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PubMed2006

A prospective assessment of porphyrins in autistic disorders: a potential marker for heavy metal exposure.

Autism was recently associated with a urinary porphyrin pattern indicative of mercury toxicity in a large cohort of French children. The IRB of the Institute for Chronic Illnesses approved the present study. A total of 37 consecutive American patients (> or = 7 years-old) with autism spectrum disorders (ASDs) (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-DSM IV), born from 1983-1998, that presented to the Genetic Centers of America for outpatient genetic evaluations were prospectively examined for urinary prophryin levels (LabCorp, Inc.) from June 2005-June 2006. Imaging and laboratory testing were conducted on each patient to rule-out other causal factors for their ASDs. As controls, age-, sex-, and race-matched neurotypical ASD siblings were examined. An apparent dose-response effect was observed between autism severity and increased urinary coproporphyrins. Patients with non-chelated autism (2.25-fold, 83% had levels > 2 SD above the control mean) and non-chelated ASDs (2-fold, 58% had levels > 2 SD above the control mean), but not patients with non-chelated pervasive developmental delay-not otherwise specified (PDD-NOS) or Asperger's disorder (1.4-fold, 46% had levels > 2 SD above the control mean), had significantly increased median coproporphyrin levels versus controls. A significant increase (1.7-fold) in median coproporphyrin levels was observed among non-chelated ASD patients versus chelated ASD patients. Porphyrins should be routinely clinically measured in ASDs, and potential ASD treatments should consider monitoring porphyrin levels. Additional research should be conducted to evaluate the potential role for mercury exposure in some ASDs.

Adolescent↗
PubMed2005

The overt aggression scale for rating aggression in outpatient youth with autistic disorder: preliminary findings.

Aggression is a common and costly problem in youth with developmental disabilities. Rating scales that accurately capture and measure subtypes of aggression phenomenology, frequency and severity are urgently needed, in both clinical practice and research. The authors studied the Overt Aggression Scale (OAS) in a preliminary sample of eight outpatients who participated in an ongoing placebo-controlled study of valproate for aggression in autism. Subjects' OAS aggression scores showed significant correlation with the already validated retrospectively rated Aberrant Behavior Checklist Community Scale irritability subscale. Further study of the OAS in outpatients with aggression and developmental disabilities is warranted.

Adolescent↗
PubMed2000

System and cost research issues in treatments for people with autistic disorders.

Parents of children with autism and pervasive developmental disorder and educational and clinical practitioners providing services to them regularly confront a wide range of service selection and financial decisions that are not as yet effectively addressed by applied research. Relevant systems issues span a very broad range of concerns: (a) systems delivery models and issues (e.g., costs of services, implementation of intensive intervention, and teacher or therapist training); (b) how best to integrate treatments; (c) providing treatment to those with limited monetary resources; (d) cost and cost/benefit analyses; (e) how to educate adult psychiatrists (as well as other practitioners and personnel) regarding autism; and (f) gaps between research and practice.

Adult↗
PubMedDate not supplied

[Clinical features, biology and neuropsychology of the autistic disorder: towards an integrative perspective].

Autism constitutes one of the most investigated disorders in child psychiatry. The heterogeneous clinical phenomena that characterize it have been exhaustibly described along the last 62 years. Multiple aetiological hypothesis, neuropsychological theories and physiopathological mechanisms, sometimes complementary and other times mutually exclusive, and different descriptions of neurobiological alterations that resulted, in general, of low replicability, have attempted to account for the marked variability of its manifestations. An integration of these different levels of analysis results even harder than the comprehension of each of them separately. In this article the author revises the three aspects considered the most characteristic of the syndrome (social interaction, communication and flexibility) and tries to integrate its clinical manifestations with some neuropsychological variables and the neurobiological substrates.

Autistic Disorder↗
PubMed1999

A comparison of social skills in adults with autistic disorder, pervasive developmental disorder not otherwise specified, and mental retardation.

We examined the social skills of adults with autism, PDDNOS, and mental retardation. All participants were diagnosed with profound mental retardation. Participants in the autism and PDDNOS groups had been previously diagnosed using the Childhood Autism Rating Scale (CARS) and record review. These diagnoses were confirmed by readministering the CARS by one author and an independent rater. Social skills were assessed by using the Vineland Adaptive Behavior Scales and the Matson Evaluation of Social Skills in the Severely Retarded. Significant differences between the autism and mental retardation groups were found on both measures. The PDDNOS group demonstrated better positive nonverbal social skills than the autism group but not the mental retardation group. Special treatment needs of institutionalized adults with autism appear warranted along with a need to clarify further the differences between PDDNOS and mental retardation.

Adult↗
PubMed2001

Cognitive styles in high-functioning adolescents with autistic disorder.

This study addressed the operationalization, the identification, and the prevalence of weak central coherence and poor cognitive shifting in 35 high-functioning adolescents with autism. Central coherence and cognitive shifting were represented by two factors in a factor analysis, each reflecting a constituent aspect of the domain in question. With regard to central coherence, these aspects were the ability of piecemeal processing and the ability to process meaning. The aspects related to cognitive shifting concerned internally and externally controlled shifting. Weak central coherence and poor cognitive shifting did not appear to be related to measures of symptom severity, social understanding, and social competence. Both these cognitive styles did not appear to be universal to autism. In our sample, weak central coherence and poor cognitive shifting were found to be significantly more common than in normative control subjects.

Adolescent↗
PubMed2005

[Epigenetic study of Rett's syndrome as an adequate model for autistic disorders].

Rett's syndrome (RTT) is a severe hereditary disorder of the nervous system. MECP2 gene mutations are considered as a primary cause of the disease. In the present study, we have found MECP2 mutations in 33 (84.6%) out of 39 RTT females. We have also studied X-inactivation patterns in 70 girls with RTT. A frequency of skewed X-inactivation was 37% (26 patients), being significantly higher (p < 0.001) than that in the controls. The investigation of inactivated X chromosome origin revealed that about 33% pairs had preferentially the inactivated maternal X chromosome. An abnormal type of chromosome X inactivation was observed in all RTT females. Thus, we conclude that skewed X-inactivation may be considered as a common feature of RTT. There is unambiguous evidence that epigenetic alterations in RTT are associated with MECP2 mutations. MeCP2 protein also appears to be involved in transcriptional regulation of chromosome X genes. RTT in females without MECP2 mutations is related to the epigenetic alterations. We suggest X chromosome inactivation study in RTT females and their mothers to be informative for investigation of genetic processes in RTT girls, even in case MECP2 mutations have not been found. RTT could be considered as an appropriate model for studying epigenetic abnormalities in relation to autistic spectrum disorders.

Child↗
PubMedDate not supplied

Characteristics of patients with autistic disorder (AD) presenting for dental treatment: a survey and chart review.

A group of 43 patients with AD (mean age, 13.5; SD, 5.9 yrs) was identified from the University Hospital School Pediatric Dentistry Clinic. We reviewed the patients' charts to obtain demographic data, dental findings, and the management techniques used for treatment. The patients were divided into groups according to Frankl's categories of behavior, ranging from definitely negative to positive. Descriptive data are provided for each group. Commonly used communications and pharmacological management techniques, as well as physical restraints, enabled us to treat all the patients in the traditional dental setting, when simple procedures were planned. Treatment under general anesthesia in the operating room was necessary in 37% of all patients when comprehensive care was required or difficult procedures were carried out. A questionnaire was also sent out to the caregivers to gather data on patients' nutrition and eating/chewing habits. In the sample surveyed, two-thirds of the individuals reportedly exhibited a normal eating pattern, while 14% pouched food. Soft, sweet, or sticky foods were preferred by 41% of the patients.

Adolescent↗
PubMed2003

Genetic and neurodevelopmental influences in autistic disorder.

OBJECTIVE: In the past, autism was considered to be largely psychogenic. However, research in the last 2 decades indicates that autism is largely caused by genetic factors that lead to abnormal brain development. This article reviews research into the genetic and neurodevelopmental factors underlying autism. METHODS: We review the findings from genetic and brain-imaging studies of autism over the past 15 years and synthesize these findings as a guide for future research. RESULTS: Genome scans and association studies have suggested potential genomic regions and genes, respectively, that may be involved in the etiology of autism, and there have been some replications of these results. Similarly, the findings that brain volume is exaggerated in autism and corpus callosum size is reduced have also been independently replicated. Unfortunately, studies of other subcortical structures remain inconclusive or contradictory. CONCLUSIONS: Overwhelming evidence now supports a neurobiological basis for autism. However, further refinements will be needed to guide future studies, particularly to identify the most informative phenotypes to investigate. Additionally, studies examining the role of genetic factors in the brain abnormalities underlying autism will likely lead to further findings that will enhance our understanding of autism's causes.

Agenesis of Corpus Callosum↗
PubMed2006

A clinical trial of combined anti-androgen and anti-heavy metal therapy in autistic disorders.

BACKGROUND: A medical hypothesis has suggested that some autism spectrum disorders (ASDs) may result from interactions between the methionine cycle-transsulfuration and androgen pathways following exposure to mercury. METHODS: The IRB of the Institute for Chronic Illnesses approved the present study. A novel treatment was utilized combining LUPRON (leuprolide acetate, TAP Pharmaceuticals, Inc.) and CHEMET (meso-2, 3-dimercaptosuccinic acid--DMSA, McNeil Consumer Products Company) on 11 consecutive children with ASDs. RESULTS: A significant (p<0.01) overall improvement from the 70-79th percentile of severity (median baseline score=87) at baseline to the 40-49th percentile of severity (median end of study period score=63) at the end of the study was observed for patients treated for a median of approximately 4 months. Significant improvements in sociability, cognitive awareness, behavior, and clinical symptoms/behaviors of hyperandrogenemia were also observed. Significant decreases in blood androgens and increases in urinary heavy metal concentrations were observed. Minimal drug adverse effects were found. CONCLUSION: This study provides the first clinical evidence for the benefit that combined anti-androgen and anti-heavy metal therapy may have on some children with ASDs. Additional studies should examine androgen and heavy metal mechanisms of action in ASDs, and future ASD treatment protocols should consider androgens and heavy metals.

Adolescent↗
PubMed2006

A clinical and laboratory evaluation of methionine cycle-transsulfuration and androgen pathway markers in children with autistic disorders.

BACKGROUND/AIMS: The prevalence of autism spectrum disorders (ASDs) is 1 in 300 children in the US. ASDs are characterized by impairments in social relatedness and communication, repetitive behaviors, abnormal movement patterns, and sensory dysfunction. Pre-pubertal age children with ASDs were assessed for metabolites in the methionine cycle-transsulfuration and androgen pathways, and for present physical development/behaviors indicative of hyperandrogenicity. METHODS: The Institutional Review Board of the Institute for Chronic Illnesses (Office for Human Research Protections, US Department of Health and Human Services IRB number: IRB00005375) approved the present study. Sixteen consecutive pre-pubertal age children (</=11 years old; mean +/- SD: 5.9 +/- 2.1 years old) with previously diagnosed ASDs that presented to the Genetic Centers of America for outpatient care were evaluated. RESULTS: Significantly (p < 0.01) increased levels of serum/plasma dehydroepiandrosterone and serum total testosterone relative to the age- and sex-specific normal laboratory reference ranges were observed. Conversely, serum follicle-stimulating hormone levels were significantly (p < 0.01) decreased. Plasma-reduced glutathione (p < 0.01), plasma cysteine (p < 0.01), plasma methionine (p < 0.01), serum cystathionine (p < 0.05), and serum homocysteine (p < 0.01) were all significantly decreased. CONCLUSION: The results suggest a possible cyclical interaction between the methionine cycle-transsulfuration and androgen pathways in some children with ASDs.

Androgens↗
PubMed2005

Risperidone treatment of autistic disorder: longer-term benefits and blinded discontinuation after 6 months.

OBJECTIVE: Risperidone is effective for short-term treatment of aggression, temper outbursts, and self-injurious behavior in children with autism. Because these behaviors may be chronic, there is a need to establish the efficacy and safety of longer-term treatment with this agent. METHOD: The authors conducted a multisite, two-part study of risperidone in children ages 5 to 17 years with autism accompanied by severe tantrums, aggression, and/or self-injurious behavior who showed a positive response in an earlier 8-week trial. Part I consisted of 4-month open-label treatment with risperidone, starting at the established optimal dose; part II was an 8-week randomized, double-blind, placebo-substitution study of risperidone withdrawal. Primary outcome measures were the Aberrant Behavior Checklist irritability subscale and the Clinical Global Impression improvement scale. RESULTS: Part I included 63 children. The mean risperidone dose was 1.96 mg/day at entry and remained stable over 16 weeks of open treatment. The change on the Aberrant Behavior Checklist irritability subscale was small and clinically insignificant. Reasons for discontinuation of part I included loss of efficacy (N=5) and adverse effects (N=1). The subjects gained an average of 5.1 kg. Part II included 32 patients. The relapse rates were 62.5% for gradual placebo substitution and 12.5% for continued risperidone; this difference was statistically significant. CONCLUSIONS: Risperidone showed persistent efficacy and good tolerability for intermediate-length treatment of children with autism characterized by tantrums, aggression, and/or self-injurious behavior. Discontinuation after 6 months was associated with a rapid return of disruptive and aggressive behavior in most subjects.

Adolescent↗
PubMed2004

Performance on Cambridge Neuropsychological Test Automated Battery subtests sensitive to frontal lobe function in people with autistic disorder: evidence from the Collaborative Programs of Excellence in Autism network.

Recent structural and functional imaging work, as well as neuropathology and neuropsychology studies, provide strong empirical support for the involvement of frontal cortex in autism. The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a computer-administered set of neuropsychological tests developed to examine specific components of cognition. Previous studies document the role of frontal cortex in performance of two CANTAB subtests: the Stockings of Cambridge, a planning task, and the Intradimensional/Extradimensional Shift task, a measure of cognitive set shifting. To examine the integrity of frontal functions, these subtests were administered to 79 participants with autism and 70 typical controls recruited from seven universities who are part of the Collaborative Programs of Excellence in Autism network. The two groups were matched on age, sex, and full-scale IQ. Significant group differences were found in performance on both subtests, with the autism group showing deficits in planning efficiency and extradimensional shifting relative to controls. Deficits were found in both lower- and higher-IQ individuals with autism across the age range of 6 to 47 years. Impairment on the CANTAB executive function subtests did not predict autism severity or specific autism symptoms (as measured by the ADI-R and ADOS), but it was correlated with adaptive behavior. If these CANTAB subtests do indeed measure prefrontal function, as suggested by previous research with animals and lesion patients, this adds to the accumulating evidence of frontal involvement in autism and indicates that this brain region should remain an active area of investigation.

Adolescent↗
PubMed2006

An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as risk factors for autistic disorder.

Gene-gene interactions are likely involved in many complex genetic disorders and new statistical approaches for detecting such interactions are needed. We propose a multi-analytic paradigm, relying on convergence of evidence across multiple analysis tools. Our paradigm tests for main and interactive effects, through allele, genotype and haplotype association. We applied our paradigm to genotype data from three GABAA receptor subunit genes (GABRB3, GABRA5, and GABRG3) on chromosome 15 in 470 Caucasian autism families. Previously implicated in autism, we hypothesized these genes interact to contribute to risk. We detected no evidence of main effects by allelic (PDT, FBAT) or genotypic (genotype-PDT) association at individual markers. However, three two-marker haplotypes in GABRG3 were significant (HBAT). We detected no significant multi-locus associations using genotype-PDT analysis or the EMDR data reduction program. However, consistent with the haplotype findings, the best single locus EMDR model selected a GABRG3 marker. Further, the best pairwise genotype-PDT result involved GABRB3 and GABRG3, and all multi-locus EMDR models also selected GABRB3 and GABRG3 markers. GABA receptor subunit genes do not significantly interact to contribute to autism risk in our overall data set. However, the consistency of results across analyses suggests that we have defined a useful framework for evaluating gene-gene interactions.

Autistic Disorder↗
PubMed2000

Increased growth hormone response to sumatriptan challenge in adult autistic disorders.

Serotonergic (5-HT) abnormalities have been documented in autism. To assess sensitivity of the 5-HT1d receptor, growth hormone response to the 5-HT1d receptor agonist sumatriptan was studied in adult autistic patients and matched normal controls. In this study, 11 adult patients with autism or Asperger's disorder were compared with nine matched controls. All subjects were randomized to single dose sumatriptan (6 mg SQ) and placebo challenges, separated by a 1-week interval, and growth hormone was measured before and during the challenges. The results showed a highly significant diagnosisxdrugxtime interaction on repeated measure analysis covaried for baseline. This suggests that autistic patients had significantly greater growth hormone response to sumatriptan than normal controls, independent of placebo effects. Therefore, abnormalities in 5-HT regulation in autism may be related to increased sensitivity of the 5-HT1d inhibitory receptor in autism.

Adolescent↗
PubMed2003

Molecular genetics of autism spectrum disorders.

Autistic disorder belongs to a broad spectrum of pervasive developmental disorders. Autism is a clinically and genetically heterogeneous condition. It is characterized by impairment in a broad range of social interactions, communication, and repetitive patterns of behavior and interest. Although the exact etiology of the condition is not known, family and twin studies strongly support genetic factors in autism. Genome-wide scans suggest several susceptibility loci that may contain one or more predisposing genes. However, no such genes have been identified so far that predispose patients to autism. The condition is over 90% heritable, but the mode of inheritance is not clear. Moreover, it does not seem to be a single gene disorder. There is no cure for autism. Individualized structured education, family support services, and antipsychotic drugs are recommended. These may alleviate some behavioral problems. The identification of autism genes, an understanding of the neurobiology of the condition, and additional clinical studies may help to develop pharmacological interventions in the future.

Autistic Disorder↗