1. Balfe M, Tantam D. {{A descriptive social and health profile of a community sample of adults and adolescents with Asperger syndrome}}. {BMC Res Notes};2010 (Nov 12);3(1):300.
ABSTRACT: BACKGROUND: Little is known about the health and social profile of adolescents and adults with Asperger syndrome (AS) living in the community. We conducted a study to describe the living, employment and psycho-social situation of a community sample of forty two adults and adolescents with AS, and to describe these indivdiuals’ experiences of accessing health services and taking medication. FINDINGS: Most respondents (including those over eighteen years of age) lived at home with their parents. Most had trouble reading and responding to other people’s feelings, and coping with unexpected changes. Difficulties with life skills, such as cleaning, washing and hygiene were prevalent. The majority of respondents were socially isolated and a large minority had been sexually or financially exploited. Almost all respondents had been bullied. Mental health problems such as anxiety or depression were common. 30% of respondents said that they regularly became violent and hit other people and 15% had attempted suicide. More positively, the majority of respondents felt that they could access health services if they had a health problem. CONCLUSIONS: The results of this study suggest a relatively poor social and health profile for many people with Asperger syndrome living in the community, with high levels of social problems and social exclusion, and difficulties managing day to day tasks such as washing and cleaning; these findings support the results of other studies that have examined psycho-social functioning in this group.
2. Chao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, Neul JL, Gong S, Lu HC, Heintz N, Ekker M, Rubenstein JL, Noebels JL, Rosenmund C, Zoghbi HY. {{Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes}}. {Nature};2010 (Nov 11);468(7321):263-269.
Mutations in the X-linked MECP2 gene, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2), cause Rett syndrome and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia and encephalopathy with early lethality. Rett syndrome is characterized by apparently normal early development followed by regression, motor abnormalities, seizures and features of autism, especially stereotyped behaviours. The mechanisms mediating these features are poorly understood. Here we show that mice lacking Mecp2 from GABA (gamma-aminobutyric acid)-releasing neurons recapitulate numerous Rett syndrome and autistic features, including repetitive behaviours. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of Rett syndrome. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase 1 (Gad1) and glutamic acid decarboxylase 2 (Gad2) levels, and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.
3. Connolly BS, Feigenbaum AS, Robinson BH, Dipchand AI, Simon DK, Tarnopolsky MA. {{MELAS syndrome, cardiomyopathy, rhabdomyolysis, and autism associated with the A3260G mitochondrial DNA mutation}}. {Biochem Biophys Res Commun};2010 (Nov 12);402(2):443-447.
The A to G transition mutation at position 3260 of the mitochondrial genome is usually associated with cardiomyopathy and myopathy. One Japanese kindred reported the phenotype of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS syndrome) in association with the A3260G mtDNA mutation. We describe the first Caucasian cases of MELAS syndrome associated with the A3260G mutation. Furthermore, this mutation was associated with exercise-induced rhabdomyolysis, hearing loss, seizures, cardiomyopathy, and autism in the large kindred. We conclude that the A3260G mtDNA mutation is associated with wide phenotypic heterogeneity with MELAS and other « classical » mitochondrial phenotypes being manifestations.
4. Curtis JT, Hood AN, Chen Y, Cobb GP, Wallace DR. {{Chronic metals ingestion by prairie voles produces sex-specific deficits in social behavior: an animal model of autism}}. {Behav Brain Res};2010 (Nov 12);213(1):42-49.
We examined the effects of chronic metals ingestion on social behavior in the normally highly social prairie vole to test the hypothesis that metals may interact with central dopamine systems to produce the social withdrawal characteristic of autism. Relative to water-treated controls, 10 weeks of chronic ingestion of either Hg(++) or Cd(++) via drinking water significantly reduced social contact by male voles when they were given a choice between isolation or contact with an unfamiliar same-sex conspecific. The effects of metals ingestion were specific to males: no effects of metals exposure were seen in females. Metals ingestion did not alter behavior of males allowed to choose between isolation or their familiar cage-mates, rather than strangers. We also examined the possibility that metals ingestion affects central dopamine functioning by testing the voles’ locomotor responses to peripheral administration of amphetamine. As with the social behavior, we found a sex-specific effect of metals on amphetamine responses. Males that consumed Hg(++) did not increase their locomotor activity in response to amphetamine, whereas similarly treated females and males that ingested only water significantly increased their locomotor activities. Thus, an ecologically relevant stimulus, metals ingestion, produced two of the hallmark characteristics of autism – social avoidance and a male-oriented bias. These results suggest that metals exposure may contribute to the development of autism, possibly by interacting with central dopamine function, and support the use of prairie voles as a model organism in which to study autism.
5. Ghanizadeh A. {{Oxidative stress may mediate association of stereotypy and immunity in autism, a novel explanation with clinical and research implications}}. {J Neuroimmunol};2010 (Nov 12)
6. Hamdan FF, Daoud H, Rochefort D, Piton A, Gauthier J, Langlois M, Foomani G, Dobrzeniecka S, Krebs MO, Joober R, Lafreniere RG, Lacaille JC, Mottron L, Drapeau P, Beauchamp MH, Phillips MS, Fombonne E, Rouleau GA, Michaud JL. {{De Novo Mutations in FOXP1 in Cases with Intellectual Disability, Autism, and Language Impairment}}. {Am J Hum Genet};2010 (Nov 12);87(5):671-678.
Heterozygous mutations in FOXP2, which encodes a forkhead transcription factor, have been shown to cause developmental verbal dyspraxia and language impairment. FOXP2 and its closest homolog, FOXP1, are coexpressed in brain regions that are important for language and cooperatively regulate developmental processes, raising the possibility that FOXP1 may also be involved in developmental conditions that are associated with language impairment. In order to explore this possibility, we searched for mutations in FOXP1 in patients with intellectual disability (ID; mental retardation) and/or autism spectrum disorders (ASD). We first performed array-based genomic hybridization on sporadic nonsyndromic ID (NSID) (n = 30) or ASD (n = 80) cases. We identified a de novo intragenic deletion encompassing exons 4-14 of FOXP1 in a patient with NSID and autistic features. In addition, sequencing of all coding exons of FOXP1 in sporadic NSID (n = 110) or ASD (n = 135) cases, as well as in 570 controls, revealed the presence of a de novo nonsense mutation (c.1573C>T [p.R525X]) in the conserved forkhead DNA-binding domain in a patient with NSID and autism. Luciferase reporter assays showed that the p.R525X alteration disrupts the activity of the protein. Formal assessments revealed that both patients with de novo mutations in FOXP1 also show severe language impairment, mood lability with physical aggressiveness, and specific obsessions and compulsions. In conclusion, both FOXP1 and FOXP2 are associated with language impairment, but decrease of the former has a more global impact on brain development than that of the latter.
7. Liu X, Solehdin F, Cohen IL, Gonzalez MG, Jenkins EC, Lewis ME, Holden JJ. {{Population- and Family-Based Studies Associate the MTHFR Gene with Idiopathic Autism in Simplex Families}}. {J Autism Dev Disord};2010 (Nov 12)
Two methylenetetrahydrofolate reductase gene (MTHFR) functional polymorphisms were studied in 205 North American simplex (SPX) and 307 multiplex (MPX) families having one or more children with an autism spectrum disorder. Case-control comparisons revealed a significantly higher frequency of the low-activity 677T allele, higher prevalence of the 677TT genotype and higher frequencies of the 677T-1298A haplotype and double homozygous 677TT/1298AA genotype in affected individuals relative to controls. Family-based association testing demonstrated significant preferential transmission of the 677T and 1298A alleles and the 677T-1298A haplotype to affected offspring. The results were not replicated in MPX families. The results associate the MTHFR gene with autism in SPX families only, suggesting that reduced MTHFR activity is a risk factor for autism in these families.
8. Marchetto MC, Carromeu C, Acab A, Yu D, Yeo GW, Mu Y, Chen G, Gage FH, Muotri AR. {{A model for neural development and treatment of rett syndrome using human induced pluripotent stem cells}}. {Cell};2010 (Nov 12);143(4):527-539.
Autism spectrum disorders (ASD) are complex neurodevelopmental diseases in which different combinations of genetic mutations may contribute to the phenotype. Using Rett syndrome (RTT) as an ASD genetic model, we developed a culture system using induced pluripotent stem cells (iPSCs) from RTT patients’ fibroblasts. RTT patients’ iPSCs are able to undergo X-inactivation and generate functional neurons. Neurons derived from RTT-iPSCs had fewer synapses, reduced spine density, smaller soma size, altered calcium signaling and electrophysiological defects when compared to controls. Our data uncovered early alterations in developing human RTT neurons. Finally, we used RTT neurons to test the effects of drugs in rescuing synaptic defects. Our data provide evidence of an unexplored developmental window, before disease onset, in RTT syndrome where potential therapies could be successfully employed. Our model recapitulates early stages of a human neurodevelopmental disease and represents a promising cellular tool for drug screening, diagnosis and personalized treatment.
9. McAleer P, Kay JW, Pollick FE, Rutherford MD. {{Intention Perception in High Functioning People with Autism Spectrum Disorders Using Animacy Displays Derived from Human Actions}}. {J Autism Dev Disord};2010 (Nov 11)
The perception of intent in Autism Spectrum Disorders (ASD) often relies on synthetic animacy displays. This study tests intention perception in ASD via animacy stimuli derived from human motion. Using a forced choice task, 28 participants (14 ASDs; 14 age and verbal-I.Q. matched controls) categorized displays of Chasing, Fighting, Flirting, Following, Guarding and Playing, from two viewpoints (side, overhead) in both animacy and full video displays. Detailed analysis revealed no differences between populations in accuracy, or response patterns. Collapsing across groups revealed Following and Video displays to be most accurately perceived. The stimuli and intentions used are compared to those of previous studies, and the implication of our results on the understanding of Theory of Mind in ASD is discussed.
10. Moreno-De-Luca D, Mulle JG, Kaminsky EB, Sanders SJ, Myers SM, Adam MP, Pakula AT, Eisenhauer NJ, Uhas K, Weik L, Guy L, Care ME, Morel CF, Boni C, Salbert BA, Chandrareddy A, Demmer LA, Chow EW, Surti U, Aradhya S, Pickering DL, Golden DM, Sanger WG, Aston E, Brothman AR, Gliem TJ, Thorland EC, Ackley T, Iyer R, Huang S, Barber JC, Crolla JA, Warren ST, Martin CL, Ledbetter DH. {{Deletion 17q12 Is a Recurrent Copy Number Variant that Confers High Risk of Autism and Schizophrenia}}. {Am J Hum Genet};2010 (Nov 12);87(5):618-630.
Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 x 10(-5)). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only.
11. Olson CD. {{New insights regarding possible association between prenatal ultrasound and autism}}. {J Am Osteopath Assoc};2010 (Oct);110(10):578-608.
12. Shukla DK, Keehn B, Muller RA. {{Tract-specific analyses of diffusion tensor imaging show widespread white matter compromise in autism spectrum disorder}}. {J Child Psychol Psychiatry};2010 (Nov 12)
Background: Previous diffusion tensor imaging (DTI) studies have shown white matter compromise in children and adults with autism spectrum disorder (ASD), which may relate to reduced connectivity and impaired function of distributed networks. However, tract-specific evidence remains limited in ASD. We applied tract-based spatial statistics (TBSS) for an unbiased whole-brain quantitative estimation of the fractional anisotropy (FA), mean diffusion (MD) and axial and radial diffusion of the white matter tracts in children and adolescents with ASD. Methods: DTI was performed in 26 ASD and 24 typically developing (TD) participants, aged 9-20 years. Groups were matched for age and IQ. Each participant’s aligned FA, MD and axial and radial diffusion data were projected onto the mean FA skeleton representing the centers of all tracts and the resulting data fed into voxelwise group statistics. Results: TBSS revealed decreased FA and increased MD and radial diffusion in the ASD group compared to the TD group in the corpus callosum, anterior and posterior limbs of the internal capsule, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, cingulum, anterior thalamic radiation, and corticospinal tract. No single site with inverse effects (increased FA, reduced MD or radial diffusion in the ASD group) was detected. In clusters of significant group difference, age was positively correlated with FA and negatively correlated with MD and radial diffusion in the TD, but not the ASD group. Conclusions: Our findings reveal white matter compromise affecting numerous tracts in children and adolescents with ASD. Slightly varying patterns of diffusion abnormalities detected for some tracts may suggest tract-specific patterns of white matter abnormalities associated with ASD. Age-dependent effects further show that maturational changes (increasing FA, decreasing MD and radial diffusion with age) are diminished in ASD from school-age childhood into young adulthood.
13. Stanley-Cary C, Rinehart N, Tonge B, White O, Fielding J. {{Greater Disruption to Control of Voluntary Saccades in Autistic Disorder than Asperger’s Disorder: Evidence for Greater Cerebellar Involvement in Autism?}}. {Cerebellum};2010 (Nov 12)
It remains unclear whether autism and Asperger’s disorder (AD) exist on a symptom continuum or are separate disorders with discrete neurobiological underpinnings. In addition to impairments in communication and social cognition, motor deficits constitute a significant clinical feature in both disorders. It has been suggested that motor deficits and in particular the integrity of cerebellar modulation of movement may differentiate these disorders. We used a simple volitional saccade task to comprehensively profile the integrity of voluntary ocular motor behaviour in individuals with high functioning autism (HFA) or AD, and included measures sensitive to cerebellar dysfunction. We tested three groups of age-matched young males with normal intelligence (full scale, verbal, and performance IQ estimates >70) aged between 11 and 19 years; nine with AD, eight with HFA, and ten normally developing males as the comparison group. Overall, the metrics and dynamics of the voluntary saccades produced in this task were preserved in the AD group. In contrast, the HFA group demonstrated relatively preserved mean measures of ocular motricity with cerebellar-like deficits demonstrated in increased variability on measures of response time, final eye position, and movement dynamics. These deficits were considered to be consistent with reduced cerebellar online adaptation of movement. The results support the notion that the integrity of cerebellar modulation of movement may be different in AD and HFA, suggesting potentially differential neurobiological substrates may underpin these complex disorders.
14. Walsh RM, Hochedlinger K. {{Modeling rett syndrome with stem cells}}. {Cell};2010 (Nov 12);143(4):499-500.
The discovery that somatic cells can be reprogrammed into induced pluripotent stem cells (iPSCs) raised the exciting possibility of modeling diseases with patient-specific cells. Marchetto et al. (2010) now use iPSC technology to generate, characterize, and treat an in vitro model for the autism spectrum disorder Rett syndrome.
