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PubMed2004

[Chromosome 22q11 deletion syndrome and its relevance for child and adolescent psychiatry. An overview of etiology, physical symptoms, aspects of child development and psychiatric disorders].

22q11.2 deletion syndrome is the most common interstitial deletion syndrome in humans. Patients with this syndrome can show a variety of somatic symptoms, especially characteristic facial abnormalities, heart defects, thymic hypo- or aplasia and velopharyngeal dysfunction with or without cleft palate. Disturbancies in motor, language, cognitive and social development are typical, as well as psychiatric disorders. Psychiatric disorders in children and adolescents are mostly attention-deficit/hyperactivity disorder, affective disorders, and autism spectrum problems. Schizophrenia in adults seems to be caused by 22q11.2 deletion in about 2% of all patients. We review current knowledge about etiology, physical features, developmental aspects and psychiatric comorbidity in 22q11.2 deletion syndrome as well as possible therapeutic interventions. Clinical criteria for genetic examinations on 22q11.2 deletion in children and adolescents with psychiatric disorders are defined. Until now 22q11.2 deletion is underdiagnosed in this population--despite of its clinical relevance.

Abnormalities, Multiple↗

PubMed2005

Homologous pairing of 15q11-13 imprinted domains in brain is developmentally regulated but deficient in Rett and autism samples.

Rett syndrome (RTT), caused by mutations in MECP2 (encoding methyl CpG binding protein 2), and Angelman syndrome (AS), caused by maternal deficiency of chromosome 15q11-13, are autism-spectrum neurodevelopmental disorders. MeCP2 is a transcriptional repressor of methylated genes, but MECP2 mutation does not directly affect the imprinted expression of genes within 15q11-13. We tested a potential role for MeCP2 in the homologous pairing of imprinted 15q11-13 alleles in human brain tissue and differentiated neurons by fluorescence in situ hybridization (FISH). FISH analysis of control cerebral samples demonstrated a significant increase in homologous pairing specific to chromosome 15 from infant to juvenile brain samples. Significant and specific deficiencies in the percentage of paired chromosome 15 alleles were observed in RTT, AS and autism brain samples when compared with normal controls. SH-SY5Y neuroblastoma cells also showed a significant and specific increase in the percentage of chromosome 15q11-13 paired alleles following induced differentiation in vitro. Transfection with a methylated oligonucleotide decoy specifically blocked binding of MeCP2 to the SNURF/SNRPN promoter within 15q11-13 and significantly lowered the percentage of paired 15q11-13 alleles in SH-SY5Y cells. These combined results suggest a role for MeCP2 in chromosome organization in the developing brain and provide a potential mechanistic association between several related neurodevelopmental disorders.

Autistic Disorder↗

PubMed2006

Pervasive developmental disorders in Prader-Willi syndrome: the Leuven experience in 59 subjects and controls.

In the present study we investigated the co-morbidity of pervasive developmental disorder (PDD) in 59 Prader-Willi syndrome (PWS) individuals and in 59 non-specific mentally retarded controls, matched for IQ, gender, and age. The 'Pervasive Developmental Disorder Mentally Retardation Scale' (PDD-MRScale), a screening questionnaire based on the DSM-III-R criteria for PDD, has been applied in the PWS group and in the control group. Results of the present study revealed a striking autistic-like behavioral phenotype in the majority of the PWS individuals, particularly deficits in the quality of language and communication and of imagination and interests. This intersection with autistic symptomatology is an important addition to the behavioral phenotype in PWS persons. A first approach to delineate subtypes of autistic symptomalogy among PWS persons was performed. Nineteen percent of the PWS group did meet the full diagnostic DSM-III-R criteria for PDD in comparison with 15% in the control group. Results revealed that a higher IQ in PWS does not protect to develop genuine PDD and that uniparental disomy/imprinting mutation as genetic origin seems to be an additional risk factor for developing genuine PDD. The results of the present study suggest the importance of reconsidering the commonly recognized obsessive-compulsive like behavior in PWS persons within the broader spectrum of autism disorders.

Adolescent↗

PubMed2026

Transcriptomic landscape of microglia in mouse models of social dysfunction and oxytocin-mediated recovery.

Atypical sociability is a hallmark of neurodevelopmental disorders arising from genetic susceptibility and prenatal environmental perturbations that can affect diverse brain cell types. Using single-cell transcriptomics, we previously identified selective vulnerability of parvocellular oxytocin (OT) neurons in the paraventricular hypothalamus (PVH) following embryonic exposure to valproic acid (VPA), a teratogen that induces social deficits. Neonatal chemogenetic activation of OT neurons rescued these behavioral abnormalities and partially restored dysregulated gene expression. However, the effects of VPA exposure and OT neuron stimulation on non-neuronal PVH cells remained unclear. Here, we show that VPA induces transcriptional abnormalities in PVH microglia. Spatial transcriptomics revealed altered distributions of PVH microglial subtypes. Notably, neonatal OT neuron stimulation reversed a subset of VPA-induced microglial gene downregulation, while pharmacological manipulation of microglia normalized aberrant OT gene expression in putative parvocellular OT neurons. These findings support bidirectional OT neuron-microglia interactions that may underlie social dysfunction following embryonic VPA exposure.

autism spectrum disorder↗

PubMed2021

High-impact rare genetic variants in severe schizophrenia.

Extreme phenotype sequencing has led to the identification of high-impact rare genetic variants for many complex disorders but has not been applied to studies of severe schizophrenia. We sequenced 112 individuals with severe, extremely treatment-resistant schizophrenia, 218 individuals with typical schizophrenia, and 4,929 controls. We compared the burden of rare, damaging missense and loss-of-function variants between severe, extremely treatment-resistant schizophrenia, typical schizophrenia, and controls across mutation intolerant genes. Individuals with severe, extremely treatment-resistant schizophrenia had a high burden of rare loss-of-function (odds ratio, 1.91; 95% CI, 1.39 to 2.63; P = 7.8 × 10-5) and damaging missense variants in intolerant genes (odds ratio, 2.90; 95% CI, 2.02 to 4.15; P = 3.2 × 10-9). A total of 48.2% of individuals with severe, extremely treatment-resistant schizophrenia carried at least one rare, damaging missense or loss-of-function variant in intolerant genes compared to 29.8% of typical schizophrenia individuals (odds ratio, 2.18; 95% CI, 1.33 to 3.60; P = 1.6 × 10-3) and 25.4% of controls (odds ratio, 2.74; 95% CI, 1.85 to 4.06; P = 2.9 × 10-7). Restricting to genes previously associated with schizophrenia risk strengthened the enrichment with 8.9% of individuals with severe, extremely treatment-resistant schizophrenia carrying a damaging missense or loss-of-function variant compared to 2.3% of typical schizophrenia (odds ratio, 5.48; 95% CI, 1.52 to 19.74; P = 0.02) and 1.6% of controls (odds ratio, 5.82; 95% CI, 3.00 to 11.28; P = 2.6 × 10-8). These results demonstrate the power of extreme phenotype case selection in psychiatric genetics and an approach to augment schizophrenia gene discovery efforts.

Aged↗

PubMed2005

Neurophysiological evidence for cortical discrimination impairment of prosody in Asperger syndrome.

Asperger syndrome (AS), belonging to the autism spectrum of disorders, is one of the pervasive developmental disorders. Individuals with AS usually have normal development of formal speech but pronounced problems in perceiving and producing speech prosody. The present study addressed the discrimination of speech prosody in AS by recording the mismatch negativity (MMN) and behavioural responses to natural utterances with different emotional connotations. MMN responses were abnormal in the adults with AS in several ways. In these subjects, fewer significantly elicited MMNs, diminished MMN amplitudes, as well as prolonged latencies were found. In addition, the MMN generator loci differed between the subjects with AS and control subjects. These findings were predominant over the right cerebral hemisphere. These results show impaired neurobiological basis for speech-prosody processing at an early, pre-attentive auditory discrimination stage in AS.

Adult↗

PubMed2026

Atypical cytokine profiles in people on the autism spectrum: a comprehensive systematic review and meta-analysis including 54 cytokines.

Atypical peripheral blood cytokine concentrations have been shown in autism, but no clear pattern has been observed. This systematic review and meta-analysis summarised current state of findings, expanded the range of cytokines, accounted for study risk of bias, and examined relations between cytokines and autism traits. Literature comparing peripheral blood cytokine in autistic and non-autistic people was systematically searched in Ovid® Embase, MEDLINE and APA PsycINFO, Web of Science™ and Scopus, resulting in 98 studies and 54 cytokines (4236 autistic, 3333 non-autistic controls; age 2 to 65 years) in the meta-analysis. Study risk of bias was assessed using adapted Newcastle-Ottawa Scale. Compared to controls, autistic people had elevated levels of IL1-beta (Hedges' g = 0.620, 95%CI[0.32, 0.92]), IL4 (g = 0.245, 95%CI [0.07, 0.42]), IL6 (g = 0.365, 95%CI [0.011, 0.62]), IL8 (g = 0.384, 95%CI [0.15, 0.62]), IFN-gamma (g = 0.404, 95%CI [0.09, 0.72]), TNF-alpha (g = 0.31, 95%CI [0.11, 0.51]), CXCL1/GRO-α (g = 0.364, 95%CI [0.058, 0.670]) and MIF (g = 0.560, 95%CI [0.14, 0.98]). Over a third of studies were classified as having a high risk of bias; their removal revealed higher IL7 and IL1RA in autism relative to controls. Narrative synthesis produced no strong evidence for an association between cytokine and autism traits among autistic individuals. Altogether, our findings support a predominance of pro-inflammatory cytokines, while also indicating potential modulatory contributions from inhibitory cytokines, which reflect group-level differences between autistic and non-autistic individuals, but not variations of autism traits within the autistic population. However, higher-quality studies with low risk of bias are needed before firm conclusions can be drawn.

Humans↗

PubMed2006

Cortical serotonin 5-HT2A receptor binding and social communication in adults with Asperger's syndrome: an in vivo SPECT study.

OBJECTIVE: The cause of autistic spectrum disorder (i.e., autism and Asperger's syndrome) is unknown. The serotonergic (5-HT) system may be especially implicated. However, cortical 5-HT2A receptor density in adults with the disorder has not been examined, to the authors' knowledge. METHOD: The authors investigated cortical 5-HT2A receptor binding in eight adults with Asperger's syndrome and in 10 healthy comparison subjects with single photon emission computed tomography and the selective 5-HT2A receptor ligand 123I iodinated 4-amino-N-[1-[3-(4-fluorophenoxy)propyl]-4-methyl-4-piperidinyl]-5-iodo-2-methoxybenzamide (123I-5-I-R91150). RESULTS: People with Asperger's syndrome had a significant reduction in cortical 5-HT2A receptor binding in the total, anterior, and posterior cingulate; bilaterally in the frontal and superior temporal lobes; and in the left parietal lobe. Also, reduced receptor binding was significantly related to abnormal social communication. CONCLUSIONS: The authors' findings suggest that adults with Asperger's syndrome have abnormalities in cortical 5-HT2A receptor density and that this deficit may underlie some clinical symptoms.

Adult↗

PubMed2006

Structural equation analysis of a hypothesised symptom model in the autism spectrum.

BACKGROUND: Several studies showed a different symptom structure underlying the spectrum of autistic-like disorders from the behaviour triad as mentioned in the DSM-IV. In the present study, a hypothesised symptom model for autism was constructed, based on earlier explorative findings, and was put to a confirmatory test. METHOD: Items from the Autism Diagnostic Interview-Revised (ADI-R) were used to examine the goodness of fit of the DSM-IV model, the hypothesised symptom model, and two additional models for autism. All models were tested in a group of 255 verbal and nonverbal individuals with minor to severe autistic symptomatology. RESULTS: The DSM-IV model encountered estimation problems. Conversely, the hypothesised symptom model had no such problems and proved to have a better fit to the sample data than the two additional models for autism. However, some of the observed variables were weak indicators of the three latent factors in the model. CONCLUSIONS: The hypothesised symptom model appeared to be a plausible model in a group of individuals with a broad range of autistic behaviours and levels of functioning. Nevertheless, the stability of the model needs further examination in a larger group of individuals with disorders in the autism spectrum, and with varying degrees of intellectual functioning.

Autistic Disorder↗

PubMedDate not supplied

What's going on? The question of time trends in autism.

Increases in the reported prevalence of autism and autistic spectrum disorders in recent years have fueled concern over possible environmental causes. The author reviews the available survey literature and finds evidence of large increases in prevalence in both the United States and the United Kingdom that cannot be explained by changes in diagnostic criteria or improvements in case ascertainment. Incomplete ascertainment of autism cases in young child populations is the largest source of predictable bias in prevalence surveys; however, this bias has, if anything, worked against the detection of an upward trend in recent surveys. Comparison of autism rates by year of birth for specific geographies provides the strongest basis for trend assessment. Such comparisons show large recent increases in rates of autism and autistic spectrum disorders in both the U.S. and the U.K. Reported rates of autism in the United States increased from < 3 per 10,000 children in the 1970s to > 30 per 10,000 children in the 1990s, a 10-fold increase. In the United Kingdom, autism rates rose from < 10 per 10,000 in the 1980s to roughly 30 per 10,000 in the 1990s. Reported rates for the full spectrum of autistic disorders rose from the 5 to 10 per 10,000 range to the 50 to 80 per 10,000 range in the two countries. A precautionary approach suggests that the rising incidence of autism should be a matter of urgent public concern.

Autistic Disorder↗

PubMed2006

[Variations of heterochromatic chromosomal regions and chromosome abnormalities in children with autism: identification of genetic markers in autistic spectrum disorders].

In the present study, the cytogenetic and molecular cytogenetic analysis of 90 children with autism and their mothers (18 subjects) was carried out. Chromosome fragility and abnormalities were found in four cases: mos 47,XXX[98]/ 46,XX[2]; 46,XY,r(22)(p11q13); 46,XY,inv(2)(p11.2q13),16qh-; 46Y,fra(X)(q27.3)16qh-. Using C-banding and quantitative fluorescent in situ hybridization (FISH), the significantly increased incidence of heterochromatic region variation was shown in autism as compared to the controls (48 and 16%, respectively). Pericentric 9phqh inversion was not characteristic of the patients with autism whereas heterochromatic variations 1phqh, 9qh+ and 16qh- were more frequent in autism (p<0,05). Basing on the data obtained, a possible role of position effect in autism pathogenesis as well as a potential of heterochromatic region variation analysis for the search of biological markers of autistic spectrum disorders are discussed.

Adolescent↗

PubMed2006

Gene expression profiling of lymphoblastoid cell lines from monozygotic twins discordant in severity of autism reveals differential regulation of neurologically relevant genes.

BACKGROUND: The autism spectrum encompasses a set of complex multigenic developmental disorders that severely impact the development of language, non-verbal communication, and social skills, and are associated with odd, stereotyped, repetitive behavior and restricted interests. To date, diagnosis of these neurologically based disorders relies predominantly upon behavioral observations often prompted by delayed speech or aberrant behavior, and there are no known genes that can serve as definitive biomarkers for the disorders. RESULTS: Here we demonstrate, for the first time, that lymphoblastoid cell lines from monozygotic twins discordant with respect to severity of autism and/or language impairment exhibit differential gene expression patterns on DNA microarrays. Furthermore, we show that genes important to the development, structure, and/or function of the nervous system are among the most differentially expressed genes, and that many of these genes map closely in silico to chromosomal regions containing previously reported autism candidate genes or quantitative trait loci. CONCLUSION: Our results provide evidence that novel candidate genes for autism may be differentially expressed in lymphoid cell lines from individuals with autism spectrum disorders. This finding further suggests the possibility of developing a molecular screen for autism based on expressed biomarkers in peripheral blood lymphocytes, an easily accessible tissue. In addition, gene networks are identified that may play a role in the pathophysiology of autism.

Autistic Disorder↗

PubMed2003

Association between thimerosal-containing vaccine and autism.

CONTEXT: Mercuric compounds are nephrotoxic and neurotoxic at high doses. Thimerosal, a preservative used widely in vaccine formulations, contains ethylmercury. Thus it has been suggested that childhood vaccination with thimerosal-containing vaccine could be causally related to neurodevelopmental disorders such as autism. OBJECTIVE: To determine whether vaccination with a thimerosal-containing vaccine is associated with development of autism. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study of all children born in Denmark from January 1, 1990, until December 31, 1996 (N = 467 450) comparing children vaccinated with a thimerosal-containing vaccine with children vaccinated with a thimerosal-free formulation of the same vaccine. MAIN OUTCOME MEASURES: Rate ratio (RR) for autism and other autistic-spectrum disorders, including trend with dose of ethylmercury. RESULTS: During 2 986 654 person-years, we identified 440 autism cases and 787 cases of other autistic-spectrum disorders. The risk of autism and other autistic-spectrum disorders did not differ significantly between children vaccinated with thimerosal-containing vaccine and children vaccinated with thimerosal-free vaccine (RR, 0.85 [95% confidence interval [CI], 0.60-1.20] for autism; RR, 1.12 [95% CI, 0.88-1.43] for other autistic-spectrum disorders). Furthermore, we found no evidence of a dose-response association (increase in RR per 25 microg of ethylmercury, 0.98 [95% CI, 0.90-1.06] for autism and 1.03 [95% CI, 0.98-1.09] for other autistic-spectrum disorders). CONCLUSION: The results do not support a causal relationship between childhood vaccination with thimerosal-containing vaccines and development of autistic-spectrum disorders.

Autistic Disorder↗

PubMed2005

[The social deficit in autism: focus on joint attention].

INTRODUCTION AND DEVELOPMENT: Autism is best thought of as a spectrum disorder with the dimensional components of social cognition, communication and flexibility varying between individuals meeting the criteria of autism. The core clinical feature that defines autism is a disturbance in social interaction which is not absolute and differs depending on a child's cognitive level, developmental stage, and the type of social structure in which they are observed. Social skills are under strong genetic influence with a continuous distribution of social interaction deficits in the general population with arbitrary cutoffs defining who is and is not affected with an autism spectrum disorder; this is the result of a complex interplay between numerous biological and environmental factors. Joint attention refers to the capacity of individuals to coordinate attention with a social partner in relation to some object or event and a disturbance in this early skill and in particular impairment in the ability to initiate joint attention, is a central symptom of autism. CONCLUSIONS: There are data to suggest that dorso-medial frontal cortex and anterior cingulate contribute to the development of an infant's ability to maintain representations of self, a social partner and an interesting object. The ability to engage frequently in social orienting behaviors and ultimately in numerous episodes of social attention coordination, or joint attention, may be a critical experience during a particular developmental window that serves to organize social neurodevelopment. A neurodevelopmental model explaining how these early deficits in social cognition may lead to autism is reviewed.

Autistic Disorder↗

PubMed2005

Autism-Spectrum Quotient-Japanese version and its short forms for screening normally intelligent persons with pervasive developmental disorders.

A Japanese version of the Autism Spectrum Quotient (AQ), AQ-J was administered to 25 normally intelligent high-functioning pervasive developmental disorder (HPDD) patients (mean age, 24.2 years; 24 male, one female) and 215 controls (mean age, 30.4 years; 86 male, 129 female) randomly selected from the general population. The AQ-J had satisfactory internal consistency reliability (Cronbach's alpha > 0.70 in the two groups), test-retest reliability, and discriminant validity [i.e. the AQ-J score was significantly higher in the HPDD (mean, 29.6) than controls (mean, 22.2)]. At a cut-off of 26, the AQ-J had satisfactory sensitivity, specificity, and negative predictive value, but it had low positive predictive value (0.24) possibly due to the facts that the 25 mild HPDD patients scored lower and the controls scored higher on the AQ-J than British counterparts on the AQ. The AQ-J-21 (consisting of 21 items significantly associated with HPDD diagnosis) and the AQ-J-10 (consisting of 10 of the 21 items with an effect size > 0.17) had higher, although not satisfactory, positive predictive values of 0.35 and 0.46 at cut-offs of 12 and 7, respectively, than the AQ-J. The AQ-J and two short forms are useful not to predict but to rule out mild HPDD, the most difficult part of HPDD to be distinguished from non-PDD conditions, in persons scoring under the cut-offs and to consider professionals' examination of HPDD in persons scoring over them, because their negative predictive values were satisfactory.

Adolescent↗

PubMed2002

The potential of virtual reality in social skills training for people with autistic spectrum disorders.

BACKGROUND: People with autism experience profound and pervasive difficulties in the social domain. Attempts to teach social behaviours tend to adopt either a behavioural or a 'theory of mind' (ToM) approach. The beneficial aspects and limitations of both paradigms are summarized before an examination of how virtual reality technology may offer a way to combine the strengths from both approaches. METHODS: This is not an exhaustive review of the literature; rather, the papers are chosen as representative of the current understanding within each broad topic. Web of Science ISI, EMBASE and PsycInfo were searched for relevant articles. RESULTS: Behavioural and ToM approaches to social skills training achieve some success in improving specific skills or understanding. However, the failure to generalize learned behaviours to novel environments, and the unwieldy nature of some behavioural methodologies, means that there is a need for a training package that is easy to administer and successful in promoting learning across contexts. CONCLUSIONS: Virtual reality technology may be an ideal tool for allowing participants to practise behaviours in role-play situations, whilst also providing a safe environment for rule learning and repetition of tasks. Role-play within virtual environments could promote the mental simulation of social events, potentially allowing a greater insight into minds. Practice of behaviours, both within and across contexts, could also encourage a more flexible approach to social problem solving. Virtual environments offer a new and exciting perspective on social skills training for people with autistic spectrum disorders.

Autistic Disorder↗

PubMed2004

Brief report: cognitive processing of own emotions in individuals with autistic spectrum disorder and in their relatives.

Difficulties in the cognitive processing of emotions--including difficulties identifying and describing feelings--are assumed to be an integral part of autism. We studied such difficulties via self-report in 27 high-functioning adults with autistic spectrum disorders, their biological relatives (n = 49), and normal adult controls (n = 35), using the 20-item Toronto Alexithymia Scale and the Beck Depression Inventory. The individuals with autism spectrum disorders were significantly more impaired in their emotion processing and were more depressed than those in the control and relative groups.

Adolescent↗

PubMed2002

Head circumference in autism, Asperger syndrome, and ADHD: a comparative study.

This study was undertaken to test the hypothesis that children with autistic spectrum disorders often have macrocephalus, and that those without comorbid learning disability are most frequently affected. Fifty consecutive children with Asperger syndrome (45 males, five females; mean age 9 years, range 1 year 6 months to 16 years) without indications of underlying medical disorders were matched for birth year and sex with 50 children (45 males, five females; mean age 6 years 4 months, range 1 year 4 months to 13 years 11 months) who met criteria for autistic disorder (a lower-functioning disorder within the autism spectrum) and with 50 children (45 males, five females; mean age 8 years 4 months, range 1 year 6 months to 15 years 5 months) who met criteria for attention-deficit-hyperactivity disorder. Birth and neuropsychiatric follow-up records were examined and data relating to occipitofrontal circumference, weight, and height were detailed. The group with Asperger syndrome included a subset of individuals with macrocephalus recorded both at birth and at follow-up after the first year of life. Another subgroup developed macrocephalus during early childhood. Autistic spectrum disorders include a subgroup with macrocephalus characterized by a relatively high level of functioning and a clinical presentation most often consistent with a diagnosis of Asperger syndrome.

Adolescent↗