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A Twin Study of Autism in Denmark, Finland, Iceland, Norway and Sweden
Journal of Child Psychology and Psychiatry
Abstract
The Nordic countries were screened for the occurrence of cases of autism with a same-sexed twin under age 25 years. Twenty-one pairs (11 monozygotic and 10 dizygotic) of twins and one set of identical triplets were found and extensively examined. The concordance for autism by pair was 91% in the monoygotic and 0% in the dizygotic pairs. The corresponding concordances for cognitive disorder were 91% and 30%, respectively. In most of the pairs discordant for autism, the autistic twin had more perinatal stress. The results lend support for the notion that autism sometimes has a hereditary component and that perinatal stress is involved in some cases.
... Although ASD is a neurobiological disorder of early brain development, diagnosis is currently based on a behavioral phenotype with no convincing evidence of consistent biomarkers, suggesting biological heterogeneity [1]. Multiple studies have demonstrated strong heritability components in ASD, suggesting underling genetic mechanisms (biological vulnerability, [2][3][4]). However, substantial asymmetry in the phenotype of first-degree relatives carrying the same major-disease-associated DNA variant, and frequent acute or subacute development of ASD features following a physiological stressor, suggest the addition of strong environmental components (triggers [5]). ...
... Highlighting in other columns is explained in the text. 3 This is an incomplete listing limited to selected manifestations recorded in the clinical records available. Within, GI refers to gastrointestinal manifestations, which most often included reflux, bacterial overgrowth, and/or irritable bowel. ...
... accessed on 23 December 2023). 3 Part of a contiguous gene deletion. Where a specific gene is listed, it is believed to be the Primary Diagnostic Variant (PDV). ...
Autism spectrum disorder (ASD) is a common condition with lifelong implications. The last decade has seen dramatic improvements in DNA sequencing and related bioinformatics and databases. We analyzed the raw DNA sequencing files on the Variantyx® bioinformatics platform for the last 50 ASD patients evaluated with trio whole-genome sequencing (trio-WGS). “Qualified” variants were defined as coding, rare, and evolutionarily conserved. Primary Diagnostic Variants (PDV), additionally, were present in genes directly linked to ASD and matched clinical correlation. A PDV was identified in 34/50 (68%) of cases, including 25 (50%) cases with heterozygous de novo and 10 (20%) with inherited variants. De novo variants in genes directly associated with ASD were far more likely to be Qualifying than non-Qualifying versus a control group of genes (p = 0.0002), validating that most are indeed disease related. Sequence reanalysis increased diagnostic yield from 28% to 68%, mostly through inclusion of de novo PDVs in genes not yet reported as ASD associated. Thirty-three subjects (66%) had treatment recommendation(s) based on DNA analyses. Our results demonstrate a high yield of trio-WGS for revealing molecular diagnoses in ASD, which is greatly enhanced by reanalyzing DNA sequencing files. In contrast to previous reports, de novo variants dominate the findings, mostly representing novel conditions. This has implications to the cause and rising prevalence of autism.
... Although ASD is a neurobiological disorder of early brain development, diagnosis is currently based on a behavioral phenotype with no convincing evidence of consistent biomarkers, suggesting biological heterogeneity [1]. Multiple studies have demonstrated strong heritability components in ASD, suggesting underling genetic mechanisms (biological vulnerability, [2][3][4]). However, substantial asymmetry in the phenotype of first-degree relatives carrying the same major disease-associated DNA variant, and frequent acute or subacute development of ASD features following a physiological stressor, suggest the addition of strong environmental components (triggers, [5]). ...
... This study was approved by the Advarra IRB (human subjects committee, cirbi@advarra.com) as a retrospective chart review of clinical records already available to the corresponding author prior 3 to March 1, 2023. No additional testing was performed for the purpose of this study. ...
... See Methods section for details. 2 Monogenic only, including de novo, Xlinked, autosomal recessive, autosomal dominant, maternal (mtDNA) inheritance. 3 Information available from subject is a good clinical match for phenotype described. This qualification was 4 lowered for de novo variants with little to no reported phenotype (see text). 4 See Methods section for details. . ...
Autism spectrum disorder (ASD) is a common condition with lifelong implications and a strong hereditary component suggesting genetic underpinnings. The last decade has seen dramatic improvements in DNA sequencing and related bioinformatics and databases. We analyzed the raw DNA sequencing files on the Variantyx® bioinformatics platform for the last 50 ASD patients evaluated with trio whole genome sequencing (trio-WGS). “Qualified” variants were defined as coding, rare, and evolutionarily conserved. Primary Diagnostic Variants (PDV) additionally were in genes directly linked to ASD and matched clinical correlation. A PDV was identified in 34/50 (68%) of cases, including 25 (50%) cases with heterozygous de novo and 10 (20%) with inherited variants. De novo variants in genes directly associated with ASD were far more likely to be Qualifying than non-Qualifying versus a control group of genes not associated with ASD (P = 0.0002, odds ratio 29), validating that most are indeed disease related. Only 14/34 (41%) of PDV cases had the variant listed on the laboratory report, and reanalysis increased diagnostic yield from 28% to 68%. Variants that we assigned as PDVs yet not on the report were predominately de novo in genes not yet reported as ASD associated. Many subjects both with and without a PDV had inherited Qualifying variants in known ASD-associated genes, suggesting polygenic inheritance. Thirty-three subjects (66%) had treatment recommendation(s) based on DNA analyses. Our results demonstrate high yield of trio-WGS for revealing molecular diagnoses in ASD that is greatly enhanced by re-analyzing DNA sequencing files. In contrast to previous reports, de novo variants dominate the findings, mostly representing novel conditions. This has implications to the cause and rising prevalence of autism.
... Although ASD is a neurobiological disorder of early brain development, diagnosis is currently based on a behavioral phenotype with no convincing evidence of consistent biomarkers, suggesting biological heterogeneity [1]. Multiple studies have demonstrated strong heritability components in ASD, suggesting underling genetic mechanisms (biological vulnerability, [2][3][4]). However, substantial asymmetry in the phenotype of first-degree relatives carrying the same major disease-associated DNA variant, and frequent acute or subacute development of ASD features following a physiological stressor, suggest the addition of strong environmental components (triggers, [5]). ...
... See Methods section for details. 2 De novo, X-linked, autosomal recessive, autosomal dominant, maternal (mtDNA) inheritance. 3 Information available from participant is a good clinical match for phenotype described. This qualification was waived for de novo variants with little to no reported phenotype. ...
... 2Highlighting in the penultimate column of Table 2 is for tics (13 cases, 26%) as a marker for potential PANS/PANDAS, as some level of obsessive traits is so common in autism that OCD is difficult to differentiate from background. 3 Gastrointestinal manifestations (not otherwise specified herein, often reflux, bacterial overgrowth, and/or irritable bowel). 8 ...
Autism spectrum disorder (ASD) is a common condition with lifelong implications and a strong hereditary component suggesting genetic underpinnings. The last decade has seen dramatic improvements in DNA sequencing, bioinformatics, and databases. We analyzed the raw DNA sequencing files on the Variantyx® (Framingham, MA, USA) bioinformatics platform for the last 50 autism patients evaluated with trio whole genome sequencing (trio-WGS). “Qualified” variants were defined as coding, very rare, and evolutionarily conserved. Primary Diagnostic Variants (PDV) additionally were in genes directly linked to ASD. A PDV was identified in 34/50 (68%) of cases, including 25 (50%) heterozygous de novo, 3 X-linked, 4 autosomal recessive, 2 autosomal dominant, and 1 heteroplasmic mtDNA variants. De novo variants in genes associated with ASD were far more likely to be Qualified than non-Qualified (control group, P = 0.002), validating that most are indeed disease causal. Only 14/34 (41%) of PDV cases had the variant listed on the laboratory report, and reanalysis increased diagnostic yield from 28% to 68%. The “missed” cases predominately included genes with zero (14 cases) to ≤5 prior reported case reports. Many cases both with and without a PDV had inherited Qualifying variants in known ASD-associated genes, suggesting polygenic inheritance. Thirty-three participants (66%) had treatment recommendation(s) based on DNA analyses. Our results demonstrate high yield of trio-WGS for revealing molecular diagnoses in ASD that is greatly enhanced by re-analyzing DNA sequencing files. Many are de novo and represent un/under-published conditions.
... We did not find any association between paternal perinatal mood disorders and ASD, conflicting with finding of the previous study that reported an association between paternal perinatal depression and ASD of offspring (Chen et al. 2020). ASD is known as a highly heritable developmental disorder (Bailey et al. 1995;Folstein and Rutter 1977;Lichtenstein et al. 2010;Muhle et al. 2004;Steffenburg et al. 1989), and mood disorders often coexist in people with ASD (Lainhart 1999). Presumably, fathers with genetic traits for ASD would be more likely to develop depressive symptoms during the perinatal period than those without these genetic traits. ...
Perinatal mood disorders affect both parents, impacting their children negatively. Little is known on the association between parental perinatal mood disorders and pediatric outcomes in Japan considering relevant covariates. Our objective was to investigate the association between paternal and maternal perinatal mood disorders and adverse physical and psychological child outcomes by the age of 36 months, adjusting for covariates such as the child’s sex, age of parent at child’s birth, perinatal mood disorders of the other parent, and perinatal antidepressant use.
We identified parents in the JMDC Claims Database in Japan from 2012 to 2020. Perinatal mood disorders were defined using International Classification of Diseases, 10th codes for mood disorders during the perinatal period combined with psychiatric treatment codes. We evaluated the association between parental perinatal mood disorders and pediatric adverse outcomes by the age of 36 months using Cox proportional hazard models adjusted for the covariates.
Of the 116,423 father-mother-child triads, 2.8% of fathers and 2.3% of mothers had perinatal mood disorders. Paternal perinatal mood disorders were not significantly associated with adverse child outcomes. After adjusting for paternal perinatal mood disorders and antidepressant use, maternal perinatal mood disorders were associated with delayed motor development, language development disorders, autism spectrum disorders, and behavioral and emotional disorders (adjusted hazard ratio [95% confidence interval]: 1.65 [1.01–2.69], 2.26 [1.36–3.75], 4.16 [2.64–6.55], and 6.12 [1.35–27.81], respectively).
Paternal perinatal mood disorders were not associated with adverse child outcomes in this population. Maternal perinatal mood disorders were associated with multiple child outcomes.
... In contrast, the risk of ASD in second-and third-degree relatives of patients with ASD is about 0.18% and 0.12%, respectively [29,33,34]. In twin studies, monozygotic twins show a higher concordance rate than dizygotic twins [35][36][37][38]. ...
Autism spectrum disorder (ASD) is a heterogeneous developmental disorder characterized by impairments in two core areas: 1) social communication and interaction and 2) restricted and repetitive patterns of behaviors and interests. In general, ASD is known to be a lifelong disorder. Follow-up studies from childhood to adulthood have reported that the severity of the key symptoms ASD decreases over time. However, chronic health problems including mental health occur in many patients with ASD. The prevalence of ASD has increased from around 0.04% in the 1970s to 2.8% at present. The average age of diagnosis in developed countries is 38–120 months of age. Recent evidence suggests that biological factors which include genetic, congenital, immunological, neuroanatomical, biochemical, and environmental ones are important in causing autism. Until now, early signs and various risk factors of ASD have been suggested.
... The etiology of autism spectrum disorder (ASD) and epilepsy is still not fully known so far. They were once regarded as genetic diseases [28][29][30]. However, some studies have reported that both genetic and environmental factors can contribute to these diseases [31][32][33]. ...
The objective of this study was to evaluate the effects of high levels of maternal exposure to ambient air pollution and heavy metals on risks of autism spectrum disorder (ASD) and epilepsy using the National Health Insurance claims data of South Korea. The data of mothers and their newborns from 2016 to 2018 provided by the National Health Insurance Service were used (n = 843,134). Data on exposure to ambient air pollutants (PM2.5, CO, SO2, NO2, and O3) and heavy metals (Pb, Cd, Cr, Cu, Mn, Fe, Ni, and As) during pregnancy were matched based on the mother’s National Health Insurance registration area. SO2 (OR: 2.723, 95% CI: 1.971–3.761) and Pb (OR: 1.063, 95% CI: 1.019–1.11) were more closely associated with the incidence of ASD when infants were exposed to them in the third trimester of pregnancy. Pb (OR: 1.109, 95% CI: 1.043–1.179) in the first trimester of pregnancy and Cd (OR: 2.193, 95% CI: 1.074–4.477) in the third trimester of pregnancy were associated with the incidence of epilepsy. Thus, exposure to SO2, NO2, and Pb during pregnancy could affect the development of a neurologic disorder based on the timing of exposure, suggesting a relationship with fetal development. However, further research is needed.
... The pathogenesis of ASD is complicated, with genetic factors being one of the important factors causing ASD (Abrahams and Geschwind, 2008;Rylaarsdam and Guemez-Gamboa, 2019). Some early studies showed that the incidence of ASD in monozygotic twins was 30-90% while that in dizygotic twins was only 0-10%, suggesting that ASD may have a genetic provenance (Bailey et al., 1995;Steffenburg et al., 1989). In addition, some cases of ASD have been observed to be accompanied by immune abnormalities, which indicates that dysfunction of the immune system may play a role in the development of ASD (Careaga et al., 2010). ...
Autism spectrum disorders (ASD), also known as childhood autism, is a common neurological developmental disorder. Although it is generally believed that genetic factors are a primary cause for ASD development, more and more studies show that an increasing number of ASD diagnoses are related to environmental exposure. Epidemiological studies indicated that perinatal exposure to endocrine disruptors might cause neurodevelopmental disorders in children. Di-(2-ethylhexyl) phthalate (DEHP) is widely used as a plasticizer in many products. To explore the neurodevelopmental effect induced by perinatal exposure to DEHP on rat offspring, and the potential mechanisms, female Wistar rats were exposed to 1, 10, and 100 mg/kg/day DEHP during pregnancy and lactation, while valproic acid (VPA) was used as a positive control. The behavior tests showed that rat pups exposed to VPA and 100 mg/kg/day DEHP were not good as those from the control group in both their socialability and social novelty. Expression of mTOR pathway-related components increased while the number of autophagosomes decreased in the brain tissue of the rat offspring exposed to 100 mg/kg/day DEHP. In addition, perinatal exposure to DEHP at all dosages decreased the level of autophagy proteins LC3II and Beclin1 in the brain tissue of rat pups. Our results indicated that perinatal DEHP exposure would induce ASD-like behavioral changes in rat offspring, which might be mediated by activation of the mTOR signaling pathway, and inhibition of autophagy in the brain.
... Considering that the heritable contribution in ASDs spans from 40% [37] to 80% [38,39], GWAS genetic studies have been instrumental in disentangling the etiology of these disorders. Common genetic variants [40], inherited gene disruptive mutations [41], and rare variants [32] are the main players in disease pathogenesis. ...
The advent of next-generation sequencing (NGS) is heavily changing both the diagnosis of human conditions and basic biological research. It is now possible to dig deep inside the genome of hundreds of thousands or even millions of people and find both common and rare genomic variants and to perform detailed phenotypic characterizations of both physiological organs and experimental models. Recent years have seen the introduction of multiple techniques using NGS to profile transcription, DNA and chromatin modifications, protein binding, etc., that are now allowing us to profile cells in bulk or even at a single-cell level. Although rare and ultra-rare diseases only affect a few people, each of these diseases represent scholarly cases from which a great deal can be learned about the pathological and physiological function of genes, pathways, and mechanisms. Therefore, for rare diseases, state-of-the-art investigations using NGS have double valence: their genomic cause (new variants) and the characterize the underlining the mechanisms associated with them (discov-ery of gene function) can be found. In a non-exhaustive manner, this review will outline the main usage of NGS-based techniques for the diagnosis and characterization of neurodevelopmental disorders (NDDs), under whose umbrella many rare and ultra-rare diseases fall.
... sequencing studies have led to the identification of a growing list of "high confidence" genes that are strongly associated with ASD and are beginning to reveal common biological pathways. ASDs are known to be highly heritable, with greater concordance rates among monozygotic (50-90%) compared to dizygotic (up to 30%) twins (12)(13)(14)(15)(16)(17)(18). Early efforts at gene discovery in ASD led to the identification of genes associated with rare monogenic disorders, including Fragile X syndrome (FMR1), tuberous sclerosis complex (TSC1, TSC2), Rett syndrome (MECP2), and PTEN hamartoma tumor syndrome (PTEN) [reviewed in (19)]. ...
Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders associated with deficits in social communication and restrictive, repetitive patterns of behavior, that affect up to 1 in 54 children. ASDs clearly demonstrate a male bias, occurring ~4 times more frequently in males than females, though the basis for this male predominance is not well-understood. In recent years, ASD risk gene discovery has accelerated, with many whole-exome sequencing studies identifying genes that converge on common pathways, such as neuronal communication and regulation of gene expression. ASD genetics studies have suggested that there may be a “female protective effect,” such that females may have a higher threshold for ASD risk, yet its etiology is not well-understood. Here, we review common biological pathways implicated by ASD genetics studies as well as recent analyses of sex differential processes in ASD using imaging genomics, transcriptomics, and animal models. Additionally, we discuss recent investigations of ASD risk genes that have suggested a potential role for estrogens as modulators of biological pathways in ASD, and highlight relevant molecular and cellular pathways downstream of estrogen signaling as potential avenues for further investigation.
... ASD was regarded as a genetic disease previously [3,22,42,43], but the concordance of monozygotic pairs was not fully explained by genetics [1]. Recent twin studies estimated that environmental factors contribute about as equally as genetic factors, and the reasons for this change may include the limitations in case numbers, inclusion criteria, and case definition in early studies [23,24]. ...
Air pollutants have been linked to some diseases in humans, but their effects on the nervous system were less frequently evaluated. Autism spectrum disorder (ASD) is a group of neurondevelopmental disorders of which the etiology is still unknown. We conducted a study in Taiwan to evaluate the possible associations between prenatal exposure to air pollutants and ASD. From a random sample of one million people in the National Insurance Research Database, we identified all the infants born between 1996 and 2000. We followed them till the end of 2013 and identified cases of ASD. We traced back the mothers’ residence and assessed the exposure to air pollutants using the data obtained from the air quality monitoring database maintained by the government, which included ozone (O3), carbon monoxide (CO), nitrogen dioxide (NO2), sulfur dioxide (SO2), and particulate matters with diameter less than 10 µm (PM10). Cox proportional hazard models were constructed to evaluate the associations between childhood ASD and exposures to the pollutants in the three trimesters and the whole gestation. We identified a total of 63,376 newborns and included 62,919 as the study cohort. After adjusting for other risk factors, we observed trimester-specific associations between levels of CO, NO2, and PM10 and the risk of childhood ASD. An increase of 1 ppm of CO in the first, second, and third trimester was associated with a hazard ratio (HR) of 1.93 (95% confidence interval [CI]: 1.55–2.39), 1.77 (95%CI: 1.41–2.22), and 1.75 (95%CI: 1.39–2.21), respectively. An increase of 10 ppb in the level of NO2 in the first, second, and third trimester was associated with an HR of 1.39 (95%CI: 1.22–1.58), 1.25 (95%CI: 1.10–1.42), and 1.18 (95%CI: 1.03–1.34), respectively. In conclusion, we found that exposures to CO and NO2 in all three trimesters were associated with increased risks of developing ASD.
... accessed on 2 July 2021), currently, the prevalence of ASD is 1 in 54 children and is more common among boys. Autism is a heterogeneous disorder with a high heritability [3,4]. A meta-analysis of twin studies on ASD show high heritability for monozygotic twins (MZ), with estimates ranging between 64-91% [5]. ...
Autism Spectrum Disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders with a strong heritable genetic component. At present, ASD is diagnosed solely by behavioral criteria. Advances in genomic analysis have contributed to numerous candidate genes for the risk of ASD, where rare mutations and s common variants contribute to its susceptibility. Moreover, studies show rare de novo variants, copy number variation and single nucleotide polymorphisms (SNPs) also impact neurodevelopment signaling. Exploration of rare and common variants involved in common dysregulated pathways can provide new diagnostic and therapeutic strategies for ASD. Contributions of current innovative molecular strategies to understand etiology of ASD will be explored which are focused on whole exome sequencing (WES), whole genome sequencing (WGS), microRNA, long non-coding RNAs and CRISPR/Cas9 models. Some promising areas of pharmacogenomic and endophenotype directed therapies as novel personalized treatment and prevention will be discussed.
... Considerable evidence from family and twin studies indicate that the etiology of autism is largely genetic (Bourgeron, 2016;Steffenburg et al., 1989). Concordance rates range from 60-96% in monozygotic (MZ) twins compared to 0-23% in dizygotic (DZ) twins depending upon the sample and diagnostic boundaries (Bailey et al., 1995); a 2009 study of 277 twin pairs (Rosenberg et al., 2009) found concordance of 31% for DZ and 88% for MZ pairs. ...
Objective: Given the high population prevalence of Autism Spectrum Disorder (ASD) and overlapping symptoms with medically complex groups, ASD is a common rule out diagnosis for neuropsychologists even when not identified in the referral or initial presenting concerns. This paper presents practical guidance to support neuropsychologists in their ability to accurately assess, diagnose, and/or rule out ASD, especially in patients with more subtle presentations. Method: This paper combines clinical experience and empirical literature to highlight important assessment measures and related considerations, differential diagnostic considerations, common misconceptions about ASD and person/family characteristics, as well as variability in presentation and comorbidities that can obscure the diagnosis. Characteristics that may be considered “red flags” (clearly diagnostic, classic symptoms) and “pink flags” (associated features and symptoms that are suggestive of ASD but not quite definitive and that may overlap with symptoms seen in other neurodevelopmental or psychiatric diagnoses) will be discussed. Conclusions: Neuropsychologists in all clinical settings should be able to effectively screen for and/or diagnose ASD, even when its presentation is more subtle and/or when symptoms are masked by patient strengths in a way that makes their clinical presentation less obvious. Practical strategies for communicating the diagnosis and next steps/recommendations for interventions are reviewed.
... Autism spectrum disorder (ASD) is a highly heritable neurodevelopmental disability with an estimated clinical concordance of about 60-95% between monozygotic twins and 0-10% between dizygotic twins (Le Couteur et al., 1995;Steffenburg et al., 1989). ASD is characterized by earlyonset in childhood, atypical and repetitive behaviors, sensory anomalies and limitations in communication and social interaction (Bacchelli et al., 2019;Lord et al., 2020). ...
Autism spectrum disorder (ASD) is a neurodevelopmental disability with high heritability yet the genetic etiology remains elusive. Therefore, it is necessary to elucidate new genotype–phenotype relationships for ASD to improve both the etiological knowledge and diagnosis. In this work, a copy‐number variant and whole‐exome sequencing analysis were performed in an ASD patient with a complex neurobehavioral phenotype with epilepsy and attention deficit hyperactivity disorder. We identified rare recessive single nucleotide variants in the two genes, PLXNA2 encoding Plexin A2 that participates in neurodevelopment, and LRRC40, which encodes Leucine‐rich repeat containing protein 40, a protein of unknown function. PLXNA2 showed the heterozygous missense variants c.614G>A (p.Arg205Gln) and c.4904G>A (p.Arg1635Gln) while LRRC40 presented the homozygous missense variant c.1461G>T (p.Leu487Phe). In silico analysis predicted that these variants could be pathogenic. We studied PLXNA2 and LRRC40 mRNA and proteins in fibroblasts from the patient and controls. We observed a significant PlxnA2 subcellular delocalization and very low levels of LRRC40 in the patient. Moreover, we found a novel interaction between PlxnA2 and LRRC40 suggesting that participate in a common neural pathway. This interaction was significant decreased in the patient's fibroblasts. In conclusion, our results identified PLXNA2 and LRRC40 genes as candidates in ASD providing novel clues for the pathogenesis. Further attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD.
Lay Summary
Genomics is improving the knowledge and diagnosis of patients with autism spectrum disorder (ASD) yet the genetic etiology remains elusive. Here, using genomic analysis together with experimental functional studies, we identified in an ASD complex patient the PLXNA2 and LRRC40 recessive genes as ASD candidates. Furthermore, we found that the proteins of these genes interact in a common neural network. Therefore, more attention to these genes is warranted in genetic studies of patients with neurodevelopmental disorders, particularly ASD.
... Each of these SNPs has a small effect size, but their additive action determines the difference in liability within the population [9]. While population-based studies [9] and twin studies [10][11][12][13] have provided compelling evidence for a role of common variation in ASD risk, the reproducibility of candidate loci has been hampered by the small sample size (and consequent limited statistical power) of early genome-wide associated studies (GWAS) [14][15][16]. Recently, a much larger GWAS meta-analysis on >18,000 ASD cases contrasted to >27,900 ancestry-matched controls has pinpointed 5 genome-wide significant loci [17]. ...
Autism spectrum disorder (ASD) is a prevalent neurodevelopmental disorder characterized by impairments in social communication and social interaction, and the presence of repetitive behaviors and/or restricted interests. In the past few years, large-scale whole-exome sequencing and genome-wide association studies have made enormous progress in our understanding of the genetic risk architecture of ASD. While showing a complex and heterogeneous landscape, these studies have led to the identification of genetic loci associated with ASD risk. The intersection of genetic and transcriptomic analyses have also begun to shed light on functional convergences between risk genes, with the mid-fetal development of the cerebral cortex emerging as a critical nexus for ASD. In this review, we provide a concise summary of the latest genetic discoveries on ASD. We then discuss the studies in postmortem tissues, stem cell models, and rodent models that implicate recently identified ASD risk genes in cortical development.
... El riesgo de padecer un Trastorno del Espectro Autista en familiares de personas autistas sería del 20% (Ozonoff et al., 2011). Por último, las posibilidades de que aparezca el trastorno aumentan de forma considerable cuando se trata de gemelos monocigóticos (70-90%) frente a gemelos dicigóticos (0-10%) (Bailey et al., 1995;Ronald & Hoekstra, 2011;Steffenburg et al., 1989). Por otro lado, se observa una prevalencia aproximada del 4% entre hermanos no gemelos de personas con autismo (Bonora, Lamb, Barnby, Bailey & Monaco, 2006) que difiere bastante de la prevalencia en la población general, que se estima que es entre el 0.1% y 0.16% (Fombonne, 2005). ...
Based on the distinction between "hot" and "cool" executive functions
(Zelazo & Müller, 2002), a research line that aims to study the relationship
between executive functions related to emotions (―hot") and socio-emotional
deficits observed in ASD, began. The main objective of this study is to analyze
the psychopathological correlates of emotional deficits in ASD.
This work arises in this theoretical framework and aims to study socioemotional
deficits in adults with autism, in relation to both "hot" and ―cool‖
executive dysfunctions, social maturity, autistic traits and comorbid
psychopathology, specifying which variables influence or explain the perception
of emotions in Autism Spectrum Disorders. Four experiments were designed,
linked to the 4 general objectives of the research:
1. Confirm the presence of emotional perception deficits in adults with ASD, compared to the control group (no TEA).
2. Confirm the presence of deficits in executive functions attributed to the ASD group, compared to the control group (no TEA).
3. Specify which variables influence, or explain, the perception of emotions in adults with autism, in order to find out the nature of emotional deficits in people with autism.
4. Establish if certain emotional permeability exists in the experimental group (TEA), through a task of emotion induction.
... Secondly, if a new-born infant has an affected sibling, the risk of ASD development increase to 25-fold compared to the normal population risk (Abrahams and Geschwind 2008). Thirdly, twin studies have shown that identical twins have around a 60-90% chance of being diagnosed with autism, while the risk of autism in nonidentical twins declines noticeably to 0-24% (Bailey et al. 1995;Steffenburg et al. 1989). Nevertheless, according to the most comprehensive study, completed with 503 ASD twins in California, the risk levels in the heritability rate have been overestimated. ...
Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous with hundreds of identified risk genes, most affecting only a few patients. Novel missense variants in these genes are being discovered as clinical exome sequencing is now routinely integrated into diagnosis, yet most of them are annotated as variants of uncertain significance (VUS). VUSs are a major roadblock in using patient genetics to inform clinical action. We developed a framework to characterize VUSs in Coiled-coil and C2 domain containing 1A (CC2D1A), a gene causing autosomal recessive ID with comorbid ASD in 40% of cases. We analyzed seven VUSs (p.Pro319Leu, p.Ser327Leu, p.Gly441Val, p.Val449Met, p.Thr580Ile, p.Arg886His and p.Glu910Lys) from four cases of individuals with ID and ASD. Variants were cloned and overexpressed in HEK293 individually and in their respective heterozygous combination. CC2D1A is a signaling scaffold that positively regulates PKA-CREB signaling by repressing phosphodiesterase 4D (PDE4D) to prevent cAMP degradation. After testing multiple parameters including direct interaction between PDE4D and CC2D1A, cAMP levels and CREB activation, we found that the most sensitive readout was CREB transcriptional activity using a luciferase assay. Compared to WT CC2D1A, five VUSs (p.Pro319Leu, p.Gly441Val, p.Val449Met, p.Thr580Ile, and p.Arg886His) led to significantly blunted response to forskolin induced CREB activation. This luciferase assay approach can be scaled up to annotate ~150 CC2D1A VUSs that are currently listed in ClinVar. Since CREB activation is a common denominator for multiple ASD/ID genes, our paradigm can also be adapted for their VUSs.
Autism Spectrum Disorders (ASDs) is a complex neurodevelopmental disorder characterized by restrictive repetitive behaviour and impairment in social and communication skills. It is extremely heterogeneous with a strong genetic preponderance. It’s clinically highly convoluted, represented with multiple comorbid conditions and syndromic features. More than 100 genes have been identified till date that are associated with syndromic ASDs. Whole exome sequencing (WES) has emerged as a valuable tool in evaluating the genetic underpinnings of ASDs, be it the syndromic or the idiopathic variants. The current study leverages the utility of WES in a multiplex family of Indian origin to identify the disease etiology in the siblings (01S1 (Female) and 01S2 (Male)) exhibiting ASD syndromic features, at both clinical and molecular levels.
Our systematic bioinformatic analysis identified a missense mutation (NM_030665.4:c.5320C > T; p.Arg1774Trp) in 01S1 resulting in RAI1 haploinsufficiency. Validation by sanger sequencing confirmed the novelty of the said mutation and that it was true positive and maternally transmitted in the subject. Likewise, we report a missense mutation at the same locus (17p11.2) corresponding to the FLII gene (NM_002018.4:c.2030A > C;p.Glu677Ala) in the other sibling, 01S2. Both the mutations were reported in the Smith Magenis Syndrome (SMS) critical region justifying its contribution to the presentation of the syndromic SMS features. These WES findings were consistent with the clinical findings that imply SMS features in both siblings. The current study employs WES to provide insights into the complex molecular mechanism associated with syndromic ASD highlighting the different processes that contribute to the disease heterogeneity. Moving forward, combinatorial approaches and findings from syndromic ASDs can potentially act as indicators to understand the genetic and phenotypic variations seen in the idiopathic ASD.
Understanding the genetic basis for complex, heterogeneous disorders, such as autism spectrum disorder (ASD), is a persistent challenge in human medicine. Owing to their phenotypic complexity, the genetic mechanisms underlying these disorders may be highly variable across individual patients. Furthermore, much of their heritability is unexplained by known regulatory or coding variants. Indeed, there is evidence that much of the causal genetic variation stems from rare and de novo variants arising from ongoing mutation. These variants occur mostly in noncoding regions, likely affecting regulatory processes for genes linked to the phenotype of interest. However, because there is no uniform code for assessing regulatory function, it is difficult to separate these mutations into likely functional and nonfunctional subsets. This makes finding associations between complex diseases and potentially causal de novo single-nucleotide variants (dnSNVs) a difficult task. To date, most published studies have struggled to find any significant associations between dnSNVs from ASD patients and any class of known regulatory elements. We sought to identify the underlying reasons for this and present strategies for overcoming these challenges. We show that, contrary to previous claims, the main reason for failure to find robust statistical enrichments is not only the number of families sampled, but also the quality and relevance to ASD of the annotations used to prioritize dnSNVs, and the reliability of the set of dnSNVs itself. We present a list of recommendations for designing future studies of this sort that will help researchers avoid common pitfalls.
A neurological abnormality called autism spectrum disorder (ASD) affects how a person perceives and interacts with others, leading to social interaction and communication issues. Limited and recurring behavioural patterns are another feature of the illness. Multiple mutations throughout development are the source of the neurodevelopmental disorder autism. However, a well-established model and perfect treatment for this spectrum disease has not been discovered. The rising era of the clustered regularly interspaced palindromic repeats (CRISPR)-associated protein 9 (Cas9) system can streamline the complexity underlying the pathogenesis of ASD. The CRISPR-Cas9 system is a powerful genetic engineering tool used to edit the genome at the targeted site in a precise manner. The major hurdle in studying ASD is the lack of appropriate animal models presenting the complex symptoms of ASD. Therefore, CRISPR-Cas9 is being used worldwide to mimic the ASD-like pathology in various systems like in vitro cell lines, in vitro 3D organoid models and in vivo animal models. Apart from being used in establishing ASD models, CRISPR-Cas9 can also be used to treat the complexities of ASD. The aim of this review was to summarize and critically analyse the CRISPR-Cas9-mediated discoveries in the field of ASD.
Specific and effective treatments for autism spectrum disorder (ASD) are lacking due to a poor understanding of disease mechanisms. Here we test the idea that similarities between diverse ASD mouse models are caused by deficits in common molecular pathways at neuronal synapses. To do this, we leverage the availability of multiple genetic models of ASD that exhibit shared synaptic and behavioral deficits and use quantitative mass spectrometry with isobaric tandem mass tagging (TMT) to compare their hippocampal synaptic proteomes. Comparative analyses of mouse models for Fragile X syndrome ( Fmr1 knockout), cortical dysplasia focal epilepsy syndrome ( Cntnap2 knockout), PTEN hamartoma tumor syndrome ( Pten haploinsufficiency), ANKS1B syndrome ( Anks1b haploinsufficiency), and idiopathic autism (BTBR+) revealed several common altered cellular and molecular pathways at the synapse, including changes in oxidative phosphorylation, and Rho family small GTPase signaling. Functional validation of one of these aberrant pathways, Rac1 signaling, confirms that the ANKS1B model displays altered Rac1 activity counter to that observed in other models, as predicted by the bioinformatic analyses. Overall similarity analyses reveal clusters of synaptic profiles, which may form the basis for molecular subtypes that explain genetic heterogeneity in ASD despite a common clinical diagnosis. Our results suggest that ASD-linked susceptibility genes ultimately converge on common signaling pathways regulating synaptic function and propose that these points of convergence are key to understanding the pathogenesis of this disorder.
Background
Identifying signs of autism is essential for enabling timely diagnosis and intervention. Children from multiethnic and socioeconomic disadvantaged settings are typically diagnosed with autism later than their general peers. This feasibility study explored the psychometric properties of a new instrument, Joint Attention Observation Schedule Preschool (JA-OBS Preschool), in children with suspected autism.
Methods
Data were collected from a prospective longitudinal study of 46 children aged 2–4 years who lived in a multiethnic, low resource area. The children had been referred from the Child Health Centre to a multiprofessional team for a neuropsychiatric assessment. In the diagnostic process, the instrument JA-OBS Preschool for observation of a child's capability of engaging in joint attention was included. Descriptive statistics and Cronbach's alfa were used to analyze the psychometric properties, including internal consistency reliability and inter-rater consistency.
Results
All 46 children with suspected autism screened positive on the JA-OBS Preschool. The internal consistency reliability of the instrument was calculated at 0.8 (Cronbach's alfa). Percent agreement between two examiners in JA-OBS Preschool ranged from 77% to 100%.
Conclusion
JA-OBS Preschool was found to be a promising instrument for identifying signs of autism in children in this setting. However, further research is needed to determine the psychometric properties of the JA-OBS Preschool in a general child population as well as in a younger age group.
O Transtorno do Espectro do Autista (TEA) inclui estados clínicos variados, identificados por dificuldades de linguagem e interação social. Recentemente, pesquisas demonstraram que uma inflamação em células cerebrais pode estar associada ao desenvolvimento de uma forma grave do TEA. Tendo em vista que distúrbios gestacionais prejudicam diretamente o desenvolvimento fetal, o Diabetes Mellitus Gestacional (DMG), geralmente se desenvolve perto do terceiro trimestre de gravidez devido à uma resistência à insulina provocada pelos hormônios da gestação. Essa condição tem se apresentado como um grande fator responsável pelo surgimento do TEA nesta fase, devido ao aumento do índice glicêmico estar diretamente relacionado com as disfunções do desenvolvimento cerebral do feto. A hiperglicemia intrauterina pode afetar as conexões neurais ao formar toxinas que são formadas por meio de uma reação não enzimática entre açúcares redutores e proteínas, fosfolipídeos ou ácidos nucleicos. Portanto, realizou-se uma revisão bibliográfica sobre a influência da DMG no TEA, evidenciando sua relação de tal maneira a elucidar e otimizar tanto as áreas de pesquisas e estudos, quanto às unidades de saúde e gestantes, trabalhando na conscientização e no acompanhamento. O abordamento do TEA vem sendo muito discutido nos dias atuais, por ser denominado como um novo transtorno gera-se a necessidade de encontrar as causas para a formação deste distúrbio neuronal. Por tal razão, torna-se indispensável o estudo da formação das primeiras conexões neurais, formadas no momento da gestação, e quais questões podem acometê-las.
Statistics have shown an endemic worldwide increase of Autistic Spectrum Disorders (ASD) since the 1960s. Autistic disorders are characterized by three major behavioral disorders: impaired social interaction, impaired communication, and impaired imagination and social creativity. The usage of Socially Assistive Robots (SAR) in autism screening and treatment has been increasing in recent years. In this chapter, after reviewing the most important findings of using SAR in autism area, I present some of our recent findings on the clinical application of two interactive social humanoid robots (i.e., NAO and ALICE with the Iranian names of Nima and Mina) as medical assistants in the treatment and education of children with autism in Iran in order to improve their social and cognitive skills. We, i.e., my colleagues and I, have designed and implemented a set of robot-assisted therapeutic games based on the regular tasks done in autism therapy centers with the following topics: (a) Investigation of social robots’ acceptability and effect on improving the fine/gross movement imitation of children with autism, (b) Individual clinical intervention program: Exploring the effect of a robot-assisted music-education program on children with ASD's fundamental knowledge of music and their socio-cognitive skills improvement, (c) Group clinical intervention program: The impact of humanoid robots on improving the social and cognitive skills of children with high-functioning autism, and (d) Human-Robot interaction for autism treatment on a pair of twins with autism, one of whom was high-functioning and the other low-functioning. During our experimental setup, the results indicated that our social robots, Nima and Mina, were accepted by ∼70% of the participants with ASD as a communication tool from the first interaction. We also observed some improvement in joint attention and fine movement imitation skills (especially during the music-education program) of both the high-functioning and low-functioning subjects with ASD. It was observed that the high-functioning children's social skills improved due to the robot-assisted group therapy sessions, while the stereotyped behaviors of the low-functioning subjects decreased somewhat during the course of this program. Our hope is such studies aid in effective improvement in autism treatment as well as reduces its applicable costs in the world.
Purpose
This meta-analysis aimed to clarify the relationship between particulate matter (PM) and autism spectrum disorder (ASD) in detail.
Methods
A systematic literature search was performed using eight databases before April 9, 2022. The estimated effects were combined separately according to the PM type. Subgroup analyses were conducted in terms of the study design type, study location, exposure window, birth year, and sex.
Results
PM2.5 was associated with an increased risk of ASD, while PM10 was not. PMc, PM1, and diesel particulate matter (DPM) were also associated with an increased risk of ASD. Specifically, a 10 μg/m³ increase in PM2.5 was associated with a 1.337-fold increased risk of ASD in children, and a 10 μg/m³ increase in PMc and PM1 may increase the risk of ASD by 1.062 and 3.643 times, respectively. PM2.5 exposure may increase the risk of ASD in boys. Exposure to PMc might increase the risk of ASD in children born after the year 2000. The combined results of different PM differed between studies with continuous and non-continuous data for different study design type, study location, and birth year. The sensitive window for PM2.5 exposure to increase the risk of ASD may be from the first, second, and third trimesters to the first year of the postnatal period. Exposure to PMc during pregnancy was significantly associated with ASD.
Conclusion
Exposure to PM2.5 may increase the risk of ASD in boys. Exposure to PM2.5 during the first, second, and third trimesters and postnatally increased the risk of ASD.
Etiology of autism spectrum disorders (ASD) is as enigmatic as it is complex. Linking genetic, hormonal and environmental factors, several studies proposed a multi-hit model, were the interactions between increased testosterone, certain genetic mutations and prenatal immunological stress drive ASD development. Stimuli that induce maternal immune activation are however heterogenous and while some have reported an association between ASD manifestation and an infection during fetal development, others did not reproduce these findings. Common outcome of various pathogenic as well as sterile stimuli that induce immune response is the formation of neutrophil extracellular traps (NETs). Since NETs themselves are pro-inflammatory and may affect blood-brain barrier permeability, we hypothesize that their formation might be an initiating factor of ASD development in predisposed individuals. NETs can also induce formation of other NETs, so the initial immune response resulting in their formation may perpetuate the inflammation even without further stimuli. We propose that NETs formation in mother induced during fetal development may be a potential driver of ASD phenotypic manifestation and therefore constitute a potential therapeutic target.
Autism spectrum disorder (ASD) is a neurodevelopmental illness that leads to repetitive behavior and debilitates social communication. Genetic changes such as susceptible genes and environmental factors promote ASD pathogenesis. Mutations in neuroligins ( NLGNs ) and neurexin ( NRXNs ) complex which encode cell adhesion molecules have a significant part in synapses formation, transcription, and excitatory–inhibitory balance. The ASD pathogenesis could partly, at the least, be related to synaptic dysfunction. Here, the NRXNs and NLGNs genes and signaling pathways involved in the synaptic malfunction that causes ASD have been reviewed. Besides, a new insight of NLGNs and NRXNs genes in ASD will be conferred.
More than a hundred genes have been identified that, when disrupted, impart large risk for autism spectrum disorder (ASD). Current knowledge about the encoded proteins — although incomplete — points to a very wide range of developmentally dynamic and diverse biological processes. Moreover, the core symptoms of ASD involve distinctly human characteristics, presenting challenges to interpreting evolutionarily distant model systems. Indeed, despite a decade of striking progress in gene discovery, an actionable understanding of pathobiology remains elusive. Increasingly, convergent neuroscience approaches have been recognized as an important complement to traditional uses of genetics to illuminate the biology of human disorders. These methods seek to identify intersection among molecular-level, cellular-level and circuit-level functions across multiple risk genes and have highlighted developing excitatory neurons in the human mid-gestational prefrontal cortex as an important pathobiological nexus in ASD. In addition, neurogenesis, chromatin modification and synaptic function have emerged as key potential mediators of genetic vulnerability. The continued expansion of foundational ‘omics’ data sets, the application of higher-throughput model systems and incorporating developmental trajectories and sex differences into future analyses will refine and extend these results. Ultimately, a systems-level understanding of ASD genetic risk holds promise for clarifying pathobiology and advancing therapeutics. A large number of genes have been associated with risk of developing autism spectrum disorder (ASD). In this Review, State and colleagues examine the genetics and genomics of ASD and discuss findings from convergent neuroscience approaches that aim to understand how such genes may contribute to ASD pathobiology.
Background: Autism spectrum disorder (ASD) is a clinically and genetically heterogeneous group of pervasive neurodevelopmental disorders with a strong hereditary component. Although, genome-wide linkage scans (GWLS) and association studies (GWAS) have previously identified hundreds of ASD risk gene loci, the results remain inconclusive. Method: We performed a heterogeneity-based genome search meta-analysis (HEGESMA) of 15 genome scans of autism and ASD. Results: For strictly defined autism, data were analyzed across six separate genome scans. Region 7q22-q34 reached statistical significance in both weighted and unweighted analyses, with evidence of significantly low between-scan heterogeneity. For ASDs (data from 12 separate scans), chromosomal regions 5p15.33-5p15.1 and 15q22.32-15q26.1 reached significance in both weighted and unweighted analyses but did not reach significance for either low or high heterogeneity. Region 1q23.2-1q31.1 was significant in unweighted analyses with low between-scan heterogeneity. Finally, region 8p21.1-8q13.2 reached significant linkage peak in all our meta-analyses. When we combined all available genome scans (15), the same results were produced. Conclusions: This meta-analysis suggests that these regions should be further investigated for autism susceptibility genes, with the caveat that autism spectrum disorders have different linkage signals across genome scans, possibly because of the high genetic heterogeneity of the disease.
To determine the contribution of defective splicing in Autism Spectrum Disorders (ASD), the most common neurodevelopmental disorder, a high throughput Ma ssively P arallel S plicing Assa y (MaPSY) was employed and identified 42 exonic splicing mutants out of 725 coding de novo variants discovered in the sequencing of ASD families. A redesign of the minigene constructs in MaPSY revealed that upstream exons with strong 5’ splice sites increase the magnitude of skipping phenotypes observed in downstream exons. Select hits were validated by RT-PCR and amplicon sequencing in patient cell lines. Exonic splicing mutants were enriched in probands relative to unaffected siblings -especially synonymous variants (7.5% vs 3.5%, respectively). Of the 26 genes disrupted by exonic splicing mutations, 6 were in known ASD genes and 3 were in paralogs of known ASD genes. Of particular interest was a synonymous variant in TNRC6C - an ASD gene paralog with interactions with other ASD genes. Clinical records of 3 ASD patients with TNRC6C variant revealed respiratory issues consistent with phenotypes observed in TNRC6 depleted mice. Overall, this study highlights the need for splicing analysis in determining variant pathogenicity, especially as it relates to ASD.
Background
The prevalence of autism spectrum disorder (ASD) has increased rapidly in recent years. Environmental factors may play an important role in the pathogenesis of ASD. These factors may include socioeconomic factors, nutritional factors, heavy metal exposure, air pollution, etc. Our aim is to analyze possible environmental factors associated with the severity of ASD.
Methods
All participating children were divided into two groups (mild and moderate/severe) according to the severity of their symptoms, as determined by their Childhood Autism Rating Scale (CARS) scores. The socioeconomic, demographic factors and the nutritional factors that may affect the severity of ASD were included in the logistic regression to analyze whether they were predictors that affected the severity of ASD.
Results
Logistic regression showed that caregivers(P = 0.042), maternal education (P = 0.030), gastrointestinal problems (P = 0.041) and a high serum concentration of lead (P = 0.003) were statistically significantly associated with ASD severity.
Conclusion
Many environmental factors affect the severity of ASD. We concluded that non-parental caregivers, low maternal education, gastrointestinal problems and high blood lead level maybe predictors that affected the severity of ASD in northeast China.
Background:
Measles, mumps, rubella, and varicella (chickenpox) are serious diseases that can lead to serious complications, disability, and death. However, public debate over the safety of the trivalent MMR vaccine and the resultant drop in vaccination coverage in several countries persists, despite its almost universal use and accepted effectiveness. This is an update of a review published in 2005 and updated in 2012.
Objectives:
To assess the effectiveness, safety, and long- and short-term adverse effects associated with the trivalent vaccine, containing measles, rubella, mumps strains (MMR), or concurrent administration of MMR vaccine and varicella vaccine (MMR+V), or tetravalent vaccine containing measles, rubella, mumps, and varicella strains (MMRV), given to children aged up to 15 years.
Search methods:
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2019, Issue 5), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to 2 May 2019), Embase (1974 to 2 May 2019), the WHO International Clinical Trials Registry Platform (2 May 2019), and ClinicalTrials.gov (2 May 2019).
Selection criteria:
We included randomised controlled trials (RCTs), controlled clinical trials (CCTs), prospective and retrospective cohort studies (PCS/RCS), case-control studies (CCS), interrupted time-series (ITS) studies, case cross-over (CCO) studies, case-only ecological method (COEM) studies, self-controlled case series (SCCS) studies, person-time cohort (PTC) studies, and case-coverage design/screening methods (CCD/SM) studies, assessing any combined MMR or MMRV / MMR+V vaccine given in any dose, preparation or time schedule compared with no intervention or placebo, on healthy children up to 15 years of age.
Data collection and analysis:
Two review authors independently extracted data and assessed the methodological quality of the included studies. We grouped studies for quantitative analysis according to study design, vaccine type (MMR, MMRV, MMR+V), virus strain, and study settings. Outcomes of interest were cases of measles, mumps, rubella, and varicella, and harms. Certainty of evidence of was rated using GRADE.
Main results:
We included 138 studies (23,480,668 participants). Fifty-one studies (10,248,159 children) assessed vaccine effectiveness and 87 studies (13,232,509 children) assessed the association between vaccines and a variety of harms. We included 74 new studies to this 2019 version of the review. Effectiveness Vaccine effectiveness in preventing measles was 95% after one dose (relative risk (RR) 0.05, 95% CI 0.02 to 0.13; 7 cohort studies; 12,039 children; moderate certainty evidence) and 96% after two doses (RR 0.04, 95% CI 0.01 to 0.28; 5 cohort studies; 21,604 children; moderate certainty evidence). The effectiveness in preventing cases among household contacts or preventing transmission to others the children were in contact with after one dose was 81% (RR 0.19, 95% CI 0.04 to 0.89; 3 cohort studies; 151 children; low certainty evidence), after two doses 85% (RR 0.15, 95% CI 0.03 to 0.75; 3 cohort studies; 378 children; low certainty evidence), and after three doses was 96% (RR 0.04, 95% CI 0.01 to 0.23; 2 cohort studies; 151 children; low certainty evidence). The effectiveness (at least one dose) in preventing measles after exposure (post-exposure prophylaxis) was 74% (RR 0.26, 95% CI 0.14 to 0.50; 2 cohort studies; 283 children; low certainty evidence). The effectiveness of Jeryl Lynn containing MMR vaccine in preventing mumps was 72% after one dose (RR 0.24, 95% CI 0.08 to 0.76; 6 cohort studies; 9915 children; moderate certainty evidence), 86% after two doses (RR 0.12, 95% CI 0.04 to 0.35; 5 cohort studies; 7792 children; moderate certainty evidence). Effectiveness in preventing cases among household contacts was 74% (RR 0.26, 95% CI 0.13 to 0.49; 3 cohort studies; 1036 children; moderate certainty evidence). Vaccine effectiveness against rubella, using a vaccine with the BRD2 strain which is only used in China, is 89% (RR 0.11, 95% CI 0.03 to 0.42; 1 cohort study; 1621 children; moderate certainty evidence). Vaccine effectiveness against varicella (any severity) after two doses in children aged 11 to 22 months is 95% in a 10 years follow-up (rate ratio (rr) 0.05, 95% CI 0.03 to 0.08; 1 RCT; 2279 children; high certainty evidence). Safety There is evidence supporting an association between aseptic meningitis and MMR vaccines containing Urabe and Leningrad-Zagreb mumps strains, but no evidence supporting this association for MMR vaccines containing Jeryl Lynn mumps strains (rr 1.30, 95% CI 0.66 to 2.56; low certainty evidence). The analyses provide evidence supporting an association between MMR/MMR+V/MMRV vaccines (Jeryl Lynn strain) and febrile seizures. Febrile seizures normally occur in 2% to 4% of healthy children at least once before the age of 5. The attributable risk febrile seizures vaccine-induced is estimated to be from 1 per 1700 to 1 per 1150 administered doses. The analyses provide evidence supporting an association between MMR vaccination and idiopathic thrombocytopaenic purpura (ITP). However, the risk of ITP after vaccination is smaller than after natural infection with these viruses. Natural infection of ITP occur in 5 cases per 100,000 (1 case per 20,000) per year. The attributable risk is estimated about 1 case of ITP per 40,000 administered MMR doses. There is no evidence of an association between MMR immunisation and encephalitis or encephalopathy (rate ratio 0.90, 95% CI 0.50 to 1.61; 2 observational studies; 1,071,088 children; low certainty evidence), and autistic spectrum disorders (rate ratio 0.93, 95% CI 0.85 to 1.01; 2 observational studies; 1,194,764 children; moderate certainty). There is insufficient evidence to determine the association between MMR immunisation and inflammatory bowel disease (odds ratio 1.42, 95% CI 0.93 to 2.16; 3 observational studies; 409 cases and 1416 controls; moderate certainty evidence). Additionally, there is no evidence supporting an association between MMR immunisation and cognitive delay, type 1 diabetes, asthma, dermatitis/eczema, hay fever, leukaemia, multiple sclerosis, gait disturbance, and bacterial or viral infections. AUTHORS' CONCLUSIONS: Existing evidence on the safety and effectiveness of MMR/MMRV vaccines support their use for mass immunisation. Campaigns aimed at global eradication should assess epidemiological and socioeconomic situations of the countries as well as the capacity to achieve high vaccination coverage. More evidence is needed to assess whether the protective effect of MMR/MMRV could wane with time since immunisation.
The lack of effective treatments for autism spectrum disorder (ASD) and congenital hydrocephalus (CH) reflects the limited understanding of the biology underlying these common neurodevelopmental disorders. Although ASD and CH have been extensively studied as independent entities, recent human genomic and preclinical animal studies have uncovered shared molecular pathophysiology. Here, we review and discuss phenotypic, genomic, and molecular similarities between ASD and CH, and identify the PTEN–PI3K–mTOR (phosphatase and tensin homolog–phosphoinositide 3-kinase–mammalian target of rapamycin) pathway as a common underlying mechanism that holds diagnostic, prognostic, and therapeutic promise for individuals with ASD and CH.
Otizm spektrum bozukluğu, sosyal etkileşimde ve iletişimde güçlükler ile kısıtlı/tekrarlayan davranışlar ve ilgi alanları temelinde tanımlanmaktadır. Otizmin etiyolojisini anlamak ve etkili müdahale yolları üretmek, bozukluğun karmaşık doğası ve belirtilerin farklı şekillerde görülebilmesi gibi sebeplerden dolayı zorlayıcı olabilmektedir. Konu hakkında kısıtlı ilerlemenin sebeplerinden biri birbirinden oldukça farklı belirti gruplarını açıklayan tek bir sebep aranması olabilir. Parçalanabilir otizm üçlemesi hipotezi, otizmi karakterize eden belirti gruplarının davranışsal, bilişsel ve genetik düzeylerde büyük ölçüde birbirinden bağımsız olabileceğini önermektedir. Bu makale, söz konusu hipoteze kanıt teşkil edebilecek nicel genetik yöntemler ile elde edilen bulguları değerlendirmeyi amaçlamaktadır. Söz konusu bulgular, otizm belirtilerinin genetik temellerinin farklılık gösterebildiğine işaret etmekte ve parçalanabilir otizm üçlemesi hipotezini desteklemektedir. Tek yumurta ikizlerinde görülen fenotipik varyanslar, belirti grupları arasında yeterli düzeyde anlamlı ilişkinin bulunamayışı ve hem genetik hem de çevresel faktörlerin etkisi açısından tespit edilen farklılıklar otizm belirtilerinin birbirinden bağımsız değerlendirilebileceğine işaret etmektedir. Belirli kısıtlılıklar ve bunlara yönelik öneriler ışığında tartışılan bulgular otizmin heterojen yapısını anlamayı kolaylaştırmakta ve etkili müdahale teknikleri geliştirilebilmesi için yol göstermektedir. Böylece, belirli belirti gruplarında daha çok güçlüğü bulunan otizm tanısı almış bireyler kadar tanı kriterini karşılayacak kadar çeşitli belirtilere sahip olmayan ancak yoğun güçlük yaşayan bireyler için faydalı olacak müdahale protokollerinin oluşturulabileceğine dikkat çekilmiştir.
Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders with early childhood onset and complex etiology involving multiple genetic and environmental factors. Besides deficits in social interaction people affected by ASDs also show deficits on verbal and nonverbal communication and exhibit restricted and repetitive behaviors and interests. Whereas their genetic components and animal models have been intensively investigated, research on ASDs are not often connected to information emerging from studies performed on postmortem brain tissue. Descriptive data such as gene expression profiles and cell morphology changes in the context of ASDs provided by postmortem brain studies, however, constitute very interesting phenotypes that can guide more mechanistic investigations currently being performed on human cellular models such as induced pluripotent stem cells (iPSCs)-derived cells leading to therapeutic strategy. The current review analyses how studies performed on human iPSCs complements and is related to human genetics and postmortem brain tissue studies in the field of ASD research. The review also examines the logistics required to generate therapeutic strategies from research focused on patient-derived iPSCs. Thus, combined, data emerging from human genetics, postmortem brain studies and human iPSC models should improve our current state of knowledge on the ASD and generate information leading to personalized treatment of ASDs.
Background:
Environmental Enrichment (EE) has been suggested as a possible therapeutic intervention for neurodevelopmental disorders such as autism. Although the benefits of this therapeutic method have been reported in some animal models and human studies, the unknown pathophysiology of autism as well as number of conflicting results, urge for further examination of the therapeutic potential of EE in autism. Therefore, the aim of this study was to examine the effects of environmental enrichment on autism-related behaviors which were induced in the maternal separation (MS) animal model.
Material and methods:
Maternally separated (post-natal day (PND) 1-14, 3h/day) and control male rats were at weaning (PND21) age equally divided into rats housed in enriched environment and normal environment. At adolescence (PND42-50), the four groups were behaviorally tested for direct social interaction, sociability, repetitive behaviors, anxiety behavior, and locomotion. Following completion of the behavioral tests, the blood and brain tissue samples were harvested in order to assess plasma level of brain derived neurotrophic factor (BDNF) and structural plasticity of brain using ELISA and stereological methods respectively.
Results:
We found that environmental enrichment reduced repetitive behaviors but failed to improve the impaired sociability and anxiety behaviors which were induced by maternal separation. Indeed, EE exacerbated anxiety and social behaviors deficits in association with increased plasma BDNF level, larger volume of the hippocampus and infra-limbic region and higher number of neurons in the infra-limbic area (p < 0.05). Conclusion: We conclude that environmental enrichment has a significant improvement effect on the repetitive behavior as one of the core autistic-like behaviors induced by maternal separation but has negative effect on the anxiety and social behaviors which might have been modulated by BDNF.
Autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) are common neurodevelopmental disorders (NDDs) that may impact brain maturation. A number of studies have examined cortical gyrification morphology in both NDDs. Here we review and when possible pool their results to better understand the shared and potentially disorder-specific gyrification features. We searched MEDLINE, PsycINFO, and EMBASE databases, and 24 and 10 studies met the criteria to be included in the systematic review and meta-analysis portions, respectively. Meta-analysis of local Gyrification Index (lGI) findings across ASD studies was conducted with SDM software adapted for surface-based morphometry studies. Meta-regressions were used to explore effects of age, sex, and sample size on gyrification differences. There were no significant differences in gyrification across groups. Qualitative synthesis of remaining ASD studies highlighted heterogeneity in findings. Large-scale ADHD studies reported no differences in gyrification between cases and controls suggesting that, similar to ASD, there is currently no evidence of differences in gyrification morphology compared with controls. Larger, longitudinal studies are needed to further clarify the effects of age, sex, and IQ on cortical gyrification in these NDDs.
Parallel processing circuits are thought to dramatically expand the network capabilities of the nervous system. Magnocellular and parvocellular oxytocin neurons have been proposed to subserve two parallel streams of social information processing, which allow a single molecule to encode a diverse array of ethologically distinct behaviors. Here we provide the first comprehensive characterization of magnocellular and parvocellular oxytocin neurons in male mice, validated across anatomical, projection target, electrophysiological, and transcriptional criteria. We next use novel multiple feature selection tools in Fmr1-KO mice to provide direct evidence that normal functioning of the parvocellular but not magnocellular oxytocin pathway is required for autism-relevant social reward behavior. Finally, we demonstrate that autism risk genes are enriched in parvocellular compared with magnocellular oxytocin neurons. Taken together, these results provide the first evidence that oxytocin-pathway-specific pathogenic mechanisms account for social impairments across a broad range of autism etiologies.
Background:
In order to be able to provide accurate genetic counseling to patients with Autism Spectrum Disorder (ASD), it is crucial to identify correlations between heterogeneous phenotypes and genetic alterations. Among the hundreds of de novo pathogenic variants reported in ASD, single-nucleotide variations and small insertions/deletions were reported in TBR1. This gene encodes a transcription factor that plays a key role in brain development. Pathogenic variants in TBR1 are often associated with severe forms of ASD, including intellectual disability and language impairment.
Methods:
Adults diagnosed with ASD but without intellectual disability (diagnosis of Asperger syndrome, according to the DSM-IV) took part in a genetic consultation encompassing metabolic assessments, a molecular karyotype and the screening of a panel of 268 genes involved in intellectual disability, ASD and epilepsy. In addition, the patient reported here went through a neuropsychological assessment, structural magnetic resonance imaging and magnetic resonance spectroscopy measurements.
Results:
Here, we report the case of a young adult male who presents with a typical form of ASD. Importantly, this patient presents with no intellectual disability or language impairment, despite a de novo heterozygous frameshift pathogenic variant in TBR1, leading to an early premature termination codon (c.26del, p.(Pro9Leufs*12)).
Conclusion:
Based on this case report, we discuss the role of TBR1 in general brain development, language development, intellectual disability and other symptoms of ASD. Providing a detailed clinical description of the individuals with such pathogenic variants should help to understand the genotype-phenotype relationships in ASD.
Autism spectrum disorders (ASDs) are a group of heterogenous neurodevelopmental disorders affecting 1 in 59 children. Syndromic ASDs are commonly associated with chromosomal rearrangements or dosage imbalance involving a single gene. Many of genes are dosage-sensitive and regulate transcription, protein homeostasis, and synaptic function in the brain. Despite vastly different molecular perturbations, syndromic ASDs share core symptoms including social dysfunction and repetitive behavior. However, each ASD subtype has a unique pathogenic mechanism and combination of comorbidities that require individual attention. We have learned a great deal about how these dosage-sensitive genes control brain development and behaviors from genetically-engineered mice. Here we describe the clinical features of eight monogenic neurodevelopmental disorders caused by dosage imbalance of four genes, as well as recent advances in using genetic mouse models to understand their pathogenic mechanisms and develop intervention strategies. We propose that applying newly developed quantitative molecular and neuroscience technologies will advance our understanding of the unique neurobiology of each disorder and enable the development of personalized therapy.
While neurodevelopmental disorders (NDDs) are highly heritable, several environmental risk factors have also been suggested. However, the role of familial confounding is unclear. To shed more light on this, we reviewed the evidence from twin and sibling studies. A systematic review was performed on case control and cohort studies including a twin or sibling within-pair comparison of neurodevelopmental outcomes, with environmental exposures until the sixth birthday. From 7,315 screened abstracts, 140 eligible articles were identified. After adjustment for familial confounding advanced paternal age, low birth weight, birth defects, and perinatal hypoxia and respiratory stress were associated with autism spectrum disorder (ASD), and low birth weight, gestational age and family income were associated with attention-deficit/hyperactivity disorder (ADHD), categorically and dimensionally. Several previously suspected factors, including pregnancy-related factors, were deemed due to familial confounding. Most studies were conducted in North America and Scandinavia, pointing to a global research bias. Moreover, most studies focused on ASD and ADHD. This genetically informed review showed evidence for a range of environmental factors of potential casual significance in NDDs, but also points to a critical need of more genetically informed studies of good quality in the quest of the environmental causes of NDDs.
Background
Early psycho-social experiences influence the developing brain and possible onset of various neurodevelopmental disorders, such as Autism Spectrum Disorder (ASD). ASD is characterized by a variety of brain abnormalities, including alteration of oxytocin receptors in the brain. Recently, early life adverse experiences, such as maternal separation (MS), have been shown to constitute risk factors for ASD in preclinical studies. Therefore, the main aims of the current study were to i) explore the association between onset of autistic-like behaviours and molecular/structural changes in the brain following MS, and ii) evaluate the possible beneficial effects of oxytocin treatment on the same parameters.
Method and Material
Male rats were exposed to the maternal separation from post-natal day (PND) 1 to PND14. After weaning, daily injections of oxytocin (1 mg/kg, ip) were administered (PND22-30), followed by examination of autism-related behaviours at adolescence (PND 42-50). Brain structural plasticity was examined using stereological methods, and the plasma level of brain derived neurotrophic factor (BDNF) was analysed using ELISA.
Results
We found that maternal separation induced autistic-like behaviours, which was associated with increase in the hippocampal CA1 stratum radiatum (CA1.SR) volume. In addition, we observed increase in the infralimbic brain region volume and in the number of the pyramidal neurons in the same brain region. Maternal separation significantly increased the plasma BDNF levels. Treatment with oxytocin improved autistic like behaviours, normalized the number of neurons and the volume of the infralimbic region as well as the plasma BDNF level (p < 0.05).
Conclusion
Maternal separation induced autistic-like behaviours, brain structural impairment together with plasma BDNF level abnormality, which could be improved by oxytocin treatment.
Variations in SLC9A9 gene expression and protein function are associated with multiple human diseases, which range from Attention‐deficit/hyperactivity disorder (ADHD) to glioblastoma multiforme. In an effort to determine the full spectrum of human disease associations with SLC9A9, we performed a systematic review of the literature. We also review SLC9A9's biochemistry, protein structure, and function, as well as its interacting partners with the goal of identifying mechanisms of disease and druggable targets. We report gaps in the literature regarding the genes function along with consistent trends in disease associations that can be used to further research into treating the respective diseases. We report that SLC9A9 has strong associations with neuropsychiatric diseases and various cancers. Interestingly, we find strong overlap in SLC9A9 disease associations and propose a novel role for SLC9A9 in neuropsychiatric comorbidity. In conclusion, SLC9A9 is a multifunctional protein that, through both its endosome regulatory function and its protein–protein interaction network, has the ability to modulate signaling axes, such as the PI3K pathway, among others.
Resumen
El progreso en la identificación de los factores de vulnerabilidad genética en el autismo requiere la identificación correcta del fenotipo o fenotipos heredados. Esto se puede lograr no sólo por la descripción precisa del sujeto afectado, sino también por la identificación de los rasgos de vulnerabilidad en familiares no afectados de los probandos autistas. Esta revisión se centrará en esta última estrategia y principalmente en los rasgos clínicos, bioquímicos y cognitivos.
Background:
Measles, mumps, rubella, and varicella (chickenpox) are serious diseases that can lead to serious complications, disability, and death. However, public debate over the safety of the trivalent MMR vaccine and the resultant drop in vaccination coverage in several countries persists, despite its almost universal use and accepted effectiveness. This is an update of a review published in 2005 and updated in 2012.
Objectives:
To assess the effectiveness, safety, and long- and short-term adverse effects associated with the trivalent vaccine, containing measles, rubella, mumps strains (MMR), or concurrent administration of MMR vaccine and varicella vaccine (MMR+V), or tetravalent vaccine containing measles, rubella, mumps, and varicella strains (MMRV), given to children aged up to 15 years.
Search methods:
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2019, Issue 5), which includes the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to 2 May 2019), Embase (1974 to 2 May 2019), the WHO International Clinical Trials Registry Platform (2 May 2019), and ClinicalTrials.gov (2 May 2019).
Selection criteria:
We included randomised controlled trials (RCTs), controlled clinical trials (CCTs), prospective and retrospective cohort studies (PCS/RCS), case-control studies (CCS), interrupted time-series (ITS) studies, case cross-over (CCO) studies, case-only ecological method (COEM) studies, self-controlled case series (SCCS) studies, person-time cohort (PTC) studies, and case-coverage design/screening methods (CCD/SM) studies, assessing any combined MMR or MMRV / MMR+V vaccine given in any dose, preparation or time schedule compared with no intervention or placebo, on healthy children up to 15 years of age.
Data collection and analysis:
Two review authors independently extracted data and assessed the methodological quality of the included studies. We grouped studies for quantitative analysis according to study design, vaccine type (MMR, MMRV, MMR+V), virus strain, and study settings. Outcomes of interest were cases of measles, mumps, rubella, and varicella, and harms. Certainty of evidence of was rated using GRADE.
Main results:
We included 138 studies (23,480,668 participants). Fifty-one studies (10,248,159 children) assessed vaccine effectiveness and 87 studies (13,232,509 children) assessed the association between vaccines and a variety of harms. We included 74 new studies to this 2019 version of the review. Effectiveness Vaccine effectiveness in preventing measles was 95% after one dose (relative risk (RR) 0.05, 95% CI 0.02 to 0.13; 7 cohort studies; 12,039 children; moderate certainty evidence) and 96% after two doses (RR 0.04, 95% CI 0.01 to 0.28; 5 cohort studies; 21,604 children; moderate certainty evidence). The effectiveness in preventing cases among household contacts or preventing transmission to others the children were in contact with after one dose was 81% (RR 0.19, 95% CI 0.04 to 0.89; 3 cohort studies; 151 children; low certainty evidence), after two doses 85% (RR 0.15, 95% CI 0.03 to 0.75; 3 cohort studies; 378 children; low certainty evidence), and after three doses was 96% (RR 0.04, 95% CI 0.01 to 0.23; 2 cohort studies; 151 children; low certainty evidence). The effectiveness (at least one dose) in preventing measles after exposure (post-exposure prophylaxis) was 74% (RR 0.26, 95% CI 0.14 to 0.50; 2 cohort studies; 283 children; low certainty evidence). The effectiveness of Jeryl Lynn containing MMR vaccine in preventing mumps was 72% after one dose (RR 0.24, 95% CI 0.08 to 0.76; 6 cohort studies; 9915 children; moderate certainty evidence), 86% after two doses (RR 0.12, 95% CI 0.04 to 0.35; 5 cohort studies; 7792 children; moderate certainty evidence). Effectiveness in preventing cases among household contacts was 74% (RR 0.26, 95% CI 0.13 to 0.49; 3 cohort studies; 1036 children; moderate certainty evidence). Vaccine effectiveness against rubella is 89% (RR 0.11, 95% CI 0.03 to 0.42; 1 cohort study; 1621 children; moderate certainty evidence). Vaccine effectiveness against varicella (any severity) after two doses in children aged 11 to 22 months is 95% in a 10 years follow-up (rate ratio (rr) 0.05, 95% CI 0.03 to 0.08; 1 RCT; 2279 children; high certainty evidence). Safety There is evidence supporting an association between aseptic meningitis and MMR vaccines containing Urabe and Leningrad-Zagreb mumps strains, but no evidence supporting this association for MMR vaccines containing Jeryl Lynn mumps strains (rr 1.30, 95% CI 0.66 to 2.56; low certainty evidence). The analyses provide evidence supporting an association between MMR/MMR+V/MMRV vaccines (Jeryl Lynn strain) and febrile seizures. Febrile seizures normally occur in 2% to 4% of healthy children at least once before the age of 5. The attributable risk febrile seizures vaccine-induced is estimated to be from 1 per 1700 to 1 per 1150 administered doses. The analyses provide evidence supporting an association between MMR vaccination and idiopathic thrombocytopaenic purpura (ITP). However, the risk of ITP after vaccination is smaller than after natural infection with these viruses. Natural infection of ITP occur in 5 cases per 100,000 (1 case per 20,000) per year. The attributable risk is estimated about 1 case of ITP per 40,000 administered MMR doses. There is no evidence of an association between MMR immunisation and encephalitis or encephalopathy (rate ratio 0.90, 95% CI 0.50 to 1.61; 2 observational studies; 1,071,088 children; low certainty evidence), and autistic spectrum disorders (rate ratio 0.93, 95% CI 0.85 to 1.01; 2 observational studies; 1,194,764 children; moderate certainty). There is insufficient evidence to determine the association between MMR immunisation and inflammatory bowel disease (odds ratio 1.42, 95% CI 0.93 to 2.16; 3 observational studies; 409 cases and 1416 controls; moderate certainty evidence). Additionally, there is no evidence supporting an association between MMR immunisation and cognitive delay, type 1 diabetes, asthma, dermatitis/eczema, hay fever, leukaemia, multiple sclerosis, gait disturbance, and bacterial or viral infections.
Authors' conclusions:
Existing evidence on the safety and effectiveness of MMR/MMRV vaccines support their use for mass immunisation. Campaigns aimed at global eradication should assess epidemiological and socioeconomic situations of the countries as well as the capacity to achieve high vaccination coverage. More evidence is needed to assess whether the protective effect of MMR/MMRV could wane with time since immunisation.
Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders of genetic and environmental aetiologies. Some ASD cases are syndromic: associated with clinically defined patterns of somatic abnormalities and a neurobehavioural phenotype (e.g. Fragile X syndrome). Many cases, however, are idiopathic or non-syndromic. Such disorders present themselves during the early postnatal period when language, speech and personality start to develop. ASDs manifest by deficits in social communication and interaction, restricted and repetitive patterns of behaviour across multiple contexts, sensory abnormalities across multiple modalities and comorbidities, such as epilepsy amongst many others. ASDs are disorders of connectivity, as synaptic dysfunction is common to both syndromic and idiopathic forms. Whilst multiple theories have been proposed, particularly in idiopathic ASDs, none address why certain brain areas (e.g. frontotemporal) appear more vulnerable than others or identify factors that may affect phenotypic specificity. In this hypothesis article, we identify possible routes leading to, and the consequences of, altered connectivity and review the evidence of central and peripheral synaptic dysfunction in ASDs. We postulate that phenotypic specificity could arise from aberrant experience-dependent plasticity mechanisms in frontal brain areas and peripheral sensory networks and propose why the vulnerability of these areas could be part of a model to unify pre-existing pathophysiological theories.
This volume aims to provide the reader with an up-to-date account of knowledge, research, education, and clinical practice in the field of au tism, from an international perspective. The emphasis throughout is on the growing points of knowledge and on the new developments in prac tice. We have tried to keep a balance between the need for rigorous research and systematic evaluation and the importance of expressing new ideas and concepts so that they may influence thinking at a stage when questions are being formulated and fresh approaches to treatment are being developed. The book had its origins in the 1976 International Symposium on Autism held in St. Gallen, Switzerland but it is not in any sense a proceed ings of that meeting. Most papers have been extensively rewritten to provide a fuller coverage of the topic and also to take account of the issues raised at the meeting. Discussion dialogues have been revised and re structured to stand as self-contained chapters. Many significant contribu tions to the conference have not been induded in order to maintain the balance of a definitive review; however a few extra chapters have been added to fill crucial gaps 0 We hope the result is a vivid picture ofthe current state of the art. As editors we have been most impressed by the advances since the 1970 international conference in London.
Data concerning 32 autistic children identified in a previously reported survey of the County of Middlesex made in 1963/64 are presented, in comparison with a group of 22 non-autistic handicapped children with certain behavioural similarities. - Parents of the autistic probands were superior in socio-economic status, intelligence and education. Mothers in the autistic group were educationally and intellectually superior to those in the comparison group in all social classes. - Previous reports indicating no raised incidence of psychotic illnesses in relatives of autistic children were confirmed, but there was a greater incidence of other serious mental illness in the families of the autistic group than in the comparison group. In parents and collateral relatives of the autistic children, 3.2% had a serious mental illness, and 4.8% of siblings were markedly abnormal. Five of 32 autistic children had a mentally ill parent. - No birth-order effect was found, and maternal age was not raised. There was no excess of immature births. Complications in pregnancy and birth were infrequent; in the autistic probands fewer were found than in the comparison group, but more than in their own siblings. - The incidence of neurological and other abnormalities was less in the autistic than in the comparison group. These signs were found mainly in low grade probands with early developmental retardation. - The need for the reporting of detailed uniform data is emphasised, so that comparisons between different groups of autistic children may be more productive.
Most of the chapters in this book take for granted the definition of infantile autism and the criteria to be used in its diagnosis. That is right and proper, but the questions of definition and diagnosis have given rise to such controversy over the years that it is necessary to set the scene for what follows by some discussion of the issues involved.
A total population screening of children born during 1962-1976 and living in the Gothenburg region at the end of 1980 was carried out in order to obtain prevalence figures for infantile autism and other childhood psychoses. It was found that the prevalence figure for infantile autism was 2.0 per 10,000 and for other childhood psychoses 1.9 per 10,000. Boys were much more often affected by infantile autism than girls. In the case of other psychoses, no such over-representation was seen. A majority of the children were mentally retarded, and only 4% had tested IQs exceeding 100. The results are in good agreement with the three earlier epidemiological studies concerned with childhood psychosis.
SummaryA systematic study was made of a representative group of 21 same-sexed twin pairs (11 MZ and 10 DZ) in which at least one twin showed the syndrome of infantile autism. There was a 36 per cent pair-wise concordance rate for autism in MZ pairs compared with o per cent concordance in DZ pairs. The concordance for cognitive abnormalities was 82 per cent in MZ pairs and 10 per cent in DZ pairs. It was concluded that there were important hereditary influences concerning a cognitive deficit which included but was not restricted to autism. In 12 out of 17 pairs discordant for autism, the presence of autism was associated with a biological hazard liable to cause brain damage. It was concluded that brain injury in the infancy period may lead to autism on its own or in combination with a genetic predisposition. Uncertainty remains on both the mode of inheritance and exactly what is inherited.
Basing case selection on behavioural criteria, the entire 8–10 year old population of the County of Middlesex was screened to identify children with autistic behaviour. Screening was accomplished by behaviour questionnaires, completed by teachers or other supervisors, examination of case records and interviews with selected children and informants. Among 54 children who were found to show some evidence of the syndrome, two “autistic” subgroups and one “non-autistic” subgroup were defined, according to ratings on 24 behavioural items. The 35 “autistic” cases represent a prevalence rate of 4.5 per 10,000. Data for 32 of these were analyzed. Boys were more common than girls in a ratio of 2.6 to 1. The relationship between early development, type of onset and I.Q. at the survey mean age of 9 years 9 months, is discussed. The numbers of autistic children found are compared with those of children with other handicaps such as blindness. It is pointed out that sub-division according to the presence of developmental retardation is necessary for the useful comparison of reported groups, particularly with respect to estimates of prognosis.
The incidence of autism and cognitive disability was assessed in the biological siblings of 29 autistic probands subdivided on the basis of IQ. A significant clustering of autism and nonspecific intellectual retardation was found in the siblings of severely retarded autistic probands which was not present in the siblings of our higherfunctioning autistic sample. These findings suggest that there may be etiological differences in autism, depending on the degree of associated mental retardation.
The prevalence, in children aged under 15, of severe impairments of social interaction, language abnormalities, and repetitive stereotyped behaviors was investigated in an area of London. A "socially impaired" group (more than half of whom were severely retarded) and a comparison group of "sociable severely mentally retarded" children were identified. Mutism or echolalia, and repetitive stereotyped behaviors were found in almost all the socially impaired children, but to a less marked extent in a minority of the sociable severely retarded. Certain organic conditions were found more often in the socially impaired group. A subgroup with a history of Kanner's early childhood autism could be identified reliably but shared many abnormalities with other socially impaired children. The relationships between mental retardation, typical autism, and other conditions involving social impairment were discussed, and a system of classification based on quality of social interaction was considered.
The purpose of this research project was to identify children with psychotic behavior in the Institutions for the Mentally Retarded in Denmark and to analyze psychotic behavior. The subjects for study were 392 children, partly selected as a representative sample, partly selected as a sample of children with psychotic behavior. A combined observation and interview scheme was constructed containing 17 behavioral items and 6 developmental scales. Scoring systems for psychotic behavior were constructed and their consistency analyzed by the Rasch item-analysis model. Two major behavioral dimensions, "bizarre behavior" and "psychotic withdrawal," were used for the diagnostic grouping of the subjects. The distributions of the children in regard to developmental retardation, organic brain damage, and psychiatric diagnoses were investigated. Conclusions regarding guidelines for reorganization of present services and establishment of new services are proposed.
Identical female twins with the combination of infantile autism, mild-moderate mental retardation and the fragile-X (q27.3) chromosome abnormality are described. The case report highlights the need for chromosomal cultures in both boys and girls presenting with the "Kanner syndrome".
In a population-based study from Göteborg, Sweden, of infantile autism in children under age 10 years, we found epilepsy in 20% of the cases. Twice as many children among those with "autisticlike conditions" had epilepsy. All types of epilepsy were seen. Of the children in the study who had epilepsy, almost 75% (10/14) had psychomotor epilepsy. The association between autism-autisticlike conditions and epilepsy seemed to be with the behavioral disorder and not with the often concomitant mental retardation. Abnormalities evidenced on electroencephalograms seemed to be generated from the temporal regions and phylogenetically older parts of the brain in a majority of the cases.
Recent changes in the estimated incidence of monozygotic twinning in 15 European populations are described. The overall trend was an increase in the monozygotic twinning rate (MZTR) since the 1960s, particularly in those countries in which the use of oral contraceptives (OC) was widespread. A slower increase or even a decrease in the MZTR was observed in countries with low use of OC. Some countries, eg, Sweden, demonstrated an unexpectedly sharp increase since the 1960s. In Poland and the Federal Republic of Germany the MZTR was already strongly increasing as early as in the 1950s, clearly before the introduction of the pill. The influence of several other factors on the MZTR is discussed, such as toxic and teratogenic agents, pelvic infection diseases caused by the use of intrauterine devices, the increased use of ovulation inducers and neuroleptics as well as changes in the registration of perinatal deaths.
The total population of children under 10 years in one Swedish urban area and one rural area was screened for infantile autism (IA) and autistic-like conditions (AC). A total prevalence of 6.6 per 10 000 was found, which is somewhat higher than in previous similar studies of the same region. Infantile autism accounted for two-thirds of the cases. Boys far outnumbered girls, but this was entirely accounted for by the IA group. The preponderance of autistic boys was less pronounced among the severely mentally retarded children. Mental retardation was seen in almost 90% of cases and only one child had an IQ exceeding 100; clinical and laboratory signs of brain dysfunction were also found in a majority of cases. Distribution by social class was no different in either patient group from the general population.
The UCLA Registry for Genetic Studies in Autism was established in 1980 to test the hypothesis that genetic factors may be etiologically significant in subsets of patients. To date 61 pairs of twins have enrolled and 40 meet research diagnostic criteria for autism. The authors found a concordance for autism in these 40 pairs of 95.7% in the monozygotic twins (22 of 23) and 23.5% in the dizygotic twins (four of 17).
Individual components of cognitive disability were assessed in the siblings of 41 autistic probands and compared with similar measures from a control group of siblings of Down's syndrome individuals. The results showed a significant familial clustering of cognitive disabilities in the siblings of autistic probands. These cognitive impairments included disturbances in expressive and receptive language, specific learning disabilities, and varying degrees of mental subnormality.
In a continuing twin study of autism in Scandinavia and Finland, moderately mentally retarded triplets fulfilling Rutter's criteria for infantile autism were reported. Judging by physical appearance the triplets were identical. Behaviourally they were extremely similar though one was intellectually slightly better than the other two. All three showed the physical stigmata characteristic of the fragile-X syndrome, in spite of their overall appearance being non-conspicuous. The triplets had between 8 and 12 per cent of fragile-X positive cells and showed a distinct pattern of urinary excretion of substances yielding absorbency at 280 nM. Their mother and sister also had a high count of fragile-X positive cells.
The application of immunogenetic concepts to schizophrenia appears to have lagged somewhat, despite the facts that an autoimmune hypothesis of schizophrenia was put forward as long ago as 1967 and that there is good evidence for a weak association with the red cell surface antigens. For schizophrenia, there have been some 40 studies of ABO associations, covering over 12000 patients. Though the results differ among themselves, there is a strong suggestion of an elevated incidence of blood group B. Schizophrenia is the only one of the psychoses to show such an association, and of the several classical genetic markers examined in schizophrenia only the B blood group demonstrates an association. It is possible that further exploration in an immunogenetic context would provide the clue for the next stage of advance in the understanding of the disorder. One area of immunogenetics in which there has been recent interest in schizophrenia is the HLA association. The HLA (human leukocyte antigen) histocompatibility system is controlled by several loci situated close together on the short arm of human chromosome 6. There is great polymorphism in this system, in that at each locus there are many different alleles available, so that millions of distinguishable antigenic configurations can be derived - a veritable demonstration of the individuality of the human genotype. Other genes also are thought to occur in this region analogous to the immune response (Ir) genes that are known in animals. The demonstration of associations between histocompatibility antigens and disease has been particularly useful. It has caused reconsideration of aetiologies, has demonstrated relationships between a number of diseases, and has shown what a wide range of disorders stems from immunopathology. There have now been some 20 studies of HLA types in schizophrenia. There is little concordance in results, either between studies or between subgroups of patients within a study. Overall, the most consistent increase in frequency appears for antigens A28, Cw4, B18, B9 and B5, though each of these is visible in only a minority of studies. Several groups of workers have tried to delineate the paranoid and hebephrenic subtypes - a dubious exercise - and here increased frequencies of A1 in hebephrenic and A9 in paranoid are the most consistent; of critical relevance is that the diagnostic criteria of these subtypes differ in the different studies. Practically all such studies refer to analyses of patient populations, and while they are useful in providing pointers, the interpretation of their results is often ambivalent. Sample size is all too frequently small, so that an apparent association may be a sampling artefact, even assuming that techniques are reliable. If an antigen association is validated, it may indicate that the antigen itself contributes to the aetiology, perhaps because of its antigenic similarity to some virus or as part of a polygenic system making for liability to the disorder. One major criticism lies in the diagnostic criteria. Only when the patients for inclusion in such studies are accepted on the basis of rigorous criteria would it be meaningful to attempt comparison between series. In this respect, it is interesting that the elevation of A1 was found in one study in 57 patients with Schneiderian first-rank criteria (McGuffin et al. 1978). Another criticism is the absence of family studies, for these supply essential information that population surveys cannot. They are crucial to the establishment of the correctness of the interpretations suggested by population studies. Only they can elucidate the relationship of the HLA (or indeed any other) genotype to the disease-conferring genes: whether it is the HLA antigen itself, whether it is some other linked gene, whether the association represents a multifactorial or monogenic inheritance and, if the former, whether it is the antigen itself that is involved or whether it reflects the susceptibility of particular families with their particular genetic constitution quite independent of the antigen.
Twenty-five autistic children, constituting a total population sample of children with infantile autism, were compared with 25 sex- and maternity-clinic-matched controls for occurrence of reduced optimality in the pre-, peri, and neonatal period, as noted in medical records. Autistic children showed greatly increased scores for reduced optimality, especially with regard to prenatal factors. The findings are at odds with early reports that children with autism had not suffered potential brain injury. The reasons for the discrepancy are discussed.
Twenty infantile autistic children, constituting what is likely to be the majority of the total population of autistic children born in the years 1962 through 1973 and living in Göteborg, Sweden, by the end of 1978, were compared with a random population sample of 59 7-year-old Göteborg children with regard to social class. Two different social classification systems were used, one that takes account only of the father's occupation and one that includes several other parameters. The distributions of social class were almost identical in the infantile autism group and in the random group. With respect to some other social circumstances the two groups were very similar. Thus, the present results lend no support for the view that autistic children tend to come from high social classes.
An autism checklist was developed with behaviors selected from a variety of checklists and instruments used to identify autism. Content validity of the behaviors was established, and 3000 of the checklists were sent throughout the United States and Canada to professionals acquainted with handicapped children. 1049 checklists completed on individuals 18 months to 35 years old were returned. A chi-square analysis indicated that 55 of the 57 behaviors listed were significant predictors of autism (P<0.001) when compared to severe mental retardation. A weighted score, determined by statistics (4 indicating the highest predictor of autism, 1 the lowest), was assigned to each other.
Twins: History and science Identical triplets with infantile autism and the fragile-X syndrome
- L Gedda
Gedda, L. (1961). Twins: History and science. Springfield, IL: C. C. Thomas. Gillberg, C. (1983). Identical triplets with infantile autism and the fragile-X syndrome. British Journal of Psychiatry, 143, 256-260.
Diagnosis and definition Autism: A reappraisal of concepts and treatment (pp. 1-25) The genetics of mental disorders
- M Rutter
Rutter, M. (1978). Diagnosis and definition. In M. Rutter and E. Schopler (Eds), Autism: A reappraisal of concepts and treatment (pp. 1-25). New York: Plenum. Slater, E. & Cowie, V. (1971). The genetics of mental disorders. Oxford: Oxford University Press.
Chromosome findings in twins with infantile autism
- J. Wahlström
- S. Steffenburg
- L. Hellgren
- C. Gillberg
A prevalence investigation of childhood psychosis. Paper given at the 16th Scandinvian Congress of Psychiatry
- B H Brask
Chromosome findings in twins with infantile autism
- Wahlström J.