1. Bennabi M, Delorme R, Oliveira J, Fortier C, Lajnef M, Boukouaci W, Feugeas JP, Marzais F, Gaman A, Charron D, Ghaleh B, Krishnamoorthy R, Leboyer M, Tamouza R. {{Dectin-1 Polymorphism: A Genetic Disease Specifier in Autism Spectrum Disorders?}}. {PLoS One};2015;10(9):e0137339.
INTRODUCTION: In autism spectrum disorders (ASD), complex gene-environment interactions contribute to disease onset and progress. Given that gastro-intestinal dysfunctions are common in ASD, we postulated involvement of microbial dysbiosis in ASD and investigated, under a case-control design, the influence of DNA polymorphisms in the CLEC7A gene that encodes a pivotal fungal sensor, Dectin-1. MATERIAL AND METHODS: DNAs from 478 ASD patients and 351 healthy controls (HC) were analyzed for the CLEC7A rs16910631G/A and rs2078178 A/G single nucleotide polymorphisms (SNPs). Differences in the distribution of allele, genotype and haplotype by Chi-square testing and nonparametric analysis by Kruskal-Wallis/Mann-Whitney tests, where appropriate, were performed. The free statistical package R.2.13 software was used for the statistical analysis. RESULTS: We found that the CLEC7A rs2078178 G allele and GG genotype were more prevalent in HC as compared to ASD but failed to reach statistical significance for the latter (pc = 0.01, 0.06 respectively). However, after phenotype-based stratification, the CLEC7A rs2078178 G allele and GG genotype were found to be significantly more frequent in the Asperger group as compared to other ASD subsets (pc = 0.02, 0.01), a finding reinforced by haplotype analysis (rs2078178/rs16910631 G-G/G-G) (pc = 0.002). Further, intellectual quotient (IQ)-based stratification of ASD patients revealed that IQ values increase linearly along the CLEC7A rs2078178 AA, AG and GG genotypes (p = 0.05) and in a recessive manner (GG vs. AA+AG p = 0.02), further confirmed by haplotype distribution (CLEC7A rs2078178-16910631; A-G/A-G, A-G/G-G and G-G/G-G, p = 0.02, G-G/G-G vs. others, p = 0.01). CONCLUSION: Our data suggest that the genetic diversity of CLEC7A gene influences the ASD phenotype by behaving as a disease specifier and imply that the genetic control of innate immune response could determine the ASD phenotype.
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2. Brand S, Jossen S, Holsboer-Trachsler E, Puhse U, Gerber M. {{Impact of aerobic exercise on sleep and motor skills in children with autism spectrum disorders – a pilot study}}. {Neuropsychiatr Dis Treat};2015;11:1911-1920.
BACKGROUND: Prevalence rates of autism spectrum disorder (ASD) have increased dramatically in the last two decades. In addition to the core symptoms such as impaired communication, difficulties in social interaction, and restricted and stereotypical patterns of behavior and interests, poor sleep and motor skill (MS) deficits have also been observed in children with ASD. On the other hand, there is evidence that aerobic exercise training (AET) has a positive impact on sleep, and that specific training improves MSs. Accordingly, the aim of the present pilot study was to investigate to what extent a combination of AET and MS training (MST) would improve sleep and physical performance in a small sample of children with ASD. METHODS: Ten children with ASD (mean age: 10 years) took part in the study. After a thorough medical examination and psychiatric assessment, children participated in thrice-weekly 60-minute sessions of AET and MST lasting for 3 consecutive weeks. Sleep was assessed both objectively (sleep-encephalography [sleep-EEG]) and subjectively (parents’ questionnaire). MSs were assessed via standardized test batteries. Parents completed sleep and mood logs, and ratings of mood. RESULTS: Mild-to-moderate insomnia was reported in 70% of children. Compared to nights without previous AET and MS, on nights following AET and MS, sleep efficiency increased (d=1.07), sleep onset latency shortened (d=0.38), and wake time after sleep onset decreased for 63% of the sample (d=1.09), as assessed via sleep-EEG. Mood in the morning, as rated by parents, improved after three weeks (d=0.90), as did MSs (ball playing, balance exercise: ds>0.6). CONCLUSION: The pattern of results of this pilot study suggests that regular AET and MST impact positively on sleep, MSs, and mood among children with ASD.
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3. Cop E, Yurtbasi P, Oner O, Munir KM. {{Genetic testing in children with autism spectrum disorders}}. {Anadolu Psikiyatri Derg};2015;16(6):426-432.
OBJECTIVE: The aim of this study was to investigate karyotype abnormalities, MECP2 mutations, and Fragile X in a clinical population of children with Autism Spectrum Disorders (ASD) using The Clinical Report published by the American Academy of Pediatrics. METHODS: Ninety-six children with ASD were evaluated for genetic testing and factors associated with this testing. RESULTS: Abnormalities were found on karyotype in 9.7% and in DNA for fragile X in 1.4%. Karyotype abnormalities include inv(9)(p12q13); inv(9)(p11q13); inv(Y)(p11q11); Robertsonian translocation (13;14)(8q10q10) and (13,14)(q10q10); 9qh+; Yqh+; 15ps+; deletion 13(p11.2). CONCLUSION: Genetic testing should be offered to all families of a child with an ASD, even not all of them would follow this recommendation. Although karyotype and FRAXA assessment will yield almost 10% positive results, a detailed history and physical examination are still the most important aspect of the etiological evaluation for children with ASD. Also, it is important to have geneticists to help in interpreting the information obtained from genetic testing.
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4. Dell’Osso L, Dalle Luche R, Maj M. {{Adult autism spectrum as a transnosographic dimension}}. {CNS Spectr};2015 (Sep 9):1-3.
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5. Hardy S, Haisley L, Manning C, Fein D. {{Can Screening with the Ages and Stages Questionnaire Detect Autism?}}. {J Dev Behav Pediatr};2015 (Sep);36(7):536-543.
OBJECTIVE: Parents rely on pediatricians to monitor their child’s development. The American Academy of Pediatrics recommends routine developmental screening with both broadband and autism-specific instruments at specified ages. If broadband screeners can detect autism risk, this might minimize the burden of administering autism-specific screens to all children. The current study examines the ability of the Ages and Stages Questionnaire-Third Edition (ASQ-3) to identify children at risk for autism. We looked at ASQ-3 scores of children who screen positive on the Modified Checklist for Autism in Toddlers-Revised (M-CHAT-R), children who continue to screen positive on the M-CHAT-R Follow-up Interview, and children diagnosed with autism spectrum disorder (ASD). METHODS: A total of 2848 toddlers, aged 16 to 30 months, were screened with the ASQ-3 and M-CHAT-R across 20 pediatric sites. Children who screened positive on the M-CHAT-R and its follow-up interview were offered a diagnostic evaluation. RESULTS: Using the « monitor and/or fail » cutoff on any domain, the ASQ-3 identified 87% of the children who screened positive on the M-CHAT-R with follow-up and 95% (20/21) of those diagnosed with an ASD. Monitor and/or fail on the Communication domain alone also identified 95% of the diagnosed children. CONCLUSIONS: Scores below the « monitor » cutoff on the Communication domain of the ASQ-3 can indicate initial concern requiring autism-specific follow-up. If these results are confirmed with a sample large enough to separately examine toddlers of different ages and different cultural backgrounds, it may be feasible to implement a 2-stage screening strategy, with autism-specific screening reserved for those who are positive on a broadband screen.
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6. Hayes SJ, Andrew M, Elliott D, Gowen E, Bennett SJ. {{Low Fidelity Imitation of Atypical Biological Kinematics in Autism Spectrum Disorders Is Modulated by Self-Generated Selective Attention}}. {J Autism Dev Disord};2015 (Sep 9)
We examined whether adults with autism had difficulty imitating atypical biological kinematics. To reduce the impact that higher-order processes have on imitation we used a non-human agent model to control social attention, and removed end-state target goals in half of the trials to minimise goal-directed attention. Findings showed that only neurotypical adults imitated atypical biological kinematics. Adults with autism did, however, become significantly more accurate at imitating movement time. This confirmed they engaged in the task, and that sensorimotor adaptation was self-regulated. The attentional bias to movement time suggests the attenuation in imitating kinematics might be a compensatory strategy due to deficits in lower-level visuomotor processes associated with self-other mapping, or selective attention modulated the processes that represent biological kinematics.
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7. Lera-Miguel S, Rosa M, Puig O, Kaland N, Lazaro L, Castro-Formieles J, Calvo R. {{Assessing Advanced Theory of Mind in Children and Adolescents with High-Functioning Autism: The Spanish Version of the Stories of Everyday Life}}. {J Autism Dev Disord};2015 (Sep 7)
Most individuals with autism spectrum disorders often fail in tasks of theory of mind (ToM). However, those with normal intellectual functioning known as high functioning ASD (HF-ASD) sometimes succeed in mentalizing inferences. Some tools have been developed to more accurately test their ToM abilities. The aims of this study were to examine the psychometric properties of the Spanish version of Stories of Everyday Life Test (SEL) in a sample of 29 children and adolescents with HF-ASD and 25 typically developing controls and to compare their performance. The Spanish-SEL demonstrated good internal consistency, strong convergence with clinical severity and another ToM test, and adequate discriminant validity from intellectual capability and age, identifying the condition of 70 % of participants.
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8. Li Q, Chen CF, Wang DY, Lu YT, Huan Y, Liu M, Ge RC, Chen XW, Qi HS, An L, Hu X. {{Transplantation of umbilical cord blood mononuclear cells increases levels of nerve growth factor in the cerebrospinal fluid of patients with autism}}. {Genet Mol Res};2015;14(3):8725-8732.
We aimed to evaluate the levels of growth factors in the cerebrospinal fluid (CSF) of patients with autism after transplantation of umbilical cord blood mononuclear cells (CBMNCs). Fourteen subjects diagnosed with autism received transplantation of CBMNCs first through intravenous infusion, and three times subsequently through intrathecal injections. A 2-mL sample of CSF was taken before each intrathecal injection. CSF levels of nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (bFGF) were determined by enzyme-linked immunosorbent assay. All data are reported as means +/- SD and were analyzed using the SPSS 10.0 software. One-way analysis of variance with post-hoc F-and Q-tests were performed for comparisons. NGF levels in the CSF were significantly increased after transplantation (213.54 +/- 56.38 after the third versus 28.32 +/- 12.22 ng/L after the first transplantation; P < 0.05), while VEGF and bFGF levels did not change significantly. Therefore, transplantation of CBMNCs could increase NGF levels in the CSF of patients with autism.
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9. Moreno-Ramos OA, Olivares AM, Haider NB, de Autismo LC, Lattig MC. {{Whole-Exome Sequencing in a South American Cohort Links ALDH1A3, FOXN1 and Retinoic Acid Regulation Pathways to Autism Spectrum Disorders}}. {PLoS One};2015;10(9):e0135927.
Autism spectrum disorders (ASDs) are a range of complex neurodevelopmental conditions principally characterized by dysfunctions linked to mental development. Previous studies have shown that there are more than 1000 genes likely involved in ASD, expressed mainly in brain and highly interconnected among them. We applied whole exome sequencing in Colombian-South American trios. Two missense novel SNVs were found in the same child: ALDH1A3 (RefSeq NM_000693: c.1514T>C (p.I505T)) and FOXN1 (RefSeq NM_003593: c.146C>T (p.S49L)). Gene expression studies reveal that Aldh1a3 and Foxn1 are expressed in ~E13.5 mouse embryonic brain, as well as in adult piriform cortex (PC; ~P30). Conserved Retinoic Acid Response Elements (RAREs) upstream of human ALDH1A3 and FOXN1 and in mouse Aldh1a3 and Foxn1 genes were revealed using bioinformatic approximation. Chromatin immunoprecipitation (ChIP) assay using Retinoid Acid Receptor B (Rarb) as the immunoprecipitation target suggests RA regulation of Aldh1a3 and Foxn1 in mice. Our results frame a possible link of RA regulation in brain to ASD etiology, and a feasible non-additive effect of two apparently unrelated variants in ALDH1A3 and FOXN1 recognizing that every result given by next generation sequencing should be cautiously analyzed, as it might be an incidental finding.
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10. Northrup JB, Iverson JM. {{Vocal Coordination During Early Parent-Infant Interactions Predicts Language Outcome in Infant Siblings of Children with Autism Spectrum Disorder}}. {Infancy};2015 (Sep-Oct);20(5):523-547.
This study examined vocal coordination during mother-infant interactions in the infant siblings (high risk infants; HR) of children with autism spectrum disorder (ASD), a population at heightened risk for developing language delays. Vocal coordination between mothers and HR infants was compared to a group of low risk (LR; no first- or second-degree relative with ASD) dyads, and used to predict later language development. Nine-month-old infants were videotaped at home playing with their mothers, and interactions were coded for the frequency and timing of vocalizations. Percent infant simultaneous speech was predictive of later language delay (LD), and dyads with LD infants were less coordinated with one another in average latency to respond than dyads with non-delayed (ND) infants. The degree of coordination between mothers and infants on this variable predicted a continuous measure of language development in the third year. This research underscores the importance of understanding early development in the context of interaction.
11. Pu J, Wu W, Huang L. {{Will ASD Closure Under Echocardiography Guidance be Widely Used?}}. {J Interv Cardiol};2015 (Sep 8)
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12. Pugliese CE, Anthony LG, Strang JF, Dudley K, Wallace GL, Naiman DQ, Kenworthy L. {{Longitudinal Examination of Adaptive Behavior in Autism Spectrum Disorders: Influence of Executive Function}}. {J Autism Dev Disord};2015 (Sep 9)
This study characterizes longitudinal change in adaptive behavior in 64 children and adolescents with autism spectrum disorder (ASD) without intellectual disability evaluated on multiple occasions, and examines whether prior estimate of executive function (EF) problems predicts future adaptive behavior scores. Compared to standardized estimates for their developmental stage, adaptive behavior in most participants was impaired and did not improve over time. Prior EF predicted later adaptive behavior in daily living skills and socialization domains after controlling for age and IQ. Self-monitoring behaviors robustly predicted later adaptive behavior in all domains (d = 0.60-0.94). Results support targeting treatment of adaptive skills in ASD, as well as the importance of assessing for EF problems that may contribute to adaptive behavior difficulties.
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13. Richter JD, Bassell GJ, Klann E. {{Dysregulation and restoration of translational homeostasis in fragile X syndrome}}. {Nat Rev Neurosci};2015 (Sep 9)
Fragile X syndrome (FXS), the most-frequently inherited form of intellectual disability and the most-prevalent single-gene cause of autism, results from a lack of fragile X mental retardation protein (FMRP), an RNA-binding protein that acts, in most cases, to repress translation. Multiple pharmacological and genetic manipulations that target receptors, scaffolding proteins, kinases and translational control proteins can rescue neuronal morphology, synaptic function and behavioural phenotypes in FXS model mice, presumably by reducing excessive neuronal translation to normal levels. Such rescue strategies might also be explored in the future to identify the mRNAs that are critical for FXS pathophysiology.
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14. Schufreider A, McQueen DB, Lee SM, Allon R, Uhler ML, Davie J, Feinberg EC. {{Diminished ovarian reserve is not observed in infertility patients with high normal CGG repeats on the fragile X mental retardation 1 (FMR1) gene}}. {Hum Reprod};2015 (Sep 6)
STUDY QUESTION: Does an association exist between high normal numbers of CGG trinucleotide repeats on the fragile X mental retardation 1 (FMR1) gene and diminished ovarian reserve (DOR)? SUMMARY ANSWER: This large data set demonstrated that a high normal number of CGG repeats (35-54 repeats) on the FMR1 gene was not significantly correlated with DOR. WHAT IS KNOWN ALREADY: The FMR1 premutation (55-200 repeats) is a known cause of primary ovarian insufficiency. However, the relationship between high normal CGG repeat numbers (35-54 repeats) and ovarian reserve has yet to be conclusively demonstrated. STUDY DESIGN, SIZE, DURATION: This is a retrospective data analysis conducted between January 2012 and February 2014 that included 1287 women. Over 1140 women had complete data. PARTICIPANTS/MATERIALS, SETTING, METHODS: All women, excluding oocyte donors, who presented to a large private practice specializing in reproductive endocrinology and infertility for treatment and who underwent both fragile X and ovarian reserve testing were included. All fragile X testing was performed using triplet repeat PCR, with confirmation of positives by Southern blot. CGG repeat numbers from both alleles were recorded, and the allele with the higher number of repeats was used for statistical calculations. We did not differentiate between patients with one or two high normal alleles. Women with >54 CGG repeats were excluded from the analysis. For our analysis, we considered both a ‘high normal’ number of CGG repeats (35-44) and an intermediate number of GCC repeats (45-54) as ‘high normal’. Ovarian reserve testing was carried out on Cycle Day 2 or 3 and included measurements of FSH, anti-Mullerian hormone (AMH) and antral follicle count (AFC). A generalized linear regression model assuming gamma distribution and log link function that controlled for age was used to assess correlation between CGG repeat number and FSH, AMH and AFC. MAIN RESULTS AND THE ROLE OF CHANCE: As expected, there was a significant correlation between increasing age and increasing FSH and decreasing AFC and AMH for the patients in this study. For every 1-year increase in age, FSH increased by a factor of 1.04, AFC decreased by a factor of 0.93 and AMH decreased by a factor of 0.89. After controlling for age, there was no significant correlation between FMR1 CGG trinucleotide repeat number and FSH (P = 0.23), AFC (P = 0.14) or AMH (P = 0.53). Three subgroup analyses were also performed. We found a significant relationship between increasing CGG repeat number and decreasing AMH levels (P = 0.01) in women >44 years old. The second subgroup analysis included only Caucasian patients and found no significant correlation between CGG repeat number and DOR. In a subgroup analysis comparing women with at least one allele <26 repeats, at least one allele >35 and women with both alleles between 29 and 32, there were no significant associations regarding ovarian reserve in any of these groups. LIMITATIONS, REASONS FOR CAUTION: One limitation of this study is that it involved a heterogeneous population of infertile women with mixed diagnoses. Factors that could affect ovarian reserve, such as medical comorbidities, prior surgeries, family history and endometriosis, were not accounted for. Finally, there was a lack of racial diversity, with Caucasians representing 67.8% of the total population. WIDER IMPLICATIONS OF THE FINDINGS: The findings of this study are generalizable to an infertility population and are in line with several previously published studies. Women who are found to have high normal CGG repeat numbers can be counseled that this is not causative for DOR. Further studies are needed to investigate whether increasing CGG repeat numbers are associated with ovarian responsiveness to gonadotrophin stimulation or IVF outcome. STUDY FUNDING/COMPETING INTERESTS: Funding was provided by The University of Chicago, Department of Obstetrics and Gynecology. The authors have no conflict of interest to declare except for Jocelyn Davie, who was an employee of Good Start Genetics(R) during the period of data acquisition.
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15. Supekar K, Menon V. {{Sex differences in structural organization of motor systems and their dissociable links with repetitive/restricted behaviors in children with autism}}. {Mol Autism};2015;6:50.
BACKGROUND: Autism spectrum disorder (ASD) is diagnosed much less often in females than males. Emerging behavioral accounts suggest that the clinical presentation of autism is different in females and males, yet research examining sex differences in core symptoms of autism in affected children has been limited. Additionally, to date, there have been no systematic attempts to characterize neuroanatomical differences underlying the distinct behavioral profiles observed in girls and boys with ASD. This is in part because extant ASD studies have included a small number of girls. METHODS: Leveraging the National Database for Autism Research (NDAR), we first analyzed symptom severity in a large sample consisting of 128 ASD girls and 614 age- and IQ-matched ASD boys. We then examined symptom severity and structural imaging data using novel multivariate pattern analysis in a well-matched group of 25 ASD girls, 25 ASD boys, 19 typically developing (TD) girls, and 19 TD boys, obtained from the Autism Brain Imaging Data Exchange (ABIDE). RESULTS: In both the NDAR and ABIDE datasets, girls, compared to boys, with ASD showed less severe repetitive/restricted behaviors (RRBs) and comparable deficits in the social and communication domains. In the ABIDE imaging dataset, gray matter (GM) patterns in the motor cortex, supplementary motor area (SMA), cerebellum, fusiform gyrus, and amygdala accurately discriminated girls and boys with ASD. This sex difference pattern was specific to ASD as the GM in these brain regions did not discriminate TD girls and boys. Moreover, GM in the motor cortex, SMA, and crus 1 subdivision of the cerebellum was correlated with RRB in girls whereas GM in the right putamen-the region that discriminated TD girls and boys-was correlated with RRB in boys. CONCLUSIONS: We found robust evidence for reduced levels of RRB in girls, compared to boys, with ASD, providing the strongest evidence to date for sex differences in a core phenotypic feature of childhood ASD. Sex differences in brain morphometry are prominent in the motor system and in areas that comprise the « social brain. » Notably, RRB severity is associated with sex differences in GM morphometry in distinct motor regions. Our findings provide novel insights into the neurobiology of sex differences in childhood autism.
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16. Vanmarcke S, Van Der Hallen R, Evers K, Noens I, Steyaert J, Wagemans J. {{Ultra-Rapid Categorization of Meaningful Real-Life Scenes in Adults With and Without ASD}}. {J Autism Dev Disord};2015 (Sep 9)
In comparison to typically developing (TD) individuals, people with autism spectrum disorder (ASD) appear to be worse in the fast extraction of the global meaning of a situation or picture. Ultra-rapid categorization [paradigm developed by Thorpe et al. (Nature 381:520-522, 1996)] involves such global information processing. We therefore tested a group of adults with and without ASD, without intellectual disability, on a set of ultra-rapid categorization tasks. Individuals with ASD performed equally well as TD individuals except when the task required the categorization of social interactions. These results argue against a general deficit in ultra-rapid gist perception in people with ASD, while suggesting a more specific problem with the fast processing of information about social relations.
