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Intravenous secretin for autism spectrum disorder.

BACKGROUND: Secretin is a gastro-intestinal hormone which has been presented as an effective treatment for autism based on anecdotal evidence. OBJECTIVES: To determine if intravenous secretin:1. improves the core features of autism (social interaction, communication and behaviour problems); 2. improves the non-core aspects of behaviour or function such as self injurious behaviour;3. improves the quality of life of affected individuals and their carers; 4. has short term and long term effects on outcome; 5. causes harm. SEARCH STRATEGY: Results of electronic searches of CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, ERIC, HealthStar and Sociofile (1998 - March 2005) were independently examined by two authors. Reference lists of trials and reviews were searched; experts and trialists were contacted to find unpublished studies. SELECTION CRITERIA: Randomised controlled trials of intravenous secretin comparing secretin with a placebo treatment in children or adults diagnosed with autism spectrum disorders, where at least one standardised outcome measure was reported. DATA COLLECTION AND ANALYSIS: Fourteen studies met inclusion criteria. All outcome data were continuous. Where trials used cross-over designs, analysis was conducted on results from first treatment phase, allowing combined analysis with parallel design trials. Where standardised assessment tools generated scores as outcome measures, comparisons were made between means of these scores. Where baseline means were reported, differences between treatment and control were determined to assess possible bias. Where mean change from baseline was reported, this was used in preference to post-treatment scores for meta-analyses or forest plots. As meta-analysis was possible for only one outcome (Childhood Autism Rating Scale), it was impossible to use sensitivity or subgroup analyses to assess impact of study quality, clinical differences in the intervention, or clinically relevant differences between groups, such as age or presence of gastrointestinal symptoms. MAIN RESULTS: Twenty-five established standardised outcome measures were reported to assess core features of autism, communication, behaviour, visio-spatial skills, affect and adverse events within fourteen included studies. No more than four studies used any one outcome measure similarly. Outcomes were reported between three and six weeks. RCTs of efficacy of secretin in autism have not shown improvements for core features of autism. AUTHORS' CONCLUSIONS: There is no evidence that single or multiple dose intravenous secretin is effective and as such it should not currently be recommended or administered as a treatment for autism. Further experimental assessment of secretin's effectiveness for autism can only be justified if methodological problems of existing research can be overcome.

Autistic Disorder↗

Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders.

SHANK3 (also known as ProSAP2) regulates the structural organization of dendritic spines and is a binding partner of neuroligins; genes encoding neuroligins are mutated in autism and Asperger syndrome. Here, we report that a mutation of a single copy of SHANK3 on chromosome 22q13 can result in language and/or social communication disorders. These mutations concern only a small number of individuals, but they shed light on one gene dosage-sensitive synaptic pathway that is involved in autism spectrum disorders.

Autistic Disorder↗

The near universal presence of autism spectrum disorders in children with Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive condition caused by a defect in cholesterol synthesis. Affected children often have malformations and mental retardation. Autistic behaviors also are evident. The purpose of the present study was to determine the prevalence of autism spectrum disorders (ASDs) in children with SLOS. Fourteen children, 3-16 years old, were evaluated using three different methods to document autistic symptoms: (a) parent interview, (b) direct observation, and (c) a behavior checklist. Blood sterols were also measured at regular intervals. Each subject was determined to have Autistic Disorder, Pervasive Developmental Disorder, not otherwise specified (PDD NOS), or no diagnosis on the autism spectrum, based on DSM-IV criteria. Correlations among variables were calculated, and blood sterol levels were compared between diagnostic groups. Approximately three-fourths of the children with SLOS (71-86% depending on the evaluation method) had an ASD, about 50% diagnosed with Autistic Disorder and the rest with PDD NOS. The children's baseline cholesterol, 7-dehydrocholesterol (7-DHC), and 8-dehydrocholesterol (8-DHC) levels, and cholesterol levels following supplementation did not correlate with the presence or severity of autistic symptoms. These results suggest that most children with SLOS have some variant of autism. SLOS appears to have the most consistent relationship with autism of any single gene disorder. Therefore, a link between cholesterol metabolism and autism is suggested. With further study, these findings, together with knowledge of the genetic and biochemical defects in SLOS, will likely provide valuable insights into the causes of autism in general.

Adolescent↗

Association of adenomatous polyposis coli (APC) gene polymorphisms with autism spectrum disorder (ASD).

We serendipitously identified a single nucleotide polymorphism (SNP), 8636C>A (rs1804197) in the 3'-untranslated region of the adenomatous polyposis coli (APC) gene to be associated with autism spectrum disorder (ASD). In order to gain further evidence for the association between the APC locus and ASD, we genotyped four additional adjacent common SNPs (rs2229992, rs42427, rs459552, and rs465899) in the coding regions within the APC gene in a set of Swedish ASDs and controls. One common haplotype TGAG was found to be associated with ASD after haplotype analysis using both Haploview v3.1.1 (P = 0.006) and COCAPHASE v2.403 (P = 0.030). This result is the first to suggest that the genomic locus at APC is associated with ASD, and that the APC gene itself is a good predisposing candidate to be evaluated in future studies due to its important role in neuronal development and function.

Adolescent↗

Elevated cytokine levels in children with autism spectrum disorder.

UNLABELLED: This study compared production of IL-2, IFN-gamma, IL-4, IL-13, IL-5 and IL-10 in peripheral blood mononuclear cells from 20 children with autism spectrum disorder to those from matched controls. Levels of all Th2 cytokines were significantly higher in cases after incubation in media alone, but the IFN-gamma/IL-13 ratio was not significantly different between cases and controls. Cases had significantly higher IL-13/IL-10 and IFN-gamma/IL-10 than controls. CONCLUSION: Children with ASD had increased activation of both Th2 and Th1 arms of the adaptive immune response, with a Th2 predominance, and without the compensatory increase in the regulatory cytokine IL-10.

Autistic Disorder↗

Randomized comparison of two communication interventions for preschoolers with autism spectrum disorders.

This randomized group experiment compared the efficacy of 2 communication interventions (Responsive Education and Prelinguistic Milieu Teaching [RPMT] and the Picture Exchange Communication System [PECS]) in 36 preschoolers with autism spectrum disorders. Each treatment was delivered 3 times per week, in 20-min sessions, for 6 months. The results revealed that the RPMT facilitated the frequency of generalized turn taking and generalized initiating joint attention more than did the PECS. The latter effect occurred only for children who began treatment with at least some initiating joint attention. In contrast, the PECS facilitated generalized requests more than the RPMT in children with very little initiating joint attention prior to treatment. These effect sizes were large.

Autistic Disorder↗

MMR-vaccine and regression in autism spectrum disorders: negative results presented from Japan.

It has been suggested that the measles, mumps, and rubella vaccine (MMR) is a cause of regressive autism. As MMR was used in Japan only between 1989 and 1993, this time period affords a natural experiment to examine this hypothesis. Data on 904 patients with autism spectrum disorders (ASD) were analyzed. During the period of MMR usage no significant difference was found in the incidence of regression between MMR-vaccinated children and non-vaccinated children. Among the proportion and incidence of regression across the three MMR-program-related periods (before, during and after MMR usage), no significant difference was found between those who had received MMR and those who had not. Moreover, the incidence of regression did not change significantly across the three periods.

Autistic Disorder↗

Impact of comorbid autism spectrum disorders on stimulant response in children with attention deficit hyperactivity disorder: a retrospective and prospective effectiveness study.

BACKGROUND: In the recent past, psychiatrists and paediatricians have avoided prescribing stimulant medication, such as methylphenidate and dexamphetamine to patients with autism spectrum disorders (ASD) because of both doubts about efficacy and concern that these medications make stereotypies worse. Recently, a number of small trials have suggested that methyphenidate does have a role in the management of hyperactivity in children with autistic spectrum disorders. METHODS: Children with ASD and attention deficit hyperactivity disorder (ADHD), and children with ADHD without ASD received standard treatment with methyphenidate from one specialist centre. A combination of standardized and novel outcome tools was used to allow both an exploratory retrospective study of 174 children and then a prospective study of a further 52 children to be carried out. RESULTS: After treatment with stimulants, the subjects in both groups showed statistically significant improvements in target symptoms of 'hyperactivity', 'impulsivity', 'inattention', 'oppositionality', 'aggression' and 'intermittent explosive rage'. The Clinical Global Impression-Improvement and efficacy index measures also improved in each group. In both the retrospective and the prospective studies, there was no statistically significant difference in the degree of improvements between each group. Importantly, neither tics nor repetitive behaviours worsened in either group. Children in the 'ADHD-only' group who were prescribed stimulants experienced significant 'nausea', 'giddiness', 'headaches' and 'sleep difficulties', whereas sleep difficulties were the only side effect that emerged in children in the ASD with ADHD group. CONCLUSIONS: Both studies presented here support previous findings from smaller studies that show children with autism and ADHD can respond as well to stimulants as children with ADHD alone. Although randomized controlled trials remain the gold standard for efficacy studies, systems like this that allow clinicians to continue rigorous and consistent monitoring for many years have a valuable role to play. Furthermore, such monitoring systems which now exist electronically can easily accumulate large data sets and reveal details about long-term effectiveness and long-term side effects of medication that are unlikely to be discovered in short-term trials.

Adolescent↗

Social communication profiles of children with autism spectrum disorders late in the second year of life.

This study examined social communication profiles from behavior samples videotaped between 18 and 24 months of age in three groups of children: 50 with autism spectrum disorders (ASD), 23 with developmental delays (DD), and 50 with typical development (TD). The ASD group scored significantly lower than the DD group on 5 social communication measures and the TD group on all 14 measures, indicating distinct profiles late in the second year. Understanding was the strongest predictor of developmental level and behavior regulation and inventory of gestures were the strongest predictors of autism symptoms at 3 years of age. The predictive relations suggest five pivotal skills late in the second year that have a cascading effect on outcomes of children with ASD.

Attention↗

Evaluation of an association between gastrointestinal symptoms and cytokine production against common dietary proteins in children with autism spectrum disorders.

OBJECTIVE: To evaluate an association between cytokine production with common dietary proteins as a marker of non-allergic food hypersensitivity (NFH) and gastrointestinal (GI) symptoms in young children with autism spectrum disorders (ASD). STUDY DESIGN: Peripheral blood mononuclear cells (PBMCs) were obtained from 109 ASD children with or without GI symptoms (GI [+] ASD, N = 75 and GI (-) ASD, N = 34], from children with NFH (N = 15), and control subjects (N = 19). Diarrhea and constipation were the major GI symptoms. We measured production of type 1 T-helper cells (Th1), type 2 T-helper cells (Th2), and regulatory cytokines by PBMCs stimulated with whole cow's milk protein (CMP), its major components (casein, beta-lactoglobulin, and alpha-lactoalbumin), gliadin, and soy. RESULTS: PBMCs obtained from GI (+) ASD children produced more tumor necrosis factor-alpha (TNF-alpha)/interleukin-12 (IL-12) than those obtained from control subjects with CMP, beta-lactoglobulin, and alpha-lactoalbumin, irrespective of objective GI symptoms. They also produced more TNF-alpha with gliadin, which was more frequently observed in the group with loose stools. PBMCs obtained from GI (-) ASD children produced more TNF-alpha/IL-12 with CMP than those from control subjects, but not with beta-lactoglobulin, alpha-lactoalbumin, or gliadin. Cytokine production with casein and soy were unremarkable. CONCLUSION: A high prevalence of elevated TNF-alpha/IL-12 production by GI (+) ASD PBMCs with CMP and its major components indicates a role of NFH in GI symptoms observed in children with ASD.

Autistic Disorder↗

Brain structural abnormalities in young children with autism spectrum disorder.

OBJECTIVE: To explore the specific gross neuroanatomic substrates of this brain developmental disorder, the authors examine brain morphometric features in a large sample of carefully diagnosed 3- to 4-year-old children with autism spectrum disorder (ASD) compared with age-matched control groups of typically developing (TD) children and developmentally delayed (DD) children. METHODS: Volumes of the cerebrum, cerebellum, amygdala, and hippocampus were measured from three-dimensional coronal MR images acquired from 45 children with ASD, 26 TD children, and 14 DD children. The volumes were analyzed with respect to age, sex, volume of the cerebrum, and clinical status. RESULTS: Children with ASD were found to have significantly increased cerebral volumes compared with TD and DD children. Cerebellar volume for the ASD group was increased in comparison with the TD group, but this increase was proportional to overall increases in cerebral volume. The DD group had smaller cerebellar volumes compared with both of the other groups. Measurements of amygdalae and hippocampi in this group of young children with ASD revealed enlargement bilaterally that was proportional to overall increases in total cerebral volume. There were similar findings of cerebral enlargement for both girls and boys with ASD. For subregion analyses, structural abnormalities were observed primarily in boys, although this may reflect low statistical power issues because of the small sample (seven girls with ASD) studied. Among the ASD group, structural findings were independent of nonverbal IQ. In a subgroup of children with ASD with strictly defined autism, amygdalar enlargement was in excess of increased cerebral volume. CONCLUSIONS: These structural findings suggest abnormal brain developmental processes early in the clinical course of autism. Research currently is underway to better elucidate mechanisms underlying these structural abnormalities and their longitudinal progression.

Amygdala↗

Imitation and pantomime in high-functioning adolescents with autism spectrum disorders.

A study was designed to test 2 alternative hypotheses--a symbolic hypothesis and an executive function hypotheses--for the imitation and pantomime deficits found in previous studies of autism. The subjects were 17 adolescent high-functioning subjects with autism spectrum disorders and 15 clinical comparison subjects who were matched on chronological age and verbal IQ. Meaning and sequence were manipulated in facial and manual imitation tasks. Sequence was manipulated in the pantomime and control tasks. Recognition memory and motor control tasks were matched to the experimental tasks. The results provided no support for the symbolic deficit hypothesis; meaning aided rather than hindered the performance of the group with autism. Partial support for the executive deficit hypothesis was found. There were no group differences on motor control tasks, and few on the memory control tasks, arguing against deficits in motor initiation, basic motor coordination, or visual recognition memory.

Adolescent↗

Catatonia in individuals with autism spectrum disorders in adolescence and early adulthood: a long-term prospective study.

The objective is to cast light on diagnosis and catastasis, course, and comorbidity as concerned with catatonia in patients with autism spectrum disorders (ASDs) with respect to long-term prospective follow-up. Eleven patients (all male) were enrolled. The mean age and the mean follow-up duration were 27.6 years (standard deviation (SD) 5.5) and 18.7 years (SD 8.7), respectively. The mean IQ was 27 (SD 16.4). Information was garnered from medical case records; current examination and observation of patients, interview of parents, and questionnaires completed by parents or other caretakers. Informed consent was obtained from the parents. Criteria for catatonia in this study were: (1) abrupt stop of movements and maintenance of immobility or bizarre posture beginning in adolescence and early adult life, (2) such a cataleptic state had continued for at least several minutes and appeared many times a day to the point of interfering with daily activities. We described two typical catatonic cases of ASDs. The average onset age was 19 years (SD 6). In all cases, our diagnostic criteria of catatonia evaluating at worse are fully compatible with those of Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-VI). In 8 out of 11, the onset of catatonia was clearly preceded by the appearance of slowness in movements accompanying the exacerbation of obsessive-compulsive symptoms. Catatonia was also found to have some connection with Tourette syndrome (3 cases), adjustment disorders (N=1), and depressive mood disorders (N=1). In one case, the manifestations of catatonia had to be distinguished from parkinsonism caused by antipsychotics. Catatonia in ASDs seems to be a chronic condition in most cases. However, there were also a few cases in which catatonia repeatedly aggravated over short spans of time. Catatonia in ASDs may be considered an epiphenomenon of ASDs or a manifestation of comorbidity in adolescence or early adulthood.

Adolescent↗

Alternative seating for young children with Autism Spectrum Disorder: effects on classroom behavior.

A single subject, withdrawal design was used to investigate the effects of therapy balls as seating on engagement and in-seat behavior of young children with Autism Spectrum Disorder (ASD). In addition, social validity was assessed to evaluate teachers' opinions regarding the intervention. During baseline and withdrawal (A phases) participants used their typical classroom seating device (chair, bench or carpet square). During the intervention (B phases) participants sat on therapy balls. Results indicated substantial improvements in engagement and in-seat behavior when participants were seated on therapy balls. Social validity findings indicated that the teachers' preferred the therapy balls. This study suggests therapy balls as classroom seating may facilitate engagement and in-seat behavior and create opportunities to provide effective instruction.

Autistic Disorder↗

Early predictors of communication development in young children with autism spectrum disorder: joint attention, imitation, and toy play.

This study investigated the unique contributions of joint attention, imitation, and toy play to language ability and rate of development of communication skills in young children with autism spectrum disorder (ASD). Sixty preschool-aged children with ASD were assessed using measures of joint attention, imitation, toy play, language, and communication ability. Two skills, initiating protodeclarative joint attention and immediate imitation, were most strongly associated with language ability at age 3-4 years, whereas toy play and deferred imitation were the best predictors of rate of communication development from age 4 to 6.5 years. The implications of these results for understanding the nature and course of language development in autism and for the development of targeted early interventions are discussed.

Attention↗

Psychological distress and well-being of Latina and non-Latina White mothers of youth and adults with an autism spectrum disorder: cultural attitudes towards coresidence status.

This article examined the emotional well-being of 108 Latina and non-Latina White mothers who were coresiding with a youth or adult with an autism spectrum disorder (ASD). It was hypothesized that Latina mothers would be more satisfied with coresidence than non-Latina White mothers, and that satisfaction with coresidence would mediate the relationship between ethnicity and outcomes. When controlling for demographic characteristics, non-Latina White mothers were more distressed and had lower levels of psychological well-being than Latina mothers. As hypothesized, satisfaction with coresidence mediated this difference. Qualitative analysis revealed that both groups of mothers valued family cohesion as a positive aspect of coresidence. However, Latina mothers were less likely to report negative aspects of coresidence than non-Latina White mothers.

Adaptation, Psychological↗

Early social communicative behaviours of preschoolers with autism spectrum disorder during interaction with their mothers.

The present study examined spontaneous symbolic play, declarative joint attention, social referencing and imitation of symbolic play in 3- to 6-year-old children with an autism spectrum disorder (ASD; n = 20) during interaction with their mothers. Compared to a control group (n = 20) matched on age and IQ, the children with ASD initiated less joint attention with their mothers when confronted with a pleasant event and they showed a tendency to play less symbolically and more non-functionally. Contrary to expectations, children with ASD showed no social referencing or imitation deficits. Interestingly, two clusters of intercorrelating behaviours were found in the ASD group: one suggesting symbolic or metarepresentational abilities, the other comprising interpersonal behaviours. The findings support the hypothesis that early social communicative abilities may follow a different developmental pathway in ASD, and stress the importance of a contextual factor, namely the presence of the mother.

Attention↗

Symbolic play in children with autism spectrum disorder.

The relationship between symbolic play and other domains, such as degree of autistic symptomatology, nonverbal cognitive ability, receptive language, expressive language, and social development, was investigated. The assessment files of 101 children with Autism Spectrum Disorder were studied. Nonverbal cognitive ability and expressive language were both significantly and uniquely related to symbolic play, although receptive language was not. Autistic symptomatology ceased to be significantly related to symbolic play when controlling for two or more other variables. Social development was related to symbolic play in those children with high nonverbal cognitive ability but not those with low nonverbal cognitive ability. The diagnostic and treatment implications of these results are discussed.

Autistic Disorder↗