Some authors have reported higher blood mercury (Hg) levels in persons with autism, relative to unaffected controls.
We compared blood total Hg concentrations in children with autism or autism spectrum disorder (AU/ASD) and typically developing (TD) controls in population-based samples, and determined the role of fish consumption in differences observed.
The Childhood Autism Risk from Genetics and the Environment (CHARGE) Study enrolled children 2–5 years of age. After diagnostic evaluation, we analyzed three groups: AU/ASD, non-AU/ASD with developmental delay (DD), and population-based TD controls. Mothers were interviewed about household, medical, and dietary exposures. Blood Hg was measured by inductively coupled plasma mass spectrometry. Multiple linear regression analysis was conducted (n = 452) to predict blood Hg from diagnostic status controlling for Hg sources.
Fish consumption strongly predicted total Hg concentration. AU/ASD children ate less fish. After adjustment for fish and other Hg sources, blood Hg levels in AU/ASD children were similar to those of TD children (p = 0.75); this was also true among non-fish eaters (p = 0.73). The direct effect of AU/ASD diagnosis on blood Hg not through the indirect pathway of altered fish consumption was a 12% reduction. DD children had lower blood Hg concentrations in all analyses. Dental amalgams in children with gum-chewing or teeth-grinding habits predicted higher levels.
After accounting for dietary and other differences in Hg exposures, total Hg in blood was neither elevated nor reduced in CHARGE Study preschoolers with AU/ASD compared with unaffected controls, and resembled those of nationally representative samples.
autism; autism spectrum disorders; child development; dental amalgams; developmental delay; fish; mercury; metabolism; metals
Etiology is unknown in the majority of individuals with autism spectrum disorder (ASD). One strategy to investigate pathogenesis is to stratify this heterogeneous disorder based on a prominent phenotypic feature that enriches for homogeneity within population strata. Co-occurring gastrointestinal dysfunction (GID) characterizes a subset of children with ASD. Our current objective was to investigate a potential pathophysiological measure to test the hypothesis that children with both ASD and GID have a more severe metabolic dysfunction than children with ASD-only, given that the highly metabolically active brain and gastrointestinal system may additively contribute measurable impairment. Plasma levels of F2t-Isoprostanes (F2-IsoPs), a gold standard biomarker of oxidative stress, were measured in 87 children in four groups: ASD-GID, ASD-only, GID-only and Unaffected. F2-IsoP levels were elevated in all 3 clinical groups compared to the Unaffected group, with the ASD-GID group significantly elevated above the ASD-only group (mean, SD in pg/mg: ASD-GID 53.6, 24.4; ASD-only 36.5, 13.3; p = 0.007). Adjusting for age, sex, and triglyceride levels, F2-IsoP levels remained significantly different between study groups, with a moderate effect size of ηp2 = 0.187 (p = 0.001). Elevation in peripheral oxidative stress is consistent with, and may contribute to, the more severe functional impairments in the ASD-GID group. With unique medical, metabolic, and behavioral features in children with ASD-GID, the present findings serve as a compelling rationale for both individualized approaches to clinical care and integrated studies of biomarker enrichment in ASD subgroups that may better address the complex etiology of ASD.
We investigated brain chemistry of the primary region of the brain involved in auditory processing in adults with autism spectrum disorder (ASD). Due to the highly heritable nature of ASD and the lack of prior brain chemistry data on unaffected first-degree relatives, we also enrolled parents of children with ASD (pASD), comparing both groups to a healthy adult control group. The technique used to quantify chemical signals was magnetic resonance spectroscopy (MRS), which we used to assess the concentration of auditory glutamate, the primary excitatory brain neurotransmitter, as well as other metabolites that assess neuronal integrity and metabolism. We found significantly higher levels of auditory glutamate in persons with ASD. In addition, increases in two other metabolites, n-acetyl-aspartate (NAA), and creatine (Cr), were observed in the ASD group. No differences were observed in the pASD group in any MRS measurement. We interpret the glutamate finding as suggestive of an increase in brain excitability, and the NAA and Cr findings as indicative of a change in brain energy metabolism in ASD.
Increased glutamate levels have been reported in the hippocampal and frontal regions of persons with autism using proton magnetic resonance spectroscopy (1H-MRS). Although autism spectrum disorders (ASD) are highly heritable, MRS studies have not included relatives of persons with ASD. We therefore conducted a study to determine if glutamate levels are elevated in people with autism and parents of children with autism.
Single-voxel, point resolved spectroscopy (PRESS) data were acquired at 3T for left and right hemisphere auditory cortical voxels in 13 adults with autism, 15 parents of children with autism, and 15 adult control subjects. The primary measure was Glx. Additional measures included n-acetyl-aspartate (NAA), choline (Cho), myoinositol (mI) and creatine (Cr).
The autism group had significantly higher Glx, NAA and Cr concentrations than the control subjects. Parents did not differ from control subjects on any measures. No significant differences in Cho or mI levels were seen among groups. No reliable correlations between autism symptom measures and MRS variables were seen after Bonferroni correction for multiple comparisons.
The elevation in Glx in autism is consistent with prior MRS data in the hippocampus and frontal lobe and may suggest increased cortical excitability. Increased NAA and Cr may indicate brain metabolism disturbances in autism. In the current study, we found no reliable evidence of a familial effect for any spectroscopy measure. This may indicate that these metabolites have no heritable component in autism, the presence of a compensatory factor in parents, or sample specific limitations such the participation of singleton families.
glutamate; n-acetyl-aspartate; creatine; spectroscopy; auditory cortex
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder estimated to affect 1 in 110 children in the U.S., yet the pathology of this disorder is not fully understood. Abnormal levels of several growth factors have been demonstrated in adults with ASD, including epidermal growth factor (EGF) and hepatocyte growth factor (HGF). Both of these growth factors serve important roles in neurodevelopment and immune function. In this study, concentrations of EGF and HGF were assessed in the plasma of 49 children with ASD aged 2–4 years old and 31 typically developing controls of a similar age as part of the Autism Phenome Project (APP). Levels of EGF were significantly reduced in the ASD group compared to typically developing controls (P = 0.003). There were no significant differences in HGF levels in young children with ASD and typically developing controls. EGF plays an important role in regulating neural growth, proliferation, differentiation and migration, and reduced levels of this molecule may negatively impact neurodevelopment in young children with ASD.
Urinary mercury concentrations are used in research exploring mercury exposure. Some theorists have proposed that autism is caused by mercury toxicity. We set out to test whether mercury concentrations in the urine of children with autism were significantly increased or decreased compared to controls or siblings.
Blinded cohort analyses were carried out on the urine of 56 children with autism spectrum disorders (ASD) compared to their siblings (n = 42) and a control sample of children without ASD in mainstream (n = 121) and special schools (n = 34).
There were no statistically significant differences in creatinine levels, in uncorrected urinary mercury levels or in levels of mercury corrected for creatinine, whether or not the analysis is controlled for age, gender and amalgam fillings.
This study lends no support for the hypothesis of differences in urinary mercury excretion in children with autism compared to other groups. Some of the results, however, do suggest further research in the area may be warranted to replicate this in a larger group and with clear measurement of potential confounding factors.
The prevalence of sleep related complaints is reported by questionnaire studies to be as high as 83.3% in children with autism spectrum disorders (ASD). Questionnaire studies report the presence of various parasomnia in ASD. However, no polysomnographic study reports non-REM parasomnias and only a single study reports REM related parasomnias in ASD. We investigated the prevalence and characteristics of sleep disorders by polysomnographic study and questionnaires in a cohort of 23 children with ASD and 23 age-matched children of a non-autistic comparison group. The results showed significantly more non-REM parasomnias in 14 children with ASD on polysomnograms (PSG) and 16 ASD children by questionnaire, a finding that was not associated with medication use, other comorbid medical or psychiatric disorders, or sleep disordered breathing. Of the 14 children with ASD who had PSG evidence of parasomnia, 11 of them had a history suggestive of parasomnia by questionnaire. There was a high sensitivity but a low specificity of parasomnia in ASD by questionnaire in predicting the presence of parasomnia in the PSG. Of the parasomnias recorded in the laboratory, 13 ASD children had Disorders of Partial Arousal, consistent with sleep terrors or confusional arousals. Furthermore, multiple episodes of partial arousal occurred in 11 of the 13 ASD children who had PSG evidence of Disorders of Partial Arousal. Of the 11 ASD children with multiple episodes of partial arousal, 6 ASD children had multiple partial arousals during both nights’ PSG study. Sleep architecture was abnormal in children with ASD, characterized by increased spontaneous arousals, prolonged REM latency and reduced REM percentage. These results suggest a high prevalence of parasomnia in this cohort of children with ASD and a careful history intake of symptoms compatible with parasomnia could be prudent to diagnose parasomnia in ASD children when performing a PSG is not possible.
Autism spectrum disorders; parasomnia; sleep terror; confusional arousal; disorders of partial arousal
Research studies have uncovered several metabolic abnormalities associated with autism spectrum disorder (ASD), including mitochondrial disease (MD) and abnormal redox metabolism. Despite the close connection between mitochondrial dysfunction and oxidative stress, the relation between MD and oxidative stress in children with ASD has not been studied. Plasma markers of oxidative stress and measures of cognitive and language development and ASD behavior were obtained from 18 children diagnosed with ASD who met criteria for probable or definite MD per the Morava et al. criteria (ASD/MD) and 18 age and gender-matched ASD children without any biological markers or symptoms of MD (ASD/NoMD). Plasma measures of redox metabolism included reduced free glutathione (fGSH), oxidized glutathione (GSSG), the fGSH/GSSG ratio and 3-nitrotyrosine (3NT). In addition, a plasma measure of chronic immune activation, 3-chlorotyrosine (3CT), was also measured. Language was measured using the preschool language scale or the expressive one-word vocabulary test (depending on the age), adaptive behaviour was measured using the Vineland Adaptive Behavior Scale (VABS) and core autism symptoms were measured using the Autism Symptoms Questionnaire and the Social Responsiveness Scale. Children with ASD/MD were found to have lower scores on the communication and daily living skill subscales of the VABS despite having similar language and ASD symptoms. Children with ASD/MD demonstrated significantly higher levels of fGSH/GSSG and lower levels of GSSG as compared with children with ASD/NoMD, suggesting an overall more favourable glutathione redox status in the ASD/MD group. However, compare with controls, both ASD groups demonstrated lower fGSH and fGSH/GSSG, demonstrating that both groups suffer from redox abnormalities. Younger ASD/MD children had higher levels of 3CT than younger ASD/NoMD children because of an age-related effect in the ASD/MD group. Both ASD groups demonstrated significantly higher 3CT levels than control subjects, suggesting that chronic inflammation was present in both groups of children with ASD. Interestingly, 3NT was found to correlate positively with several measures of cognitive function, development and behavior for the ASD/MD group, but not the ASD/NoMD group, such that higher 3NT concentrations were associated with more favourable adaptive behaviour, language and ASD-related behavior. To determine whether difference in receiving medications and/or supplements could account for the differences in redox and inflammatory biomarkers across ASD groups, we examined differences in medication and supplements across groups and their effect of redox and inflammatory biomarkers. Overall, significantly more participants in the ASD/MD group were receiving folate, vitamin B12, carnitine, co-enzyme Q10, B vitamins and antioxidants. We then determined whether folate, carnitine, co-enzyme Q10, B vitamins and/or antioxidants influenced redox or inflammatory biomarkers. Antioxidant supplementation was associated with a significantly lower GSSG, whereas antioxidants, co-enzyme Q10 and B vitamins were associated with a higher fGSH/GSSG ratio. There was no relation between folate, carnitine, co-enzyme Q10, B vitamins and antioxidants with 3NT, 3CT or fGSH. Overall, our findings suggest that ASD/MD children with a more chronic oxidized microenvironment have better development. We interpret this finding in light of the fact that more active mitochondrial can create a greater oxidized microenvironment especially when dysfunctional. Thus, compensatory upregulation of mitochondria which are dysfunctional may both increase activity and function at the expense of a more oxidized microenvironment. Although more ASD/MD children were receiving certain supplements, the use of such supplements were not found to be related to the redox biomarkers that were related to cognitive development or behavior in the ASD/MD group but could possibly account for the difference in glutathione metabolism noted between groups. This study suggests that different subgroups of children with ASD have different redox abnormalities, which may arise from different sources. A better understanding of the relationship between mitochondrial dysfunction in ASD and oxidative stress, along with other factors that may contribute to oxidative stress, will be critical to understanding how to guide treatment and management of ASD children. This study also suggests that it is important to identify ASD/MD children as they may respond differently to specific treatments because of their specific metabolic profile.
autism; inflammation; endophenotypes; mitochondrial disease; oxidative stress
A role for immune dysfunction has been suggested in autism spectrum disorders (ASD). Elevated levels of chemokines have been detected in the brain and CSF of individuals with ASD but, to date, no study has examined chemokine levels in the plasma of children with this disorder. In the current study, we determined whether there were differential profiles of chemokines in the plasma of children with ASD compared to age-matched typically developing controls and children with developmental disabilities other than ASD. Increased MCP-1, RANTES and eotaxin levels were observed in ASD children compared with both control groups (p<0.03), and increased chemokine production was associated with higher aberrant behavior scores and more impaired developmental and adaptive function.. Elevated MCP-1, RANTES and eotaxin in some ASD children and their association with more impaired behaviors may have etiological significance. Chemokines and their receptors might provide unique targets for future therapies in ASD.
Dysfunctions of the prefrontal cortex have been previously reported in individuals with autism spectrum disorders (ASD). Previous studies reported that first-degree relatives of individuals with ASD show atypical brain activity during tasks associated with social function. However, developmental changes in prefrontal dysfunction in ASD and genetic influences on the phenomena remain unclear. In the present study, we investigated the change in hemoglobin concentration in the prefrontal cortex as measured with near-infrared spectroscopy, in children and adults with ASD during the letter fluency test. Moreover, to clarify the genetic influences on developmental changes in the prefrontal dysfunction in ASD, unaffected siblings of the ASD participants were also assessed.
Study participants included 27 individuals with high-functioning ASD, age- and IQ-matched 24 healthy non-affected siblings, and 27 unrelated healthy controls aged 5 to 39 years. The relative concentration of hemoglobin ([Hb]) in the prefrontal cortex was measured during the letter fluency task. For children, neither the [oxy-Hb] change during the task nor task performances differed significantly among three groups. For adults, the [oxy-Hb] increases during the task were significantly smaller in the bilateral prefrontal cortex in ASD than those in control subjects, although task performances were similar. In the adult siblings the [oxy-Hb] change was intermediate between those in controls and ASDs.
Although indirectly due to a cross-sectional design, the results of this study indicate altered age-related change of prefrontal activity during executive processing in ASD. This is a first near-infrared spectroscopy study that implies alteration in the age-related changes of prefrontal activity in ASD and genetic influences on the phenomena.
Autism spectrum disorder (ASD) is often described as a disorder of aberrant neural connectivity and/or aberrant hemispheric lateralization. Although it is important to study the pathophysiology of the developing ASD cortex, the physiological connectivity of the brain in young children with ASD under conscious conditions has not yet been described. Magnetoencephalography (MEG) is a noninvasive brain imaging technique that is practical for use in young children. MEG produces a reference-free signal and is, therefore, an ideal tool for computing the coherence between two distant cortical rhythms. Using a custom child-sized MEG, we recently reported that 5- to 7-year-old children with ASD (n = 26) have inherently different neural pathways than typically developing (TD) children that contribute to their relatively preserved performance of visual tasks. In this study, we performed non-invasive measurements of the brain activity of 70 young children (3–7 years old, of which 18 were aged 3-4 years), a sample consisting of 35 ASD children and 35 TD children. Physiological connectivity and the laterality of physiological connectivity were assessed using intrahemispheric coherence for 9 frequency bands. As a result, significant rightward connectivity between the parietotemporal areas, via gamma band oscillations, was found in the ASD group. As we obtained the non-invasive measurements using a custom child-sized MEG, this is the first study to demonstrate a rightward-lateralized neurophysiological network in conscious young children (including children aged 3–4 years) with ASD.
•A custom child-sized magnetoencephalography system was used for young children.•Rightward intrahemispheric connectivity was observed in autism spectrum disorder.•Rightward connectivity via gamma band was observed in autism spectrum disorder.
Autism spectrum disorder (ASD); Connectivity; Laterality index; Magnetoencephalography (MEG); Young children
Recent evidence shows that subjects diagnosed with an autism spectrum disorder (ASD) have significantly lower levels of glutathione than typically developing children. The purpose of this study was to examine the use of two commonly used glutathione supplements in subjects diagnosed with an ASD to determine their efficacy in increasing blood glutathione levels in subjects diagnosed with an ASD.
The study was an eight-week, open-label trial using oral lipoceutical glutathione (n=13) or transdermal glutathione (n=13) in children, 3–13 years of age, with a diagnosis of an ASD. Subjects underwent pre- and post-treatment lab testing to evaluate plasma reduced glutathione, oxidized glutathione, cysteine, taurine, free and total sulfate, and whole-blood glutathione levels.
The oral treatment group showed significant increases in plasma reduced glutathione, but not whole-blood glutathione levels following supplementation. Both the oral and transdermal treatment groups showed significant increases in plasma sulfate, cysteine, and taurine following supplementation.
The results suggest that oral and transdermal glutathione supplementation may have some benefit in improving some of the transsulfuration metabolites. Future studies among subjects diagnosed with an ASD should further explore the pharmacokinetics of glutathione supplementation and evaluate the potential effects of glutathione supplementation upon clinical symptoms.
autism; glutathione; transsulfuration metabolites; oral; transdermal
Autism spectrum disorder (ASD) is a severe neuropsychiatric disorder which has complex pathobiology with profound influences of genetic factors in its development. Although the numerous autism susceptible genes were identified, the etiology of autism is not fully explained. Using DNA microarray, we examined gene expression profiling in peripheral blood from 21 individuals in each of the four groups; young adults with ASD, age- and gender-matched healthy subjects (ASD control), healthy mothers having children with ASD (asdMO), and asdMO control. There was no blood relationship between ASD and asdMO. Comparing the ASD group with control, 19 genes were found to be significantly changed. These genes were mainly involved in cell morphology, cellular assembly and organization, and nerve system development and function. In addition, the asdMO group possessed a unique gene expression signature shown as significant alterations of protein synthesis despite of their nonautistic diagnostic status. Moreover, an ASD-associated gene expression signature was commonly observed in both individuals with ASD and asdMO. This unique gene expression profiling detected in peripheral leukocytes from affected subjects with ASD and unaffected mothers having ASD children suggest that a genetic predisposition to ASD may be detectable even in peripheral cells. Altered expression of several autism candidate genes such as FMR-1 and MECP2, could be detected in leukocytes. Taken together, these findings suggest that the ASD-associated genes identified in leukocytes are informative to explore the genetic, epigenetic, and environmental background of ASD and might become potential tools to assess the crucial factors related to the clinical onset of the disorder.
Autism spectrum disorders (ASDs) are neurodevelopmental and behavioural syndromes affecting social orientation, behaviour, and communication that can be classified as developmental disorders. ASD is also associated with immune system abnormality. Immune system abnormalities may be caused partly by complement system factor I deficiency. Complement factor I is a serine protease present in human plasma that is involved in the degradation of complement protein C3b, which is a major opsonin of the complement system. Deficiency in factor I activity is associated with an increased incidence of infections in humans. In this paper, we show that the mean level of factor I activity in the ASD group is significantly higher than in the control group of typically developed and healthy children, suggesting that high activity of complement factor I might have an impact on the development of ASD.
This study provides new evidence of deficient auditory cortical processing of speech in noise in autism spectrum disorders (ASD). Speech-evoked responses (~100–300 ms) in quiet and background noise were evaluated in typically-developing (TD) children and children with ASD. ASD responses showed delayed timing (both conditions) and reduced amplitudes (quiet) compared to TD responses. As expected, TD responses in noise were delayed and reduced compared to quiet responses. However, minimal quiet-to-noise response differences were found in children with ASD, presumably because quiet responses were already severely degraded. Moreover, ASD quiet responses resembled TD noise responses, implying that children with ASD process speech in quiet only as well as TD children do in background noise.
Autism; Cortical encoding; Speech; Background noise; Children; Evoked potentials
The diagnosis of autism spectrum disorder (ASD) during early childhood has a profound effect not only on young children but on their families. Aside from the physical and behavioural issues that need to be dealt with, there are significant emotional and financial costs associated with living with someone diagnosed with ASD. Understanding how autism occurs will assist in preparing families to deal with ASD, if not preventing or lessening its occurrence.
Serotonin plays a vital role in the development of the brain during the prenatal and postnatal periods, yet very little is known about the serotonergic systems that affect children with ASD. This review seeks to provide an understanding of the biochemistry and physiological actions of serotonin and its termination of action through the serotonin reuptake transporter (SERT). Epidemiological studies investigating prenatal conditions that can increase the risk of ASD describe a number of factors which elevate plasma cortisol levels causing such symptoms during pregnancy such as hypertension, gestational diabetes and depression. Because cortisol plays an important role in driving dysregulation of serotonergic signalling through elevating SERT production in the developing brain, it is also necessary to investigate the physiological functions of cortisol, its action during gestation and metabolic syndromes.
Autism spectrum disorder; Cortisol; Serotonin; SERT
Impairments in language and communication are core features of Autism Spectrum Disorder (ASD), and a substantial percentage of children with ASD do not develop speech. ASD is often characterized as a disorder of brain connectivity, and a number of studies have identified white matter impairments in affected individuals. The current study investigated white matter integrity in the speech network of high-functioning adults with ASD. Diffusion tensor imaging (DTI) scans were collected from 18 participants with ASD and 18 neurotypical participants. Probabilistic tractography was used to estimate the connection strength between ventral premotor cortex (vPMC), a cortical region responsible for speech motor planning, and five other cortical regions in the network of areas involved in speech production. We found a weaker connection between the left vPMC and the supplementary motor area in the ASD group. This pathway has been hypothesized to underlie the initiation of speech motor programs. Our results indicate that a key pathway in the speech production network is impaired in ASD, and that this impairment can occur even in the presence of normal language abilities. Therapies that result in normalization of this pathway may hold particular promise for improving speech output in ASD.
•We used diffusion tensor imaging to measure white matter (WM) tracts in autism.•Autistic participants were high-functioning individuals with normal language skills.•WM between left supplementary motor and premotor areas is impaired in autism.•This tract is believed to be involved in the initiation of speech articulation.•Speech production may be impaired in the absence of language deficits in autism.
Autism; ASD; Speech; Diffusion tensor imaging; Tractography; Communication
Having a ‘theory of mind’, or having the ability to attribute mental states to oneself or others, is considered one of the most central domains of impairment among children with an autism spectrum disorder (ASD). Many interventions focus on improving theory of mind skills in children with ASD. Nonetheless, the empirical evidence for the effect of these interventions is limited. The main goal of this study is to examine the effectiveness of a short theory of mind intervention for children with ASD. A second objective is to determine which subgroups within the autism spectrum profit most from the intervention.
This study is a randomized controlled trial. One hundred children with ASD, aged 7 to 12 years will be randomly assigned to an intervention or a waiting list control group. Outcome measures include the completion of theory of mind and emotion understanding tasks, and parent and teacher questionnaires on children’s social skills. Follow-up data for the intervention group will be collected 6 months after the interventions.
This study evaluates the efficacy of a theory of mind intervention for children with ASD. Hypotheses, strengths, and limitations of the study are discussed.
Netherlands Trial Register NTR2327
Autism spectrum disorder (ASD) has been associated with decreased coherent dot motion (CDM) performance, a task that measures magnocellular sensitivity as well as fronto-parietal attentional integration processing. In order to clarify the role of spatial attention in CDM tasks, we measured the perception of coherently moving dots displayed in the central or peripheral visual field in ASD and typically developing children. A dorsal-stream deficit in children with ASD should predict a generally poorer performance in both conditions. In our study, however, we show that in children with ASD, CDM perception was selectively impaired in the central condition. In addition, in the ASD group, CDM efficiency was correlated to the ability to zoom out the attentional focus. Importantly, autism symptoms severity was related to both the CDM and attentional zooming-out impairment. These findings suggest that a dysfunction in the attentional network might help to explain decreased CDM discrimination as well as the “core” social cognition deficits of ASD.
Cerebral folate deficiency (CFD) syndrome is a neurodevelopmental disorder typically caused by folate receptor autoantibodies (FRAs) that interfere with folate transport across the blood–brain barrier. Autism spectrum disorders (ASDs) and improvements in ASD symptoms with leucovorin (folinic acid) treatment have been reported in some children with CFD. In children with ASD, the prevalence of FRAs and the response to leucovorin in FRA-positive children has not been systematically investigated. In this study, serum FRA concentrations were measured in 93 children with ASD and a high prevalence (75.3%) of FRAs was found. In 16 children, the concentration of blocking FRA significantly correlated with cerebrospinal fluid 5-methyltetrahydrofolate concentrations, which were below the normative mean in every case. Children with FRAs were treated with oral leucovorin calcium (2 mg kg−1 per day; maximum 50 mg per day). Treatment response was measured and compared with a wait-list control group. Compared with controls, significantly higher improvement ratings were observed in treated children over a mean period of 4 months in verbal communication, receptive and expressive language, attention and stereotypical behavior. Approximately one-third of treated children demonstrated moderate to much improvement. The incidence of adverse effects was low. This study suggests that FRAs may be important in ASD and that FRA-positive children with ASD may benefit from leucovorin calcium treatment. Given these results, empirical treatment with leucovorin calcium may be a reasonable and non-invasive approach in FRA-positive children with ASD. Additional studies of folate receptor autoimmunity and leucovorin calcium treatment in children with ASD are warranted.
autism spectrum disorders; cerebral folate deficiency; folate receptor autoantibody; folinic acid; leucovorin calcium
Recent estimates suggest that over 30% of children with autism spectrum disorders (ASD) meet diagnostic criteria for attention deficit/hyperactivity disorder (ADHD), and another 20% of children with ASD exhibit subthreshold clinical ADHD symptoms. Presence of ADHD symptoms in the context of ASD could have a variety of effects on cognition, autistic traits, and adaptive/maladaptive behaviors including: exacerbating core ASD impairments; adding unique impairments specific to ADHD; producing new problems unreported in ASD or ADHD; having no clear impact; or producing some combination of these scenarios. Children with ASD and co-morbid ADHD symptoms (ASD+ADHD; n=21), children with ASD without ADHD (ASD; n=28), and a typically developing control group (n=21) were included in the study; all groups were matched on age, gender-ratio, IQ, and socioeconomic status. Data were collected on verbal and spatial working memory, response inhibition, global executive control, autistic traits, adaptive functioning, and maladaptive behavior problems. In this sample, the presence of ADHD symptoms in ASD exacerbated impairments in executive control and adaptive behavior and resulted in higher autistic trait, and externalizing behavior ratings. ADHD symptoms were also associated with greater impairments on a lab measure of verbal working memory. These findings suggest that children with ASD+ADHD symptoms present with exacerbated impairments in some but not all domains of functioning relative to children with ASD, most notably in adaptive behavior and working memory. Therefore, ADHD may moderate the expression of components of the ASD cognitive and behavioral phenotype, but ASD+ADHD may not represent an etiologically distinct phenotype from ASD alone.
Autism is widely believed to be a heterogeneous disorder; diagnosis is currently based solely on clinical criteria, although genetic, as well as environmental, influences are thought to be prominent factors in the etiology of most forms of autism. Our goal is to determine whether a predictive model based on single-nucleotide polymorphisms (SNPs) can predict symptom severity of autism spectrum disorder (ASD). We divided 118 ASD children into a mild/moderate autism group (n = 65) and a severe autism group (n = 53), based on the Childhood Autism Rating Scale (CARS). For each child, we obtained 29 SNPs of 9 ASD-related genes. To generate predictive models, we employed three machine-learning techniques: decision stumps (DSs), alternating decision trees (ADTrees), and FlexTrees. DS and FlexTree generated modestly better classifiers, with accuracy = 67%, sensitivity = 0.88 and specificity = 0.42. The SNP rs878960 in GABRB3 was selected by all models, and was related associated with CARS assessment. Our results suggest that SNPs have the potential to offer accurate classification of ASD symptom severity.
autism-spectrum disorder; single-nucleotide polymorphisms; diagnostic model; genotype-phenotype analysis; data mining
To describe the hospitalisation patterns in children with intellectual disability (ID) and/or autism spectrum disorder (ASD) after the first year of life and compare with those unaffected.
Prospective cohort study using data linkage between health, ID and hospitalisation population-based datasets.
416 611 individuals born between 1983 and 1999 involving 1 027 962 hospital admission records. Five case categories were defined (mild/moderate ID, severe ID, biomedically caused ID, ASD with ID and ASD without ID) and compared with the remainder of children and young people.
Primary and secondary outcome measures
Time to event analysis was used to compare time hospitalisation and rate of hospitalisation between the different case-groups by estimating HR, accounting for birth year and preterm birth status.
ID and/or ASD were found to be associated with an increased risk of hospitalisation compared with the remainder of the population. The increase in risk was highest in those with severe ID and no ASD (HR=10.33, 95% CI 8.66 to 12.31). For those with ID of known biomedical cause or mild ID of unknown cause, the risk of hospitalisation was lower (HR=7.36, 95% CI 6.73 to 8.07 and HR=3.08, 95% CI 2.78 to 3.40, respectively). Those with ASDs had slightly increased risk (HR=2.82, 95% CI 2.26 to 3.50 for those with ID and HR=2.09, 95% CI 1.85 to 2.36 for those without ID).
Children with an ID or ASD experience an increased risk of hospitalisation after the first year of life which varied from 2 to 10 times that of the rest of the population. Findings can inform service planning or resource allocation for these children with special needs.
EPIDEMIOLOGY; PUBLIC HEALTH
We compared the occurrence and timing of divorce in 391 parents of children with an autism spectrum disorder (ASD) and a matched representative sample of parents of children without disabilities using a survival analysis. Parents of children with an ASD had a higher rate of divorce than the comparison group (23.5% vs. 13.8%). The rate of divorce remained high throughout the son/daughter’s childhood, adolescence, and early adulthood for parents of children with an ASD, whereas it decreased following the son/daughter’s childhood (after about age 8 years) in the comparison group. Younger maternal age when the son/daughter with ASD was born and having the son/daughter born later in the birth order were positively predictive of divorce for parents of children with an ASD. Findings have implications for interventions focused on ameliorating ongoing and long term marital strains for parents of children with an ASD.
Autism spectrum disorders; Divorce; Marital Relationship; and Parent
The purpose of this pilot study was to establish a model for randomized controlled trial research, identify appropriate outcome measures, and address the effectiveness of sensory integration (SI) interventions in children with autism spectrum disorders (ASD). Children ages 6–12 with ASD were randomly assigned to a fine motor or SI treatment group. Pretests and posttests measured social responsiveness, sensory processing, functional motor skills, and social–emotional factors. Results identified significant positive changes in Goal Attainment Scaling scores for both groups; more significant changes occurred in the SI group, and a significant decrease in autistic mannerisms occurred in the SI group. No other results were significant. The study discusses considerations for designing future outcome studies for children with ASD.
autistic disorder; child development disorders, pervasive; outcome assessment (health care); psychomotor performance; research design; sensation disorders
Traditionally, hyperbaric oxygen treatment (HBOT) is indicated in several clinical disorders include decompression sickness, healing of problem wounds and arterial gas embolism. However, some investigators have used HBOT to treat individuals with autism spectrum disorders (ASD). A number of individuals with ASD possess certain physiological abnormalities that HBOT might ameliorate, including cerebral hypoperfusion, inflammation, mitochondrial dysfunction and oxidative stress. Studies of children with ASD have found positive changes in physiology and/or behavior from HBOT. For example, several studies have reported that HBOT improved cerebral perfusion, decreased markers of inflammation and did not worsen oxidative stress markers in children with ASD. Most studies of HBOT in children with ASD examined changes in behaviors and reported improvements in several behavioral domains although many of these studies were not controlled. Although the two trials employing a control group reported conflicting results, a recent systematic review noted several important distinctions between these trials. In the reviewed studies, HBOT had minimal adverse effects and was well tolerated. Studies which used a higher frequency of HBOT sessions (e.g., 10 sessions per week as opposed to 5 sessions per week) generally reported more significant improvements. Many of the studies had limitations which may have contributed to inconsistent findings across studies, including the use of many different standardized and non-standardized instruments, making it difficult to directly compare the results of studies or to know if there are specific areas of behavior in which HBOT is most effective. The variability in results between studies could also have been due to certain subgroups of children with ASD responding differently to HBOT. Most of the reviewed studies relied on changes in behavioral measurements, which may lag behind physiological changes. Additional studies enrolling children with ASD who have certain physiological abnormalities (such as inflammation, cerebral hypoperfusion, and mitochondrial dysfunction) and which measure changes in these physiological parameters would be helpful in further defining the effects of HBOT in ASD.
Hyperbaric oxygen treatment; Autism; Oxidative stress; Inflammation; Behavior