Background : Phelan–McDermid syndrome (PMS) is a neurodevelopmental disorder caused by pathogenic variants involving the SHANK3 gene, a key postsynaptic scaffolding protein regulating synaptic function. SHANK3 alterations range from sequence variants to large chromosomal deletions on chromosome 22q13. While SHANK3 haploinsufficiency alone produces core PMS features, larger deletions encompassing adjacent genes are associated with more severe motor, speech, and cognitive phenotypes, whereas smaller deletions may lead to distinct neurobehavioral profiles. Methods : We conducted a multimodal study integrating molecular genetics and neuropsychological assessment with structural MRI, voxel-based morphometry (VBM) and arterial spin labeling (ASL) perfusion imaging in 36 individuals with de novo SHANK3 variants, including 21 sequence variants and 15 deletions ranging from (68.64 kb to 8.7 Mb). Deletions were stratified into Class I (involving SHANK3 only or with ARSA , ACR , and/or RABL2B ) and Class II (all other deletions). Results : Class II deletions were strongly associated with cortico-subcortical atrophy (10/15 vs. 0/21; p = 0.00001) and corpus callosum abnormalities. The group with larger deletions (Class II) showed a distinctive anomaly of the forceps minor, characterized by marked enlargement and dysmorphism (8/8 vs 0 in other groups; p < 0.001) and severe nonverbal social communication deficits. This feature was absent in Class I deletions and sequence variants. A minimal 760 kb critical region, including CERK , TBC1D22A , CELSR1 , and GRAMD4 , was implicated in these anomalies. VBM analyses revealed widespread reductions in gray and white matter volumes in carriers of Class II deletions, predominantly in frontotemporal and parietal regions, whereas sequence variants showed no significant volume loss. ASL imaging demonstrated reduced cerebral blood flow in key regions of the social brain network, particularly within the bilateral superior temporal cortex. Limitations : Multimodal MRI without premedication remains challenging in children older than 5 years due to motion, particularly with longer acquisition times. Conclusions : The identification of a minimal overlapping deleted region encompassing multiple candidate genes supports the contribution of additional loci within 22q13 to disease expression. These findings refine genotype–phenotype correlations in PMS and provide evidence that the disorder associated with larger deletions may be regarded as a contiguous gene syndrome.

Autism spectrum disorder (ASD) is characterized by marked difficulties in social interaction, with atypical eye-gaze behavior as a core feature. Eye-tracking studies have consistently reported reduced attention to social information in ASD across a large range of paradigms, suggesting that social perception abnormalities span multiple levels of processing, from initial orienting toward socially salient stimuli to fine-grained allocation of attention to social cues. Most studies have relied on group-level comparisons, and how these levels relate at the individual level remains unclear, particularly regarding inter-individual variability and whether these processes rely on shared mechanisms across development. We collected eye-tracking data from 150 participants with ASD and typical development (TD), from 2.6 to 26.7 years old, using two paradigms: (i) a preferential looking task contrasting human motion versus geometric motion to assess social orienting, and (ii) a naturalistic paradigm with complex social scenes to measure attention to socially informative regions (eyes). Inter-individual variability was characterized using Shapiro–Wilk and Levene’s tests. Group differences and associations between paradigms were analyzed using general linear models controlling for age and sex. Individuals with ASD looked significantly less to human motion (p = 1.4 × 10⁻⁵) and to the eyes of characters (p = 4.6 × 10⁻⁴) compared to TD participants, across the full age range. Both groups exhibited substantial inter-individual variability in gaze behavior, with continuous and normally distributed patterns. A significant positive association was found between social orienting and attention to the eyes across all participants (p = 0.004), independent of age, sex, and diagnosis. These findings show that initial social orienting and later fine-grained social attention are linked at the individual level, supporting an integrated multi-level model of social perception. Preferential looking differences in ASD extend beyond early childhood, and the results reveal within-subject coherence across levels of social processing. Substantial inter-individual variability further supports a dimensional organization of social perception across development. Even though the cross-sectional design precludes conclusions about developmental trajectories and heterogeneity in cognitive and language abilities was not accounted for, together, these findings provide a framework for linking behavioral markers of social perception to underlying neurodevelopmental mechanisms.

Even though deficits in social cognition constitute a core characteristic of autism spectrum disorders, a large heterogeneity exists regarding individual social performances and its neural basis remains poorly investigated. Here, we used eye-tracking to objectively measure interindividual variability in social perception and its correlation with white matter microstructure, measured with diffusion tensor imaging MRI, in 25 children with autism spectrum disorder (8.5 ± 3.8 years). Beyond confirming deficits in social perception in participants with autism spectrum disorder compared 24 typically developing controls (10.5 ± 2.9 years), results revealed a large interindividual variability of such behavior among individuals with autism spectrum disorder. Whole-brain analysis showed in both autism spectrum disorder and typically developing groups a positive correlation between number of fixations to the eyes and fractional anisotropy values mainly in right and left superior longitudinal tracts. In children with autism spectrum disorder a correlation was also observed in right and left inferior longitudinal tracts. Importantly, a significant interaction between group and number of fixations to the eyes was observed within the anterior portion of the right inferior longitudinal fasciculus, mainly in the right anterior temporal region. This additional correlation in a supplementary region suggests the existence of a compensatory brain mechanism, which may support enhanced performance in social perception among children with autism spectrum disorder.

BackgroundIndividuals with Phelan-McDermid syndrome (PMS) present with a wide range of diagnoses: autism spectrum disorder, intellectual disability, or schizophrenia. Differences in the genetic background could explain these different neurodevelopmental trajectories. However, a more parsimonious hypothesis is to consider that they may be the same phenotypic entity. Catatonic disturbances occasionally reported from adolescence onwards in PMS prompts exploration of the hypothesis that this clinical entity may be an early-onset form of catatonia. The largest cohort of children with childhood catatonia was studied by the Wernicke-Kleist-Leonhard school (WKL school), which regards catatonia as a collection of qualitative abnormalities of psychomotricity that predominantly affecting involuntary motricity (reactive and expressive). The aim of this study was to investigate the presence of psychomotor signs in three young adults carrying a mutation or intragenic deletion of the SHANK3 gene through the prism of the WKL school conception of catatonia.MethodsThis study was designed as an exploratory case study. Current and childhood psychomotor phenomena were investigated through semi-structured interviews with the parents, direct interaction with the participants, and the study of documents reporting observations of the participants at school or by other healthcare professionals.ResultsThe findings show catatonic manifestations from childhood that evolved into a chronic form, with possible phases of sub-acute exacerbations starting from adolescence.ConclusionThe presence of catatonic symptoms from childhood associated with autistic traits leads us to consider that this singular entity fundamentally related to SHANK3 mutations could be a form of early-onset catatonia. Further case studies are needed to confirm our observations.

Next-generation sequencing techniques have accelerated the discovery of rare mutations responsible for autism spectrum disorder (ASD) in genes involved in a large number of physiological processes, including the control of gene expression, chromatin remodeling, signaling pathways, synaptic scaffolding, neurotransmitter receptors, and lipid metabolism. Genetic diagnosis provides subjects with an explanation of the cause of their disorder. However, it does not, or at least does not yet, shed light on the psychopathological phenomena specific to the individual. It could be hypothesized that each physiological impact of a mutation corresponds to a specific psychopathological phenomenon of ASD, i.e., “a psychopathological natural kind”. We discuss here the difficulties identifying this specificity of underlying psychopathology in individuals with ASD due to a rare mutation with a major effect. A comparison of Newson's pathological demand avoidance and Wing's Asperger's syndrome with Asperger's autistic psychopathy highlights different ways of approaching psychopathological descriptions and diagnosis, by focusing on either common or unusual features. Such a comparison calls into question the principles of clinical research recommended by Falret for characterizing “disease individuality” of ASD due to a rare mutation.

TEDIS, an information system dedicated to patients affected with neuro-developmental disorders including autism, focuses on patient data generated during in-depth clinical assessment in nine expert centers in Ile-de-France region. Long term partnership involving methodologists and domain experts is necessary to support quality data production and analyses and to guarantee quality data and information governance in a domain characterized by frequent evolutions in clinical assessment instruments and in diagnostic criteria and classification.

Advances in neuroimaging techniques have significantly improved our understanding of the neural basis of autism spectrum disorder (ASD). Several attempts have been made to label the main neuroimaging phenotype of ASD, mostly by anatomical and functional activation studies, but none of the frameworks have been without controversy. Over the past decade, a renewed interest for rest brain functioning has emerged in the scientific community, reflected on a large number of resting state fMRI (rs-fMRI) studies, but results remain heterogeneous. It is possible today to investigate rest brain functioning by measuring rest cerebral blood flow (CBF) with MRI using arterial spin labeling (ASL). Here, we investigated rest CBF abnormalities using non-invasive ASL-MRI in 18 children with ASD without cognitive delay (10.4 ± 2.8 y) and 30 typically developing children (10.6 ± 3.0 y). Following quality control, images from a final sample of 12 children with ASD (11.2 ± 2.9 y) and 28 typically developing children (10.1 ± 2.5 y) were analyzed. Whole brain voxel-by-voxel analysis showed significant rest CBF decrease in temporal regions, mainly in the superior temporal sulcus (STS), in children with ASD. This hypoperfusion was individually detected in 83% of children with ASD. Finally, negative correlation was observed between ASD severity scores and rest CBF in the right posterior STS. Strikingly, despite the small sample studied here, our results are extremely similar to previous PET and SPECT findings describing decreased rest CBF in the same superior temporal regions at group and individual levels, as well as correlation with symptoms severity. The congruence between these results, with different methods and in different ASD profiles, reinforce the strength of rest functional abnormalities within these superior temporal regions in ASD and strongly indicates it might be a core characteristic of the disorder. Identifying a core dysfunctional region in ASD bears direct implications to the development of novel therapeutic interventions, such as transcranial magnetic stimulation. In addition, if confirmed in a larger sample, rest temporal hypoperfusion could become a reliable brain imaging biomarker in ASD.

Pediatric catatonia is a rare and severe neuropsychiatric syndrome. We previously reported, in 58 children and adolescents with catatonia, a high prevalence (up to 20%) of medical conditions, some of which have specific treatments.1 Here we extend the cohort inclusion and report the first systematic molecular genetic data for this syndrome. Among the 89 patients consecutively admitted for catatonia (according to the pediatric catatonia rating scale)2 between 1993 and 2014, we identify 51 patients (57.3%) who had genetic laboratory testing, of whom 37 had single nucleotide polymorphism (SNP) microarray tests for CNVs and 14 had routine genetic explorations (karyotyping and searches for specific chromosomal abnormalities by fluorescence in situ hybridization [FISH]) or a specific diagnosis test based on clinical history. To assess the causality of observed genetic findings in each patient, we used a causality assessment score (CAUS)3 including 5 causality-support criteria on a 3-point scale (0 = absent; 1 = moderate; 2 = high): the existence of similar cases in the literature; the presence of a clinical contributing factor; the presence of a biological contributing factor; the presence of other paraclinical symptoms; and response to a specific treatment related to the suspected genetic or medical condition.

22q11.2 microduplication (22q11.2DupS) is associated with a broad spectrum of phenotypes, including normality. Psychiatric disorders are described in 13% of these patients, including Attention Deficit and Hyperactivity Disorder (ADHD), Intellectual Deficiency (ID), and Autism Spectrum Disorder (ASD), but not schizophrenia. We report changes in the psychiatric symptom profile in the course of development of a young boy with a 22q11.2DupS syndrome, from early childhood to adolescence. The boy's psychiatric presentation was characterized by features of Pervasive Developmental Disorder (PDD), with ADHD in early childhood, a single psychotic episode in mid-infancy, and executive impairment in adolescence. We discuss the importance of an in-depth assessment of cognitive functions in children with22q11.2DupS throughout their development.

L’évitement pathologique des demandes (pathological demand avoidance [PDA]) désigne un syndrome conceptualisé par E. Newson en 1980 surtout connu au Royaume-Uni et dans les pays d’Europe du Nord. La résistance obsessionnelle aux exigences quotidiennes faisant appel à des stratégies manipulatrices, une sociabilité superficielle marquée par une position égocentrée, une labilité de l’humeur liée à un besoin de contrôle de la relation et un intérêt prononcé pour le monde imaginaire en sont les signes cardinaux. Les difficultés de communication et d’interactions sociales de ces enfants amènent à se poser la question d’une appartenance ou d’une parenté avec les troubles envahissant du développement (TED). Le débat sur ce sujet reste ouvert dans la mesure où certaines descriptions de TED (« psychopathie autistique », syndrome d’Asperger, trouble envahissant du développement non spécifié, autisme atypique…) englobent parfois ce phénotype comportemental. Cet article vise à réactualiser la description clinique, à présenter un outil à visée diagnostique en cours d’élaboration et à discuter les principaux diagnostics différentiels de ce syndrome. Versant sémiologique ou entité clinique, cette pathologie contient en soi suffisamment d’éléments de spécificité pour poursuivre les études afin de préciser sa place dans la nosographie actuelle et dégager des axes pédagogiques et éducatifs qui lui sont propres.

In this study, we aimed to objectify social perception process in children with ASD using eye tracking to investigate a putative correlation between social perception impairments and rest functional brain activity. For this purpose, MRI arterial spin labeling (ASL) was used to measure rest cerebral blood flow (rCBF).

Background: Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders caused by the interaction between genetic vulnerability and environmental factors. MicroRNAs (miRNAs) are key posttranscriptional regulators involved in multiple aspects of brain development and function. Previous studies have investigated miRNAs expression in ASD using non-neural cells like lymphoblastoid cell lines (LCL) or postmortem tissues. However, the relevance of LCLs is questionable in the context of a neurodevelopmental disorder, and the impact of the cause of death and/or post-death handling of tissue likely contributes to the variations observed between studies on brain samples.Methods: miRNA profiling using TLDA high-throughput real-time qPCR was performed on miRNAs extracted from olfactory mucosal stem cells (OMSCs) biopsied from eight patients and six controls. This tissue is considered as a closer tissue to neural stem cells that could be sampled in living patients and was never investigated for such a purpose before. Real-time PCR was used to validate a set of differentially expressed miRNAs, and bioinformatics analysis determined common pathways and gene targets. Luciferase assays and real-time PCR analysis were used to evaluate the effect of miRNAs misregulation on the expression and translation of several autism-related transcripts. Viral vector-mediated expression was used to evaluate the impact of miRNAs deregulation on neuronal or glial cells functions.Results: We identified a signature of four miRNAs (miR-146a, miR-221, miR-654-5p, and miR-656) commonly deregulated in ASD. This signature is conserved in primary skin fibroblasts and may allow discriminating between ASD and intellectual disability samples. Putative target genes of the differentially expressed miRNAs were enriched for pathways previously associated to ASD, and altered levels of neuronal transcripts targeted by miR-146a, miR-221, and miR-656 were observed in patients' cells. In the mouse brain, miR-146a, and miR-221 display strong neuronal expression in regions important for high cognitive functions, and we demonstrated that reproducing abnormal miR-146a expression in mouse primary cell cultures leads to impaired neuronal dendritic arborization and increased astrocyte glutamate uptake capacities.Conclusions: While independent replication experiments are needed to clarify whether these four miRNAS could serve as early biomarkers of ASD, these findings may have important diagnostic implications. They also provide mechanistic connection between miRNA dysregulation and ASD pathophysiology and may open up new opportunities for therapeutic.

Avec le DSM-IV et le DSM-IV-TR, la terminologie de troubles envahissants du développement (TED) recouvre deux grandes catégories de troubles infantiles : les troubles de nature « strictement » autistique et les troubles envahissants du développement non spécifiés ou TED-NoS. Le terme de multiple complex developmental disorder (MCDD) est proposé pour classer les enfants diagnostiqués TED-NoS présentant un tableau clinique semblable à celui des dysharmonies psychotiques. Actuellement, cette catégorie de troubles développementaux est incluse sans distinction nosographique dans les troubles du spectre autistique (TSA) de la dernière publication du DCM (DSM-V). Nous rapportons l’observation clinique transdisciplinaire d’un garçon de 6ans présentant une symptomatologie complexe de type TED-NoS/MCDD. Cet enfant présente des troubles multiples : des signes neurologiques mineurs, des troubles neuro-psychomoteurs avérés avec un trouble de l’acquisition de la coordination (TAC), des altérations de la communication, de la pensée et de la régulation des émotions, un trouble du déficit de l’attention (TDA) ; en présence d’un haut potentiel verbal rendant ardue la pose d’un diagnostic clair. L’IRM cérébrale révélera la présence d’un kyste arachnoïdien cérébral temporal gauche congénital volumineux exerçant un effet de masse sur les structures cérébrales pouvant expliquer une partie de la symptomatologie. Une intervention chirurgicale (décompression par fenestration microchirurgicale) permettra de constater une nette diminution des signes neurologiques mineurs, notamment des troubles neuro-développementaux moteurs, et des troubles autistiques, soulignant la réversibilité des troubles après décompression. Ce cas clinique rare montre l’importance d’appréhender l’individu dans sa globalité par le biais de la transdisciplinarité, afin de proposer des évaluations et prises en charges adaptées. À notre connaissance, c’est le premier cas clinique chez l’enfant, rapporté dans la littérature et montrant une association entre kyste arachnoïdien temporal et TED-NoS/MCDD.

Left temporal arachnoid cyst and specific learning disorders associated with pervasive developmental disorders - not otherwise specified (PDD-NOS): contributions of an integrative neuro-psychomotor, neuropsychological, psychopathological and neurosurgical approach about a case report in a child (Francois). With DSM-IV and DSM-IV-TR, the terminology of pervasive developmental disorders (PDD) covers two main categories of infantile disorders: disorders of "strictly" autistic nature and pervasive developmental disorders - not otherwise specified (PDD-NOS). Under the terminology of multiple complex developmental disorder (MCDD), it is proposed to classify children presenting symptoms approaching the psychotic disharmonies and usually diagnosed as PDD-NOS. Such a category of developmental disorders is now included without nosographic distinction in the autistic spectrum in the Diagnostic and Statistical Manual of mental disorders (DSM-V).Case report. - We are reporting a case report of a 6-year-old boy which shows a PDD-NoS/MCDD complex symptomatology type. This child presents multiple disorders: minor neurological signs (soft signs), neuro-psychomotor disorders, developmental coordination disorder (DCD), communication, thought, and regulation of emotions disorders, attention deficit disorders (ADb); in the presence of a high verbal intellectual potential, which makes it difficult to establish a clear diagnosis. A cerebral magnetic resonance imaging (MRI) was carried out due to the presence of minor neurological signs (soft signs) and of neurodevelopmental multiple disorders. The MRI revealed a voluminous arachnoid temporo-polar left cyst with a marked mass effect on the left temporal lobe.Discussion. - A neurosurgical intervention allowed to observe the gradual disappearance of the specific symptomatology (in particular soft signs, neuro-psychomotor functions and autistic symptoms) secondary to the interference of the cyst's pressure with intracranial areas involving neurological and psychopathological abnormalities, underlying at the same time the reversibility of the disorders after decompression as demonstrated in some studies. There are always, with a quantitative and qualitative decrease, an emotional dysregulation, a DCD, an ADD as well as impairments in the executive functions.Conclusion. - This clinical case underlines the necessity of an evaluation in a transdisciplinary way and to follow the developmental evolution of the child in order to focus adapted therapeutics. Furthermore, with neurodevelopmental disorders not specified, it is important to examine the presence of soft signs with standardized neuro-psychomotor assessment, and then, to propose an MRI investigation. To our knowledge, this is the first report in the literature with a school age child of an unusual association between a temporal arachnoid cyst associated with PDD-NOS/MCDD. (C) 2016 L'Encephale, Paris.

IntroductionAn overlap between autism spectrum disorder (ASD), in particular Asperger Syndrome (AS), and high intellectual potential (HIP–Total IQ > 2 SD) is often discussed.ObjectivesExplore differences between homogeneous and heterogeneous Wisc-profiles among HIP children, and between HIP and ASD children, on cognitive and clinical assessments.MethodsForty-nine participants (mean age 11.2 years) were divided in 4 groups: High Functioning Autism (HFA), AS, Homogenous HIP and Heterogeneous HIP. Data of WISC-IV and questionnaires – Autism Quotient (AQ), Empathy Quotient (EQ), Systemizing Quotient (SQ), Children's Communication Checklist (CCC) – were compared.(Preliminary) ResultsOn the WISC-IV, the Z scores curves follow similar trajectories but highlight quantitative differences between AS and heterogeneous HIP: verbal comprehension is the highest index (+1,6 SD in AS; +3,1 SD in heterogeneous HIP) followed by perceptual reasoning, working memory, and processing speed indexes (–1,2 SD in AS; +0,5 SD in heterogeneous HIP), respectively. The questionnaires show that scores of Homogenous HIP children are all in the average. Heterogeneous HIP children score 2,1 SD above average on the AQ (+1,6 SD on “Social Skills” and +1,3 SD on “Local Detail” subscales), whereas ASD children score 4 SD above average on the AQ. In addition, heterogeneous HIP children show pragmatic difficulties (–2,4 SD on the CCC, with a peak on “Area of Interest” subscale), also present in ASD children (–4 SD).ConclusionsAS and heterogeneous HIP children show similar cognitive profiles on the WISC-IV. Furthermore, heterogeneous HIP children exhibit high scores on the AQ and have pragmatic difficulties.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The Xq25 duplications syndrome has recently emerged as a distinct clinical entity. We report here on six new patients belonging to two unrelated families and harbouring an Xq25 microduplication detected by array CGH. Similarly to previously reported cases, the phenotype of our patients is characterized by delayed milestones, speech disturbance, intellectual disability, abnormal behaviours and a characteristic facial dysmorphism. The common duplicated interval allowed further refinement of the shortest region of overlap to 173 kb, including only one gene, STAG2, which encodes a component of the cohesin complex. We suggest that increased STAG2 gene copy number and dysregulation of its downstream target genes may be responsible for the specific clinical findings of this syndrome. Therefore, the Xq25 microduplication could be considered as a novel cohesinopathy, thus increasing the group of these disorders.

La duplication Xq25 a récemment été décrite dans la littérature comme une entité cliniquement reconnaissable. Le phénotype associé à cette microduplication est caractérisé par un retard des acquisitions, un retard de langage, une hypotonie, une déficience intellectuelle, des troubles du comportement et une dysmorphie faciale caractéristique (un visage hypotonique, une éversion de la paupière inférieure, un épicanthus, des sourcils fins et/ou arqués, une hypoplasie malaire et un vermillon des lèvres épais). Nous rapportons ici six nouveaux patients provenant de 2 familles différentes, porteurs d'une microduplication Xq25 détectée grâce à la technique de CGH array. La grande similitude phénotypique de ces patients entre eux et avec ceux rapportés dans la littérature confirme bien qu'il s'agit d'un nouveau syndrome cliniquement identifiable. De plus, l'analyse des intervalles dupliqués chez nos patients a permis de redéfinir la région minimale critique de ce syndrome. En effet, le segment dupliqué commun entre les différents patients a une taille de 173 kb et ne comprend plus qu'un seul gène, STAG2, qui code une sous-unité du complexe cohésine. Nous émettons l'hypothèse que l'augmentation du nombre de copies du gène STAG2, et la dérégulation de l'expression de ses gènes cibles, pourrait être responsable des caractéristiques cliniques spécifiques observées dans ce syndrome. De ce fait, la microduplication Xq25 peut ainsi être considérée comme une nouvelle « cohésinopathie ».