1. Bailey AR, Hou H, Obregon DF, Tian J, Zhu Y, Zou Q, Nikolic WV, Bengtson M, Mori T, Murphy T, Tan J. {{Aberrant T-lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein-alpha: implications for autism}}. {FASEB J};2011 (Nov 15)
Abnormalities in T-lymphocyte populations and function are observed in autism. Soluble amyloid precursor protein alpha (sAPP-alpha) is elevated in some patients with autism and is known to be produced by immune cells. In light of the well-established role of sAPP-alpha in proliferation, growth, and survival of neurons, we hypothesized an analogous role in the immune system. Thus, we explored whether sAPP-alpha could modulate immune development and function, especially aspects of the pinnacle cell of the adaptive arm of the immune system: the T cell. To do this, we generated mice overexpressing human sAPP-alpha and characterized elements of T-cell development, signal transduction, cytokine production, and innate/adaptive immune functions. Here, we report that transgenic sAPP-alpha-overexpressing (TgsAPP-alpha) mice displayed increased proportions of CD8(+) T cells, while effector memory T cells were decreased in the thymus. Overall apoptotic signal transduction was decreased in the thymus, an effect that correlated with dramatic elevations in Notch1 activation; while active-caspase-3/total-caspase-3 and Bax/Bcl-2 ratios were decreased. Greater levels of IFN-gamma, IL-2, and IL-4 were observed after ex vivo challenge of TgsAPP-alpha mouse splenocytes with T-cell mitogen. Finally, after immunization, splenocytes from TgsAPP-alpha mice displayed decreased levels IFN-gamma, IL-2, and IL-4, as well as suppressed ZAP70 activation, after recall antigen stimulation. Given elevated levels of circulating sAPP-alpha in some patients with autism, sAPP-alpha could potentially drive aspects of immune dysfunction observed in these patients, including dysregulated T-cell apoptosis, aberrant PI3K/AKT signaling, cytokine alterations, and impaired T-cell recall stimulation.-Bailey, A. R., Hou, H., Obregon, D. F., Tian, J., Zhu, Y., Zou, Q., Nikolic, W. V., Bengtson, M., Mori, T., Murphy, T., Tan, J. Aberrant T-lymphocyte development and function in mice overexpressing human soluble amyloid precursor protein-alpha: implications for autism.
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2. Baird G. {{2.64% of South Korean children aged 7 to 12 have autism spectrum disorders}}. {Evid Based Ment Health};2011 (Nov 15)
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3. Barrett B, Byford S, Sharac J, Hudry K, Leadbitter K, Temple K, Aldred C, Slonims V, Green J. {{Service and Wider Societal Costs of Very Young Children with Autism in the UK}}. {J Autism Dev Disord};2011 (Nov 17)
Autism spectrum disorders (ASD) are associated with a substantial economic burden, but there is little evidence of the costs in the early years; the period in which children are increasingly likely to be diagnosed. We describe the services used by 152 children aged 24-60 months with autism, report family out-of-pocket expenses and productivity losses, and explore the relationship between family characteristics and costs. Children received a wide range of hospital and community services including relatively high levels of contact with speech and language therapists and paediatricians. Total service costs varied greatly (mean pound430 per month; range pound53 to pound1,116), with some families receiving little statutory support. Higher costs were associated with increasing age and symptom severity.
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4. Chung BH, Mullegama S, Marshall CR, Lionel AC, Weksberg R, Dupuis L, Brick L, Li C, Scherer SW, Aradhya S, Stavropoulos DJ, Elsea SH, Mendoza-Londono R. {{Severe intellectual disability and autistic features associated with microduplication 2q23.1}}. {Eur J Hum Genet};2011 (Nov 16)
We report on two patients with developmental delay, hypotonia, and autistic features associated with duplications of chromosome region 2q23.1-2q23.2 detected by chromosome microarray analysis. The duplications include one OMIM Morbid Map gene, MBD5, as well as seven known RefSeq genes (ACVR2A, ORC4L, EPC2, KIF5C, MIR1978, LYPD6B, and LYPD6). MBD5 lies in the minimum area of overlap of the 2q23.1 microdeletion syndrome. This report provides the first detailed clinical examination of two individuals with a duplication of this region and suggests that brain development and cognitive function may be affected by an increased dosage of the genes involved.European Journal of Human Genetics advance online publication, 16 November 2011; doi:10.1038/ejhg.2011.199.
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5. Guinchat V, Thorsen P, Laurent C, Cans C, Bodeau N, Cohen D. {{Pre-, peri-, and neonatal risk factors for autism}}. {Acta Obstet Gynecol Scand};2011 (Nov 15)
Objective. To identify pre-, peri-, and neonatal risk factors for Pervasive Developmental disorders (PDD). Methods. We searched the Medline database through March 2011 for relevant case control and population based studies on pre-, peri-, and neonatal hazards related to Pervasive Developmental Disorders (PDD) including autism. We identified 85 studies for this review. Data were extracted systematically and organised according to risk factors related to family history, pregnancy, gestational age, delivery, birth milestones and the neonate’s condition at birth. Results. During the prenatal period, risk factors for PDD were advanced maternal or paternal ages, being firstborn vs. third or later, maternal prenatal medication use, and mother’s status as foreign born. During the perinatal and neonatal periods, the risk factors for PDD were preterm birth, breech presentation, planned cesarean section, low Apgar scores, hyperbilirubinemia, birth defect, and a birthweight small-for-gestational age. The influence of maternal preeclampsia, diabetes, vomiting, infections, and stress during pregnancy need to be studied more are insufficiently studied, to state. Discussion. Despite evidence for the association of some pre-, peri-, and neonatal risk factors associated with PDD, it remains unclear whether these risks are causal or play a secondary role in shaping clinical expression in individuals with genetic vulnerability. A plausible hypothsesis is that improvements in obstetrical and neonatal management have led to an increased rate of survivors with pre-existing brain damage. Given the variety of risk factors, we propose that future studies should investigate combinations of multiple factors, rather than focusing on a single factor.
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6. Kuo MH, Orsmond GI, Cohn ES, Coster WJ. {{Friendship Characteristics and Activity Patterns of Adolescents With an Autism Spectrum Disorder}}. {Autism};2011 (Nov 15)
This study compared perceptions of adolescents’ friendships between adolescents with an autism spectrum disorder (ASD) and their parents, examined factors associated with friendship qualities, and investigated the adolescents’ reports on the activities they did with friends and how activity patterns differed by gender. Ninety-one adolescents with an ASD and their parents completed mail-based surveys during the summer months. Adolescents with an ASD identified more friends than did their parents, but they agreed on the friends’ characteristics. About half of the adolescents spent an average of 4 hours per day with friends during the summer months. Male adolescents with an ASD most frequently played video games with friends, whereas females most frequently had conversations with friends. The findings suggest that adolescents with an ASD and their parents identify different peers as the adolescent’s friends. The findings also reveal similarities and differences in friendships between adolescents with an ASD and typically developing adolescents.
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7. Lanni KE, Schupp CW, Simon D, Corbett BA. {{Verbal ability, social stress, and anxiety in children with Autistic Disorder}}. {Autism};2011 (Nov 15)
The aims of this study were to evaluate the physiological stress and anxiety responses in children with autism following completion of a standardized, social-evaluative stressor (Trier Social Stress Test A -Child version), document the relationship between verbal ability,stress, and anxiety, and determine the association between stress and anxiety in children with autism and typical development. Results demonstrated the Trier Social StressTest A -Child version to be a benign stressor for children with autism. Lower verbal ability in children with autism did not predict salivary cortisol or anxiety responses. There was a lack of association between stress andanxiety for both groups, highlighting the importance of considering these terms as separate constructs. Clinical implications and the limited utility of the Trier Social Stress Test A -Child version in evaluating psychosocial stress in autism are discussed.
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8. Lee HS, Kim MJ, Lim CK, Cho JW, Song IO, Kang IS. {{Multiple displacement amplification for preimplantation genetic diagnosis of fragile X syndrome}}. {Genet Mol Res};2011;10(4):2851-2859.
Preimplantation genetic diagnosis (PGD) has become an assisted reproductive technique for couples that have genetic risks. Despite the many advantages provided by PGD, there are several problems, including amplification failure, allele drop-out and amplification inefficiency. We evaluated multiple displacement amplification (MDA) for PGD of the fragile X syndrome. Whole genome amplification was performed using MDA. MDA products were subjected to fluorescent PCR of fragile X mental retardation-1 (FMR1) CGG repeats, amelogenin and two polymorphic markers. In the pre-clinical tests, the amplification rates of the FMR1 CGG repeat, DXS1215 and FRAXAC1 were 84.2, 87.5 and 75.0%, respectively, while the allele dropout rates were 31.3, 57.1 and 50.0%, respectively. In two PGD treatment cycles, 20 embryos among 30 embryos were successfully diagnosed as 10 normal embryos, four mutated embryos and six heterozygous carriers. Three healthy embryos were transferred to the uterus; however, no clinical pregnancy was achieved. Our data indicate that MDA and fluorescent PCR with four loci can be successfully applied to PGD for fragile X syndrome. Advanced methods for amplification of minuscule amounts of DNA could improve the sensitivity and reliability of PGD for complicated single gene disorders.
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9. Lehnhardt FG, Gawronski A, Volpert K, Schilbach L, Tepest R, Vogeley K. {{[Psychosocial Functioning of Adults with Late Diagnosed Autism Spectrum Disorders – A Retrospective Study.]}}. {Fortschr Neurol Psychiatr};2011 (Nov 15)
BACKGROUND: The first time diagnosis of autism spectrum disorder (ASD) after passing childhood and adolescence is still considered a rare event. However, in recent years an increasing demand for diagnostic clarifications with suspected ASD in adulthood challenges this view. There is insufficient knowledge about the neuropsychological characterisation and psychosocial outcome of this adult subgroup in the autistic spectrum. AIM: To determine the psychosocial functioning (living status, partnerships, level of education, psychiatric history) of adult patients with late diagnosed ASD. METHODS: In a retrospective study, a chart review was conducted on 178 consecutively diagnosed individuals at a specialised outpatient clinic for adults with ASD. Global ratings of psychosocial functioning, assessment of psychiatric history and neuropsychological and psychopathological investigations were evaluated. RESULTS: The majority of patients (92 %) diagnosed with ASD suffered from high-functioning autism (HFA)/Asperger syndrome (AS) according to the criteria of ICD-10 (F84.5). The gender ratio was 2:1 favouring males. Mean age at diagnosis (34.1 +/- 9.5 years), general intelligence (HAWIE-R, global-IQ 115 +/- 20) and self-rated autistic symptoms (autism spectrum quotient [AQ] 39 +/- 6) were not discriminative to gender. The psychiatric history revealed a lifetime consultation rate of 78 %, most frequently with depression (50 %). The self-report instrument Beck depression inventory (BDI) identified 30 % of individuals presenting with depressive symptoms in clinical relevant intensity (BDI > 17). Achievement of an independent living status was reported by 68 % of individuals, 58 % reported about current or past intimate partnerships and almost two-thirds of the patients had achieved a higher educational status. DISCUSSION: The majority of ASD diagnosed late in lifetime turned out to be HFA/AS, presenting with high psychosocial adjustment with regard to independent living, educational status and partnerships. The high level of global intelligence supports the hypothesis of cognitively compensated autistic disturbances leading to the diagnosis comparably late in lifetime. The lifetime rate of psychiatric consultations is high, reflecting the importance to consider a diagnosis of ASD even late in life.
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10. McGrew SG, Peters BR, Crittendon JA, Veenstra-Vanderweele J. {{Diagnostic Yield of Chromosomal Microarray Analysis in an Autism Primary Care Practice: Which Guidelines to Implement?}}. {J Autism Dev Disord};2011 (Nov 17)
Genetic testing is recommended for patients with ASD; however specific recommendations vary by specialty. American Academy of Pediatrics and American Academy of Neurology guidelines recommend G-banded karyotype and Fragile X DNA. The American College of Medical Genetics recommends Chromosomal Microarray Analysis (CMA). We determined the yield of CMA (N = 85), karyotype (N = 119), and fragile X (N = 174) testing in a primary pediatrics autism practice. We found twenty (24%) patients with abnormal CMA results (eight were clinically significant), three abnormal karyotypes and one Fragile X syndrome. There was no relationship between CMA result and cognitive level, seizures, dysmorphology, congenital malformations or behavior. We conclude that CMA should be the clinical standard in all specialties for first tier genetic testing in ASD.
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11. Minne EP, Semrud-Clikeman M. {{A Social Competence Intervention for Young Children With High Functioning Autism and Asperger Syndrome: a Pilot Study}}. {Autism};2011 (Nov 15)
The key features of Asperger Syndrome (AS) and high functioning autism (HFA) include marked and sustained impairment in social interactions. A multi-session, small group program was developed to increase social perception based on the assumption perceptual or interpretive problems underlying these social difficulties. Additionally, the group format espoused a play therapy orientation and the use of sociodramatic play was the primary therapeutic modality used. Qualitative analyses of the data resulted in an explanation of the key changes in social interactions that took place through the course of the intervention. Although each participant’s experience in this group was unique, all children in this program demonstrated improvements in their social interactions, as they experienced development both emotionally and behaviorally. Findings suggest that, despite their rigid interests and behavior patterns, the social limitations of these children improved when provided with the necessary environmental resources.
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12. Poot M, van der Smagt JJ, Brilstra EH, Bourgeron T. {{Disentangling the Myriad Genomics of Complex Disorders, Specifically Focusing on Autism, Epilepsy, and Schizophrenia}}. {Cytogenet Genome Res};2011 (Nov 12)
Analyses of structural genome variation by array-CGH have dramatically enhanced our ability to detect copy number variations (CNVs). De novo CNVs and those co-segregating with disease in a family are generally interpreted as pathogenic. Yet, often CNVs, such as recurrent microdeletions in region 15q13.3, are not so clearly pathogenic. Here we discuss potential confounding mechanisms that may lead to the phenotypic pleiotropy of CNVs, such as unmasking of recessive alleles by hemizygous deletions, interaction of CNVs with other loci and genes, genetic epistasis, allelic exclusion, and somatic mosaicism. We illustrate some of these mechanisms with a detailed analysis of recent studies of CNVs involving MCPH1, AUTS2, CNTNAP2, and mutations in GRIN2B. Next we discuss the clinical ramifications of these findings and urge workers to avoid ‘diagnostic fatalism’ (i.e., halting all genetic investigation after the detection of a single CNV) and address some of the future challenges likely to result from implementations of next generation sequencing techniques.
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13. Tauber JM, Vanlandingham PA, Zhang B. {{Elevated levels of the vesicular monoamine transporter and a novel repetitive behavior in the Drosophila model of fragile x syndrome}}. {PLoS One};2011;6(11):e27100.
Fragile X Syndrome (FXS) is characterized by mental impairment and autism in humans, and it often features hyperactivity and repetitive behaviors. The mechanisms for the disease, however, remain poorly understood. Here we report that the dfmr1 mutant in the Drosophila model of FXS grooms excessively, which may be regulated differentially by two signaling pathways. Blocking metabotropic glutamate receptor signaling enhances grooming in dfmr1 mutant flies, whereas blocking the vesicular monoamine transporter (VMAT) suppresses excessive grooming. dfmr1 mutant flies also exhibit elevated levels of VMAT mRNA and protein. These results suggest that enhanced monoamine signaling correlates with repetitive behaviors and hyperactivity associated with FXS.
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14. Whyte EM, Nelson KE, Khan KS. {{Learning of Idiomatic Language Expressions in a Group Intervention for Children With Autism}}. {Autism};2011 (Nov 15)
In typical development, children learn an extensive range of idioms and other figurative (non-literal) language expressions during childhood and adolescence. However, many children with autism fall far behind in their idiom comprehension and production and never fully reach adult levels. The current study measured the effectiveness of a group idiom intervention for ten children, aged 7 to 12 years, with autism spectrum disorders. This intervention was conducted by a community-based social skills program. The children were initially very low in idiom understanding, but were able to learn and remember the meaning of idiomatic phrases that they were taught during the 2-week-long intervention. The children showed greater increases at a delayed post-test for idioms trained in the intervention than idioms that were untrained controls. Implications for future educational possibilities are discussed.
