Link between neurodevelopmental disorders and suicidal risk in children.

INTRODUCTION: Suicide represents a significant public health issue among children and adolescents. However, in this population, while the literature seems to support a link between suicidal risk and neurodevelopmental disorders, there are still few studies on the subject. The psychopathological description of children who have realized a suicide attempt with a high potential for lethality, which can be defined as "serious", appears to resemble that of children who have died by suicide. This study aimed to characterize the dimensional aspects of the neurodevelopmental profile of a population of children and adolescents hospitalized at Necker-Enfants-Malades Hospital for a serious suicide attempt. METHODS: This is an observational, prospective, and single-center study. Questionnaires for collecting general information and dimensional scales of neurodevelopment (Autism-Tics, ADHD, and Other Comorbidities Inventory, Social Responsiveness Scale, and Conners-3 for parents) were used. This study included 21 patients aged 9 to 15 years at the time of their hospitalization. RESULTS: The results supported the presence of at least one neurodevelopmental disorder (autistic traits, attention-deficit/hyperactivity disorder, learning disorder, or motor disorder) in 70% (n=14) of the subjects, and at least one behavioral disorder (oppositional defiant disorder, conduct disorder) in 65% (n=13) of these subjects. CONCLUSION: The observed frequency of traits indicative of neurodevelopmental disorders in our population was higher than that observed in the general population, without the presented symptoms being eligible for categorical diagnosis. Considering the dimensional aspects of neurodevelopmental symptoms would therefore enable better identification of children at suicidal risk and more tailored interventions to contribute to the prevention of suicide in children.

Parental involvement and adjustment during the diagnostic evaluation of autism spectrum disorder at two diagnostic centers.

OBJECTIVES: The primary objective of this study was to determine the effects of permanent, mediated parental presence during all autism spectrum disorder diagnostic evaluations on parental adjustment (perceived parental stress and sense of parental competence) compared with procedures that traditionally only involve parents in pivotal periods of the diagnosis. The level of satisfaction with the diagnostic procedure and parents' needs were also evaluated to complete this first objective. The secondary objective was to assess the effects of psychosocial, individual, and contextual variables on perceived parental stress and sense of parental competence. METHODS: The total sample of 49 parents was divided (using simple randomization) into two subgroups, each for a different procedure. Participants were met with once before the first consultation and once after. They completed self-reported questionnaires on parental stress, sense of parental competence, satisfaction with the procedure, social support, locus of control, and appraisal of life events. Statistical analysis was conducted using SPAD and SPSS software. RESULTS: There was no difference between the two groups in the variables assessed. Satisfaction with the diagnostic procedure was high in both groups, but parents highlighted that they had important needs following the diagnosis. The child's level of autonomy, the presence of disruptive behaviors, and satisfaction with social support were found to be important for determining parental adjustment. CONCLUSIONS: Several hypotheses may explain the lack of differences between the two groups, including that parents may not yet have been in a position to benefit from the procedure aimed at integrating them. Our suggestion is that professional interventions should focus on improving the child's autonomy and helping the parent to develop a satisfactory support network. Finally, parents' needs for the post-diagnosis phase should be given greater consideration, particularly in future research.

The Bulle: Support and Prevention of Psychological Decompensation of Health Care Workers During the Trauma of the COVID-19 Epidemic.

The coronavirus disease 2019 pandemic presents unprecedented challenges for the health care system. The pressure on health care staff continues to intensify, accentuated by the confinement (lockdown) of the population and the unprecedented duration of this emergency. Separately and especially together, overwork, degraded conditions of care because of the never-ending emergency, and the risk of exposure to the virus can lead to acute psychological distress or signs of burnout. This original program was developed at Cochin Hospital in Paris, France to prevent these potentially dramatic psychological consequences, support the medical staff, and identify those most affected to offer them specific care. A program and a space for relaxation and support for hospital caregivers by hospital caregivers, the Port Royal Bulle (the Bubble) offers these workers help in decompression and relaxation. It combines a warm and caring welcome that promotes attention, listening, conversations, and exchanges as needed, empathetic support, and the ability to participate in soothing, relaxing, or low-impact physical activities. It takes care of caregivers. The Bubble is a program that is simple to set up and that appears to meet professionals' expectations. Making it permanent and enlarging its scale, as a complement to existing programs, might help to support health care personnel in their work.

TEDIS, a Comprehensive Data Model for In-Depth Clinical Assessment of Patients Affected with Neuro-Developmental Disorders Including Autism.

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.

Telepsychiatry for Children and Adolescents: A Review of the PROMETTED Project.

BACKGROUND: Telemedicine for children and adolescents is a public health topic, and since 2009 in France, the legal framework defines practical modalities. Some children with Attention Deficit with or without Hyperactivity Disorder, social anxiety, or Autism Spectrum Disorder (ASD) can be easily engaged within a teleconsultation model. Literature suggests new opportunities to facilitate the care process for the ASD person and his family: diagnosis with the use of validated instruments and parental accompaniment. METHODS: Since 2015, a pilot project called PROMETTED was supported by the Regional Health Agency of Ile de France. It was developed and managed by the team of the Center for Diagnosis and Evaluation for Autism (CDEA) of Sainte-Anne Hospital and associated PEDIATED, the CDEA of Versailles. RESULTS: Five medico-social structures for children and adolescents with ASD and the two CDEAs co-elaborated a scheme of intervention with telemedicine. The remote evaluation is a four-step process structured around the medical history and the observation of the young subject; the Autism Diagnostic Interview; the use of the Childhood Autism Rating Scale and the Vineland Adaptive Behavior Scales; and feedback to parents. CONCLUSIONS: Medico-economic and satisfaction evaluations are in progress.

Disruption of melatonin synthesis is associated with impaired 14-3-3 and miR-451 levels in patients with autism spectrum disorders.

Autism spectrum disorders (ASD) are characterized by a wide genetic and clinical heterogeneity. However, some biochemical impairments, including decreased melatonin (crucial for circadian regulation) and elevated platelet N-acetylserotonin (the precursor of melatonin) have been reported as very frequent features in individuals with ASD. To address the mechanisms of these dysfunctions, we investigated melatonin synthesis in post-mortem pineal glands - the main source of melatonin (9 patients and 22 controls) - and gut samples - the main source of serotonin (11 patients and 13 controls), and in blood platelets from 239 individuals with ASD, their first-degree relatives and 278 controls. Our results elucidate the enzymatic mechanism for melatonin deficit in ASD, involving a reduction of both enzyme activities contributing to melatonin synthesis (AANAT and ASMT), observed in the pineal gland as well as in gut and platelets of patients. Further investigations suggest new, post-translational (reduced levels of 14-3-3 proteins which regulate AANAT and ASMT activities) and post-transcriptional (increased levels of miR-451, targeting 14-3-3ζ) mechanisms to these impairments. This study thus gives insights into the pathophysiological pathways involved in ASD.

The Yin and Yang of Autism Genetics: How Rare De Novo and Common Variations Affect Liability.

The etiology of autism spectrum disorder (ASD) is complex, involving both genetic and environmental contributions to individual and population-level liability. Early researchers hypothesized that ASD arises from polygenic inheritance, but later results, such as the identification of mutations in certain genes that are responsible for syndromes associated with ASD, led others to propose that de novo mutations of major effect would account for most cases. This yin and yang of monogenic causes and polygenic inheritance continues to this day. The development of genome-wide genotyping and sequencing techniques has resulted in remarkable advances in our understanding of the genetic architecture of risk for ASD. The combined research findings provide solid evidence that ASD is a complex polygenic disorder. Rare de novo and inherited variations act within the context of a common-variant genetic load, and this load accounts for the largest portion of ASD liability.

Microdeletions of ELP4 Are Associated with Language Impairment, Autism Spectrum Disorder, and Mental Retardation.

Copy-number variations (CNVs) are important in the aetiology of neurodevelopmental disorders and show broad phenotypic manifestations. We compared the presence of small CNVs disrupting the ELP4-PAX6 locus in 4,092 UK individuals with a range of neurodevelopmental conditions, clinically referred for array comparative genomic hybridization, with WTCCC controls (n = 4,783). The phenotypic analysis was then extended using the DECIPHER database. We followed up association using an autism patient cohort (n = 3,143) compared with six additional control groups (n = 6,469). In the clinical discovery series, we identified eight cases with ELP4 deletions, and one with a partial duplication of ELP4 and PAX6. These cases were referred for neurological phenotypes including language impairment, developmental delay, autism, and epilepsy. Six further cases with a primary diagnosis of autism spectrum disorder (ASD) and similar secondary phenotypes were identified with ELP4 deletions, as well as another six (out of nine) with neurodevelopmental phenotypes from DECIPHER. CNVs at ELP4 were only present in 1/11,252 controls. We found a significant excess of CNVs in discovery cases compared with controls, P = 7.5 × 10(-3) , as well as for autism, P = 2.7 × 10(-3) . Our results suggest that ELP4 deletions are highly likely to be pathogenic, predisposing to a range of neurodevelopmental phenotypes from ASD to language impairment and epilepsy.

A genome-wide association study of autism using the Simons Simplex Collection: Does reducing phenotypic heterogeneity in autism increase genetic homogeneity?

BACKGROUND: Phenotypic heterogeneity in autism has long been conjectured to be a major hindrance to the discovery of genetic risk factors, leading to numerous attempts to stratify children based on phenotype to increase power of discovery studies. This approach, however, is based on the hypothesis that phenotypic heterogeneity closely maps to genetic variation, which has not been tested. Our study examines the impact of subphenotyping of a well-characterized autism spectrum disorder (ASD) sample on genetic homogeneity and the ability to discover common genetic variants conferring liability to ASD. METHODS: Genome-wide genotypic data of 2576 families from the Simons Simplex Collection were analyzed in the overall sample and phenotypic subgroups defined on the basis of diagnosis, IQ, and symptom profiles. We conducted a family-based association study, as well as estimating heritability and evaluating allele scores for each phenotypic subgroup. RESULTS: Association analyses revealed no genome-wide significant association signal. Subphenotyping did not increase power substantially. Moreover, allele scores built from the most associated single nucleotide polymorphisms, based on the odds ratio in the full sample, predicted case status in subsets of the sample equally well and heritability estimates were very similar for all subgroups. CONCLUSIONS: In genome-wide association analysis of the Simons Simplex Collection sample, reducing phenotypic heterogeneity had at most a modest impact on genetic homogeneity. Our results are based on a relatively small sample, one with greater homogeneity than the entire population; if they apply more broadly, they imply that analysis of subphenotypes is not a productive path forward for discovering genetic risk variants in ASD.

Feelings of regret and disappointment in adults with high-functioning autism.

Impairments in emotional processing in Autism Spectrum Disorders (ASDs) can be characterised by failure to generate and recognize self-reflective, cognitive-based emotions, such as pride, embarrassment and shame. Among this type of emotions, regret and disappointment, as well as their positive counterparts, result from a counterfactual comparison, that is the comparison between an actual value ("what is") and a fictive value ("what might have been"). However, while disappointment is experienced when the obtained outcome is worse than the expected outcome that might have occurred from the same choice, regret occurs when one experiences an outcome that is worse than the outcome of foregone choices. By manipulating a simple gambling task, we examined subjective reports on the intensity of negative and positive emotions in a group of adults with High-Functioning Autism or Asperger syndrome (HFA/AS), and a control group matched for age, gender and educational level. Participants were asked to choose between two lotteries with different levels of risk under two conditions of outcome feedback: (i) Partial, in which only the outcome of the chosen lottery was visible, (ii) Complete, in which the outcomes of the two lotteries were simultaneously visible. By comparing partial and complete conditions, we aimed to investigate the differential effect between disappointment and regret, as well as between their positive counterparts. Relative to the control participants (CP), the group with HFA/AS reported reduced regret and no difference between regret and disappointment, along with a preserved ability to use counterfactual thinking and similar choice behaviour. Difficulties to distinguish the feeling of regret in participants with HFA/AS can be explained by diminished emotional awareness, likely associated with an abnormal fronto-limbic connectivity.

Modest impact on risk for autism spectrum disorder of rare copy number variants at 15q11.2, specifically breakpoints 1 to 2.

The proximal region of chromosome 15 is one of the genomic hotspots for copy number variants (CNVs). Among the rearrangements observed in this region, CNVs from the interval between the common breakpoints 1 and 2 (BP1 and BP2) have been reported cosegregating with autism spectrum disorder (ASD). Although evidence supporting an association between BP1-BP2 CNVs and autism accumulates, the magnitude of the effect of BP1-BP2 CNVs remains elusive, posing a great challenge to recurrence-risk counseling. To gain further insight into their pathogenicity for ASD, we estimated the penetrance of the BP1-BP2 CNVs for ASD as well as their effects on ASD-related phenotypes in a well-characterized ASD sample (n = 2525 families). Transmission disequilibrium test revealed significant preferential transmission only for the duplicated chromosome in probands (20T:9NT). The penetrance of the BP1-BP2 CNVs for ASD was low, conferring additional risks of 0.3% (deletion) and 0.8% (duplication). Stepwise regression analyses suggest a greater effect of the CNVs on ASD-related phenotype in males and when maternally inherited. Taken together, the results are consistent with BP1-BP2 CNVs as risk factors for autism. However, their effect is modest, more akin to that seen for common variants. To be consistent with the current American College of Medical Genetics guidelines for interpretation of postnatal CNV, the BP1-BP2 deletion and duplication CNVs would probably best be classified as variants of uncertain significance (VOUS): they appear to have an impact on risk, but one so modest that these CNVs do not merit pathogenic status.

Individuals with autism spectrum disorders do not use social stereotypes in irony comprehension.

Social and communication impairments are part of the essential diagnostic criteria used to define Autism Spectrum Disorders (ASDs). Difficulties in appreciating non-literal speech, such as irony in ASDs have been explained as due to impairments in social understanding and in recognizing the speaker's communicative intention. It has been shown that social-interactional factors, such as a listener's beliefs about the speaker's attitudinal propensities (e.g., a tendency to use sarcasm, to be mocking, less sincere and more prone to criticism), as conveyed by an occupational stereotype, do influence a listener's interpretation of potentially ironic remarks. We investigate the effect of occupational stereotype on irony detection in adults with High Functioning Autism or Asperger Syndrome (HFA/AS) and a comparison group of typically developed adults. We used a series of verbally presented stories containing ironic or literal utterances produced by a speaker having either a "sarcastic" or a "non-sarcastic" occupation. Although individuals with HFA/AS were able to recognize ironic intent and occupational stereotypes when the latter are made salient, stereotype information enhanced irony detection and modulated its social meaning (i.e., mockery and politeness) only in comparison participants. We concluded that when stereotype knowledge is not made salient, it does not automatically affect pragmatic communicative processes in individuals with HFA/AS.

Adjusting head circumference for covariates in autism: clinical correlates of a highly heritable continuous trait.

BACKGROUND: Brain development follows a different trajectory in children with autism spectrum disorders (ASD) than in typically developing children. A proxy for neurodevelopment could be head circumference (HC), but studies assessing HC and its clinical correlates in ASD have been inconsistent. This study investigates HC and clinical correlates in the Simons Simplex Collection cohort. METHODS: We used a mixed linear model to estimate effects of covariates and the deviation from the expected HC given parental HC (genetic deviation). After excluding individuals with incomplete data, 7225 individuals in 1891 families remained for analysis. We examined the relationship between HC/genetic deviation of HC and clinical parameters. RESULTS: Gender, age, height, weight, genetic ancestry, and ASD status were significant predictors of HC (estimate of the ASD effect = .2 cm). HC was approximately normally distributed in probands and unaffected relatives, with only a few outliers. Genetic deviation of HC was also normally distributed, consistent with a random sampling of parental genes. Whereas larger HC than expected was associated with ASD symptom severity and regression, IQ decreased with the absolute value of the genetic deviation of HC. CONCLUSIONS: Measured against expected values derived from covariates of ASD subjects, statistical outliers for HC were uncommon. HC is a strongly heritable trait, and population norms for HC would be far more accurate if covariates including genetic ancestry, height, and age were taken into account. The association of diminishing IQ with absolute deviation from predicted HC values suggests HC could reflect subtle underlying brain development and warrants further investigation.

The role of causal and intentional judgments in moral reasoning in individuals with high functioning autism.

In the present study, we investigated the ability to assign moral responsibility and punishment in adults with high functioning autism or Asperger Syndrome (HFA/AS), using non-verbal cartoons depicting an aggression, an accidental harm or a mere coincidence. Participants were asked to evaluate the agent's causal and intentional roles, his responsibility and the punishment he deserves for his action. Adults with HFA/AS did not differ in judgments of suffering and causality from adults with typical development. However, subtle difficulties with judgments of intentional action and moral judgments were observed in participants with HFA/AS. These results are discussed in the light of emerging studies that deal with integrity of moral reasoning in individuals with autism spectrum disorders.

Autism risk factors: genes, environment, and gene-environment interactions.

The aim of this review is to summarize the key findings from genetic and epidemiological research, which show that autism is a complex disorder resulting from the combination of genetic and environmental factors. Remarkable advances in the knowledge of genetic causes of autism have resulted from the great efforts made in the field of genetics. The identification of specific alleles contributing to the autism spectrum has supplied important pieces for the autism puzzle. However, many questions remain unanswered, and new questions are raised by recent results. Moreover, given the amount of evidence supporting a significant contribution of environmental factors to autism risk, it is now clear that the search for environmental factors should be reinforced. One aspect of this search that has been neglected so far is the study of interactions between genes and environmental factors.

Common genetic variants, acting additively, are a major source of risk for autism.

BACKGROUND: Autism spectrum disorders (ASD) are early onset neurodevelopmental syndromes typified by impairments in reciprocal social interaction and communication, accompanied by restricted and repetitive behaviors. While rare and especially de novo genetic variation are known to affect liability, whether common genetic polymorphism plays a substantial role is an open question and the relative contribution of genes and environment is contentious. It is probable that the relative contributions of rare and common variation, as well as environment, differs between ASD families having only a single affected individual (simplex) versus multiplex families who have two or more affected individuals. METHODS: By using quantitative genetics techniques and the contrast of ASD subjects to controls, we estimate what portion of liability can be explained by additive genetic effects, known as narrow-sense heritability. We evaluate relatives of ASD subjects using the same methods to evaluate the assumptions of the additive model and partition families by simplex/multiplex status to determine how heritability changes with status. RESULTS: By analyzing common variation throughout the genome, we show that common genetic polymorphism exerts substantial additive genetic effects on ASD liability and that simplex/multiplex family status has an impact on the identified composition of that risk. As a fraction of the total variation in liability, the estimated narrow-sense heritability exceeds 60% for ASD individuals from multiplex families and is approximately 40% for simplex families. By analyzing parents, unaffected siblings and alleles not transmitted from parents to their affected children, we conclude that the data for simplex ASD families follow the expectation for additive models closely. The data from multiplex families deviate somewhat from an additive model, possibly due to parental assortative mating. CONCLUSIONS: Our results, when viewed in the context of results from genome-wide association studies, demonstrate that a myriad of common variants of very small effect impacts ASD liability.

High-functioning autism spectrum disorder and fragile X syndrome: report of two affected sisters.

BACKGROUND: Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability (ID), as well as the most frequent monogenic cause of autism spectrum disorder (ASD). Men with FXS exhibit ID, often associated with autistics features, whereas women heterozygous for the full mutation are typically less severely affected; about half have a normal or borderline intelligence quotient (IQ). Previous findings have shown a strong association between ID and ASD in both men and women with FXS. We describe here the case of two sisters with ASD and FXS but without ID. One of the sisters presented with high-functioning autism, the other one with pervasive developmental disorder not otherwise specified and low normal IQ. METHODS: The methylation status of the mutated FMR1 alleles was examined by Southern blot and methylation-sensitive polymerase chain reaction. The X-chromosome inactivation was determined by analyzing the methylation status of the androgen receptor at Xq12. RESULTS: Both sisters carried a full mutation in the FMR1 gene, with complete methylation and random X chromosome inactivation. We present the phenotype of the two sisters and other family members. CONCLUSIONS: These findings suggest that autistic behaviors and cognitive impairment can manifest as independent traits in FXS. Mutations in FMR1, known to cause syndromic autism, may also contribute to the etiology of high-functioning, non-syndromic ASD, particularly in women. Thus, screening for FXS in patients with ASD should not be limited to those with comorbid ID.

Genetic and functional analyses of SHANK2 mutations suggest a multiple hit model of autism spectrum disorders.

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders with a complex inheritance pattern. While many rare variants in synaptic proteins have been identified in patients with ASD, little is known about their effects at the synapse and their interactions with other genetic variations. Here, following the discovery of two de novo SHANK2 deletions by the Autism Genome Project, we identified a novel 421 kb de novo SHANK2 deletion in a patient with autism. We then sequenced SHANK2 in 455 patients with ASD and 431 controls and integrated these results with those reported by Berkel et al. 2010 (n = 396 patients and n = 659 controls). We observed a significant enrichment of variants affecting conserved amino acids in 29 of 851 (3.4%) patients and in 16 of 1,090 (1.5%) controls (P = 0.004, OR = 2.37, 95% CI = 1.23-4.70). In neuronal cell cultures, the variants identified in patients were associated with a reduced synaptic density at dendrites compared to the variants only detected in controls (P = 0.0013). Interestingly, the three patients with de novo SHANK2 deletions also carried inherited CNVs at 15q11-q13 previously associated with neuropsychiatric disorders. In two cases, the nicotinic receptor CHRNA7 was duplicated and in one case the synaptic translation repressor CYFIP1 was deleted. These results strengthen the role of synaptic gene dysfunction in ASD but also highlight the presence of putative modifier genes, which is in keeping with the "multiple hit model" for ASD. A better knowledge of these genetic interactions will be necessary to understand the complex inheritance pattern of ASD.

Genetic variations of the melatonin pathway in patients with attention-deficit and hyperactivity disorders.

Melatonin is a powerful antioxidant and a synchronizer of many physiological processes. Alteration in melatonin signaling has been reported in a broad range of diseases, but little is known about the genetic variability of this pathway in humans. Here, we sequenced all the genes of the melatonin pathway -AA-NAT, ASMT, MTNR1A, MTNR1B and GPR50 - in 321 individuals from Sweden including 101 patients with attention-deficit/hyperactivity disorder (ADHD) and 220 controls from the general population. We could find several damaging mutations in patients with ADHD, but no significant enrichment compared with the general population. Among these variations, we found a splice site mutation in ASMT (IVS5+2T>C) and one stop mutation in MTNR1A (Y170X) - detected exclusively in patients with ADHD - for which biochemical analyses indicated that they abolish the activity of ASMT and MTNR1A. These genetic and functional results represent the first comprehensive ascertainment of melatonin signaling deficiency in ADHD.

Variations of the candidate SEZ6L2 gene on Chromosome 16p11.2 in patients with autism spectrum disorders and in human populations.

BACKGROUND: Autism spectrum disorders (ASD) are a group of severe childhood neurodevelopmental disorders with still unknown etiology. One of the most frequently reported associations is the presence of recurrent de novo or inherited microdeletions and microduplications on chromosome 16p11.2. The analysis of rare variations of 8 candidate genes among the 27 genes located in this region suggested SEZ6L2 as a compelling candidate. METHODOLOGY/PRINCIPAL FINDINGS: We further explored the role of SEZ6L2 variations by screening its coding part in a group of 452 individuals, including 170 patients with ASD and 282 individuals from different ethnic backgrounds of the Human Genome Diversity Panel (HGDP), complementing the previously reported screening. We detected 7 previously unidentified non-synonymous variations of SEZ6L2 in ASD patients. We also identified 6 non-synonymous variations present only in HGDP. When we merged our results with the previously published, no enrichment of non-synonymous variation in SEZ6L2 was observed in the ASD group compared with controls. CONCLUSIONS/SIGNIFICANCE: Our results provide an extensive ascertainment of the genetic variability of SEZ6L2 in human populations and do not support a major role for SEZ6L2 sequence variations in the susceptibility to ASD.