Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries.

Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages.

Adiponectin blood levels and autism spectrum disorders: a systematic review.

OBJECTIVE: To review the relationship between adiponectin levels and autism spectrum disorders (ASDs) in children. BACKGROUND: ASDs are associated with pervasive social interaction and communication abnormalities. Researchers have studied various pathophysiological mechanisms underlying ASDs to identify predictors for an early diagnosis to optimize treatment outcomes. Immune dysfunction, perhaps mediated by a decrease in anti-inflammatory adipokine, adiponectin, along with changes in other adipokines, may play a central role in increasing the risk for ASDs. However, other factors, such as low maternal vitamin D levels, atherosclerosis, diabetes, obesity, cardio-metabolic diseases, preterm delivery, and oxytocin gene polymorphism may also contribute to increased risk for ASDs. METHODS: Searches on the database; PubMed, Google Scholar, and Cochrane using keywords; adiponectin, adipokines, ASD, autism, autistic disorder, included English-language studies published till September 2022. Data were extracted on mean differences between adiponectin levels in children with and without ASDs. RESULTS: The search yielded six studies providing data on adiponectin levels in young patients with ASDs. As can be seen from Table 1, four of the six studies were positive for an inverse correlation between ASD and adiponectin levels. In addition, two of the four positive and one negative studies found low adiponectin levels associated with and the severity of autistic symptoms. However, results from one reviewed study were insignificant. CONCLUSION: Most studies reviewed yielded lower adiponectin levels in children with ASDs as well as the severity of autistic symptoms.

Factor analysis of the autism spectrum screening questionnaire in a population-based child sample.

PURPOSE: The aim of this study was to investigate several possible factor structures of the Autism Spectrum Screening Questionnaire (ASSQ). MATERIALS AND METHODS: We used the 27-item screening tool for school-aged children in a general population of 8-year-old children (n = 3,538) and compared the occurring solutions to previously published factor models. RESULTS: A one-factor solution and a four-factor solution were identified in Exploratory Factor Analysis (EFA) and confirmed with Confirmatory Factor Analysis (CFA), while two-, three-, five- and six-factor solutions were rejected. In CFA, our four-factor solution showed the best goodness-of-fit indexes when compared with factor models previously presented by Posserud et al. and Ehlers et al. CONCLUSIONS: The results indicate a strong underlying connection between all ASSQ items which is elicited by the one-factor solution. Although as a screening tool, ASSQ is functioning with the unifactorial solution, the four factors can help to identify certain clusters of autism spectrum traits.

[Pathological Demand Avoidance: Current State of Research and Critical Discussion]. / Pathological Demand Avoidance ­ aktueller Forschungsstand und kritische Diskussion.

Pathological Demand Avoidance: Current State of Research and Critical Discussion Abstract: Pathological demand avoidance (PDA) describes children who obsessively avoid any demand to a clinically relevant extent and is presently the subject of controversial discussion. Their behavior may be interpreted as an attempt to reduce anxiety by establishing security and predictability through rigid control of the environment as well as the demands and expectations of others. The symptoms are described in the context of autism spectrum disorder. This article reviews the current state of research and discusses the questionable validity of pathological demand avoidance as an independent diagnostic entity. It also addresses the impact of the behavior profile on development and treatment. This paper concludes that PDA is not a diagnostic entity nor a subtype of autism; rather, it is a behavior profile that can be associated with adverse illness progression and unfavorable outcomes. PDA is one feature in a complex model. We must consider not only the patient's characteristics but also those of the caregiver and their psychopathology. The reactions of the interaction partners as well as the treatment decisions play a key role play for the affected individuals. Substantial research is needed concerning the occurrence of the behavior profile PDA in diverse disorders, treatment options, and treatment responses.

Early developmental delay in Leigh syndrome spectrum disorders is associated with poor clinical prognosis.

BACKGROUND: Leigh spectrum syndrome (LSS) is a primary mitochondrial disorder characterized by neurodevelopmental regression and metabolic stroke typically in early life. Developmental delay (DD) is known to follow episodes of neurologic regression in LSS, although primary developmental delay (pDD) has been rarely reported. We hypothesized that pDD precedes regression in a broader subset of LSS individuals and may associate with worse long-term educational outcomes. METHODS: From a retrospective cohort, subjects with pathogenic variant(s) in a nuclear or mitochondrial gene associated with LSS and consistent clinical manifestations and neuroradiological findings. Detailed developmental histories and neurologic outcomes were extracted. RESULTS: Of 69 LSS subjects, 47 (68.1%) had a history of pDD and 53 (76.8%) had neurodevelopmental regression. We identified 3 distinct developmental phenotypes: [1] pDD followed by regression (N = 31/69, 44.9%), [2] pDD without subsequent regression (16/69, 23.2%), [3] regression without pDD (N = 22/69, 31.9%). A history of pDD was associated with earlier disease onset (p = 0.0003) and worse educational outcomes (OR 22.14). CONCLUSION: LSS is associated with multiple developmental phenotypes and pDD is associated with negative educational outcomes. pDD occurring prior to neurologic regression suggests that mitochondrial energetics impact developmental trajectories prior to acute metabolic failure and regression, providing an opportunity for earlier diagnosis and/or therapeutic intervention.

From the genetic architecture to synaptic plasticity in autism spectrum disorder.

Genetics studies of autism spectrum disorder (ASD) have identified several risk genes that are key regulators of synaptic plasticity. Indeed, many of the risk genes that have been linked to these disorders encode synaptic scaffolding proteins, receptors, cell adhesion molecules or proteins that are involved in chromatin remodelling, transcription, protein synthesis or degradation, or actin cytoskeleton dynamics. Changes in any of these proteins can increase or decrease synaptic strength or number and, ultimately, neuronal connectivity in the brain. In addition, when deleterious mutations occur, inefficient genetic buffering and impaired synaptic homeostasis may increase an individual's risk for ASD.

Concordance between a U.S. Educational Autism Classification and the Autism Diagnostic Observation Schedule.

States in the United States differ in how they determine special education eligibility for autism services. Few states include an autism-specific diagnostic tool in their evaluation. In research, the Autism Diagnostic Observation Schedule (ADOS for first edition, ADOS-2 for second edition) is considered the gold-standard autism assessment. The purpose of this study was to estimate the proportion of children with an educational classification of autism who exceed the ADOS/ADOS-2 threshold for autism spectrum (concordance rate). Data were drawn from 4 school-based studies across 2 sites (Philadelphia, Pennsylvania, and San Diego, California). Participants comprised 627 children (2-12 years of age; 83% male) with an autism educational classification. Analyses included (a) calculating the concordance rate between educational and ADOS/ADOS-2 classifications and (b) estimating the associations between concordance and child's cognitive ability, study site, and ADOS/ADOS-2 administration year using logistic regression. More San Diego participants (97.5%, all assessed with the ADOS-2) met ADOS/ADOS-2 classification than did Philadelphia participants assessed with the ADOS-2 (92.2%) or ADOS (82.9%). Children assessed more recently were assessed with the ADOS-2; this group was more likely to meet ADOS/ADOS-2 classification than the group assessed longer ago with the ADOS. Children with higher IQ were less likely to meet ADOS/ADOS-2 classification. Most children with an educational classification of autism meet ADOS/ADOS-2 criteria, but results differ by site and by ADOS version and/or recency of assessment. Educational classification may be a reasonable but imperfect measure to include children in community-based trials.

Pervasive refusal syndrome in child asylum seekers on Nauru.

OBJECTIVES: Between 2013 and 2019, an estimated 200 children seeking asylum in Australia were detained on the island of Nauru. In 2018, 15 of these children developed the rare and life-threatening pervasive refusal syndrome (PRS). This paper describes the PRS case cluster, the complexities faced by clinicians managing these cases, and the lessons that can be learned from this outbreak. CONCLUSIONS: The emergence of PRS on Nauru highlighted the risks of long-term detention of children in settings that are unable to meet their physical and psycho-social needs. The case cluster also underscored (a) the difficulties faced by doctors working in conditions where their medical and legal obligations may be in direct conflict, and (b) the role of clinicians in patient advocacy.

Relationship of Weight Outcomes, Co-Occurring Conditions, and Severity of Autism Spectrum Disorder in the Study to Explore Early Development.

OBJECTIVE: To assess contributing factors to increased obesity risk, by comparing children with autism spectrum disorder (ASD), developmental delays/disorders, and general population controls in weight status, and to examine associations between weight status and presence of co-occurring medical, behavioral, developmental, or psychiatric conditions across groups and ASD severity among children with ASD. STUDY DESIGN: The Study to Explore Early Development is a multisite cross-sectional study of children, 2-5 years of age, classified as children with ASD (n = 668), children with developmental delays/disorders (n = 914), or general population controls (n = 884). Using an observational cohort design, we compared the 3 groups. Children's heights and weights were measured during a clinical visit. Co-occurring conditions (medical, behavioral, developmental/psychiatric) were derived from medical records, interviews, and questionnaires. ASD severity was measured by the Ohio State University Global Severity Scale for Autism. RESULTS: The odds of overweight/obesity were 1.57 times (95% CI 1.24-2.00) higher in children with ASD than general population controls and 1.38 times (95% CI 1.10-1.72) higher in children with developmental delays/disorders than general population controls. The aORs were elevated for children with ASD after controlling for child co-occurring conditions (ASD vs general population controls: aOR = 1.51; 95% CI 1.14-2.00). Among children with ASD, those with severe ASD symptoms were 1.7 times (95% CI 1.1-2.8) more likely to be classified as overweight/obese compared with children with mild ASD symptoms. CONCLUSIONS: Prevention of excess weight gain in children with ASD, especially those with severe symptoms, and in children with developmental delays/disorders represents an important target for intervention.

Diagnostic validity of the MINI-KID disorder classifications in specialized child and adolescent psychiatric outpatient clinics in Sweden.

BACKGROUND: Missing diagnostic information often results poor accuracy of the clinical diagnostic decision process. The Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) is a short standardized diagnostic interview and covers a rather broad range of diagnoses applicable to children and adolescents. MINI-KID disorder classifications have shown test-retest reliability and validity comparable to other standardized diagnostic interviews and is claimed to be a useful tool for diagnostic screening in Child and Adolescent Psychiatric care. The concordance between the Swedish language version of the MINI-KID Interview and LEAD (Longitudinal, Expert, All Data) research diagnoses was studied in secondary child and adolescent psychiatric outpatient care. METHODS: MINI-KID interviews were performed for 101 patients, boys n = 50, girls n = 51, aged 4 to 18 years. The duration of the interview was on average 46 min, the child/adolescent participating together with the parent(s) in most cases. The seven most prevalent diagnoses were included in the analyses. RESULTS: The average overall percent agreement (OPA) between MINI-KID and LEAD was 79.5%, the average percent positive agreement (PPA) 35.4 and the average percent negative agreement (NPA) 92.7. OPA was highest for Obsessive-Compulsive Disorder (OCD) (0.89), Tic disorders (0.88) and Pervasive developmental disorders (0.81). There were similar results in diagnostic agreement comparing the two versions: the standard MINI-KID and MINI-KID for parents. The specific screening questions in MINI-KID resulted in additional preliminary diagnoses compared with the regular initial clinical assessment. CONCLUSIONS: Overall, there was an acceptable agreement between MINI-KID disorder classifications and research diagnoses according to LEAD. The standardized interview MINI-KID could be considered as a tool with the possibility to give valuable information in the diagnostic process in child and adolescent care which is similar to the setting in the present study.

[Pervasive refusal syndrome in children]. / Le syndrome de refus global de l'enfant.

Pervasive refusal syndrome is a rare clinical disorder affecting children and teenagers. It is characterised by social withdrawal and opposition which significantly affects how patients function and their treatment. The twenty or so cases reported in literature help to specify the main diagnostic and therapeutic elements. Early recognition of pervasive refusal syndrome is essential in order to treat these young patients as effectively as possible.

Mercury-associated diagnoses among children diagnosed with pervasive development disorders.

Nelson and Bauman (Pediatrics 111:674-679, 2003) previously hypothesized that pervasive developmental disorder (PDD) was not associated with mercury (Hg) exposure because the medical conditions associated with Hg exposure were not associated with PDD. A hypothesis-testing longitudinal case-control study evaluated the frequency of medically diagnosed conditions previously associated with Hg poisoning, including: epilepsy, dysarthria, failure to thrive, cerebral palsy, or contact dermatitis and other eczema among children preceding their eventual PDD diagnosis (cases) compared to controls. A retrospective examination of medical records within the Vaccine Safety Datalink (VSD) was undertaken. Cases diagnosed with PDD (n = 534) were born from 1991 to 2000 and continuously enrolled until their PDD diagnosis. Controls (n = 26,367) were born from 1991 to 1993 and continuously enrolled from birth for 7.22 years. Within the first 5 years of life, cases compared to controls were significantly (p < 0.0001) more likely to be assigned a diagnosis of contact dermatitis and other eczema (odds ratio (OR) = 2.033), dysarthria (OR = 23.992), epilepsy (OR = 5.351), failure to thrive (OR = 25.3), and cerebral palsy (OR = 4.464). Similar results were observed when the data were separated by gender. Overall, the results of the present study and recently published studies provide direct evidence supporting a link in twelve of twelve categories (100%) of Hg poisoning associated symptoms as defined by Nelson and Bauman (Pediatrics 111:674-679, 2003) and symptoms observed in those with a PDD diagnosis. The results of this study support the biological plausibility of Hg poisoning to induce PDD diagnoses and rejection of the Nelson and Bauman (Pediatrics 111:674-679, 2003) hypothesis because those with a PDD diagnosis have an increased frequency of conditions previously associated with Hg poisoning.

The Family Life Impairment Scale: Factor Structure and Clinical Utility with Young Children.

Although it is well-established that young children experience significant psychopathology, diagnostic decisions continue to be challenging, in part due to the way impairment is understood, defined, and measured. Most existing clinical tools assess impairment in an individualized manner, whereas for many young children, impairment is more accurately conceptualized as a family-oriented, multidimensional construct, impacting various parental and family activities. Two studies were completed using the Family Life Impairment Scale (FLIS), a multidimensional parent-report measure of family and associated impairment designed for young children. In Study 1, factor analysis was used in a large (n = 945) representative sample (23-48 months of age). FLIS associations with measures of parent and child well-being were explored to investigate convergent validity. Study 2 was completed in a sample (n = 174) of young children (18-33 months of age) diagnosed with autism spectrum disorders to explore factorial consistency in a clinical sample. Study 1 yielded evidence of a four-factor solution, including parent impairment (affecting parental well-being), family impairment (affecting family activities and routines), childcare impairment (affecting challenges with childcare), and positive growth (parental learning and growth associated with the child's problem). Evidence of convergent validity was also found, as factors were differentially associated with established measures of child symptoms and parent stress. Factor structure was supported in the clinical sample. Results support both the factorial structure and clinical utility of the FLIS for use across clinical and nonclinical populations of young children.

[Child with extreme regression after migration and trauma]. / Extreme regressie bij een kind na migratie en trauma.

A 12-year-old boy in an asylum-seeking family suffered from extreme regression. A few days after a minor traffic accident, he regressed to the developmental stage of a young toddler. The rare diagnosis pervasive refusal syndrome (prs) was made. This is considered to be an extreme form of a conversion disorder. We provided multidisciplinary, supportive and stimulating treatment, taking into account potentially influential factors. The boy recovered slowly, resuming adequate functionality two years later. Additional reports of similar cases are necessary to improve the knowledge on prs.

Social disadvantage and developmental diagnosis in pre-schoolers.

AIM: To explore the association between social disadvantage and developmental diagnoses in pre-school children. METHODS: Between 2012 and 2015, 845 pre-school children were assessed by the Child Assessment Team at Campbelltown Hospital. A social worker interviewed 469 families and these children were eligible for inclusion in the study. Autism spectrum disorder (ASD) was confirmed in 290 children. Of those without ASD, 72 did not have global developmental delay (GDD) and were excluded from the study. The remaining 107 children with GDD were used as the comparison group. Social risk factors in the two groups were compared using χ 2 tests. Variables with statistical significance were then entered into a logistic regression. RESULTS: After logistic regression, children with ASD were more likely to be male (odds ratio (OR) 3.1, 95% CI 0.195-0.529; P < 0.001) and their parents were more likely to have a clinically significant stress score (OR 1.3, 95% CI 0.334-0.992; P = 0.047). Children with GDD were more likely to live in a disadvantaged suburb (OR 1.7, 95% CI 1.042-2.940; P = 0.034), more likely to have a sole parent (OR 1.8, 95% CI 1.062-3.082; P = 0.029) and much more likely to have had involvement with child protection services (OR 3.9, 95% CI 2.044-7.416; P < 0.001). CONCLUSIONS: Children with GDD without autism were more likely to be disadvantaged and to have had contact with child protection services than children with ASD. This has implications for the assessment, early intervention and support services for children with disabilities and their families.

Autism spectrum disorder severity reflects the average contribution of de novo and familial influences.

Autism spectrum disorders (ASDs) are a highly heterogeneous group of conditions--phenotypically and genetically--although the link between phenotypic variation and differences in genetic architecture is unclear. This study aimed to determine whether differences in cognitive impairment and symptom severity reflect variation in the degree to which ASD cases reflect de novo or familial influences. Using data from more than 2,000 simplex cases of ASD, we examined the relationship between intelligence quotient (IQ), behavior and language assessments, and rate of de novo loss of function (LOF) mutations and family history of broadly defined psychiatric disease (depressive disorders, bipolar disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ was negatively associated with de novo LOF rate (P = 0.03) and positively associated with family history of psychiatric disease (P = 0.003). Female cases had a higher frequency of sporadic genetic events across the severity distribution (P = 0.01). High rates of LOF mutation and low frequencies of family history of psychiatric illness were seen in individuals who were unable to complete a traditional IQ test, a group with the greatest degree of language and behavioral impairment. These analyses provide strong evidence that familial risk for neuropsychiatric disease becomes more relevant to ASD etiology as cases become higher functioning. The findings of this study reinforce that there are many routes to the diagnostic category of autism and could lead to genetic studies with more specific insights into individual cases.

Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills.

The neuropeptides oxytocin and vasopressin are evolutionarily conserved regulators of social perception and behavior. Evidence is building that they are critically involved in the development of social recognition skills within rodent species, primates, and humans. We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces. Our sample comprised 198 families, from the United Kingdom and Finland, in whom a single child had been diagnosed with high-functioning autism. Previous research has shown that impaired social perception, characteristic of autism, extends to the first-degree relatives of autistic individuals, implying heritable risk. Assessments of face recognition memory, discrimination of facial emotions, and direction of gaze detection were standardized for age (7-60 y) and sex. A common SNP in the oxytocin receptor (rs237887) was strongly associated with recognition memory in combined probands, parents, and siblings after correction for multiple comparisons. Homozygotes for the ancestral A allele had impairments in the range -0.6 to -1.15 SD scores, irrespective of their diagnostic status. Our findings imply that a critical role for the oxytocin system in social recognition has been conserved across perceptual boundaries through evolution, from olfaction in rodents to visual memory in humans.

Do child healthcare professionals and parents recognize social-emotional and behavioral problems in 1-year-old infants?

Growing evidence supports the existence of clinically significant social-emotional/behavioral (SEB) problems among as young as 1-year-old infants. However, a substantial proportion of early SEB problems remain unidentified during contacts with child healthcare professionals. In this study, child healthcare nurse (CHCN; N = 1008) and parental (N = 518) reports about SEB worries were gathered, along with the maternal and paternal Brief Infant-Toddler Social and Emotional Assessment (BITSEA) ratings, for 12-month-old infants randomly recruited through Finnish child health centers. Only 1.4-1.8 % of CHCNs, 3.9 % of mothers, and 3.2 % of fathers reported of being worried about the assessed child's SEB development. When the CHCNs' and parental reports were combined, 7.7 % (33/428) of the infants assessed each by all three adults had one (7.0 %), two (0.7 %) or three (0 %) worry reports. Even the combination of the CHCN's and parental worry reports identified only 7.0-13.8 % of the infants with the maternal and/or paternal BITSEA Problem or Competence rating in the of-concern range. Identified associations across the three informants' worry reports, parental BITSEA ratings and sociodemographic factors are discussed in the paper. Routine and frequent use of developmentally appropriate screening measures, such as the BITSEA, might enhance identification and intervening of early SEB problems in preventive child healthcare by guiding both professionals and parents to pay more attention to substantial aspects of young children's SEB development and encouraging them to discuss possible problems and worries.

The roles of FMRP-regulated genes in autism spectrum disorder: single- and multiple-hit genetic etiologies.

Autism spectrum disorder (ASD) is a highly heritable complex neurodevelopmental condition characterized by impairments in social interaction and communication and restricted and repetitive behaviors. Although roles for both de novo and familial genetic variation have been documented, the underlying disease mechanisms remain poorly elucidated. In this study, we defined and explored distinct etiologies of genetic variants that affect genes regulated by Fragile-X mental retardation protein (FMRP), thought to play a key role in neuroplasticity and neuronal translation, in ASD-affected individuals. In particular, we developed the Trend test, a pathway-association test that is able to robustly detect multiple-hit etiologies and is more powerful than existing approaches. Exploiting detailed spatiotemporal maps of gene expression within the human brain, we identified four discrete FMRP-target subpopulations that exhibit distinct functional biases and contribute to ASD via different types of genetic variation. We also demonstrated that FMRP target genes are more likely than other genes with similar expression patterns to contribute to disease. We developed the hypothesis that FMRP targets contribute to ASD via two distinct etiologies: (1) ultra-rare and highly penetrant single disruptions of embryonically upregulated FMRP targets ("single-hit etiology") or (2) the combination of multiple less penetrant disruptions of nonembryonic, synaptic FMRP targets ("multiple-hit etiology"). The Trend test provides rigorous support for a multiple-hit genetic etiology in a subset of autism cases and is easily extendible to combining information from multiple types of genetic variation (i.e., copy-number and exome variants), increasing its value to next-generation sequencing approaches.

Thinking globally to meet local needs: autism spectrum disorders in Africa and other low-resource environments.

PURPOSE OF REVIEW: Most people with autism spectrum disorders (ASDs) live in low and middle-income countries, yet almost everything we know about ASD comes from high-income countries. Here we review recent research from Africa, with some references to research in other low-resource environments. We examine publications on screening and diagnosis, intervention, clinical presentation of ASD, cultural perspectives, and neuroscience and technology. RECENT FINDINGS: Open-access screening and diagnostic tools represent a positive, but nontrivial, future goal. Recent efforts at 'low intensity' community-based interventions are encouraging, but many significant scalability challenges remain. Proposals that ASD in Africa is more severe and overrepresented in high socioeconomic families are likely to be attributable to ascertainment biases and the absence of standardized phenotyping tools. Cultural perspectives and innovative use of technology and neuroscience have the potential to generate novel strategies of global relevance, but research priorities have to be determined by local needs. SUMMARY: To have a real impact on clinical services, training, and research in local communities, clinician-scientists should start by thinking globally. ASD research in Africa and other low-resource environments remains limited and of questionable quality and highlights the need to build high-quality research capacity in these low-resource environments.