Serafino Buono

Disruptive CHD8 mutations define a subtype of autism early in development.

Autism spectrum disorder (ASD) is a heterogeneous disease in which efforts to define subtypes behaviorally have met with limited success. Hypothesizing that genetically based subtype identification may prove more productive, we resequenced the ASD-associated gene CHD8 in 3,730 children with developmental delay or ASD. We identified a total of 15 independent mutations; no truncating events were identified in 8,792 controls, including 2,289 unaffected siblings. In addition to a high likelihood of an ASD diagnosis among patients bearing CHD8 mutations, characteristics enriched in this group included macrocephaly, distinct faces, and gastrointestinal complaints. chd8 disruption in zebrafish recapitulates features of the human phenotype, including increased head size as a result of expansion of the forebrain/midbrain and impairment of gastrointestinal motility due to a reduction in postmitotic enteric neurons. Our findings indicate that CHD8 disruptions define a distinct ASD subtype and reveal unexpected comorbidities between brain development and enteric innervation.

Refining analyses of copy number variation identifies specific genes associated with developmental delay

Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity.

Behavioral phenotypes of genetic syndromes with intellectual disability: Comparison of adaptive profiles

The study of distinctive and consistent behaviors in the most common genetic syndromes with intellectual disability is useful to explain abnormalities or associated psychiatric disorders. The behavioral phenotypes revealed outcomes totally or partially specific for each syndrome. The aim of our study was to compare similarities and differences in the adaptive profiles of the five most frequent genetic syndromes, i.e. Down syndrome, Williams syndrome, Angelman syndrome, Prader-Willi syndrome, and Fragile-X syndrome (fully mutated), taking into account the relation with chronological age and the overall IQ level. The research was carried out using the Vineland Adaptive Behavior Scale (beside the Wechsler Intelligence scales to obtain IQ) with a sample of 181 persons (107 males and 74 females) showing genetic syndromes and mental retardation. Syndrome-based groups were matched for chronological age and mental age (excluding the Angelman group, presenting with severe mental retardation). Similarities and differences in the adaptive profiles are described, relating them to IQs and maladaptive behaviors. The results might be useful in obtaining a global index of adjustment for the assessment of intellectual disability level as well as for educational guidance and rehabilitative plans.

Relationships between visual-motor and cognitive abilities in intellectual disabilities.

The neurobiological hypothesis supports the relevance of studying visual-perceptual and visual-motor skills in relation to cognitive abilities in intellectual disabilities because the defective intellectual functioning in intellectual disabilities is not restricted to higher cognitive functions but also to more basic functions. The sample was 102 children 6 to 16 years old and with different severities of intellectual disabilities. Children were administered the Wechsler Intelligence Scale for Children, the Bender Visual Motor Gestalt Test, and the Developmental Test of Visual Perception, and data were also analysed according to the presence or absence of organic anomalies, which are etiologically relevant for mental disabilities. Children with intellectual disabilities had deficits in perceptual organisation which correlated with the severity of intellectual disabilities. Higher correlations between the spatial subtests of the Developmental Test of Visual Perception and the Performance subtests of the Wechsler Intelligence Scale for Children suggested that the spatial skills and cognitive performance may have a similar basis in information processing. Need to differentiate protocols for rehabilitation and intervention for recovery of perceptual abilities from general programs of cognitive stimulations is suggested.

The P15 - a multinational assessment battery for collecting data on health indicators relevant to adults with intellectual disabilities.

BACKGROUND Health disparities between adults with intellectual disabilities (ID) and the general population have been well documented but, to date, no dedicated assessment battery for measuring health disparity has been available. This paper reports on the development and testing of a multinational assessment battery for collecting data on a range of health indicators relevant to adults with ID. METHODS An assessment battery (the P15) was developed following piloting, and administered to samples of adults with ID, in 14 EU countries. Samples were neither random, nor representative of the countries from which they were drawn. However, within the local health administration areas selected in each country, efforts were made to ensure samples were broadly representative of the typical living circumstances, ages and ability levels of the administrative population of adults with ID. The total sample comprised 1269 adults with ID, of whom 49% were female. The mean age was 41 years (range 19 to 90). RESULTS Overall, feasibility, internal consistency and face validity of the P15 was acceptable. CONCLUSIONS With some refinement the P15 could be useful for collecting data on health indicators known to be particularly important for adults with ID. It is useable in a range of countries and has the potential to highlight health inequity for adults with ID at a national or local level. Larger scale epidemiological studies are needed to exploit the potential of the P15 to address health inequity in this group.

Schizophrenia in a patient with subtelomeric duplication of chromosome 22q

To the Editor: Schizophrenia is a common and severe psychiatric condition. To date, only a few genes have been involved as risk factors (1). Chromosomal rearrangements associated with this disorder are a valuable resource (2). Here, we report on a girl with schizophrenia showing a 22q13.3-qter duplication, without any familial neuropsychiatric disease, documented by a three-generation family history. We were not able to establish a de novo origin of the duplication because the father and his parents were dead at the time of ascertainment. Developmental milestones were reached within normal range. Menarche (13 years) was the time of onset of initial behavioural problems (agitation, social closure and passivity), followed at the age of 15 years by auditory hallucinations, loss of self-control, dysfunction of self-awareness with temporary amnesia, disorientation, aggressive acting out and sleep disturbances. At the present age of 20 years, psychometric testing with Wechsler Adult Intelligence Scale-Revised shows a global intelligence quotient (IQ) of 73, a verbal IQ of 71 and a performance IQ of 80, whereas the score is 86 at Standard Progressive Matrices. The girl presents also with psychomotor restlessness and attention deficit. Ideation is severely impaired and speech is incoherent. Marked irritability, sexually related problems, unstable temper, and aggressive reaction to disappointment are also evident. General affectivity is compromised. Difficulties in accepting and following the rules in different social contexts highlight the adaptive area. Apathy and poor personal hygiene complete the clinical picture, which satisfies the Diagnostic statistical manual, 4th Ed., Text Revised (DSM IV-TR) (3) diagnostic criteria for borderline intellectual functioning and disorganized schizophrenia. The phenotype is also characterized by muscular hypotonia, microbrachycephaly (present also in the mother), hypertelorism, moderate myopia, downslanting palpebral fissures, deviation of the nasal septum, helix hyperplasia, thick lips, retrognathia, hypothenar eminence hypoplasia, scoliosis, splayfoot with valgus hallux, and joint hyperlaxity. The brain computerized tomography scan is normal. The electroencephalogram shows low-voltage sharp-wave complexes on the posterior areas of both hemispheres. A normal 46, XX karyotype from peripheral blood lymphocytes followed by a Multiprobe FISH Assay (Chromoprobe Multiprobe-T SystemCytocell Ltd, Oxford, UK) disclosed a third 22qter signal on the p arm of chromosome 22, not present in the clinically normal mother. Segregation pattern of the informative D22S1170 microsatellite revealed in our patient one maternal and two paternal alleles. The extent of the rearrangement was then assessed by array CGH assay using Human Genome CGH Microarray Kit 44B (Agilent Technologies, Palo Alto, CA), which showed a terminal 5.4 Mb duplication (Fig. 1). Among the 21 patients with terminal 22q duplications recently reviewed (4), only two (patients 2 and 3, respectively, father and son) have a duplication size comparable with that of our patient. Interestingly, this is the smallest duplication so far reported, and the patients show minor learning disabilities, psychiatric difficulties since early childhood and mild mental retardation’. The more severe degree of mental retardation, found in larger duplications, hampers the diagnosis of schizophrenia. Linkage findings for schizophrenia have been reported on chromosome 22q13 (5, 6), suggesting that one or more genes in this region could confer susceptibility to this psychiatric disorder. Among the several genes mapping there, we want to draw the attention on two of them: SHANK3 and WNT7B. The gene SHANK3 (7–9) codes for a scaffolding protein of the post-synaptic density of excitatory synapses in the mammalian brain, and its expression increases during post-natal development especially in the cerebellum and thalamus. WNT7B belongs to Wingless (Wnt) family members, secreted glycoproteins, which are intracellular signalling molecules both during neural development and in the mature nervous system (10). The Wnt signalling pathway has

An inflammatory and trophic disconnect biomarker profile revealed in Down syndrome plasma: Relation to cognitive decline and longitudinal evaluation

Given that Alzheimers pathology develops silently over decades in Down syndrome (DS), prognostic biomarkers of dementia are a major need.

Robots in education and care of children with developmental disabilities : a study on acceptance by experienced and future professionals

Research in the area of robotics has made available numerous possibilities for further innovation in the education of children, especially in the rehabilitation of those with learning difficulties and/or intellectual disabilities. Despite the scientific evidence, there is still a strong scepticism against the use of robots in the fields of education and care of people. Here we present a study on the acceptance of robots by experienced practitioners (specialized in the treatment of intellectual disabilities) and university students in psychology and education sciences (as future professionals). The aim is to examine the factors, through the Unified Theory of Acceptance and Use of Technology (UTAUT) model, that may influence the decision to use a robot as an instrument in the practice. The overall results confirm the applicability of the model in the context of education and care of children, and suggest a positive attitude towards the use of the robot. The comparison highlights some scepticism among the practitioners, who perceive the robot as an expensive and limited tool, while students show a positive perception and a significantly higher willingness to use the robot. From this experience, we formulate the hypothesis that robots may be accepted if more integrated with standard rehabilitation protocols in a way that benefits can outweigh the costs.

Self-injury in people with intellectual disability and epilepsy: A matched controlled study

We aimed to identify the presence of self-injurious behavior in a sample of 158 people with intellectual disability and epilepsy as compared with a control sample consisting of 195 people with intellectual disability without epilepsy. The Italian Scale for the Assessment of self-injurious behaviors was used to describe self-injurious behavior in both groups. The groups were matched for ID degree: mild/moderate (20 and 20 respectively), severe/profound (45 in both samples) and unknown (4 in both samples). Seventy-four percent of the first sample were diagnosed with symptomatic partial epilepsy. The prevalence of self-injurious behaviors was 44% in the group with intellectual disability and epilepsy and 46.5% in the group with intellectual disability without epilepsy (difference not significant). The areas most affected by self-injurious behaviors in both samples were the hands, the mouth and the head. The most frequent types of self-injurious behaviors were self-biting, self-hitting with hands and with objects. Self-injurious behavior is frequently observed in individuals with epilepsy and intellectual disability. Our study does not suggest that the presence of epilepsy is a risk factor for self-injurious behavior in this patient group.

3q29 microdeletion syndrome: Cognitive and behavioral phenotype in four patients

The 3q29 microdeletion syndrome is a rare, recurrent genomic disorder, associated with a variable phenotype, despite the same deletion size, consisting in neurodevelopmental features, such as intellectual disability (ID), schizophrenia, autism, bipolar disorder, depression and mild facial morphological anomalies/congenital malformations. A thorough neuropsychiatric evaluation has never been reported in patients with such syndrome. We analyzed the clinical phenotype of four individuals with 3q29 microdeletion syndrome, with special emphasis on the cognitive and behavioral assessment, in order to delineate the neuropsychiatric phenotype related to this condition. We assessed these patients with standardized scales or checklists measuring the cognitive (WISC III or LIPS‐R), behavioral (CBCL) and adaptive (VABS) performances. An accurate evaluation in our sample highlights different degrees of ID, variable behavioral disorders, and a preservation of communicative skills among remaining adaptive areas, as the neuropsychiatric hallmark of 3q29 microdeletion syndrome.