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PubMed2006

Autism and environmental genomics.

Autism spectrum disorders (ASD) are defined by behavior and diagnosed by clinical history and observation but have no biomarkers and are presumably, etiologically and biologically heterogeneous. Given brain abnormalities and high monozygotic concordance, ASDs have been framed as neurobiologically based and highly genetic, which has shaped the research agenda and in particular criteria for choosing candidate ASD genes. Genetic studies to date have not uncovered genes of strong effect, but a move toward "genetic complexity" at the neurobiological level may not suffice, as evidence of systemic abnormalities (e.g. gastrointestinal and immune), increasing rates and less than 100% monozygotic concordance support a more inclusive reframing of autism as a multisystem disorder with genetic influence and environmental contributors. We review this evidence and also use a bioinformatic approach to explore the possibility that "environmentally responsive genes" not specifically associated with the nervous system, but potentially associated with systemic changes in autism, have not hitherto received sufficient attention in autism genetics investigations. We overlapped genes from NIEHS Environmental Genome Project, the Comparative Toxicogenomics Database, and the SeattleSNPs database of genes relevant to the human immune and inflammatory response with linkage regions identified in published autism genome scans. We identified 135 genes in overlap regions, of which 56 had never previously been studied in relation to autism and 47 had functional SNPs (in coding regions). Both our review and the bioinformatics exercise support the expansion of criteria for evaluating the relevance of genes to autism risk to include genes related to systemic impact and environmental responsiveness. This review also suggests the utility of environmental genomic resources in highlighting the potential relevance of particular genes within linkage regions. Environmental responsiveness and systems impacts consistent with system-wide findings in autism are thus supported as important considerations in identifying the numerous and complex modes of gene-environment interaction in autism.

Animals↗

PubMed1998

The long-term course of autistic disorders: update on follow-up studies.

The majority of children with autism show deviance and socially or psychiatrically handicapping conditions throughout life. Only a small proportion of those with classical childhood autism lead independent adult lives. Others, particularly those with 'high-functioning' autism and so-called Asperger syndrome will improve enough to live an independent adult life. The level of mental retardation and other comorbid conditions (such as medical syndromes and other neuropsychiatric disorders, including epilepsy) is important in predicting outcome. An IQ below 50 around school age predicts severe restriction of social and adaptive functioning in adult life. The absence of communicative speech at 5-6 years of age is indicative of a poorer long-term overall outcome. There is a clear co-variation between IQ and level of communication, but probably there is some prognostic factor in language development apart from this. Measures of flexibility and cognitive shifting abilities tend to be good predictors of social outcome in a few studies. There is a continued need for prospective, longitudinal studies of children with autism spectrum disorders, particularly in Asperger syndrome. The role of interventions of various kinds needs to be addressed in such studies.

Activities of Daily Living↗

PubMedDate not supplied

A question of balance: a proposal for new mouse models of autism.

Autism spectrum disorder (ASD) represents a major mental health problem with estimates of prevalence ranging from 1/500 to 1/2000. While generally recognized as developmental in origin, little to nothing is certain about its etiology. Currently, diagnosis is made on the basis of a variety of early developmental delays and/or regressions in behavior. There are no universally agreed upon changes in brain structure or cell composition. No biomarkers of any type are available to aid or confirm the clinical diagnosis. In addition, while estimates of the heritability of the condition range from 60 to 90%, as of this writing no disease gene has been unequivocally identified. The prevalence of autism is three- to four-fold higher in males than in females, but the reason for this sexual dimorphism is unknown. In light of all of these ambiguities, a proposal to discuss potential animal models may seem the heart of madness. However, parsing autism into its individual genetic, behavioral, and neurobiological components has already facilitated a 'conversation' between the human disease and the neuropathology and biochemistry underlying the disorder. Building on these results, it should be possible to not just replicate one aspect of autism but to connect the developmental abnormalities underlying the ultimate behavioral phenotype. A reciprocal conversation such as this, wherein the human disease informs on how to make a better animal model and the animal model teaches of the biology causal to autism, would be highly beneficial.

Animals↗

PubMed2005

A placebo controlled crossover trial of liquid fluoxetine on repetitive behaviors in childhood and adolescent autism.

Repetitive behaviors are a core symptom domain in autism that has been linked to alterations in the serotonin system. While the selective serotonin-receptive inhibitor fluvoxamine has been shown to be effective in adults with autism, as yet no published placebo controlled trials with these agents document safety and efficacy in children with autism. This study examines the selective serotonin reuptake inhibitor liquid fluoxetine in the treatment of repetitive behaviors in childhood and adolescent autism spectrum disorders (ASDs). In total, 45 child or adolescent patients with ASD were randomized into two acute 8-week phases in a double-blind placebo-controlled crossover study of liquid fluoxetine. Study design included two randomized 8-week fluoxetine and placebo phases separated by a 4-week washout phase. Outcome measures included measures of repetitive behaviors and global improvement. Low-dose liquid fluoxetine (mean final dose: 9.9+/-4.35 mg/day) was superior to placebo in the treatment of repetitive behaviors by CY-BOCS compulsion scale. The effect size was in the moderate to large range, and the doses used were low. Liquid fluoxetine was only slightly, and not significantly, superior to placebo on CGI autism score partially due to a phase order effect. However, fluoxetine was marginally superior to placebo on a composite measure of global effectiveness. Liquid fluoxetine did not significantly differ from placebo on treatment emergent side effects. Liquid fluoxetine in low doses is more effective than placebo in the treatment of repetitive behaviors in childhood autism. Limitations include small sample size and the crossover design of the study. Further replication and long-term maintenance trials are needed.

Administration, Oral↗

PubMed1997

A comparison of speaking and mute individuals with autism and autistic-like conditions on the Autism Behavior Checklist.

The item, total, and subscale scores on the Autism Behavior Checklist (ABC) were compared for 155 mute and 335 speaking individuals with autism spectrum disorders. Although no significant difference was observed between the groups on the ABC total score, the mute group demonstrated significantly more pathology on 21 of 57 items and 3 of 5 subscales. The speaking group obtained significantly higher scores on only 8 items and 1 subscale (Language). The appropriateness of providing greater pathology scores on expressive language items to speaking, rather than to mute, individuals is called into question. The authors speculate whether the expressive language items are weighted too heavily, in regard both to the Language subscale and to the ABC total score. If the expressive language items were removed, the mute group would have significantly higher ABC total scores and therefore a greater degree of autism severity.

Adolescent↗

PubMed2006

The broader cognitive phenotype of autism in parents: how specific is the tendency for local processing and executive dysfunction?

BACKGROUND: The objective of this study was to investigate the tendency for local processing style ('weak central coherence') and executive dysfunction in parents of subjects with an autism spectrum disorder (ASD) compared with parents of individuals with early onset schizophrenia (EOS) and mental retardation (MR). METHOD: Sixty-two parents of subjects with ASD, 36 parents of subjects with EOS and 30 parents of subjects with MR were examined. Data on two scales indicative of local visual processing (Embedded Figures Test, Block Design) and on three executive function tests (Wisconsin Card Sorting Test, Tower of Hanoi, Trailmaking Test) were collected for all participants. RESULTS: Parents of subjects with ASD performed significantly faster on the Embedded Figures Test compared with both control samples. No other substantial group differences were observed. CONCLUSIONS: The findings indicate that an increased tendency for local processing in terms of visual disembedding could be a relatively specific core feature of the broader cognitive phenotype of autism in parents.

Adult↗

PubMedDate not supplied

Repetitive behaviors in autism: relationships with associated clinical features.

Relationships between repetitive behaviors (RBs) and associated clinical features (i.e., cognitive and adaptive functioning levels, sleep problems, medication use, and other behavioral problems) were examined in two groups (High nonverbal IQ > or = 97 versus Low nonverbal IQ < or = 56) of children with autism spectrum disorders (n = 14; mean age = 10 years, 7 months). For the group as a whole, nonverbal cognitive ability (NVIQ) (as measured by the Leiter-R), adaptive functioning level, the presence of sleep problems, and three scales of the Aberrant Behavior Checklist (ABC) (Irritability, Lethargy, and Hyperactivity) were highly correlated with total RB scores on the Repetitive Behavior Scale-Revised (RBS-R). After controlling for NVIQ, adaptive level, sleep problems, and two scales of the ABC (Irritability and Lethargy) were not significantly associated with RB scores. However, there remained a significant positive correlation between the presence of RBs and the Hyperactivity scale of the ABC. Parent ratings of their stress levels and the presence of RBs in their children were highly correlated. The relationship between RBs and associated clinical features in autism is complex and future studies should control for cognitive ability when examining the direct and indirect relationships of these variables with RBs.

Adaptation, Psychological↗

PubMed2005

Anatomical differences in the mirror neuron system and social cognition network in autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder associated with impaired social and emotional skills, the anatomical substrate of which is still unknown. In this study, we compared a group of 14 high-functioning ASD adults with a group of controls matched for sex, age, intelligence quotient, and handedness. We used an automated technique of analysis that accurately measures the thickness of the cerebral cortex and generates cross-subject statistics in a coordinate system based on cortical anatomy. We found local decreases of gray matter in the ASD group in areas belonging to the mirror neuron system (MNS), argued to be the basis of empathic behavior. Cortical thinning of the MNS was correlated with ASD symptom severity. Cortical thinning was also observed in areas involved in emotion recognition and social cognition. These findings suggest that the social and emotional deficits characteristic of autism may reflect abnormal thinning of the MNS and the broader network of cortical areas subserving social cognition.

Adult↗

PubMed2005

Vagaries of visual perception in autism.

Three classes of perceptual phenomena have repeatedly been associated with autism spectrum disorder (ASD): superior processing of fine detail (local structure), either inferior processing of overall/global structure or an ability to ignore disruptive global/contextual information, and impaired motion perception. This review evaluates the quality of the evidence bearing on these three phenomena. We argue that while superior local processing has been robustly demonstrated, conclusions about global processing cannot be definitively drawn from the experiments to date, which have generally not precluded observers using more local cues. Perception of moving stimuli is impaired in ASD, but explanations in terms of magnocellular/dorsal deficits do not appear to be sufficient. We suggest that abnormalities in the superior temporal sulcus (STS) may provide a neural basis for the range of motion-processing deficits observed in ASD, including biological motion perception. Such an explanation may also provide a link between perceptual abnormalities and specific deficits in social cognition associated with autism.

Autistic Disorder↗

PubMed2004

Young children with autism show atypical brain responses to fearful versus neutral facial expressions of emotion.

Evidence suggests that autism is associated with impaired emotion perception, but it is unknown how early such impairments are evident. Furthermore, most studies that have assessed emotion perception in children with autism have required verbal responses, making results difficult to interpret. This study utilized high-density event-related potentials (ERPs) to investigate whether 3-4-year-old children with autism spectrum disorder (ASD) show differential brain activity to fear versus neutral facial expressions. It has been shown that normal infants as young as 7 months of age show differential brain responses to faces expressing different emotions. ERPs were recorded while children passively viewed photos of an unfamiliar woman posing a neutral and a prototypic fear expression. The sample consisted of 29 3-4-year-old children with ASD and 22 chronological age-matched children with typical development. Typically developing children exhibited a larger early negative component (N300) to the fear than to the neutral face. In contrast, children with ASD did not show the difference in amplitude of this early ERP component to the fear versus neutral face. For a later component, typically developing children exhibited a larger negative slow wave (NSW) to the fear than to the neutral face, whereas children with autism did not show a differential NSW to the two stimuli. In children with ASD, faster speed of early processing (i. e. N300 latency) of the fear face was associated with better performance on tasks assessing social attention (social orienting, joint attention and attention to distress). These data suggest that children with ASD, as young as 3 years of age, show a disordered pattern of neural responses to emotional stimuli.

Autistic Disorder↗

PubMed2006

Expression and genetic variability of PCDH11Y, a gene specific to Homo sapiens and candidate for susceptibility to psychiatric disorders.

Synaptogenesis, the formation of functional synapses, is a crucial step for the development of the central nervous system. Among the genes involved in this process are cell adhesion molecules, such as protocadherins and neuroligins, which are essential factors for the identification of the appropriate partner cell and the formation of synapses. In this work, we studied the expression and the genetic variability of two closely related members of the protocadherin family PCDH11X/Y, located on the X and the Y chromosome, respectively. PCDH11Y is one of the rare genes specific to the hominoid lineage, being absent in other primates. Expression analysis indicated that transcripts of the PCDH11X/Y genes are mainly detected in the cortex of the human brain. Mutation screening of 30 individuals with autism identified two PCDH11Y polymorphic amino acid changes, F885V and K980N. These variations are in complete association, appeared during human evolution approximately 40,000 years ago and represent informative polymorphisms to study Y chromosome variability in populations. We studied the frequency of these variants in males with autism spectrum disorders (n = 110), attention deficit hyperactivity disorder (ADHD; n = 61), bipolar disorder (n = 61), obsessive-compulsive disorder (n = 51), or schizophrenia (n = 61) and observed no significant differences when compared to ethnically-matched control populations. These findings do not support the role of PCDH11Y, or more generally of a frequent specific Y chromosome, in the susceptibility to these neuropsychiatric disorders.

Amino Acid Sequence↗

PubMed2004

Genome-wide scan for loci of Asperger syndrome.

Asperger syndrome (AS), characterised by inadequate social interaction, lack of empathy and a dependence of routines and rituals, is classified as belonging to the autism spectrum disorders (DSM-IV and ICD-10). Although the prevalence of AS has been estimated to range from 0.3 up to 48.4 per 10 000, the phenotype still remains relatively unrecognised by clinicians. Several reports, including the original description by Hans Asperger (1944), have suggested that AS has a strong genetic component. Here, we have performed a genome-wide scan on Finnish families ascertained for AS with a strictly defined phenotype. In the initial scan, Z(max)>1.5 was observed on nine chromosomal regions, 1q21-22, 3p14-24, 3q25-27, 4p14, 4q32, 6p25, 6q16, 13q31-33 and 18p11. In the fine mapping stage, the highest two-point LOD scores were observed on chromosomes 1q21-22 (D1S484, Z(max dom)=3.58), 3p14-24 (D3S2432, Z(max dom)=2.50) and 13q31-33 (D13S793, Z(max dom)=1.59). The loci on 1q21-22 and 3p14-24 overlap with previously published autism susceptibility loci, and the loci on 1q21-22 and 13q31-33 overlap with the reported schizophrenia susceptibility loci. The present study is the first genome-wide screen in AS and therefore replication data sets are needed to evaluate further the significance of the AS-loci identified here.

Asperger Syndrome↗

PubMed2003

Functional anatomy of impaired selective attention and compensatory processing in autism.

In autism, physiological indices of selective attention have been shown to be abnormal even in situations where behaviour is intact. This divergence between behaviour and physiology suggests the action of some compensatory process of attention, one which may hold clues to the aetiology of autism's characteristic cognitive phenotype. Six subjects with autism spectrum disorders and six normal control subjects were studied with functional magnetic resonance imaging while performing a bilateral visual spatial attention task. In normal subjects, the task evoked activation in a network of cortical regions including the superior parietal lobe (P<0.001), left middle temporal gyrus (P=0.002), left inferior (P<0.001) and middle (P<0.02) frontal gyri, and medial frontal gyrus (P<0.02). Autistic subjects, in contrast, showed activation in the bilateral ventral occipital cortex (P<0.03) and striate cortex (P<0.05). Within the task condition, a region-of-interest comparison of attend-left versus attend-right conditions indicated that modulation of activation in the autistic brain as a function of the lateral focus of spatial attention was abnormally decreased in the left ventral occipital cortex (P<0.03), abnormally increased in the left intraparietal sulcus (P<0.01), and abnormally variable in the superior parietal lobe (P<0.03). These results are discussed in terms of a model of autism in which a pervasive defect of neural and synaptic development produces over-connected neural systems prone to noise and crosstalk, resulting in hyper-arousal and reduced selectivity. These low-level attentional traits may be the developmental basis for higher-order cognitive styles such as weak central coherence.

Adult↗

PubMed2006

The immune response in autism: a new frontier for autism research.

Autism spectrum disorders (ASD) are part of a broad spectrum of neurodevelopmental disorders known as pervasive developmental disorders, which occur in childhood. They are characterized by impairments in social interaction, verbal and nonverbal communication and the presence of restricted and repetitive stereotyped behaviors. At the present time, the etiology of ASD is largely unknown, but genetic, environmental, immunological, and neurological factors are thought to play a role in the development of ASD. Recently, increasing research has focused on the connections between the immune system and the nervous system, including its possible role in the development of ASD. These neuroimmune interactions begin early during embryogenesis and persist throughout an individual's lifetime, with successful neurodevelopment contingent upon a normal balanced immune response. Immune aberrations consistent with a dysregulated immune response, which so far, have been reported in autistic children, include abnormal or skewed T helper cell type 1 (T(H)1)/T(H)2 cytokine profiles, decreased lymphocyte numbers, decreased T cell mitogen response, and the imbalance of serum immunoglobulin levels. In addition, autism has been linked with autoimmunity and an association with immune-based genes including human leukocyte antigen (HLA)-DRB1 and complement C4 alleles described. There is potential that such aberrant immune activity during vulnerable and critical periods of neurodevelopment could participate in the generation of neurological dysfunction characteristic of ASD. This review will examine the status of the research linking the immune response with ASD.

Animals↗

PubMed2007

Abnormal activation of the social brain during face perception in autism.

ASD involves a fundamental impairment in processing social-communicative information from faces. Several recent studies have challenged earlier findings that individuals with autism spectrum disorder (ASD) have no activation of the fusiform gyrus (fusiform face area, FFA) when viewing faces. In this study, we examined activation to faces in the broader network of face-processing modules that comprise what is known as the social brain. Using 3T functional resonance imaging, we measured BOLD signal changes in 10 ASD subjects and 7 healthy controls passively viewing nonemotional faces. We replicated our original findings of significant activation of face identity-processing areas (FFA and inferior occipital gyrus, IOG) in ASD. However, in addition, we identified hypoactivation in a more widely distributed network of brain areas involved in face processing [including the right amygdala, inferior frontal cortex (IFC), superior temporal sulcus (STS), and face-related somatosensory and premotor cortex]. In ASD, we found functional correlations between a subgroup of areas in the social brain that belong to the mirror neuron system (IFC, STS) and other face-processing areas. The severity of the social symptoms measured by the Autism Diagnostic Observation Schedule was correlated with the right IFC cortical thickness and with functional activation in that area. When viewing faces, adults with ASD show atypical patterns of activation in regions forming the broader face-processing network and social brain, outside the core FFA and IOG regions. These patterns suggest that areas belonging to the mirror neuron system are involved in the face-processing disturbances in ASD.

Adult↗

PubMed2006

An atypical deletion of the Williams-Beuren syndrome interval implicates genes associated with defective visuospatial processing and autism.

BACKGROUND: During a genetic study of autism, a female child who met diagnostic criteria for autism spectrum disorder, but also exhibited the cognitive-behavioural profile (CBP) associated with Williams-Beuren syndrome (WBS) was examined. The WBS CBP includes impaired visuospatial ability, an overly friendly personality, excessive non-social anxiety and language delay. METHODS: Using array-based comparative genomic hybridisation (aCGH), a deletion corresponding to BAC RP11-89A20 in the distal end of the WBS deletion interval was detected. Hemizygosity was confirmed using fluorescence in situ hybridisation and fine mapping was performed by measuring the copy number of genomic DNA using quantitative polymerase chain reaction. RESULTS: The proximal breakpoint was mapped to intron 1 of GTF2IRD1 and the distal breakpoint lies 2.4-3.1 Mb towards the telomere. The subject was completely hemizygous for GTF2I, commonly deleted in carriers of the classic approximately 1.5 Mb WBS deletion, and GTF2IRD2, deleted in carriers of the rare approximately 1.84 Mb WBS deletion. CONCLUSION: Hemizygosity of the GTF2 family of transcription factors is sufficient to produce many aspects of the WBS CBP, and particularly implicate the GTF2 transcription factors in the visuospatial construction deficit. Symptoms of autism in this case may be due to deletion of additional genes outside the typical WBS interval or remote effects on gene expression at other loci.

Agnosia↗

PubMed2026

[Genetic and phenotypic analysis of three children with Neurodevelopmental disorders due to variants of DEAF1 gene].

OBJECTIVE: To explore the genetic characteristics and clinical phenotypes of three children with novel DEAF1 gene variants. METHODS: Three children who were referred to Capital Children's Medical Center Affiliated to Capital Medical University between January 2018 and December 2025 were selected as study subjects and underwent whole exome sequencing (WES). Candidate variants were verified by Sanger sequencing, and their pathogenicity was evaluated based on the guidelines from American College of Medical Genetics and Genomics (ACMG). A systematic search of databases including PubMed and CNKI was conducted to compile previously reported cases of DEAF1 variants for clinical phenotype comparison. For the non-canonical splice site variant c.870+5G>C located in the intronic region, wild-type and mutant minigene reporter vectors were constructed and transfected into HeLa and 293T cells, respectively, and the splicing patterns were analyzed by RT-PCR and Sanger sequencing. This study was approved by the Medical Ethics Committee of Capital Institute of Pediatrics (Ethics No.: SHERLL 2020001). RESULTS: All three children were found to have carried de novo heterozygous variants of the DEAF1 gene, including two missense variants (c.764G>A, c.641T>C) in the important SAND domain and a splice site variant (c.870+5G>C) in a non-canonical splicing region. The c.764G>A and c.870+5G>C variants were unreported previously. All children had presented with intellectual developmental delay, and two were accompanied by autism spectrum disorder, and two had epilepsy and sleep disorders. In vitro minigene splicing assay showed that the c.870+5G>C variant can lead to abnormal splicing. CONCLUSIONS: This study reported three children with novel DEAF1 variants, two of which have not been previously described, thereby enriched the mutational spectrum of the DEAF1 gene. In vitro functional assay combined with the clinical manifestations of the patients confirmed the pathogenicity of the non-canonical splice site variant in the intronic region.

Humans↗

PubMed2005

Essential versus complex autism: definition of fundamental prognostic subtypes.

Heterogeneity within the autism diagnosis obscures the genetic basis of the disorder and impedes our ability to develop effective treatments. We found that by using two readily available tests, autism can be divided into two subgroups, "essential autism" and "complex autism," with different outcomes and recurrence risks. Complex autism consists of individuals in whom there is evidence of some abnormality of early morphogenesis, manifested by either significant dysmorphology or microcephaly. The remainder have "essential autism." From 1995 to 2001, 260 individuals who met DSM-IV criteria for autistic disorder were examined. Five percent (13/260) were microcephalic and 16% (41/260) had significant physical anomalies. Individually, each trait predicted a poorer outcome. Together they define the "complex autism" subgroup, comprising 20% (46/233) of the total autism population. Individuals with complex autism have lower IQs (P=0.006), more seizures (P=0.0008), more abnormal EEGs (46% vs. 30%), more brain abnormalities by MRI (28% vs. 13%). Everyone with an identifiable syndrome was in the complex group. Essential autism defines the more heritable group with higher sib recurrence (4% vs. 0%), more relatives with autism (20% vs. 9%), and higher male to female ratio (6.5:1 vs. 3.2:1). Their outcome was better with higher IQs (P=0.02) and fewer seizures (P=0.0008). They were more apt to develop autism with a regressive onset (43% vs. 23%, P=0.02). Analysis of the features predictive of poor outcome (IQ<55, functionally non-verbal) showed that microcephaly was 100% specific but only 14% sensitive; the presence of physical anomalies was 86% specific and 34% sensitive. The two tests combined yielded 87% specificity, 47% sensitivity, and an odds ratio of 4.8:1 for poor outcome. Separating essential from complex autism should be the first diagnostic step for children with autism spectrum disorders as it allows better prognostication and counseling. Definition of more homogeneous populations should increase power of research analyses.

Adolescent↗