Acrofrontofacionasal Dysostosis type 1 (AFFND1) is an extremely rare, autosomal recessive syndrome, comprising facial and skeletal abnormalities, short stature and intellectual disability. We ...analyzed an Indian family with two affected siblings by exome sequencing and identified a novel homozygous truncating mutation in the Neuroblastoma-Amplified Sequence (NBAS) gene in the patients' genome. Mutations in the NBAS gene have recently been associated with different phenotypes mainly involving skeletal formation, liver and cognitive development. The NBAS protein has been implicated in two key cellular processes, namely the non-sense mediated decay and the Golgi-to-Endoplasmic Reticulum retrograde traffic. Both functions were impaired in HEK293T cells overexpressing the truncated NBAS protein, as assessed by Real-Time PCR, Western blot analysis, co-immunoprecipitation, and immunofluorescence analysis. We examined the expression of NBAS protein in mouse embryos at various developmental stages by immunohistochemistry, and detected expression in developing chondrogenic and osteogenic structures of the skeleton as well as in the cortex, hippocampus and cerebellum, which is compatible with a role in bone and brain development. Functional genetics in the zebrafish model showed that depletion of endogenous z-nbas in fish embryos results in defective morphogenesis of chondrogenic cranial skeletal elements. Overall, our data point to a conserved function of NBAS in skeletal morphogenesis during development, support the hypothesis of a causative role of the mutated NBAS gene in the pathogenesis of AFFND1 and extend the spectrum of phenotypes associated with defects in this gene.
•AFFND1 is a very rare syndrome with skeletal abnormalities and intellectual disability likely due to a developmental defect•In two AFFND1 Indian siblings we found a novel homozygous mutation in the NBAS gene•In overexpression studies the putative mutant NBAS protein had impaired function in NMD pathway and Golgi-to-ER transport•NBAS is expressed in mouse embryos in diverse skeletal compartments which are affected by the disease in patients•NBAS knockdown in zebrafish embryos causes abnormal skeletal phenotypes and altered gene expression•Overall, these data are in agreement with a role of NBAS mutation in AFFND1 pathogenesis in this family
BackgroundPeople with disabilities (PWDs) are often excluded from biomedical research, but comprehensive data regarding their participation in clinical trials are not available. The objective of this ...study was to assess the rates of exclusion of PWDs from recent medical scientific research.MethodsThe protocol of the study was designed according to PRISMA-ScR (PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) extension for Scoping Reviews) guidelines. All completed interventional clinical trials registered on ClinicalTrials.gov between 2010 and 2020 regarding the 10 leading causes of global disability-adjusted life-years according to the Global Burden of Disease Study were analysed. An exclusion criterion from the study was considered explicit if it could be associated with one of the following seven categories: disability, physical impairment, cognitive impairment, behavioural or psychiatric disorders, language and communication impairment, sensory impairment. Comorbidities not more clearly defined and researcher discretion regarding exclusion of study participants were considered to be ‘implicit exclusion criteria’. We assessed the appropriateness of explicit exclusion criteria in relation to the primary objectives of the trials and labelled them as ‘absolute’, ‘relative’ or ‘questionable’.ResultsThe total number of trials analysed was 2710; 170 were paediatric trials (6.3%), 2374 were adult trials (87.6%) and 166 were trials including subjects of all ages (6.1%). Explicit exclusion criteria were found in 958 trials (35.3%). The disability category most frequently excluded was behavioural or psychiatric disorders, present in 588 trials (61.4%). In only 3% and 1% of the trials, the exclusion criteria were considered either ‘absolute’ or ‘questionable’, while in 96% the exclusion criteria were judged as ‘relative’. Implicit exclusion criteria were present in 1205 trials (44.5%).ConclusionsThis study highlights the high rate of exclusion of PWDs from biomedical research and the widespread use of ill-defined exclusion criteria in clinical trials. It underscores the importance of more inclusive study designs so that PWDs can become active participants in research.
Schilbach-Rott syndrome (SRS, OMIM%164220) is a disorder of unknown aetiology that is characterised by hypotelorism, epichantal folds, cleft palate, dysmorphic face, hypospadia in males and mild ...mental retardation in some patients. To date, 5 families and 17 patients have exhibited this phenotype, and recurrence in two of these families suggests an autosomal dominant inheritance. SRS overlaps with a mild form of holoprosencephaly (HPE), but array-CGH analysis and sequencing of some HPE-related genes (SEPT9, SHH and TWIST) did not reveal any variants in at least one family. Herein, we investigated by array-CGH analysis a 11-year-old female patient and her father, both exhibiting the typical SRS phenotype, disclosing in the daughter-father couple the same microduplication of chromosome 9q22.32q22.33 arrhg199q22.32(98,049,611_98,049,636)x3,9q22.33 (99,301,483_99,301,508)x3, involving eight genes, including PTCH1. The duplication segregated with the disease, since it was not found in the healthy paternal grandparents of the proband. The gain-of-function variants of the PTCH1 gene are responsible for a mild form of HPE. This is the first genetic variant found in SRS. This finding reinforces the hypothesis that SRS belongs to the HPE clinical spectrum and suggests to perform array-CGH in patients with SRS phenotype and, if negative, to consider a potential benefit from sequencing of HPE-related genes.
•Minimum adaptive skills are necessary for the expression of challenging behaviors.•Adaptive and challenging behaviors are related in severe and profound ID.•Challenging behaviors are related with ...more restrictive settings.
Previous studies have reported an inverse relationship between adaptive behavior and challenging behaviors in individuals with ID. However, it is unclear which characteristics might influence this relationship in individuals with ID and co-occurring conditions. We found a positive correlation between adaptive behavior (Vineland-II) and challenging behaviors (Nisonger Child Behavior Rating Form) in a study of 105 individuals who presented with mostly severe to profound ID and comorbid physical and mental health conditions. These results might be the consequence of the individual participant characteristics. Therefore, participants were separated out into two groups representing the top (n = 24) and bottom quartiles (n = 28) for presence of challenging behaviors. The participants with the highest levels of challenging behaviors had higher levels of adaptive behavior, higher frequency of intermittent explosive/conduct disorder, but lower frequency of epilepsy and cerebral palsy. All participants with the highest levels of challenging behaviors lived in an institutional setting; whereas, those with the lowest level of challenging behaviors lived in either an institutional setting or with their family. In participants with severe/profound ID and multiple co-occurring disorders, a minimum level of adaptive behavior seems to be necessary for the expression of challenging behaviors.
Aims
Bladder and bowel dysfunction (BBD) have been recognized in children affected by autism spectrum disorder (ASD), but no consistent information exist in adults with the condition. We evaluated ...the prevalence of BBD and the impact of psychiatric and behavioural profiles in adults affected by ASD.
Methods
Twenty‐two adults and 13 children/teens with ASD and a matched group of typically developing subjects (TD) were prospectively studied. Patients and TD subjects underwent the evaluation of urinary incontinence (UI: diurnal, continuous or intermittent), nocturnal enuresis (NE), and bowel disturbances with the 3‐day voiding and bowel diary. In addition, assessment of intellectual disability (ID) and psychiatric and adaptive behaviours with the Neuropsychiatric Inventory Scale (NPI) and the Vineland Adaptive Behaviour Scale 2nd Edition (Vineland‐II), was performed.
Results
In adults, any type of incontinence was observed in 81.8% of cases, and NE and intermittent UI in 59.0% and 36.3% of patients, respectively. Faecal incontinence and constipation were detected 36.3% and in 68.1% of cases, respectively. ID was severe in 2 cases and profound in 18; NPI and Vineland‐II items most affected were “Irritability/Lability,” “Motor Activity,” and “Agitation,” and IQ‐Socialization and IQ‐Communication. Significant relationships were identified between intermittent UI and greater ID (P < .02) and high “anxiety” (P < .05), and between NE and high “euphoria/elevated mood” (P < .05). These results were similar to those observed in children/teens.
Conclusions
Adults with ASD, and greater ID and mood disorders, present with a high prevalence of BBD. A shared pathogenetic mechanism could underlie the co‐occurrence of ASD, mood disorders, and BBD.
Numerous international educational institutions have sounded the alarm about the gradual increase in the number of students failing to achieve a sufficient level of proficiency in mathematical ...abilities. Thus, the growing interest in identifying possible solutions and factors interfering with learning seems justified. In recent years, special attention has accrued to the possible role played by emotional factors.
In the present investigation, students in the first grade of a technical vocational secondary school are followed to assess the influence of math anxiety (MA) on the development of skill acquisition in calculus. A math skills assessment test is administered on two occasions, at the beginning and end of the school year.
Results highlighted that the score on the anxiety scale, administered at the beginning of the year, negatively correlated with the score obtained on the mathematics test, administered at the end of the school year: the higher the level of anxiety, the worse the performance. Furthermore, the score obtained in the second administration makes it possible to divide the students tested into two groups: students who improved their performance and students who did not benefit at all from repeating the test. In these two groups, an analysis of the relationships between the outcome of the end-of-year mathematics test and the level of MA at the beginning of the year showed that MA correlates negatively with performance only in students who will fail to acquire new expertise in mathematics over the course of the school year.
The results suggest that MA may interfere with the smooth development of math skills. Assessing the level of MA at the beginning of the school year could prove to be a useful tool in identifying which and how many students are at risk of failing to achieve the skills expected from the usual course of instruction. A consideration of anxiety as one of the variables at play in the genesis of learning difficulties may prompt educators to modify teaching methodology and strategies by increasing focus on the impact of the emotional dimension on learning.
Background: Vesico- sphincter and bowel dysfunction have been frequently detected in Autism spectrum disorder (ASD)
patients, but to date no consistent information exist on adults affected by the ...disease. We evaluated the prevalence and types of
bladder and bowel disfunction (BBD) in young and adult patients affected by ASD.
Subjects and methods: Twenty- seven adults and 20 children/teens with ASD and a matched group of typically developing
subjects were enrolled. Daily pads use and episodes of urinary incontinence (UI) were recorded in a 3- day voiding diary. Patients
underwent also the measurement of post-void urinary residual volume and 3- day bowel diary. In addition, type and duration of the
pharmacological agents assumed by the patients were accurately recorded.
Results: Any type of UI was observed in 85.1% of adults and in 90% of children/teens. In adults, nocturnal enuresis (NE, 62.9%)
and diurnal intermittent UI (37%) were the most frequently observed bladder dysfunction while in children/ teens were NE (75%)
and diurnal continuous UI (40%). In all patients was demonstrated a significant relationship between urinary symptoms and
pharmacological agents, particularly NE and clotiapine (p<0.004) and periciazine (p<0.008).
Conclusions: Young and adult patients with ASD present with a high prevalence of BBD and concomitant antipsychotic
medications could to play a contribution in induction and/or maintaining of BBD.
Background: The Nisonger Child Behavior Rating Form (NCBRF) allows for the assessment of frequency and severity of challenging behaviours of individuals with ID with one combined rating. However, ...frequency and severity rating of challenging behaviours may be in disagreement. Therefore, the efficacy of frequency and severity independent ratings for each NCBRF item was investigated. Method: Professional caregivers of 105 individuals with ID completed the NCBRF with separate frequency and severity ratings and the Vineland-II. Results: Magnitudes of correlation coefficients between frequency and severity rating of each NCBRF item were mostly trivial, small, or medium. However, the differences between the magnitude of the corresponding correlation coefficients of frequency and severity rating of each NCBRF item when related to the Vineland-II adaptive behaviour dimensions were rarely statistically significantly. Conclusions: Despite the need for further comparisons with other challenging behaviour scales, the separate use of frequency and severity ratings seems to be useful.
IntroductionNumerous international educational institutions have sounded the alarm about the gradual increase in the number of students failing to achieve a sufficient level of proficiency in ...mathematical abilities. Thus, the growing interest in identifying possible solutions and factors interfering with learning seems justified. In recent years, special attention has accrued to the possible role played by emotional factors.MethodsIn the present investigation, students in the first grade of a technical vocational secondary school are followed to assess the influence of math anxiety (MA) on the development of skill acquisition in calculus. A math skills assessment test is administered on two occasions, at the beginning and end of the school year.ResultsResults highlighted that the score on the anxiety scale, administered at the beginning of the year, negatively correlated with the score obtained on the mathematics test, administered at the end of the school year: the higher the level of anxiety, the worse the performance. Furthermore, the score obtained in the second administration makes it possible to divide the students tested into two groups: students who improved their performance and students who did not benefit at all from repeating the test. In these two groups, an analysis of the relationships between the outcome of the end-of-year mathematics test and the level of MA at the beginning of the year showed that MA correlates negatively with performance only in students who will fail to acquire new expertise in mathematics over the course of the school year.DiscussionThe results suggest that MA may interfere with the smooth development of math skills. Assessing the level of MA at the beginning of the school year could prove to be a useful tool in identifying which and how many students are at risk of failing to achieve the skills expected from the usual course of instruction. A consideration of anxiety as one of the variables at play in the genesis of learning difficulties may prompt educators to modify teaching methodology and strategies by increasing focus on the impact of the emotional dimension on learning.
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