the nervous system. It also sheds light on the impact of a novel genetic mutation, identified through exome sequencing, on causing an intellectual developmental disorder in a child patient from Morocco.

Facial and ocular manifestations of male patients affected by the HUWE1-related intellectual developmental disorder.

Turner-type X-linked syndromic intellectual developmental disorder (MRXST) is a rare neurodevelopmental disorder. MRXST is caused by pathogenic variants in the HUWE1 gene on chromosome Xp11.22. The HUWE1 gene encodes a ubiquitin ligase, which has downstream effects on the n-MYC protein and DLL3 Notch ligand, ultimately affecting neuronal differentiation. In addition to intellectual disability and developmental delay, other clinical features such as absent or delayed speech, skeletal abnormalities, abnormalities in hands or feet, seizures, and hypotonia have been described in case reports. Facial dysmorphic features and eye manifestations have been reported in patients with MRXST, but have not been identified as distinctive to this condition. We report two cases of individuals affected by HUWE1-Related Intellectual Developmental Disorder and present a review of literature of male patients affected by this disorder. Based on the literature review and findings in our two patients, it is our observation that patients with MRXST present with distinctive features, which include broad nasal tip, root, or prominent nose (39%), blepharophimosis (27%), epicanthic folds (25%), ear abnormalities (25%), thin upper lip (23%), and deep set eyes (23%). Furthermore, we note that oculofacial abnormalities are seen more frequently in patients with missense variants than patients with duplications in the HUWE1 gene. The findings noted in this paper may help clinicians suspect a diagnosis of MRXST when presented with these distinctive ocular and facial features.

Parental gonadossomatic mosaicism in HIVEP2-related intellectual disability and impact on genetic counseling-case report.

Intellectual development disorder, autosomal dominant 43 (MRD43) is an autosomal dominant disorder caused by heterozygous mutations in the HIVEP2 gene. In this report, we describe a case of a 4-year-old boy with global development delay, hypotonia, and dysmorphic features, in whom the finding of a heterozygous nonsense pathogenic variant in exon 5 of HIVEP2 [c.2827C>T p. (Arg943*)] through WES established a MRD43 diagnosis. Our patient's phenotype overlaps with other MRD43 descriptions in the literature. Unlike previously reported cases, where the condition was almost invariably de novo, the healthy mother in this case presented mosaicism for the pathogenic variant. Thus, the recurrence risk increased significantly from 1% to up to 50%. The description of a variant inherited for MDR43 is singular in the literature and this description highlights the importance of parental studies for accurate genetic counseling, particularly for family planning.

The Quality of Life Supports Model as a Vehicle for Implementing Rights.

The Quality of Life Supports Model (QOLSM) is emerging as a new framework that is applicable to people with disabilities in general, but specially to people with intellectual and developmental disabilities (IDD). The aim of this conceptual paper is twofold. Firstly, it aims to show the overlap between the QOLSM and the Convention on the Rights of People with Disabilities (CRPD), highlighting how the former can be used to address many of the goals and rights embedded in the latter. Secondly, the article seeks to illustrate the connection between these two frameworks and highlight the importance of acknowledging and measuring the rights of people with IDD. Therefore, we posit that the new #Rights4MeToo scale is ideal for: (a) providing accessible means and opportunities for people with IDD to identify and communicate their needs regarding their rights; (b) enhancing the supports and services that families and professionals provide to them; and (c) guiding organizations and policies to identify strengths and needs in relation to rights and quality of life. We also discuss future research needs and summarize the main findings of this article, highlighting its implications for practice and research.

Neuropsychological and behavioural profiles of students with intellectual development disorder on parents and teachers' perceptions.

BACKGROUND: Children with intellectual development disorder (IDD) have high rates of comorbid neuropsychological and behavioural problems. However, there are not many studies on this population in middle-income and low-income countries. Therefore, we aimed to investigate the prevalence of neuropsychological and behavioural problems in students with and without IDD and to assess the correlation between the responses from informants (parents and teachers) and the clinical diagnoses in Brazil. METHODS: After clinical diagnosis, 78 male and female students (7-15 years old) were divided into two groups: children with IDD (n = 39) and children without IDD (n = 39). The Child Behaviour Checklist (CBCL) and Teacher's Report Form (TRF) scales were used to track neuropsychological and behavioural problems. Calculations of prevalence ratios were performed using Poisson regression with Wald tests. The CBCL and TRF results were compared between groups with Mann-Whitney U-tests and receiver operating characteristic (ROC) analyses. The agreement between scales was assessed using the Spearman correlation test. RESULTS: Neuropsychological and behavioural problems were significantly more prevalent in students with IDD. The average amount of CBCL problems was significantly higher than that of TRF in the dimensions of thought, attention, somatic, attention deficit/hyperactivity, opposition defiant and total problems. Low-to-moderate correlations between CBCL and TRF dimensions in the IDD group were observed. ROC analyses revealed that the dimensions of internalising problems and total scores reflecting CBCL and TRF problems were the most important factors for identifying neuropsychological and behavioural problems in the IDD group. CONCLUSIONS: Students with IDD require early identification of behavioural and emotional symptoms to avoid the underdiagnoses of various mental health problems, especially those with internalising characteristics. The CBCL and TRF may assist in the early screening of these comorbidities.

Advance in Early Intervention of Intellectual Development Disorders (review) / 中国康复理论与实践

Intellectual development disorders are a group of etiologically diverse conditions originating during the developmental period characterized by significantly below average intellectual functioning and adaptive behavior. It is important to combine the personalized intervention with games and activities of daily living in community and family. Moreover, early intervention methods such as multi-sensory stimulation, activity observation training, goals-activity-motor enrichment are needed to improve their cognitive function; special education, intervention of behavioral, medicine and training of social skills, self-esteem and emotional quotient, to improve the outcome of children with intellectual development disorder.

Work-related stress and well-being of direct care workers in intellectual disability services: a scoping review of the literature.

Background: Understanding the nature of work-related stress and burnout among intellectual disability care staff is important to protect the well-being of these workers and encourage their retention in the sector. Though reviews of specific aspects of this literature have been conducted no article has sought to fully chart the range and nature of this research. Objective: This article addresses this gap by synthesizing the findings of such research with consideration to the future implications for protecting the well-being of care workers. Methods: A scoping review of the published literature was undertaken using a framework described in a previous article. Results: The findings of this review are presented thematically across six primary categories: challenging behavior; reciprocity; coping and stress; role issues; individual differences; and settings. A seventh theme, namely the positive aspects of intellectual disability care work was also identified through this process and is discussed. Conclusion: Occupational stress and strain is an internationally experienced issue in this sector. Challenging behavior and inequality in the relationships between staff and their clients, their colleagues, and their organization appear to exert a significant impact on the stress and well-being of workers in this sector. Excessive workplace demands, a low level of control, and a lack of support have been shown to be related to higher levels of stress and burnout among intellectual disability care workers.

[Intellectual developmental disability overlapping with autism spectrum disorder and attention deficit-hyperactivity disorder]. / Trastorno del desarrollo intelectual. Superposiciones con el trastorno del espectro autista y el trastorno por déficit de atención e hiperactividad.

The subject of disabilities that include cognition and adaptability will never cease to be interesting and relevant. The genetic etiology has more weight every day. The relationship with other neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) is of clinical, diagnostic and therapeutic importance. The objective was to conduct a review of intellectual development disorder and its implication with ASD and ADHD. From Hippocrates to the present the disorders that affect learning, behavior and socialization skills have been the subject of studies and have varied, above all, in the denomination as an entity and its perception from the human and social point of view. The etiology of intellectual development disorders in most cases is an enigma and genetic advances are the cornerstone to elucidate the origin of this neurodevelopmental disorder, as well as its relationship with others such as ASD and ADHD. The disorder of intellectual development, the oldest one with respect to definition, study and approach, still presents mysteries above all of etiological origin. Its relationship with other neurodevelopmental disorders such as ASD and ADHD is evident by having common areas of involvement, which may be coincident diagnoses.

Trastorno del desarrollo intelectual: Superposiciones con el trastorno del espectro autista y el trastorno por déficit de atención e hiperactividad / Intellectual developmental disability overlapping with autism spectrum disorder and attention deficit-hyperactivity disorder

Nunca dejará de ser interesante y relevante el tema de las discapacidades que abarcan la cognición y la adaptabilidad. La etiología genética tiene cada día más peso. La relación con otros trastornos del neurodesarrollo como el trastorno del espectro autista (TEA) y el trastorno por déficit de atención e hiperactividad (TDAH), es de importancia clínica, diagnóstica y terapéutica. Realizamos una revisión sobre el trastorno del desarrollo intelectual (TDI) y su implicación con el TEA y el TDAH. Desde Hipócrates hasta la actualidad los trastornos que afectan las habilidades de aprendizaje, conducta y socialización han sido sujeto de estudios y han variado sobre todo en la denominación como entidad y su percepción desde el punto de vista humano y social. La etiología del TDI en la mayoría de los casos es un enigma y los avances genéticos son la piedra angular para dilucidar el origen de este trastorno del neurodesarrollo, así como su relación con otros como el TEA y el TDAH. El trastorno del desarrollo intelectual, el más antiguo con respecto a definición, estudio y abordaje, aún presenta incógnitas sobre todo de origen etiológico. Su relación con otros trastornos del neurodesarrollo como el TEA y el TDAH es evidente por poseer áreas comunes de afectación, pudiendo ser diagnósticos coincidentes.

The subject of disabilities that include cognition and adaptability will never cease to be interesting and relevant. The genetic etiology has more weight every day. The relationship with other neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) is of clinical, diagnostic and therapeutic importance. The objective was to conduct a review of intellectual development disorder and its implication with ASD and ADHD. From Hippocrates to the present the disorders that affect learning, behavior and socialization skills have been the subject of studies and have varied, above all, in the denomination as an entity and its perception from the human and social point of view. The etiology of intellectual development disorders in most cases is an enigma and genetic advances are the cornerstone to elucidate the origin of this neurodevelopmental disorder, as well as its relationship with others such as ASD and ADHD. The disorder of intellectual development, the oldest one with respect to definition, study and approach, still presents mysteries above all of etiological origin. Its relationship with other neurodevelopmental disorders such as ASD and ADHD is evident by having common areas of involvement, which may be coincident diagnoses.

Translation and validation of the Spanish version of the Health of the Nation Outcome Scales for People with Learning Disabilities (HoNOS-LD). / Traducción y validación de la versión española de la escala Health of the Nation Outcome Scales for People with Learning Disabilities (HoNOS-LD).

INTRODUCTION: The Health of the Nation Outcome Scales for People with Learning Disabilities (HoNOS-LD) is a brief instrument that assesses functioning in people with intellectual development disorder and mental health problems/behaviour disorders. The aim of the present study was to examine the evidence on the validity of the scores based on the Spanish version of the HoNOS-LD. MATERIAL AND METHODS: The study included 111 participants that were assessed by the Spanish version of the HoNOS-LD and other questionnaires that measured different variables related to the scale. Thirty-three participants were assessed by 2 examiners, and retested 7 days later, in order to study inter-examiner reliability and test-retest reliabilities. RESULTS: Based on clinical and conceptual criteria, and on the results of the parallel analysis, a factorial solution with one factor was selected. Internal consistency was good (Omega coefficient of 0.87). Inter-examiner and test-retest reliabilities were excellent (intraclass correlation coefficients of 0.95 and 0.98, respectively). Correlations between sections of the HoNOS-LD and the related instruments showed the expected direction, and were highly significant (P<.001), and the HoNOS-LD score increased with the intensity of the support required by the participants. These results showed evidence of the validity of association with other external variables. CONCLUSIONS: The Spanish version of the HoNOS-LD is a brief, valid and reliable instrument, which will enable a routine assessment of functioning for different uses, including diagnosis and intervention.

Global oral health status of athletes with intellectual disabilities.

BACKGROUND: The aim of this study is to identify the oral health status and treatment needs of Special Olympics athletes with intellectual disabilities from 181 countries by the assessment of oral health parameters and differences between world regions. MATERIAL AND METHODS: Data were collected through interview and oral examinations within the Healthy Athletes Screening. These data were analysed with descriptive statistics of oral health parameters of athletes from Africa, Asia Pacific, East Asia, Europe/Eurasia, Latin America, Middle East North Africa (MENA) and North America. Mean differences of untreated visible dental caries, gingival signs and missing teeth were tested between regions by one-way ANOVA test and between age groups (8-11, 12-18, 19-39 and 40+) by chi-square tests for multiple comparisons with Hochberg-adjusted p value. The level of significance for all tests was set at a p value < 0.05. RESULTS: A total of 149,272 athletes with intellectual disabilities were screened. More than 80% of the athletes reported that they cleaned their mouths at least once a day. Athletes in Europe/Eurasia, Latin America, and MENA presented higher rates of signs of gingival disease than other regions. The prevalence of untreated dental caries was significantly higher in Latin America and the group of 8-11-year-olds from Latin America, Europe/Eurasia and Asia Pacific. CONCLUSIONS: The data provided by this study demonstrate that continuous efforts for preventive and restorative oral health care are needed for the oral health of these athletes with ID especially in Latin America, MENA and Europe/Eurasia regions.

Función ejecutiva y entrenamiento computarizado en niños de 7 a 12 años con discapacidad intelectual / Executive function and computer-based training in children aged 7-12 with intellectual disability

Se presenta un estudio comparativo de la función ejecutiva (componentes de planeación y flexibilidad), por medio de un programa de entrenamiento cognitivo computarizado aplicado a niños y niñas con discapacidad intelectual. La discapacidad intelectual es una problemática mundial y local en constante crecimiento, sin embargo, son pocos los estudios encontrados en cuanto a procesos de intervención para población con discapacidad intelectual que involucran programas computarizados en relación con el funcionamiento ejecutivo y que sirvan como referente tanto para procesos de acompañamiento neuropsicológico como pedagógico. En este estudio, se empleó una muestra poblacional de 20 niños y niñas antioqueños (colombianos) con diagnóstico de discapacidad intelectual, entre los 7 y 12 años de edad, divididos en grupo caso (10) y grupo control (10). El estudio empleó un diseño pretest-postest; el grupo caso tuvo un proceso de entrenamiento con el programa computarizado Lumosity durante 15 sesiones, 3 veces por semana, con una intensidad de 40 minutos cada una, 20 minutos para flexibilidad y 20 minutos para planeación, como componentes de la función ejecutiva. Al comparar estos componentes de la función ejecutiva (antes y después del proceso), tanto en el grupo caso como en el grupo control, se encuentran resultados significativos que demuestran la generación de cambio en los componentes de planeación y flexibilidad en esta población; asimismo, se logra validar la efectividad del programa de entrenamiento cognitivo computarizado

A comparative study of executive function (planning and flexibility components) presented by a computerized cognitive training program applied to children with intellectual disabilities. Few studies found on intervention in population with intellectual disabilities involving computer programs about executive functioning, and focused on neuropsychological processes as educational support. In this study, a population sample of 20 boys and girls in Antioquia (Colombia) diagnosed with intellectual disabilities, between 7 and 12 years of age, divided into an experimental group (10) and a control group (10) was used. The study used a pretest-posttest design; the case group had a training process with the computer software Lumosity for 15 sessions, 3 times a week, with an intensity of 40 minutes each (20 for flexibility and 20 for planning) as components of executive function. Comparing these components of executive function (before and after the process), in the case group and the control group are significant results that demonstrate the generation change in the components of planning and flexibility in this population; It is also possible to validate the effectiveness of computerized cognitive training programs.