The Autistic Place

A review of: Austin, D., Shandley, K. (2008). An Investigation of Porphyrinuria in Australian Children with Autism. Journal of Toxicology and Environmental Health, Part A, 71(20), 1349-1351. DOI: 10.1080/15287390802271723

The journal of Toxicology and Environmental Health just published a study conducted in Australia examining the possible link between mercury and autism. The study examined urinary porphyrins as a measure of mercury exposure in children with autism. Porphyrinuria, or the excess urinary excretion of porphyrin, is purported to reflect heavy metal exposure and in particularly mercury. Two previous studies (Nataf et al., 2006, and Geier & Geier, 2007) used this urinary measure and reported increased levels of porphyrins in children with autism when compared to typically developing children. In the current study the authors examined urinary samples of 41 patients with ASD (detailed diagnostic procedure information was not provided). The age of the sample ranged from 1 to 16 (average 6). There were 30 boys and 11 girls. The authors did not include a control group. That is, no local comparison group of typically developing children was used. Instead, the authors compared the levels of porphyrins of the Australian sample with the control samples (typically developing kids) used by the two previous studies as well as to ‘normative’ laboratory ranges obtained from a French laboratory and the normative ranges published in a 1996 European study (Minder and Schneider-Yin, 1996).

The authors reported that the ratio of uroporphyrin to coproporphyrin (CP to UP) was significantly higher in the Australian ASD group when compared to all control samples of the previous studies. The comparison effect sizes were very large, namely: 1.60 when compared to the Geier & Geier sample, 1.54 when compared to the Nataf et al sample, and 1.46 when compared to the 1996 normative sample. Effect size is a measure of the differences between the means of two groups that is not as sensitive (not affected by) the very large differences in sample sizes between these studies. Effect sizes in this range (1.46 to 1.60) indicate that the differences between the groups were very substantial.

A final thought. I can not discuss the merits of this particular urinary measure as reflective of mercury exposure or mercury toxicity, since this is beyond my understanding of heavy metal metabolism, thus I would simple make one final comment regarding the methodology of this study. I am very surprised that the authors did not include a local comparison sample, especially since their intention was to replicate the previous findings within a local Australian group. This is a strong limitation of the study. The results indicate that the Australian ASD group is significantly different than the typically developing group used in the two previous samples (one from the USA and another from France), but the results provide no information as how this ASD group compares to typically developing children in the sample geographical regions.

However, the data is compelling in showing a strong difference in the CP to UP ratio between the Australian sample and typically developing children in the USA and France. Does this mean that mercury causes autism? Not at all. Readers should be careful not to make conclusions about causal mechanisms from these type of association studies. There are multiple possible interpretations of the data, including the possibility that heavy metal exposure may play a role in the development of ASD. However, it is also possible that CP/UP ratio differences between these groups are the result, rather than the cause, of physiological differences in Autism. The results of this study do not support one interpretation more than the other. The results simply indicate that the groups are different in CP to UP ratio. The data do not tell us why these groups are different, or whether mercury causes autism.



Geier, D. A., and Geier, M. R. 2007. A prospective study of mercury toxicity
biomarkers in autistic spectrum disorders. J. Toxicol. Environ. Health,
A 70:1723–1730.

Minder, E. I., and Schneider-Yin, X. 1996. Age-dependent reference values
of urinary porphyrins in children. Eur. J. Clin. Chem. Clin. Biochem.
34:439–443.

Nataf, R., Skorupka, C., Amet, L., Lam, A., Springbett, A., and Lathe, R. 2006.
Porphyrinuria in childhood autistic disorder: Implications for environmental
toxicity. Toxicol. Appl. Pharmacol. 214:99–108.

A review of:Roos, E.M., McDuffie, A.S., Weismer, S.E., Gernsbacher, M.A. (2008). A comparison of contexts for assessing joint attention in toddlers on the autism spectrum. Autism, 12(3), 275-291. DOI: 10.1177/1362361307089521

Earlier this year I reported on a study that showed significant improvement in joint attention after systematic training. Limited joint attention behaviors is seen as an early indicator of autism. In this new study, a team from the University of Wisconsin – Madison compared naturalistic (play interactions) and structured (Early Social Communication Scale protocol - ESCS) joint attention behaviors in toddlers, in order to examine the utility and viability of using naturalistic observations as an alternative to, or in support of, structured protocols such as the ESCS.

The ESCS assesses for two aspects of joint attention, namely: initiation of joint attention (IJA) and response to joint attention (RJA).

RJA refers to the child’s use of attention-following behaviors, such as head turns and eye gaze to follow the visual focus of a communicative partner. IJA refers to the child’s use of attention-directing behaviors, such as pointing or showing to coordinate attention with a social partner with reference to an object or event.

The authors wanted to explore IJA and RJA in multiple contexts in order to determine how stable these behaviors are across settings. To this end, the authors examined 20 toddlers with symptoms of autism (16 boys, four girls, mean age = 33.2 months). The experimenters conducted the ESCS during a first home visit and a play session during a second visit approximately one week apart. Both sessions were coded for IJA and RJA events. The authors found that the ESCS elicited significantly more IJA when compared to naturalistic play. However, the naturalistic play session elicited significantly more RJA. This indicates that the ESCS may underestimate a child’s use of RJA, and that conducting assessments in multiple contexts may provide a more valid measure of the child’s use of joint attention behaviors.

A review of: Koyama, T., Kamio, Y., Inada, N., Kurita, H. (2008). Sex Differences in WISC-III Profiles of Children with High-functioning Pervasive Developmental Disorders. Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-008-0610-6

Previous studies on IQ profiles among children with high functioning autism have usually revealed a pattern of performance characterized by lower scores on the comprehension subtest and higher scores on the block design subtest. Deficits in the comprehension subtest have been thought to reflect difficulties understanding social contexts, while above average performance on the block design test may reflect a “detailed-focus cognitive style.” However, there are no published studies examining possible sex differences in cognitive performance on IQ test among children with high functioning autism.

In this study, the author compared 26 girls (mean age 8.2) and 116 boys (mean age 9.0) meeting diagnostic criteria for PDD based on the ICD-10 (the study was conducted in Japon). The children were tested using a Japanese version of the Wechsler Intelligence Scale for Children-Third Edition. The authors did not find significant differences in total IQ scores (average 97.9 for girls and 96 for boys) or scores on the Verbal (average 99.4 for girls and 94.8 for boys) or Performance subscales (average 96.6 for girls and 98.2 for boys). However, girls performed significantly better than the boys on subtests of processing speed, coding, and symbol search, while the boys performed significantly better than the girls on the block design subtest. Performance on the comprehension subtest was the most clear relative weakness for both boys and girls.

The high performance by girls on coding and symbol search does not represent greater visual-motor skills when compared to boys, as boys outperformed girls on the block design – a test also highly dependent on visual-motor functioning. Thus, it is more likely that the sex differences in coding and symbol search are due to faster processing speed by girls, just as indicated by the processing speed index.

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Neuroligin-3 is a member of the class of cell adhesion proteins that mediate synapse development and have been implicated in autism. Mice with the human R451C mutation (NL3), identical to the point mutation found in two brothers with autism spectrum disorders, were generated and phenotyped in multiple behavioral assays with face validity to the diagnostic symptoms of autism. No differences between NL3 and their wildtype (WT) littermate controls were detected on measures of juvenile reciprocal social interaction, adult social approach, cognitive abilities, and resistance to change in a spatial habit, findings which were replicated in several cohorts of males and females. Physical and procedural abilities were similar across genotypes on measures of general health, sensory abilities, sensorimotor gating, motor functions, and anxiety-related traits. Minor developmental differences were detected between NL3 and WT, including slightly different rates of somatic growth, slower righting reflexes at postnatal days 2-6, faster homing reflexes in females, and less vocalizations on postnatal day 8 in males. Significant differences in NL3 adults included somewhat longer latencies to fall from the rotarod, less vertical activity in the open field, and less acoustic startle to high decibel tones. The humanized R451C mutation in mice did not result in apparent autism-like phenotypes, but produced detectable functional consequences that may be interpreted in terms of physical development and/or reduced sensitivity to stimuli.

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A review of: Mouridsen, S.E., Bronnum-Hansen, H., Rich, B., Isager, T. (2008). Mortality and causes of death in autism spectrum disorders: An update. Autism, 12(4), 403-414. DOI: 10.1177/1362361308091653

The issue of life expectancy and mortality rates in people with autism is a largely understudied and seldom discussed topic. Studies of mortality in people with chronic psychiatric disorders usually show higher mortality rates at all ages than what is expected in the general population. Mortality rates refer to the number of death expected up to a specific age for specific cohorts. For example, what is the expected number of death within a cohort born in year 1973 by the time they are 30?

Only a couple of studies of mortality rates in people with autism have been conducted, one in California and one Denmark. Both studies showed that the mortality rate in people with austim was more than twice as that for the general population. The present study by the Danish team intended to expand on their original findings by examining the mortality rate and causes of death among a cohort of adults with ASDs who are now in their 40s. The sample included 341 adults with various diagnoses including autism (N=118), atypical autism (N=89), childhood disintegrative disorder (N=13), and asperger’s (N=121).

The mean age for the patients was 43.4 with a range of 26 to 60. A total of 26 patients have died by 2006 (7.6%). The expected number of deaths in the general population for a similar cohort was 13.5 (3.8%). Therefore, the mortality rate in the cohort of adults with ASDs was nearly twice of what is expected in the general population. However, this effect was significantly more pronounced among women. The mortality rate for woman with ASD was 4 times higher than what is expected in the general population. Surprisingly, these effects were not moderated (reduced) by IQ, which often reflects functional capacity. That is, within the group with ASDs, the mortality rates was the same for adults regardless of their IQ. The cause of death most commonly reported among the cohort with ASDs was epilepsy.

A functional promoter variant of the gene encoding the MET receptor tyrosine kinase alters SP1 and SUB1 transcription factor binding, and is associated with autism spectrum disorder (ASD). Recent analyses of postmortem cerebral cortex from ASD patients revealed altered expression of MET protein and three transcripts encoding proteins that regulate MET signaling, hepatocyte growth factor (HGF), urokinase plasminogen activator receptor (PLAUR) and plasminogen activator inhibitor-1 (SERPINE1). To address potential risk conferred by multiple genes in the MET signaling pathway, we screened all exons and 5[prime] promoter regions for variants in the five genes encoding proteins that regulate MET expression and activity. Identified variants were genotyped in 664 families (2,712 individuals including 1,228 with ASD) and 312 unrelated controls. Replicating our initial findings, family-based association test (FBAT) analyses demonstrated that the MET promoter variant rs1858830 C allele was associated with ASD in 101 new families (P=0.033). Two other genes in the MET signaling pathway also may confer risk. A haplotype of the SERPINE1 gene exhibited significant association. In addition, the PLAUR promoter variant rs344781 T allele was associated with ASD by both FBAT (P=0.006) and case-control analyses (P=0.007). The PLAUR promoter rs344781 relative risk was 1.93 (95% confidence interval [CI]: 1.12-3.31) for genotype TT and 2.42 (95% CI: 1.38-4.25) for genotype CT compared to genotype CC. Gene-gene interaction analyses suggested a significant interaction between MET and PLAUR. These data further support our hypothesis that genetic susceptibility impacting multiple components of the MET signaling pathway contributes to ASD risk.

Two single nucleotide polymorphisms (SNP) within Mitochondrial Aspartate/Glutamate Carrier SLC25A12 gene have recently shown to be strongly associated with autism. Here, we attempted to replicate this finding in two separate Finnish samples with autism spectrum disorders. Family-based association analysis of two SNPs, rs2056202 and rs2292813, previously shown to be associated with autism was performed in two samples with different phenotypic characteristics. The samples included 97 families with strictly defined autism and 29 extended families with Asperger syndrome (AS). We detected association at rs2292813 (FBAT, P=0.0018) in the Finnish autism sample. In, addition other family-based analysis methods supported this finding. By contrast, analysis of the AS sample yielded no evidence for association. This study shows further support that genetic variants within SLC25A12 gene contribute to the etiology of autism.

A review of: Begeer, S., Bouk, S.E., Boussaid, W., Terwogt, M.M., Koot, H.M. (2008). Underdiagnosis and Referral Bias of Autism in Ethnic Minorities. Journal of Autism and Developmental Disorders DOI: 10.1007/s10803-008-0611-5


The issue of under- or over-representation of a disorder within specific ethnic groups is a complicated one. There are specific disorders that are under-represented within a specific ethnic group because of some protective factor that makes such group less likely to acquire the disorder. For example, the rates of skin cancer in the African-American population are significantly lower than in the European-American population(although this has led to increase mortality rates among African Americans due to reduced screenings leading to late diagnosis). Yet, it is possible that some disorders are under-represented within an ethnic group simply because a systemic clinical bias in diagnosis and referrals. To examine this hypothesis, the authors of this study first examined 712 case records of children referred for ASD assessment in the Netherlands. They found that ethnic minority children (Turkish and Moroccan)were under-represented in this sample of referred kids as compared to Dutch children (2.1% vs. 4.4%). But does this represent a bias or is it simply that Turkish and Moroccan children are less likely to have ASD due to some protective factor? To answer this question, the authors sent 6 clinical vignettes to 82 pediatricians. The vignettes varied in their descriptions of various autism symptoms. Three ethnic background were represented, including 1) European minority (French or English) 2) Non-European minority (Moroccan and Turkish) and 3) Majority (Dutch). However, the ethnicity was independent of the clinical vignette, so that the vignette sent to one pediatrician could describe a Dutch child, while the SAME vignette sent to another pediatrician could describe a Turkish child. The authors found that vignettes describing Dutch (majority) children elicited significantly more references to autism than did vignettes describing European minority or non-European minority children. However, the mean rate of ASD based on an objective scale was equal across all three groups. This suggests that objective assessments may help minimize any potential clinical biases.

Research indicates that relatives of individuals with autism have higher rates of affective disorders than both the general population and families of children with other developmental disabilities. In addition, individuals with autism have high rates of co-morbid mood and anxiety disorders. This study sought to identify possible reasons for these previous findings by documenting the presence of affective disorders in both probands (the individuals with autism) and their family members. A sub-sample of 17 adults with autism and their first-degree relatives from the Baltimore Family Study of Autism completed a structured psychiatric interview. The results indicated that the rates of mood and anxiety disorders were 35 and 77%, respectively, for probands, and these disorders were present in at least one first-degree relative at rates of 71 and 29%, respectively. Exploring patterns within families revealed that 80% of probands with a mother who had a mood disorder history also had a mood disorder themselves, compared to only 16% of probands whose mothers did not have a mood disorder history. The results must be considered preliminary given the small sample size. Replicating these findings in a larger sample would help clarify whether a true increased risk of mood disorder exists, which would have potential implications for prevention efforts and understanding possible genetic mechanisms.

A review of: GOODLIN-JONES, B., TANG, K., LIU, J., ANDERS, T. (2008). Sleep Patterns in Preschool-Age Children With Autism, Developmental Delay, and Typical Development. . Journal of the American Academy of Child & Adolescent Psychiatry, 47(8), 932-940.

Parents of children with autism usually report that their children experience significant sleep problems, such as difficulty falling asleep. Yet, little research has been conducted on the specific type of sleep difficulties prevalent among children with autism. The authors of this paper first discussed the need to understand the nature of the sleep problems within this population. Research on sleep difficulties among children with other developmental disabilities indicate significant variability between the different disorders. For example, children with Prader-Willi syndrome have extended nighttime sleep and daytime sleepiness, while children with Rett syndrome have difficulty staying asleep during the night and frequent daytime napping. Therefore, in order to examine the type of sleep problems experienced by children with autism the authors examined the night and daytime sleep patterns of 68 pre-school children with autism, 57 children with non-autistic developmental delays, and 69 typically developing kids.

General findings:

The mean bedtime for the entire group was 9:00pm and the children took 38 additional minutes to fall asleep. The average waking time was 7:10am. Thus, the average time in bed was 10 hours, with 9:20 hours of actual sleep.

No sex differences were noted.

Autism findings:
Children with autism slept significantly less during a 24 hours cycle than children with other developmental disabilities and typically developing kids. In regards to awakening events during the night, typically developing children had more awakenings than children with autism, but the awakenings episodes of children with autism were significantly longer. This suggests that while children with autism do not seem to have difficulty staying asleep, they do experience difficulty falling asleep after sleep interruptions.

In regards to parental reports about their children sleep patterns, parents of children with autism reported significantly more sleep difficulties than parents of typically developing kids but not significantly more than those reported by parents of children with other developmental problems. However, parents of children with autism reported significantly more personal stress than parents in the two comparison groups.

Individuals with autism spectrum disorders (ASD) are often reported to be good at detecting minute changes in the environment. This study tested two factors in this phenomenon; detail-focus and reduced top-down influence of scene-schema expectations on spontaneous attention to visual scene elements. Using a change blindness paradigm, adults with ASD and matched typically developing (TD) adults were presented with images of naturalistic scenes (e.g., living room). Scene changes involved three types of object substitution: an object was replaced with (i) an unexpected scene-unrelated object, (ii) a scene-related object of a different basic-level category, (iii) or a different exemplar of the original object category. Top-down effects of scene-schema expectations should render scene-unrelated (i) substitutions easiest to recognize; detail focus should increase detection of exemplar changes. The TD group showed the expected condition effects, detecting scene-unrelated substitutions significantly better than both types of scene-related changes. By contrast, the ASD group showed no condition effect, and was only significantly slower and less accurate than the TD group in detecting scene-unrelated objects. These findings suggest reduced influence of schematic expectations on spontaneous attention in individuals with ASD. Together with other factors, this may contribute to the tendency to notice "irrelevant" changes in the environment.

Epigenetic mechanisms have been proposed to play a role in the etiology of autism. This hypothesis is supported by the discovery of increased MECP2 promoter methylation associated with decreased MeCP2 protein expression in autism male brain. To further understand the influence of female X chromosome inactivation (XCI) and neighboring methylation patterns on aberrant MECP2 promoter methylation in autism, multiple methylation analyses were performed on brain and blood samples from individuals with autism. Bisulfite sequencing analyses of a region 0.6 kb upstream of MECP2 in brain DNA samples revealed an abrupt transition from a highly methylated region in both sexes to a region unmethylated in males and subject to XCI in females. Chromatin immunoprecipitation analysis demonstrated that the CCCTC-binding factor (CTCF) is bound to this transition region in neuronal cells, consistent with a chromatin boundary at the methylation transition. Male autism brain DNA samples displayed a slight increase in methylation in this transition region, suggesting a possible aberrant spreading of methylation into the MECP2 promoter in autism males across this boundary element. In addition, autistic female brain DNA samples showed evidence for aberrant MECP2 promoter methylation as an increase in the number of bisulfite sequenced clones with undefined XCI status for MECP2 but not androgen receptor (AR). To further investigate the specificity of MECP2 methylation alterations in autism, blood DNA samples from females and mothers of males with autism were also examined for XCI skewing at AR, but no significant increase in XCI skewing was observed compared to controls. These results suggest that the aberrant MECP2 methylation in autism brain DNA samples is due to locus-specific rather than global X chromosome methylation changes.

A review of: Aman, M.G., Hollway, J.A., McDougle, C.J., Scahill, L., Tierney, E., McCracken, J.T., Arnold, L.E., Vitiello, B., Ritz, L., Gavaletz, A., Cronin, P., Swiezy, N., Wheeler, C., Koenig, K., Ghuman, J.K., Posey, D.J. (2008). Cognitive Effects of Risperidone in Children with Autism and Irritable Behavior. Journal of Child and Adolescent Psychopharmacology, 18(3), 227-236. DOI: 10.1089/cap.2007.0133

Risperdone is a neuroleptic antipsychotic drug that has been extensively used for the treatment of schizophrenia, and more recently bi-polar disorder. Risperdone also became the first FDA approved drug for treatment of schizophrenia and bi-polar disorder in children. This drug has significant anxiolytic (calming) proprieties and thus it has been used “off-label” (outside FDA recommendation) for the treatment of anxiety, panic disorder, and even depression. In 2006, the FDA finally approved the use of Risperdone in children with autism.

Because of its mild sedation effects, researchers and clinicians have proposed that this drug may have a negative impact of cognition. However, research with adults with schizophrenia, as well as research with children with disruptive behavior problems, has generally found Risperdone to have a beneficial effect on cognitive performance. In this study, the authors examined the effect of Risperdone on the cognitive abilities of children with autism with severe behavior problems.

The study used a double-blind, placebo controlled methodology. The study included 38 children with autism who were participating in a clinical trial of Risperdone. 20 participants had been randomly assigned to take Risperdone and 18 participants were taking the placebo. The trial lasted 8 weeks. The children were tested with several cognitive measures, including a cancellation task (attention task), a verbal learning task, a motor-eye coordination task, and a classroom task (skill-dependent math task). No detriment from the use of Risperdone was observed in any of the cognitive measures. Instead, significantly better performance was noted among children taking Risperdone compared to those taking placebo on tasks of attention and verbal learning. The authors concluded that Risperdone does not appear to have any short term detrimental effects on cognitive function and may instead facilitate cognitive performance on some children.

Referential communication was studied in children with autism spectrum disorder (ASD) including children with autism and Asperger syndrome. The aim was to study alternative explanations for the children's communicative problems in such situations. Factors studied were theory of mind, IQ, verbal ability and memory. The main results demonstrated diminished performance in children with autism spectrum disorder, mirroring performance in everyday life, in comparison to verbal IQ and mental age matched typically developing children. Among children with autism spectrum disorders, there was a positive relationship between performance in referential communication and theory of mind. Memory capacity also proved to play a role in success in the task.

Are children with an autism spectrum disorder (ASD), but normal-range intelligence, impaired on theory of mind skills measured by responses to abstract animations in the form of a computerized cartoon? Fifty-six cases and closely matched comparisons were tested. We rated verbal responses according to the length of their descriptions, their appropriateness and the children's use of `mentalizing' terms. Children with ASD used `mentalizing' language to describe the animations as well as comparisons, although the content of their descriptions was significantly less appropriate. Performance on this task was not well correlated with standardized measures of parent-reported behaviour or the child's interactions with an observer. The implications of our results are discussed in relation to previous studies that have used this methodology.