The Autistic Place [A Place for Learning]

Dysfunction of cerebral cortex in autism is thought to involve alterations in inhibitory neurotransmission. Here, we screened, in prefrontal cortex (PFC) of 15 subjects diagnosed with autism and 15 matched controls the expression of 44 transcripts that are either preferentially expressed in gamma-aminobutyric acidergic interneurons of the mature cortex or important for the development of inhibitory circuitry. Significant alterations in the autism cohort included decreased expression (-45%) of RPP25 (15q24.1), which is located within the autism susceptibility locus, 15q22-26. RPP25, which encodes the 25 kDa subunit of ribonuclease P involved in tRNA and pre-ribosomal RNA processing, was developmentally regulated in cerebral cortex with peak levels of expression during late fetal development (human) or around birth (mouse). In the PFC, RPP25 chromatin showed high levels of histone H3-lysine 4 trimethylation, an epigenetic mark associated with transcriptional regulation. Unexpectedly, and in contrast to peripheral tissues, levels of RPP25 protein remained undetectable in fetal and adult cerebral cortex. Taken together, these findings suggest a potential role for the RPP25 gene transcript in the neurobiology of developmental brain disorders.

Background: Autistic Spectrum Disorder (ASD), including Asperger syndrome and autism, is a highly genetic neurodevelopmental disorder. There is a consensus that ASD has a biological basis, and it has been proposed that it is a "connectivity" disorder. Diffusion Tensor Magnetic Resonance Imaging (DT-MRI) allows measurement of the microstructural integrity of white matter (a proxy measure of "connectivity"). However, nobody has investigated the microstructural integrity of whole brain white matter in people with Asperger syndrome. Methods: We measured the fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD) of white matter, using DT-MRI, in 13 adults with Asperger syndrome and 13 controls. The groups did not differ significantly in overall intelligence and age. FA, MD and RD were assessed using whole brain voxel-based techniques. Results: Adults with Asperger syndrome had a significantly lower FA than controls in 13 clusters. These were largely bilateral and included white matter in the internal capsule, frontal, temporal, parietal and occipital lobes, cingulum and corpus callosum. Conclusions: Adults with Asperger syndrome have widespread significant differences from controls in white matter microstructural integrity.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that presents in the first three years of life. Currently, diagnosis of ASD is based on its behavioural manifestations, as laboratory diagnostic tests do not exist. Creatine deficiency syndrome (CDS) is one form of inborn error of metabolism where affected individuals have similar clinical features to individuals with ASD. Abnormal urinary creatine (CR) and guanidinoacetate (GAA) levels have been reported as biomarkers of CDS. We hypothesized that screening for abnormal levels of urinary CR and GAA in children with ASD may assist in identifying a subgroup of ASD individuals who can be managed with dietary interventions. Morning urine samples were collected from children with and without autism and analyzed for CR and GAA levels. Results showed there was no statistically significant difference in urinary CR:creatinine and GAA:creatinine between the children with ASD and sibling or unrelated controls. In conclusion, routine screening for abnormal urinary CR and GAA could be considered in ASD diagnostic protocols; however, individuals positive for CDS are likely to be rare in an ASD cohort.

Restricted and repetitive behaviors (RRBs) observed during the Autism Diagnostic Observation Schedule [ADOS: Lord et al., 2000] were examined in a longitudinal data set of 455 toddlers and preschoolers (age 8-56 months) with clinical diagnosis of Autism Spectrum Disorders (ASD; autism, n=121 and pervasive developmental disorders - not otherwise specified (PDD-NOS), n=71), a nonspectrum disorder (NS; n=90), or typical development (TD; n=173). Even in the relatively brief semi-structured observations, GEE analyses of the severity and prevalence of RRBs differentiated children with ASD from those with NS and TD across all ages. RRB total scores on the ADOS were stable over time for children with ASD and NS; however, typically developing preschoolers showed lower RRB scores than typically developing toddlers. Nonverbal IQ (NVIQ) was more strongly related to the prevalence of RRBs in older children with PDD-NOS, NS, and TD than younger children under 2 years and those with autism. Item analyses revealed different relationships between individual items and NVIQ, age, diagnosis, and gender. These findings are discussed in terms of their implications for the etiology and treatment of RRBs as well as for the framework of ASD diagnostic criteria in future diagnostic systems.

At the past meeting of INSAR, the role of autoimmunity was discussed in an educational session. This article summarizes this discussion. In immune-mediated diseases, antibodies can contribute to the pathogenesis of the disease and are sometimes the force that drives the disease process. This concept has not been established for autism. In autoimmune diseases, such as systemic lupus erythematosus (SLE), antibodies are found to react with double-stranded DNA. These antibodies also cross-react with N-methyl-D aspartate receptors. Many SLE patients suffer neurologic syndromes of the central nervous system (CNS). Similarly individuals infected with Group A streptococcus (GAS) have antibodies against the GAS carbohydrate, which cross-react with tubulin and lysoganglioside GM1 on neurons. During the acute stage of infection, GAS-infected patients develop Syndenham chorea where the disease process is driven in part by these cross-reactive antibodies. As the antibody levels decrease, the clinical features of Syndenham chorea resolve. In these two immune-mediated diseases, antibodies clearly play a role in the pathogenesis of the diseases. There are reports that mothers of individuals with autism have antibodies that react with brain proteins and when these antibodies are passively transferred to pregnant non-human primates or rodents the offspring has behavioral and nervous system changes. It is still not clear whether the antibodies found in mothers of individuals with autism actually play a role in the disease. More studies need to be performed to identify the proteins recognized by the antibodies and to determine how these could affect development, behavior and changes within the CNS.

Empathizing-Systemizing theory posits a continuum of cognitive traits extending from autism into normal cognitive variation. Covariance data on empathizing and systemizing traits have alternately suggested inversely dependent, independent, and sex-dependent (one sex dependent, the other independent) structures. A total of 144 normal undergraduates (65 men, 79 women) completed the Reading the Mind in the Eyes, Embedded Figures, and Benton face recognition tests, the Autism Spectrum Quotient, and measures of digit length ratio and field of study; some also completed tests of motion coherence threshold (64) and go/no-go motor inhibition (128). Empathizing and systemizing traits were independent in women, but largely dependent in men. In men, level of systemizing skill required by field of study was directly related to social interactive and mindreading deficits; men's social impairments correlated with prolonged go/no-go response times, and men tended to apply systemizing strategies to solve problems of empathizing or global processing: rapid perceptual disembedding predicted heightened sensitivity to facial emotion. In women, level of systemizing in field was related to male-typical digit ratios and autistic superiorities in detail orientation, but not to autistic social and communicative impairments; and perceptual disembedding was related to social interactive skills but independent of facial emotion and visual motion perception.

Successful social behavior requires the accurate detection of other people's movements. Consistent with this, typical observers demonstrate enhanced visual sensitivity to human movement relative to equally complex, nonhuman movement [e.g., Pinto & Shiffrar, ]. A psychophysical study investigated visual sensitivity to human motion relative to object motion in observers with autism spectrum disorder (ASD). Participants viewed point-light depictions of a moving person and, for comparison, a moving tractor and discriminated between coherent and scrambled versions of these stimuli in unmasked and masked displays. There were three groups of participants: young adults with ASD, typically developing young adults, and typically developing children. Across masking conditions, typical observers showed enhanced visual sensitivity to human movement while observers in the ASD group did not. Because the human body is an inherently social stimulus, this result is consistent with social brain theories [e.g., Pelphrey & Carter, ; Schultz, ] and suggests that the visual systems of individuals with ASD may not be tuned for the detection of socially relevant information such as the presence of another person. Reduced visual sensitivity to human movements could compromise important social behaviors including, for example, gesture comprehension.

The current study investigated the relationships between internalizing and externalizing (I-E) behaviors and family variables, including both parenting stress and quality of attachment relations, in children aged 8-12 with high-functioning autism spectrum disorder (ASD) or with typical development. Compared to the group with typical development, children with ASD exhibited significantly greater levels of psychopathology as assessed by the Child Behavior Checklist [Achenbach, 1991], and parents of children with ASD exhibited higher parenting stress as assessed by the Parenting Stress Index [Abidin, 1995]. In a hierarchical multiple regression analysis, parenting stress emerged as the most important predictor of children's I-E problems. Results are discussed in light of the two groups' similar relationships between parenting stress and child psychopathology.

Previous research [Ropar & Mitchell, ] has shown that autistic individuals are somewhat immune to biases induced by top-down processes, particularly the influence of previous knowledge on perception. In order to test this hypothesis within perception, 18 participants with autism who had measured intelligence in the normal range were compared against 18 matched controls in their susceptibility to the Shepard illusion. The illusion consists in misperceiving the shape of a parallelogram in the presence of depth cues. It is attributed [Mitchell, Ropar, Ackroyd, & Rajendran, ] to the effect of top-down constraints within perception. The task involved adjusting a stimulus to the dimensions of a template on a computer screen. Both groups were susceptible to the illusion and the illusion effect was stronger when three-dimensional perspective cues were prominent. Notably, participants with autism were less susceptible to the illusion than typically developing individuals. The findings raise the possibility that in some instances top-down influences are attenuated in individuals with autism.

There is a strong genetic component to autism spectrum disorders (ASD), but due to significant genetic heterogeneity, individual genetic abnormalities contribute a small percentage to the overall total. Previous studies have demonstrated PTEN mutations in a sizable proportion of individuals with ASD or mental retardation/developmental delays (MR/DD) and macrocephaly that do not have features of Cowden or Bannayan-Riley-Ruvalcaba syndrome. This study was performed to confirm our previous results. We reviewed the charts of individuals who had PTEN clinical sequencing performed at our institution from January 2008 to July 2009. There were 93 subjects tested from our institution during that period. PTEN mutations were found in 2/39 (5.1%) ASD patients and 2/51 (3.9%) MR/DD patients. Three additional patients without mutations had no diagnostic information. Multiple relatives of individuals with a PTEN mutation had macrocephaly, MR, or early onset cancer (breast, renal, and prostate). Of those relatives tested, all had the familial PTEN mutation. None of the affected relatives had previously been diagnosed with Cowden or Bannayan-Riley-Ruvalcaba syndrome. We noted in our previous study several adult relatives without any findings who carried a mutation. Combined with data from our previous cohort, we have found PTEN mutations in 7/99 (7.1%) of individuals with ASD and 8/100 (8.0%) of individuals with MR/DD, all of whom had macrocephaly. We recommend testing for mutations in PTEN for individuals with ASD or MR/DD and macrocephaly. If mutations are found, other family members should be offered testing and the adults offered cancer screening if they have a PTEN mutation.

A pervasive integration deficit could provide a powerful and elegant account of cognitive processing in autism spectrum disorders (ASD). However, in the case of visual Gestalt grouping, typically assessed by tasks that require participants explicitly to introspect on their own grouping perception, clear evidence for such a deficit remains elusive. To resolve this issue, we adopt an index of Gestalt grouping from the object-based attention literature that does not require participants to assess their own grouping perception. Children with ASD and mental- and chronological-age matched typically developing children (TD) performed speeded orientation discriminations of two diagonal lines. The lines were superimposed on circles that were either grouped together or segmented on the basis of color, proximity or these two dimensions in competition. The magnitude of performance benefits evident for grouped circles, relative to ungrouped circles, provided an index of grouping under various conditions. Children with ASD showed comparable grouping by proximity to the TD group, but reduced grouping by similarity. ASD seems characterized by a selective bias away from grouping by similarity combined with typical levels of grouping by proximity, rather than by a pervasive integration deficit.

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Purpose: To examine the association between autistic spectrum disorder (ASD) and seasons of conception and birth in a UK birth cohort: Avon Longitudinal Study of Parents and Children (ALSPAC). Methods: Seasons of conception and birth were compared in children with and without ASD with season grouped as follows: spring (March-May); summer (June-August); autumn (September-November) and winter (December-February). Results: A total of 86 children with ASD were identified in the ALSPAC cohort giving a prevalence of ASD of 61.9 per 10,000. There was some evidence for an excess of children with ASD being conceived during the summer months with a rate per 1,000 conceptions of 9.5 in summer compared to 5.1, 4.6, 5.7 in spring, autumn and winter, respectively. A doubling of the odds was suggested for summer compared to autumn (Odds ratio 2.08 [1.18, 3.70]). In agreement with previous research, there was a corresponding peak in spring births. Conclusion: Conception during the summer months was associated with an over-representation of children with ASD in this UK birth cohort. There was also an association between ASD and spring births. Further investigation of seasonal influences on the aetiology of autism is required to identify possible factors in the environment, and their mechanisms and timings.

Research suggests that children with autism spectrum disorders (ASDs) and their relatives have high rates of depression and anxiety. However, relatively few studies have looked at both factors concurrently. This study examined the potential relationship between maternal mood symptoms and depression and anxiety in their children with ASD. Participants were 31 10- to 17-year-old children with an ASD diagnosis that was supported by gold-standard measures and their biological mothers. Mothers completed the Autism Comorbidity Interview to determine whether the child with ASD met criteria for any depressive or anxiety diagnoses and a questionnaire of their own current mood symptoms. As expected, many children with ASD met criteria for lifetime diagnoses of depressive (32%) and anxiety disorders (39%). Mothers' report of their own current mood symptoms revealed averages within the normal range, though there was significant variability. Approximately 75% of children with ASD could be correctly classified as having a depressive or anxiety disorder history or not based on maternal symptoms of interpersonal sensitivity, hostility, phobic anxiety, depression, and anxiety. The results provide preliminary evidence that maternal mood symptoms may be related to depression and anxiety in their children with ASD. Although the design did not allow for testing of heritability per se, the familial transmission patterns were generally consistent with research in typical populations. While larger follow-up studies are needed, this research has implications for prevention and intervention efforts.

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