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PubMed2002

Behavioral phenotypic variation in autism multiplex families: evidence for a continuous severity gradient.

Recent genetic investigations of autism have studied multiplex families, typically including families with multiple siblings who meet criteria for a diagnosis of autism. However, little is known about the specific behavioral characteristics of siblings with autism in these multiplex families. We investigated the behavioral phenotypic variability and similarity of 351 siblings with autism in 171 multiplex families using cluster analysis and correlations. The results of cluster analyses showed that the individuals with autism could be characterized on a severity gradient: a continuum based on severity of symptoms and impairment as measured by Autism Diagnostic Interview-Revised (ADI-R) scores, verbal-nonverbal status, and nonverbal IQ scores. Clusters based on scores from the ADI-R for the autism diagnostic criteria of the DSM-IV and nonverbal IQ scores still represented a severity gradient when the effects of verbal-nonverbal status were removed. The severity gradient was shown to be heritable, with a sib correlation of 30% or a heritability of 60%. In summary, in a sample of 171 autism multiplex families, there was no evidence of discrete behaviorally defined subgroups of affected individuals or families characterized by distinct patterns of behavioral symptoms. Rather, the clusters could be characterized along a single, heritable, continuous severity dimension.

Autistic Disorder↗

PubMed2002

Mutation screening and transmission disequilibrium study of ATP10C in autism.

Autism is a complex genetic disorder. Chromosome 15 is of particular interest in this disorder, because of previous reports of individuals with autism with chromosomal abnormalities in the 15q11-q13 region. Transmission disequilibrium between polymorphisms in this region and autism has been also been reported in some, but not all studies. Recently, a novel maternally expressed gene, ATP10C, was characterized and mapped to the chromosome 15q11-q13 region, 200 kb distal to UBE3A. It encodes a putative aminophospholipid translocase likely to be involved in the asymmetric distribution of proteins in the cell membrane. Preferential maternal expression has been demonstrated in fibroblasts and brain. Because of its physical location and imprinting pattern, ATP10C was considered to be a candidate gene for chromosome 15-associated autism. In an effort to find the genes responsible for autism in this chromosomal region, 1.5 kb of the 5' flanking region, as well as the coding and splicing regions of ATP10C, were screened for sequence variants. Several polymorphic markers including five nonsynonymous SNPs were identified. To investigate transmission disequilibrium between ATP10C and autism, a family-based association study was conducted for 14 markers in 115 autism trios. No significant transmission disequilibrium was found, suggesting ATP10C is unlikely to contribute strongly to susceptibility to autism in these families. However, due to limited power to detect genes of modest effect, the possible functional role of the nonsynonymous SNPs and the functional implications of the SNPs identified from 5' flanking region and intron 2 splicing region may be evaluated in further studies.

Adenosine Triphosphatases↗

PubMed2003

Analysis of transmission of novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene in patients with autism.

Infantile autism is a pervasive developmental disorder with a strong genetic component. The mode of inheritance appears to be complex and no specific susceptibility genes have yet been identified. Chromosome 16p13.3 may contain a susceptibility gene based on findings from genome scans and reports of chromosome abnormalities in individuals with autism. The somatostatin receptor 5 (SSTR5) gene is located on chromosome 16p13.3 and is thus a positional candidate gene for autism. SSTR5 may also be a functional candidate gene for autism because somatostatin inhibits growth hormone secretion, and increased growth hormone response has been reported in some individuals with autism. Moreover, the somatostatinergic system interacts with the dopaminergic system, which has been hypothesized to be involved in the etiology of autism; in particular, somatostatin secretion is regulated by dopamine, and the dopamine D2 receptor and the SSTR5 receptor interact to form a receptor complex with enhanced functional activity. In the present study, we tested whether the alleles of twelve new single nucleotide polymorphisms (SNPs) in the SSTR5 gene were preferentially transmitted, using the transmission disequilibrium test (TDT) in a sample of 79 trios with autism (18 from Denmark and 61 from France). Furthermore, we combined four missense SNPs into haplotypes and searched for preferential transmission using the program TRANSMIT. No significant preferential transmission of the alleles and haplotypes of the twelve SNPs was found. Our results do not suggest the SSTR5 gene as a susceptibility gene for autism.

Autistic Disorder↗

PubMed2004

Familial symptom domains in monozygotic siblings with autism.

Autism is characterized by a triad of symptom domains (impaired social interaction, communication deficits, and repetitive behaviors) that vary significantly in their clinical presentation across the population. Within families with more than one affected member, however, discrepant findings exist with regard to symptom variability. Reduced intrafamily variance is of particular importance because it supports an underlying model of genetic heterogeneity in the transmission of autism, and the identification of familial clinical subtypes can be used to select more homogeneous samples for linkage analysis in the future. This study examines whether there are specific features of autism that show decreased variance within 16 families with monozygotic siblings concordant for autism. Evidence for familiality was defined as significantly decreased variance of symptom levels within monozygotic siblingships as compared to between siblingships. Using regression analysis, we demonstrated significant aggregation of symptoms within monozygotic siblingships for two of the three main symptom domains in autism: impairments in communication and social interaction showed significant familiality. Within the repetitive behavior domain, only the categories of circumscribed interests and preoccupation with part-objects showed reduced variance within siblingships. In addition, with the exception of a negative association between the social and behavior domains, partial correlation coefficients did not reveal significant associations between the levels of different symptom domains within families, suggesting that the levels of clinical features seen in autism may be a result of mainly independent genetic traits. Because of presumed genetic heterogeneity and the wide clinical variation seen in autism and other pervasive developmental disorders, selecting probands according to specific features known to show reduced variance within families may provide more homogeneous samples for genetic analysis and strengthen the power to detect the specific genes involved in autism.

Autistic Disorder↗

PubMed2002

Abnormal asymmetry in language association cortex in autism.

Autism is a neurodevelopmental disorder affecting cognitive, language, and social functioning. Although language and social communication abnormalities are characteristic, prior structural imaging studies have not examined language-related cortex in autistic and control subjects. Subjects included 16 boys with autism (aged 7-11 years), with nonverbal IQ greater than 80, and 15 age- and handedness-matched controls. Magnetic resonance brain images were segmented into gray and white matter; cerebral cortex was parcellated into 48 gyral-based divisions per hemisphere. Asymmetry was assessed a priori in language-related inferior lateral frontal and posterior superior temporal regions and assessed post hoc in all regions to determine specificity of asymmetry abnormalities. Boys with autism had significant asymmetry reversal in frontal language-related cortex: 27% larger on the right in autism and 17% larger on the left in controls. Only one additional region had significant asymmetry differences on post hoc analysis: posterior temporal fusiform gyrus (more left-sided in autism), whereas adjacent fusiform gyrus and temporooccipital inferior temporal gyrus both approached significance (more right-sided in autism). These inferior temporal regions are involved in visual face processing. In boys with autism, language and social/face processing-related regions displayed abnormal asymmetry. These structural abnormalities may relate to language and social disturbances observed in autism.

Autistic Disorder↗

PubMed2004

Toward a developmental neurobiology of autism.

Autism is a complex, behaviorally defined, developmental brain disorder with an estimated prevalence of 1 in 1,000. It is now clear that autism is not a disease, but a syndrome with a strong genetic component. The etiology of autism is poorly defined both at the cellular and the molecular levels. Based on the fact that seizure activity is frequently associated with autism and that abnormal evoked potentials have been observed in autistic individuals in response to tasks that require attention, several investigators have recently proposed that autism might be caused by an imbalance between excitation and inhibition in key neural systems including the cortex. Despite considerable ongoing effort toward the identification of chromosome regions affected in autism and the characterization of many potential gene candidates, only a few genes have been reproducibly shown to display specific mutations that segregate with autism, likely because of the complex polygenic nature of this syndrome. Among those, several candidate genes have been shown to control the early patterning and/or the late synaptic maturation of specific neuronal subpopulations controlling the balance between excitation and inhibition in the developing cortex and cerebellum. In the present article, we review our current understanding of the developmental mechanisms patterning the balance between excitation and inhibition in the context of the neurobiology of autism.

Autistic Disorder↗

PubMed2007

Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels.

Autism is a neurodevelopmental disorder of unclear etiology. The consistent finding of platelet hyperserotonemia in a proportion of patients and its heritability within affected families suggest that genes involved in the serotonin system play a role in this disorder. The role in autism etiology of seven candidate genes in the serotonin metabolic and neurotransmission pathways and mapping to autism linkage regions (SLC6A4, HTR1A, HTR1D, HTR2A, HTR5A, TPH1 and ITGB3) was analyzed in a sample of 186 nuclear families. The impact of interactions among these genes in autism was assessed using the multifactor-dimensionality reduction (MDR) method in 186 patients and 181 controls. We further evaluated whether the effect of specific gene variants or gene interactions associated with autism etiology might be mediated by their influence on serotonin levels, using the quantitative transmission disequilibrium test (QTDT) and the restricted partition method (RPM), in a sample of 109 autistic children. We report a significant main effect of the HTR5A gene in autism (P = 0.0088), and a significant three-locus model comprising a synergistic interaction between the ITGB3 and SLC6A4 genes with an additive effect of HTR5A (P < 0.0010). In addition to the previously reported contribution of SLC6A4, we found significant associations of ITGB3 haplotypes with serotonin level distribution (P = 0.0163). The most significant models contributing to serotonin distribution were found for interactions between TPH1 rs4537731 and SLC6A4 haplotypes (P = 0.002) and between HTR1D rs6300 and SLC6A4 haplotypes (P = 0.013). In addition to the significant independent effects, evidence for interaction between SLC6A4 and ITGB3 markers was also found. The overall results implicate SLC6A4 and ITGB3 gene interactions in autism etiology and in serotonin level determination, providing evidence for a common underlying genetic mechanism and a molecular explanation for the association of platelet hyperserotonemia with autism.

Adolescent↗

PubMed1995

Event-related potentials in cross-modal divided attention in autism.

The behavior and event-related potentials (ERPs) of high functioning subjects with autism (Autism group) were contrasted with the results of normal controls (Control group) during a focused visual attention, a focused auditory attention and a visual/auditory divided attention task. Detecting targets by the Autism group in the cross-modal divided attention condition was more difficult (longer RTs, lower % of correct detections) than attending to one modality. However, both the Autism and Control groups performed all tasks above chance level. The slow negative wave (SNW) was the only negative component which reflected Focused vs Divided task effect in Controls, being largest to stimuli in single channel-focused attention, intermediate when attention was divided between targets of two modalities and smallest to unattended stimuli. Task effects were more evident in the positive peaks for the Autism group. No significant divided attention task effect was noted for P3b, although it was larger for attended than ignored stimuli, of normal morphology and only slightly decreased in size in the Autism group as compared to the Control group. The failure of the Autism group to modulate the slow negative wave in response to Focused/Divided/Ignored conditions in a normal manner, the presence of relatively normal morphology despite the reduced amplitude of the P3b and other positive components, together with the high level of correct target detections are discussed in the context of a selective inhibition deficit and an alternative mechanism of selective attention in autism.

Acoustic Stimulation↗

PubMed2006

Children and adolescents with autism exhibit reduced MEG steady-state gamma responses.

BACKGROUND: Recent neuroimaging studies of autism have indicated reduced functional connectivity during both cognitive tasks and rest. These data suggest long-range connectivity may be compromised in this disorder, and current neurological theories of autism contend disrupted inter-regional interactions may be an underlying mechanism explaining behavioral symptomatology. However, it is unclear whether deficient neuronal communication is attributable to fewer long-range tracts or more of a local deficit in neural circuitry. This study examines the integrity of local circuitry by focusing on gamma band activity in auditory cortices of children and adolescents with autism. METHODS: Ten children and adolescents with autism and 10 matched controls participated. Both groups listened to 500 ms duration monaural click trains with a 25 ms inter-click interval, as magnetoencephalography was acquired from the contralateral hemisphere. To estimate 40 Hz spectral power density, we performed time-frequency decomposition of the single-trial magnetic steady-state response data using complex demodulation. RESULTS: Children and adolescents with autism exhibited significantly reduced left hemispheric 40 Hz power from 200-500 ms post-stimulus onset. In contrast, no significant between group differences were observed for right hemispheric cortices. CONCLUSIONS: The production and/or maintenance of left hemispheric gamma oscillations appeared abnormal in participants with autism. We interpret these data as indicating that in autism, particular brain regions may be unable to generate the high-frequency activity likely necessary for binding and other forms of inter-regional interactions. These findings augment connectivity theories of autism with novel evidence that aberrations in local circuitry could underlie putative deficiencies in long-range neural communication.

Acoustic Stimulation↗

PubMed2006

Inhibitory control in high-functioning autism: decreased activation and underconnectivity in inhibition networks.

BACKGROUND: Inhibiting prepotent responses is critical to optimal cognitive and behavioral function across many domains. Several behavioral studies have investigated response inhibition in autism, and the findings varied according to the components involved in inhibition. There has been only one published functional magnetic resonance imaging (fMRI) study so far on inhibition in autism, which found greater activation in participants with autism than control participants. METHODS: This study investigated the neural basis of response inhibition in 12 high-functioning adults with autism and 12 age- and intelligence quotient (IQ)-matched control participants during a simple response inhibition task and an inhibition task involving working memory. RESULTS: In both inhibition tasks, the participants with autism showed less brain activation than control participants in areas often found to be active in response inhibition tasks, namely the anterior cingulate cortex. In the more demanding inhibition condition, involving working memory, the participants with autism showed more activation than control participants in the premotor areas. In addition to the activation differences, the participants with autism showed lower levels of synchronization between the inhibition network (anterior cingulate gyrus, middle cingulate gyrus, and insula) and the right middle and inferior frontal and right inferior parietal regions. CONCLUSIONS: The results indicate that the inhibition circuitry in the autism group is activated atypically and is less synchronized, leaving inhibition to be accomplished by strategic control rather than automatically. At the behavioral level, there was no difference between the groups.

Adaptation, Psychological↗

PubMed2006

Shared executive dysfunctions in unaffected relatives of patients with autism and obsessive-compulsive disorder.

BACKGROUND: Executive dysfunctions have been studied as a potential endophenotype associated with the genetic basis of autism. Given that recent findings from clinical and molecular genetic studies suggest that autism and obsessive-compulsive disorder (OCD) could share a common pattern of heritability, we assessed executive functions as a possible common cognitive endophenotype in unaffected family members of individuals with either autism or OCD. METHODS: Five tests assessing executive functions (Tower of London, verbal fluency, design fluency, trail making and association fluency) were proposed to 58 unaffected first-degree relatives (parents and siblings) of probands with autism and 64 unaffected first-degree relatives of OCD patients. Results were compared with those of 47 healthy controls matched for age, sex, and level of education. RESULTS: In the Tower of London test, both groups of unaffected relatives showed significantly lower scores and longer response times compared with controls. No differences were observed between autism and OCD relatives and healthy controls in the four other tasks (verbal fluency, design fluency, trail making test and association fluency). CONCLUSIONS: Our findings show the existence of executive dysfunction in the unaffected first-degree relatives of probands with OCD, similar to those observed in the relatives of patients with autism. These results support and extend previous cognitive studies on probands indicating executive dysfunctions in autism and OCD. Planning and working memory processes could thus represent a common cognitive endophenotype in autism and OCD that could help in the identification of genes conferring vulnerability to these disorders.

Adolescent↗

PubMedDate not supplied

Developmental deficits in social perception in autism: the role of the amygdala and fusiform face area.

Autism is a severe developmental disorder marked by a triad of deficits, including impairments in reciprocal social interaction, delays in early language and communication, and the presence of restrictive, repetitive and stereotyped behaviors. In this review, it is argued that the search for the neurobiological bases of the autism spectrum disorders should focus on the social deficits, as they alone are specific to autism and they are likely to be most informative with respect to modeling the pathophysiology of the disorder. Many recent studies have documented the difficulties persons with an autism spectrum disorder have accurately perceiving facial identity and facial expressions. This behavioral literature on face perception abnormalities in autism is reviewed and integrated with the functional magnetic resonance imaging (fMRI) literature in this area, and a heuristic model of the pathophysiology of autism is presented. This model posits an early developmental failure in autism involving the amygdala, with a cascading influence on the development of cortical areas that mediate social perception in the visual domain, specifically the fusiform "face area" of the ventral temporal lobe. Moreover, there are now some provocative data to suggest that visual perceptual areas of the ventral temporal pathway are also involved in important ways in representations of the semantic attributes of people, social knowledge and social cognition. Social perception and social cognition are postulated as normally linked during development such that growth in social perceptual skills during childhood provides important scaffolding for social skill development. It is argued that the development of face perception and social cognitive skills are supported by the amygdala-fusiform system, and that deficits in this network are instrumental in causing autism.

Amygdala↗

PubMed2006

Consonant production patterns of young severely language-delayed children with autism.

UNLABELLED: While much attention has been given to documenting the language skills of verbal children with autism, the basic speech sound development patterns of severely language-impaired children with autism are unknown. Previous research has shown that certain consonants are generally produced earlier in development than other consonants, both in typically developing children and in children with language-learning impairments. While several large studies indicate that children with autism who have strong verbal skills have intact phonological development, there is some evidence that children with autism who are more severely language impaired may have abnormal phonological production. This study documents the speech sound development of non-verbal and minimally verbal children with autism. Prompts were administered for each individual speech sound while spontaneous and imitated sounds were recorded and scored. Results indicate that children with autism show the same general speech sound production patterns as typically developing and language-learning impaired children. LEARNING OUTCOMES: Individuals who read this manuscript will obtain information regarding: (1) normal phonological development, (2) a comparison of speech sound production of a group of 14 children with a diagnosis of autism spectrum disorder with the production of a group of 10 typically developing children, and (3) comparisons of imitated and spontaneous sound production of the children diagnosed with autism spectrum disorder.

Autistic Disorder↗

PubMed2005

Is autism caused by early hyperactivity of brain-derived neurotrophic factor?

Autism, a childhood-onset neurodevelopmental disorder, is characterized by disturbances in socialization and language skills, as well as in perception. Several studies indicate the importance of both genetic and environmental factors in the development of idiopathic autism, but the underlying pathogenesis of this disorder is still unknown. Brain-derived neurotrophic factor (BDNF) is important for normal neuronal development. Early BDNF hyperactivity may play an etiological role in autism early in life. This hypothesis is supported by the finding that serum and brain tissue BDNF levels are increased in autism compared with normal controls. Furthermore, BDNF hyperactivity may be associated with early brain outgrowth, increased prevalence of seizures in autism, and similar behaviors observed in autism and fragile X syndrome. Further studies of serum BDNF levels and genetic studies of the BDNF signaling pathway may help to clarify the role of BDNF in the pathogenesis of autism. Attempts to prove the BDNF hyperactivity hypothesis may lead investigators in a new direction for the study of the pathogenesis of autism and the development of an effective intervention of this disorder.

Alleles↗

PubMed2004

Superior temporal sulcus anatomical abnormalities in childhood autism: a voxel-based morphometry MRI study.

The underlying neurobiology of autism, a severe pervasive developmental disorder, remains unknown. Few neocortical brain MRI abnormalities have been reported. Using rest functional brain imaging, two independent studies have described localized bilateral temporal hypoperfusion in children with primary autism. In order to search for convergent evidence of anatomical abnormalities in autistic children, we performed an anatomical MRI study using optimized whole-brain voxel-based morphometry (VBM). High-resolution 3-D T1-weighted MRI data sets were acquired in 21 children with primary autism (mean age 9.3 +/- 2.2 years) and 12 healthy control children (mean age 10.8 +/- 2.7 years). By comparing autistic children to normal children, we found bilaterally significant decreases of grey matter concentration located in superior temporal sulcus (STS) (P < 0.05 corrected, after small volume correction; SVC). Children with autism were also found to have a decrease of white matter concentration located in the right temporal pole and in cerebellum (P < 0.05, corrected) compared to normal children. These results suggest that autism is associated with bilateral anatomical abnormalities localized in the STS and are remarkably consistent with functional hypoperfusion previously reported in children with autism. The multimodal STS areas are involved in highest level of cortical integration of both sensory and limbic information. Moreover, the STS is now recognized as a key cortical area of the "social brain" and is implicated in social perceptual skills that are characteristically impaired in autism. Therefore, the convergent anatomical and functional temporal abnormalities observed in autism may be important in the understanding of brain behavior relationships in this severe developmental disorder.

Adolescent↗

PubMed2006

Increased serum levels of glutamate in adult patients with autism.

BACKGROUND: Precise mechanisms underlying the pathophysiology of autism are currently unknown. Given the major role of glutamate in brain development, we have hypothesized that glutamatergic neurotransmission plays a role in the pathophysiology of autism. In this study, we studied whether amino acids (glutamate, glutamine, glycine, D-serine, and L-serine) related to glutamatergic neurotransmission are altered in serum of adult patients with autism. METHODS: We measured serum levels of amino acids in 18 male adult patients with autism and age-matched 19 male healthy subjects using high-performance liquid chromatography. RESULTS: Serum levels (mean = 89.2 microM, S.D. = 21.5) of glutamate in the patients with autism were significantly (t = -4.48, df = 35, p < 0.001) higher than those (mean = 61.1 microM, S.D. = 16.5) of normal controls. In contrast, serum levels of other amino acids (glutamine, glycine, d-serine, l-serine) in the patients with autism did not differ from those of normal controls. There was a positive correlation (r = 0.523, p = 0.026) between serum glutamate levels and Autism Diagnostic Interview-Revised (ADI-R) social scores in patients. CONCLUSIONS: The present study suggests that an abnormality in glutamatergic neurotransmission may play a role in the pathophysiology of autism.

Adolescent↗

PubMed2000

The amygdala theory of autism.

Brothers (Brothers L. Concepts in Neuroscience 1990;1:27-51) proposed a network of neural regions that comprise the "social brain", which includes the amygdala. Since the childhood psychiatric condition of autism involves deficits in "social intelligence", it is plausible that autism may be caused by an amygdala abnormality. In this paper we review the evidence for a social function of the amygdala. This includes reference to the Kluver-Bucy syndrome (which Hetzler and Griffin suggested may serve as an animal model of autism). We then review evidence for an amygdala deficit in people with autism, who are well known to have deficits in social behaviour. This includes a detailed summary of our recent functional magnetic resonance imaging (fMRI) study involving judging from the expressions of another person's eyes what that other person might be thinking or feeling. In this study, patients with autism or AS did not activate the amygdala when making mentalistic inferences from the eyes, whilst people without autism did show amygdala activity. The amygdala is therefore proposed to be one of several neural regions that are abnormal in autism. We conclude that the amygdala theory of autism contains promise and suggest some new lines of research.

Amygdala↗

PubMed2003

Autism.

Autism is a neurologic disorder with impairments in language, social communication, and behavior, which may improve over time, but which persist throughout the lifetime. The evaluation of autism requires a separation of clinical and research objectives and is done best in close cooperation with professionals in the fields of communication, education, and psychology. There are no biologic markers of autism. Regression in language and social communication is present in approximately 30% of children with autism and is most likely to occur between 18 and 24 months of age. Early deficits in social communication can be identified by the assessment of joint attention, affective reciprocity, and metacognition. Current evidence suggests that deficits in social cognition and communication in autism may be related to dysfunction in the amygdala, hippocampus, and related limbic and cortical structures. Other neuroanatomic structures, such as the cerebellum, also may form part of a distributed neuronal network responsible for social cognition and communication. Genetics play a major role in autism, but what is inherited and how broad the inheritable phenotype is remain unclear. At a neurochemical level, the principal neurotransmitter implicated in autism is serotonin. Seizures and epileptiform discharges are common in autism and are linked to cognitive dysfunction. The role of medication is to target specific symptoms and open windows of opportunity that allow implementation of a multimodal individualized educational plan.

Autistic Disorder↗