Intervenção precoce e perturbação do espetro do autismo : necessidades e prioridades das famílias de crianças dos 3-6 anos de idade

Tendo em consideração a importância da identificação das necessidades das famílias para organizar os recursos e os apoios no âmbito da intervenção centrada na família (Dunst, Trivette & Deal, 1994), o presente estudo tem como objetivos identificar e diferenciar as necessidades e prioridades das famílias de crianças com PEA apoiadas pela Intervenção Precoce. A amostra era constituída por 123 casais e respetivos filhos (116 do género masculino e 17 do género feminino) com PEA, PRC ou Síndrome de Asperger, e idades compreendidas entre os 3 e os 6 anos. As famílias eram oriundas de quatro zonas diferentes de Portugal. Foi utilizado o Inventário sobre as Necessidades e Prioridades da Família, a partir do qual nos foi possível verificar que existem diferenças entre as necessidades das famílias quanto às necessidades referentes à criança e quanto às referentes aos recursos existentes na comunidade. Também foram encontradas diferenças quando se compararam os pais e as mães, com estas a manifestarem maiores necessidades, e quando se compararam idades dos pais, com os mais novos a manifestarem maiores dificuldades. No que se refere à comparação entre níveis socioeconómicos e entre regiões geográficas de residência, os resultados não são tão conclusivos. O inventário parece, assim, ser adequado para identificar as necessidades e prioridades das famílias de crianças com PEA, facilitando a organização dos recursos e dos apoios.

Psicomotricidade e intervenção precoce no Centro de Desenvolvimento da Criança Torrado da Silva do Hospital Garcia da Orta

Nota: Os anexos referidos no índice do trabalho não foram fornecidos.

A higher mutational burden in females supports a "female protective model" in neurodevelopmental disorders.

Increased male prevalence has been repeatedly reported in several neurodevelopmental disorders (NDs), leading to the concept of a "female protective model." We investigated the molecular basis of this sex-based difference in liability and demonstrated an excess of deleterious autosomal copy-number variants (CNVs) in females compared to males (odds ratio [OR] = 1.46, p = 8 × 10(-10)) in a cohort of 15,585 probands ascertained for NDs. In an independent autism spectrum disorder (ASD) cohort of 762 families, we found a 3-fold increase in deleterious autosomal CNVs (p = 7 × 10(-4)) and an excess of private deleterious single-nucleotide variants (SNVs) in female compared to male probands (OR = 1.34, p = 0.03). We also showed that the deleteriousness of autosomal SNVs was significantly higher in female probands (p = 0.0006). A similar bias was observed in parents of probands ascertained for NDs. Deleterious CNVs (>400 kb) were maternally inherited more often (up to 64%, p = 10(-15)) than small CNVs < 400 kb (OR = 1.45, p = 0.0003). In the ASD cohort, increased maternal transmission was also observed for deleterious CNVs and SNVs. Although ASD females showed higher mutational burden and lower cognition, the excess mutational burden remained, even after adjustment for those cognitive differences. These results strongly suggest that females have an increased etiological burden unlinked to rare deleterious variants on the X chromosome. Carefully phenotyped and genotyped cohorts will be required for identifying the symptoms, which show gender-specific liability to mutational burden.

A 600 kb deletion syndrome at 16p11.2 leads to energy imbalance and neuropsychiatric disorders.

BACKGROUND: The recurrent ~600 kb 16p11.2 BP4-BP5 deletion is among the most frequent known genetic aetiologies of autism spectrum disorder (ASD) and related neurodevelopmental disorders. OBJECTIVE: To define the medical, neuropsychological, and behavioural phenotypes in carriers of this deletion. METHODS: We collected clinical data on 285 deletion carriers and performed detailed evaluations on 72 carriers and 68 intrafamilial non-carrier controls. RESULTS: When compared to intrafamilial controls, full scale intelligence quotient (FSIQ) is two standard deviations lower in carriers, and there is no difference between carriers referred for neurodevelopmental disorders and carriers identified through cascade family testing. Verbal IQ (mean 74) is lower than non-verbal IQ (mean 83) and a majority of carriers require speech therapy. Over 80% of individuals exhibit psychiatric disorders including ASD, which is present in 15% of the paediatric carriers. Increase in head circumference (HC) during infancy is similar to the HC and brain growth patterns observed in idiopathic ASD. Obesity, a major comorbidity present in 50% of the carriers by the age of 7 years, does not correlate with FSIQ or any behavioural trait. Seizures are present in 24% of carriers and occur independently of other symptoms. Malformations are infrequently found, confirming only a few of the previously reported associations. CONCLUSIONS: The 16p11.2 deletion impacts in a quantitative and independent manner FSIQ, behaviour and body mass index, possibly through direct influences on neural circuitry. Although non-specific, these features are clinically significant and reproducible. Lastly, this study demonstrates the necessity of studying large patient cohorts ascertained through multiple methods to characterise the clinical consequences of rare variants involved in common diseases.

El treball amb alumnat TEA : el treball de les habilitats socials i les emocions

En el marc d'una escola inclusiva, es busca promoure l'aprenentatge de tots els alumnes. L'alumnat amb Trastorn de l'Espectre Autista (TEA) forma part de la diversitat que ha d'atendre el professorat, un alumnat que presenta dificultats d'interacció social i de comprensió dels estats mentals dels altres, aspectes que influeixen en la seva qualitat de vida. D'aquesta manera, es presenta una intervenció que busca afavorir el desenvolupament de les capacitats relacionals, comunicatives i simbòliques dels alumnes TEA. La intervenció té en compte l'enfocament interactiu i contextual del procés de valoració proposat per Ángel Rivière (2001), la Teoria de la Ment desenvolupada per Baron-Cohen, Leslie i Firth el 1985 i el programa DIR o Floortime d'Stanley Greenspan. A més, s'han elaborat una sèrie de materials i activitats per a l'ensenyament de la comprensió de les emocions i de les habilitats socials, basades en les aportacions de Howling, Baron-Cohen i Hadwin (2006) i les historietes socials de Gray.

Molecular and clinical characterization of 25 individuals with exonic deletions of NRXN1 and comprehensive review of the literature.

This study aimed to elucidate the observed variable phenotypic expressivity associated with NRXN1 (Neurexin 1) haploinsufficiency by analyses of the largest cohort of patients with NRXN1 exonic deletions described to date and by comprehensively reviewing all comparable copy number variants in all disease cohorts that have been published in the peer reviewed literature (30 separate papers in all). Assessment of the clinical details in 25 previously undescribed individuals with NRXN1 exonic deletions demonstrated recurrent phenotypic features consisting of moderate to severe intellectual disability (91%), severe language delay (81%), autism spectrum disorder (65%), seizures (43%), and hypotonia (38%). These showed considerable overlap with previously reported NRXN1-deletion associated phenotypes in terms of both spectrum and frequency. However, we did not find evidence for an association between deletions involving the β-isoform of neurexin-1 and increased head size, as was recently published in four cases with a deletion involving the C-terminus of NRXN1. We identified additional rare copy number variants in 20% of cases. This study supports a pathogenic role for heterozygous exonic deletions of NRXN1 in neurodevelopmental disorders. The additional rare copy number variants identified may act as possible phenotypic modifiers as suggested in a recent digenic model of neurodevelopmental disorders. © 2013 Wiley Periodicals, Inc.

Entrenament en atenció : Treball amb alumnat amb NEE

The purpose of this project was to analyze theattention span of students with mental retardation with Autism Spectrum Disorder (Asperger Syndrome) and with mild intellectual disabilities and behavioral disorders of an USEE class in a secondary school.

Investigating Gaze of Children with ASD in Naturalistic Settings.

BACKGROUND: Visual behavior is known to be atypical in Autism Spectrum Disorders (ASD). Monitor-based eye-tracking studies have measured several of these atypicalities in individuals with Autism. While atypical behaviors are known to be accentuated during natural interactions, few studies have been made on gaze behavior in natural interactions. In this study we focused on i) whether the findings done in laboratory settings are also visible in a naturalistic interaction; ii) whether new atypical elements appear when studying visual behavior across the whole field of view. METHODOLOGY/PRINCIPAL FINDINGS: Ten children with ASD and ten typically developing children participated in a dyadic interaction with an experimenter administering items from the Early Social Communication Scale (ESCS). The children wore a novel head-mounted eye-tracker, measuring gaze direction and presence of faces across the child's field of view. The analysis of gaze episodes to faces revealed that children with ASD looked significantly less and for shorter lapses of time at the experimenter. The analysis of gaze patterns across the child's field of view revealed that children with ASD looked downwards and made more extensive use of their lateral field of view when exploring the environment. CONCLUSIONS/SIGNIFICANCE: The data gathered in naturalistic settings confirm findings previously obtained only in monitor-based studies. Moreover, the study allowed to observe a generalized strategy of lateral gaze in children with ASD when they were looking at the objects in their environment.

What animals can teach clinicians about the hippocampus

Abnormalities in hippocampal structure and function have been reported in a number of human neuropathological and neurodevelopmental disorders, including Alzheimer's disease, autism spectrum disorders, Down syndrome, epilepsy, and schizophrenia. Given the complexity of these disorders, animal studies are invaluable and remain to date irreplaceable, providing fundamental knowledge regarding the basic mechanisms underlying normal and pathological human brain structure and function. However, there is a prominent ill-conceived view in current research that scientists should be restricted to using animal models of human diseases that can lead to results applicable to humans within a few years. Although there is no doubt that translational studies of this kind are important and necessary, limiting animal studies to applicable questions is counterproductive and will ultimately lead to a lack of knowledge and an inability to address human health problems. Here, we discuss findings regarding the normal postnatal development of the monkey hippocampal formation, which provide an essential framework to consider the etiologies of different neuropathological disorders affecting human hippocampal structure and function. We focus on studies of gene expression in distinct hippocampal regions that shed light on some basic mechanisms that might contribute to the etiology of schizophrenia. We argue that researchers, as well as clinicians, should not consider the use of animals in research only as 'animal models' of human diseases, as they will continue to need and benefit from a better understanding of the normal structure and functions of the hippocampus in 'model animals'.

AMCHP Issue Brief, February 2012

Children and youth with autism spectrum disorder and other developmental disabilities (ASD/DD) require a comprehensive array of medical, behavioral and developmental health services that are often inadequately covered under the current system of health coverage. This leaves children at risk for missed or delayed care and their families with significant financial burdens. The Patient Protection and Affordable Care Act (ACA) is designed to increase health coverage, improve benefits, and provide important new insurance protections for all Americans. Many of the law’s provisions will impact children, including those with ASD/DD, and will be implemented over time. This report, developed by The Catalyst Center at the Boston University School of Public Health, offers a brief description of selected provisions in the ACA that have implications for children with ASD/DD. It also describes how state Title V maternal and child health (MCH) programs can maximize opportunities under the ACA to develop and strengthen systems of care for children and youth with ASD/DD.

Mirada actual des de la psicoanàlisi sobre l'espectre autista : La pràctica entre varis com a alternativa terapéutica en el TEA

Aquest treball es proposa investigar sobre la intervenció psicoanalítica i clínica en el trastorn de l'espectre autista. Es tracta de fer un recorregut crític sobre l'augment de la incidència del trastorn, la discussió sobre la etiologia de la mateixa i les alternatives d'intervenció des de la pràctica entre varis que proposa el psicoanàlisi lacanià.

El paper del joc en el desenvolupament d'infants amb TEA

Jugar no és només un sinònim de diversió, sinó que darrera d’aquesta acció s’amaguen molts elements que són imprescindible per al desenvolupament infantil, ja que l’afavoreix en tots els àmbits de la seva vida. Un nen amb Necessitats Educatives Especial té el mateix dret de gaudir d’una estona de joc, i desenvolupar-­‐se com a persona. De fet, el joc és considerat una eina d’aprenentatge a l’edat infantil. Per això, el present treball de grau té com objectiu principal analitzar la importància del joc com a eina educativa amb infants amb un Trastorn de l’Espectre Autista. S’utilitza una metodologia qualitativa, i a través de l’observació, s’analitza com el joc ajuda a un infant amb Trastorn de l’Espectre Autista a adquirir determinades habilitats i capacitats que li permeten tenir certa autonomia. Els resultats obtinguts, permeten afirmar que la Unitat de Suport a l’Educació Especial utilitza el joc com un recurs didàctic per a treballar amb infants amb Autisme. Per això, es planteja una proposta d’intervenció dins d’aquesta unitat.

A Potential Contributory Role for Ciliary Dysfunction in the 16p11.2 600 kb BP4-BP5 Pathology.

The 16p11.2 600 kb copy-number variants (CNVs) are associated with mirror phenotypes on BMI, head circumference, and brain volume and represent frequent genetic lesions in autism spectrum disorders (ASDs) and schizophrenia. Here we interrogated the transcriptome of individuals carrying reciprocal 16p11.2 CNVs. Transcript perturbations correlated with clinical endophenotypes and were enriched for genes associated with ASDs, abnormalities of head size, and ciliopathies. Ciliary gene expression was also perturbed in orthologous mouse models, raising the possibility that ciliary dysfunction contributes to 16p11.2 pathologies. In support of this hypothesis, we found structural ciliary defects in the CA1 hippocampal region of 16p11.2 duplication mice. Moreover, by using an established zebrafish model, we show genetic interaction between KCTD13, a key driver of the mirrored neuroanatomical phenotypes of the 16p11.2 CNV, and ciliopathy-associated genes. Overexpression of BBS7 rescues head size and neuroanatomical defects of kctd13 morphants, whereas suppression or overexpression of CEP290 rescues phenotypes induced by KCTD13 under- or overexpression, respectively. Our data suggest that dysregulation of ciliopathy genes contributes to the clinical phenotypes of these CNVs.

New genes for focal epilepsies with speech and language disorders.

The last 2 years have seen exciting advances in the genetics of Landau-Kleffner syndrome and related disorders, encompassed within the epilepsy-aphasia spectrum (EAS). The striking finding of mutations in the N-methyl-D-aspartate (NMDA) receptor subunit gene GRIN2A as the first monogenic cause in up to 20 % of patients with EAS suggests that excitatory glutamate receptors play a key role in these disorders. Patients with GRIN2A mutations have a recognizable speech and language phenotype that may assist with diagnosis. Other molecules involved in RNA binding and cell adhesion have been implicated in EAS; copy number variations are also found. The emerging picture highlights the overlap between the genetic determinants of EAS with speech and language disorders, intellectual disability, autism spectrum disorders and more complex developmental phenotypes.

The 16p11.2 rearrangments genetic paradigms for obesity and neurodevelopmental disorders.

Recent discoveries of recurrent and reciprocal Copy Number Variants (CNVs) using genome- wide studies have led to a new understanding of the etiology of neuropsychiatric disorders. CNVs represent loss (deletion) or gain (duplication) of genomic material. This thesis work is focused on CNVs at the 16p11.2 BP4-BP5 locus, which are among the most frequent etiologies of neurodevelopmental disorders and have been associated with Autism Spectrum Disorders (ASD), schizophrenia, cognitive impairment, alterations of brain size as well as obesity and underweight. Because deletion and duplication of the 16p11.2 locus occur frequently and recurrently (with the same breakpoints), CNVs at this locus represent a powerful paradigm to understand how a genomic region may modulate cognitive and behavioral traits as well as the relationship and shared mechanisms between distinct psychiatric diagnoses such as ASD and schizophrenia. The present dissertation includes three studies: 1) The first project aims at identifying structural brain-imaging endophenotypes in 16p11.2 CNVs carriers at risk for ASD and schizophrenia. The results show that gene dosage at the 16p11.2 locus modulates global brain volumes and neural circuitry, including the reward system, language and social cognition circuits. 2) The second investigates the neuropsychological profile in 16p11.2 deletion and duplication carriers. While deletion carriers show specific deficits in language and inhibition, the profile of duplication carriers is devoid of specific weaknesses and presents enhanced performance in a verbal memory task. 3) The third study on food-related behaviors in 16p11.2 deletion and duplication carriers shows that alterations of the reponse to satiety are present in CNV carriers before the onset of obesity, pointing toward a potential mechanism driving the Body Mass Index increase in deletion carriers. Dysfunctions in the reward system and dopaminergic circuitries could represent a common mechanism playing a role in the phenotype and could be investigated in future studies. Our data strongly suggest that complex cognitive traits correlate to gene dosage in humans. Larger studies including expression data would allow elucidating the contribution of specific genes to these different gene dosage effects. In conclusion, a systematic and careful investigation of cognitive, behavioral and intermediate phenotypes using a gene dosage paradigm has allowed us to advance our understanding of the 16p11.2 BP4-BP5 locus and its effects on neurodevelopment. -- La récente découverte de variations du nombre de copies (CNVs pour 'copy number variants') dans le génome humain a amélioré nos connaissances sur l'étiologie des troubles neuropsychiatriques. Un CNV représente une perte (délétion) ou un gain (duplication) de matériel génétique sur un segment chromosomique. Ce travail de thèse est focalisé sur les CNVs réciproques (délétion et duplication) dans la région 16p11.2 BP4-BP5. Ces CNVs sont une cause fréquente de troubles neurodéveloppementaux et ont été associés à des phénotypes « en miroir » tels que obésité/sous-poids ou macro/microcéphalie mais aussi aux troubles du spectre autistique (TSA), à la schizophrénie et au retard de développement/déficience intellectuelle. La fréquence et la récurrence de la délétion et de la duplication aux mêmes points de cassure font de ces CNVs un paradigme unique pour étudier la relation entre dosage génique et les traits cognitifs et comportementaux, ainsi que les mécanismes partagés par des troubles psychiatriques apparemment distincts tels que les TSA et la schizophrénie. Ce travail de thèse comporte trois études distinctes : 1) l'étude en neuroimagerie structurelle identifie les endophénotypes chez les porteurs de la délétion ou de la duplication. Les résultats montrent une influence du dosage génique sur le volume cérébral total et certaines structures dans les systèmes de récompense, du langage et de la cognition sociale. 2) L'étude des profils neuropsychologiques chez les porteurs de la délétion ou de la duplication montre que la délétion est associée à des troubles spécifiques du langage et de l'inhibition alors que les porteurs de la duplication ne montrent pas de faiblesse spécifique mais des performances mnésiques verbales supérieures à leur niveau cognitif global. 3) L'étude sur les comportements alimentaires met en évidence une altération de la réponse à la satiété qui est présente avant l'apparition de l'obésité. Un dysfonctionnement dans le système de récompense et les circuits dopaminergiques pourrait représenter un mécanisme commun aux différents phénotypes observés chez ces individus porteurs de CNVs au locus 16p11.2. En conclusion, l'utilisation du dosage génique comme outil d'investigation des phénotypes cliniques et endophénotypes nous a permis de mieux comprendre le rôle de la région 16p11.2 BP4-BP5 dans le neurodéveloppement.