1. Au-Yeung SK, Kaakinen JK, Liversedge SP, Benson V. {{Processing of Written Irony in Autism Spectrum Disorder: An Eye-Movement Study}}. {Autism Res};2015 (May 11)
Previous research has suggested that individuals with Autism Spectrum Disorders (ASD) have difficulties understanding others communicative intent and with using contextual information to correctly interpret irony. We recorded the eye movements of typically developing (TD) adults ASD adults when they read statements that could either be interpreted as ironic or non-ironic depending on the context of the passage. Participants with ASD performed as well as TD controls in their comprehension accuracy for speaker’s statements in both ironic and non-ironic conditions. Eye movement data showed that for both participant groups, total reading times were longer for the critical region containing the speaker’s statement and a subsequent sentence restating the context in the ironic condition compared to the non-ironic condition. The results suggest that more effortful processing is required in both ASD and TD participants for ironic compared with literal non-ironic statements, and that individuals with ASD were able to use contextual information to infer a non-literal interpretation of ironic text. Individuals with ASD, however, spent more time overall than TD controls rereading the passages, to a similar degree across both ironic and non-ironic conditions, suggesting that they either take longer to construct a coherent discourse representation of the text, or that they take longer to make the decision that their representation of the text is reasonable based on their knowledge of the world. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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2. Barad DH, Kushnir VA, Albertini D, Gleicher N. {{CDC analysis of ICSI/autism: association is not causation}}. {Hum Reprod};2015 (May 13)
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3. Demopoulos C, Lewine JD. {{Audiometric Profiles in Autism Spectrum Disorders: Does Subclinical Hearing Loss Impact Communication?}}. {Autism Res};2015 (May 11)
Rates of hearing impairment in individuals with Autism Spectrum Disorders (ASD) are higher than those reported in the general population. Although ASD is not caused by hearing impairment, it may exacerbate symptomatology. Participants with ASD (N = 60) and typically developing peers (N = 16) aged 5-18 years underwent a comprehensive audiological screening (pure tone audiometry, uncomfortable loudness level, tympanometry, acoustic reflexes, distortion product otoacoustic emissions, and auditory brainstem response) and assessment of communication abilities (expressive/receptive language, articulation, phonological awareness, and vocal affect recognition). Incidence of abnormal findings on at least one measure of audiological functioning was higher for the ASD group (55%) than controls (14.9%) or the general population estimate (6%). The presence of sound sensitivity was also considerably higher for the ASD group (37%) compared with controls (0%) or general population estimates (8-15%). When participants with ASD were dichotomized into groups with and without evidence of clinical audiological abnormality, no significant differences were identified on measures of communication; however, results of correlational analyses indicated that variability in hearing thresholds at middle range frequencies (2000 Hz) was significantly related to performance on all measures of speech articulation and language after correction for multiple comparisons (r = -0.48 to r = -0.53, P < 0.0045). These findings suggest that dichotomized classification of clinical audiology may not be sufficient to understand the role of subclinical hearing loss in ASD symptomatology and that treatment studies for mild/subclinical hearing loss in this population may be worthwhile. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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4. Furlano R, Kelley EA, Hall L, Wilson DE. {{Self-perception of competencies in adolescents with autism spectrum disorders}}. {Autism Res};2015 (May 13)
Research has demonstrated that, despite difficulties in multiple domains, children with autism spectrum disorders (ASD) show a lack of awareness of these difficulties. A misunderstanding of poor competencies may make it difficult for individuals to adjust their behaviour in accordance with feedback and may lead to greater impairments over time. This study examined self-perceptions of adolescents with ASD (n = 19) and typically developing (TD) mental-age-matched controls (n = 22) using actual performance on objective academic tasks as the basis for ratings. Before completing the tasks, participants were asked how well they thought they would do (pre-task prediction). After completing each task, they were asked how well they thought they did (immediate post-performance) and how well they would do in the future (hypothetical future post-performance). Adolescents with ASD had more positively biased self-perceptions of competence than TD controls. The ASD group tended to overestimate their performance on all ratings of self-perceptions (pre-task prediction, immediate, and hypothetical future post-performance). In contrast, while the TD group was quite accurate at estimating their performance immediately before and after performing the task, they showed some tendency to overestimate their future performance. Future investigation is needed to systematically examine possible mechanisms that may be contributing to these biased self-perceptions. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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5. Gockley J, Willsey AJ, Dong S, Dougherty JD, Constantino JN, Sanders SJ. {{The female protective effect in autism spectrum disorder is not mediated by a single genetic locus}}. {Mol Autism};2015;6:25.
BACKGROUND: A 4:1 male to female sex bias has consistently been observed in autism spectrum disorder (ASD). Epidemiological and genetic studies suggest a female protective effect (FPE) may account for part of this bias; however, the mechanism of such protection is unknown. Quantitative assessment of ASD symptoms using the Social Responsiveness Scale (SRS) shows a bimodal distribution unique to females in multiplex families. This leads to the hypothesis that a single, common genetic locus on chromosome X might mediate the FPE and produce the ASD sex bias. Such a locus would represent a major therapeutic target and is likely to have been missed by conventional genome-wide association study (GWAS) analysis. METHODS: To explore this possibility, we performed an association study in affected versus unaffected females, considering three tiers of single nucleotide polymorphisms (SNPs) as follows: 1) regions of chromosome X that escape X-inactivation, 2) all of chromosome X, and 3) genome-wide. RESULTS: No evidence of a SNP meeting the criteria for a single FPE locus was observed, despite the analysis being well powered to detect this effect. CONCLUSIONS: The results do not support the hypothesis that the FPE is mediated by a single genetic locus; however, this does not exclude the possibility of multiple genetic loci playing a role in the FPE.
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6. Gotham K, Marvin AR, Taylor JL, Warren Z, Anderson CM, Law PA, Law JK, Lipkin PH. {{Characterizing the daily life, needs, and priorities of adults with autism spectrum disorder from Interactive Autism Network data}}. {Autism};2015 (May 11)
Using online survey data from a large sample of adults with autism spectrum disorder and legal guardians, we first report outcomes across a variety of contexts for participants with a wide range of functioning, and second, summarize these stakeholders’ priorities for future research. The sample included n = 255 self-reporting adults with autism spectrum disorder aged 18-71 years (M = 38.5 years, standard deviation = 13.1 years) and n = 143 adults with autism spectrum disorder aged 18-58 years (M = 25.0 years, standard deviation = 8.2 years) whose information was provided by legal guardians. Although the self-reporting subsample had much higher rates of employment, marriage/partnership, and independent living than are typically seen in autism spectrum disorder outcome studies, they remained underemployed and had strikingly high rates of comorbid disorders. Data on both descriptive outcomes and rated priorities converged across subsamples to indicate the need for more adult research on life skills, treatments, co-occurring conditions, and vocational and educational opportunities. Stakeholders also placed priority on improving public services, health care access, and above all, public acceptance of adults with autism spectrum disorder. Findings must be interpreted in light of the self-reporting subsample’s significant proportion of females and of later-diagnosed individuals. This study underscores the need for lifespan research; initiatives will benefit from incorporating information from the unique perspectives of adults with autism spectrum disorder and their families.
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7. Hirschler-Guttenberg Y, Feldman R, Ostfeld-Etzion S, Laor N, Golan O. {{Self- and Co-regulation of Anger and Fear in Preschoolers with Autism Spectrum Disorders: The Role of Maternal Parenting Style and Temperament}}. {J Autism Dev Disord};2015 (May 13)
Emotion regulation (ER) difficulties are a major concern in children with autism spectrum disorder (ASD). Maternal temperament and parenting style have significant effects on children’s ER. However, these effects have not been studied in children with ASD. Forty preschoolers with ASD and their mothers and forty matched controls engaged in fear and anger ER paradigms, micro-coded for child self- and co-regulatory behaviors and parent’s regulation-facilitation. Mothers’ parenting style and temperament were self-reported. In the ASD group only, maternal authoritarian style predicted higher self-regulation and lower co-regulation of anger and maternal authoritative style predicted higher self-regulation of fear. Maternal temperament did not predict child’s ER. Findings emphasize the importance of maternal flexible parenting style in facilitating ER among children with ASD.
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8. Jonsson U, Choque Olsson N, Bolte S. {{Can findings from randomized controlled trials of social skills training in autism spectrum disorder be generalized? The neglected dimension of external validity}}. {Autism};2015 (May 11)
Systematic reviews have traditionally focused on internal validity, while external validity often has been overlooked. In this study, we systematically reviewed determinants of external validity in the accumulated randomized controlled trials of social skills group interventions for children and adolescents with autism spectrum disorder. We extracted data clustered into six overarching themes: source population, included population, context, treatment provider, treatment intervention, and outcome. A total of 15 eligible randomized controlled trials were identified. The eligible population was typically limited to high-functioning school-aged children with autism spectrum disorder, and the included population was predominantly male and Caucasian. Scant information about the recruitment of participants was provided, and details about treatment providers and settings were sparse. It was not evident from the trials to what extent acquired social skills were enacted in everyday life and maintained over time. We conclude that the generalizability of the accumulated evidence is unclear and that the determinants of external validity are often inadequately reported. At this point, more effectiveness-oriented randomized controlled trials of equally high internal and external validity are needed. More attention to the determinants of external validity is warranted when this new generation of randomized controlled trials are planned and reported. We provide a tentative checklist for this purpose.
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9. Kana RK, Patriquin MA, Black BS, Channell MM, Wicker B. {{Altered Medial Frontal and Superior Temporal Response to Implicit Processing of Emotions in Autism}}. {Autism Res};2015 (May 11)
Interpreting emotional expressions appropriately poses a challenge for individuals with autism spectrum disorder (ASD). In particular, difficulties with emotional processing in ASD are more pronounced in contexts where emotional expressions are subtle, automatic, and reflexive-that is, implicit. In contrast, explicit emotional processing, which requires the cognitive evaluation of an emotional experience, appears to be relatively intact in individuals with ASD. In the present study, we examined the brain activation and functional connectivity differences underlying explicit and implicit emotional processing in age- and IQ-matched adults with (n = 17) and without (n = 15) ASD. Results indicated: (1) significantly reduced levels of brain activation in participants with ASD in medial prefrontal cortex (MPFC) and superior temporal gyrus (STG) during implicit emotion processing; (2) significantly weaker functional connectivity in the ASD group in connections of the MPFC with the amygdala, temporal lobe, parietal lobe, and fusiform gyrus; (3) No group difference in performance accuracy or reaction time; and (4) Significant positive relationship between empathizing ability and STG activity in ASD but not in typically developing participants. These findings suggest that the neural mechanisms underlying implicit, but not explicit, emotion processing may be altered at multiple levels in individuals with ASD. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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10. Kastner A, Begemann M, Michel TM, Everts S, Stepniak B, Bach C, Poustka L, Becker J, Banaschewski T, Dose M, Ehrenreich H. {{Autism beyond diagnostic categories: characterization of autistic phenotypes in schizophrenia}}. {BMC Psychiatry};2015 (May 13);15(1):115.
BACKGROUND: Behavioral phenotypical continua from health to disease suggest common underlying mechanisms with quantitative rather than qualitative differences. Until recently, autism spectrum disorders and schizophrenia were considered distinct nosologic entities. However, emerging evidence contributes to the blurring of symptomatic and genetic boundaries between these conditions. The present study aimed at quantifying behavioral phenotypes shared by autism spectrum disorders and schizophrenia to prepare the ground for biological pathway analyses. METHODS: Specific items of the Positive and Negative Syndrome Scale were employed and summed up to form a dimensional autism severity score (PAUSS). The score was created in a schizophrenia sample (N = 1156) and validated in adult high-functioning autism spectrum disorder (ASD) patients (N = 165). To this end, the Autism Diagnostic Observation Schedule (ADOS), the Autism (AQ) and Empathy Quotient (EQ) self-rating questionnaires were applied back to back with the newly developed PAUSS. RESULTS: PAUSS differentiated between ASD, schizophrenia and a disease-control sample and substantially correlated with the Autism Diagnostic Observation Schedule. Patients with ADOS scores >/=12 obtained highest, those with scores <7 lowest PAUSS values. AQ and EQ were not found to vary dependent on ADOS diagnosis. ROC curves for ADOS and PAUSS resulted in AuC values of 0.9 and 0.8, whereas AQ and EQ performed at chance level in the prediction of ASD. CONCLUSIONS: This work underscores the convergence of schizophrenia negative symptoms and autistic phenotypes. PAUSS evolved as a measure capturing the continuous nature of autistic behaviors. The definition of extreme-groups based on the dimensional PAUSS may permit future investigations of genetic constellations modulating autistic phenotypes.
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11. Kieffer E, Nicod JC, Gardes N, Kastner C, Becker N, Celebi C, Pirrello O, Rongieres C, Koscinski I, Gosset P, Moutou C. {{Improving preimplantation genetic diagnosis for Fragile X syndrome: two new powerful single-round multiplex indirect and direct tests}}. {Eur J Hum Genet};2015 (May 13)
Fragile X syndrome (FraX) is caused by the expansion of an unstable CGG repeat located in the Fragile X mental retardation 1 gene (FMR1) gene. Preimplantation genetic diagnosis (PGD) can be proposed to couples at risk of transmitting the disease, that is, when the female carries a premutation or a full mutation. We describe two new single-cell, single-round multiplex PCR for indirect and direct diagnosis of FraX on biopsied embryos. These tests include five unpublished, highly heterozygous simple sequence repeats, and the co-amplification of non-expanded CGG repeats for the direct test. Heterozygosity of the new markers ranged from 69 to 81%. The mean rate of non-informative marker included in the tests was low (26% and 23% for the new indirect and direct tests, respectively). This strategy allows offering a PGD for FraX to 96% of couples requesting it in our centre. A conclusive genotype was obtained in all cells with a rate of cells presenting an allele dropout ranging from 17% for the indirect test to 26% for the direct test. The new indirect test was applied for eight PGD cycles: 32 embryos were analysed, 9 were transferred and 3 healthy babies were born. By multiplexing these highly informative markers, robustness of the diagnosis is improved and the loss of potentially healthy embryos (because they are non-diagnosed or misdiagnosed) is limited. This may increase the chances of success of couples requesting a PGD for FraX, in particular, when premature ovarian insufficiency in premutated women leads to a reduced number of embryos available for analysis.European Journal of Human Genetics advance online publication, 13 May 2015; doi:10.1038/ejhg.2015.96.
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12. Kissin DM, Zhang Y, Boulet SL, Fountain C, Bearman P, Schieve L, Yeargin-Allsopp M, Jamieson DJ. {{Reply: CDC analysis of ICSI/autism: association is not causation}}. {Hum Reprod};2015 (May 13)
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13. Lai MC, Baron-Cohen S, Buxbaum JD. {{Understanding autism in the light of sex/gender}}. {Mol Autism};2015;6:24.
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14. Mahajan R, Dirlikov B, Crocetti D, Mostofsky SH. {{Motor Circuit Anatomy in Children with Autism Spectrum Disorder With or Without Attention Deficit Hyperactivity Disorder}}. {Autism Res};2015 (May 11)
This study examined the morphology of frontal-parietal regions relevant to motor functions in children with autism spectrum disorder (ASD) with or without attention deficit hyperactivity disorder (ADHD). We also explored its associations with autism severity and motor skills, and the impact of comorbid ADHD on these associations. Participants included 126 school-age children: 30 had ASD only, 33 had ASD with ADHD, and 63 were typically developing. High resolution 3T MPRAGE images were acquired to examine the cortical morphology (gray matter volume, GMV, surface area, SA, and cortical thickness, CT) in three regions of interest (ROI): precentral gyrus (M1), postcentral gyrus (S1), and inferior parietal cortex (IPC). Children with ASD showed abnormal increases in GMV and SA in all three ROIs: (a) increased GMV in S1 bilaterally and in right M1 was specific to children with ASD without ADHD; (b) all children with ASD (with or without ADHD) showed increases in the left IPC SA. Furthermore, on measures of motor function, impaired praxis was associated with increased GMV in right S1 in the ASD group with ADHD. Children with ASD with ADHD showed a positive relationship between bilateral S1 GMV and manual dexterity, whereas children with ASD without ADHD showed a negative relationship. Our findings suggest that (a) ASD is associated with abnormal morphology of cortical circuits crucial to motor control and learning; (b) anomalous overgrowth of these regions, particularly S1, may contribute to impaired motor skill development, and (c) functional and morphological differences are apparent between children with ASD with or without ADHD. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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15. Mandleco B, Webb AE. {{Sibling perceptions of living with a young person with Down syndrome or autism spectrum disorder: An integrated review}}. {J Spec Pediatr Nurs};2015 (May 12)
PURPOSE: This integrative review synthesized current information from 28 research articles meeting inclusion criteria that examined sibling experiences when living with a young person with Down syndrome or autism spectrum disorder. CONCLUSIONS: Five themes emerged related to sibling experiences: their knowledge of the condition, relationships with others, perceptions of the condition, emotional reactions to the situation, and behavioral/personality outcomes. PRACTICE IMPLICATIONS: Nurses caring for families raising youth with Down syndrome or autism spectrum disorder can enhance sibling development by providing individual interventions reflecting siblings’ perceptions of the experience.
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16. Nordahl CW, Iosif AM, Young GS, Perry LM, Dougherty R, Lee A, Li D, Buonocore MH, Simon T, Rogers S, Wandell B, Amaral DG. {{Sex differences in the corpus callosum in preschool-aged children with autism spectrum disorder}}. {Mol Autism};2015;6:26.
BACKGROUND: Abnormalities in the corpus callosum have been reported in individuals with autism spectrum disorder (ASD), but few studies have evaluated young children. Sex differences in callosal organization and diffusion characteristics have also not been evaluated fully in ASD. METHODS: Structural and diffusion-weighted images were acquired in 139 preschool-aged children with ASD (112 males/27 females) and 82 typically developing (TD) controls (53 males/29 females). Longitudinal scanning at two additional annual time points was carried out in a subset of these participants. Callosal organization was evaluated using two approaches: 1) diffusion tensor imaging (DTI) tractography to define subregions based on cortical projection zones and 2) as a comparison to previous studies, midsagittal area analysis using Witelson subdivisions. Diffusion measures of callosal fibers were also evaluated. RESULTS: Analyses of cortical projection zone subregions revealed sex differences in the patterns of altered callosal organization. Relative to their sex-specific TD counterparts, both males and females with ASD had smaller regions dedicated to fibers projecting to superior frontal cortex, but patterns differed in callosal subregions projecting to other parts of frontal cortex. While males with ASD had a smaller callosal region dedicated to the orbitofrontal cortex, females with ASD had a smaller callosal region dedicated to the anterior frontal cortex. There were also sex differences in diffusion properties of callosal fibers. While no alterations were observed in males with ASD relative to TD males, mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were all increased in females with ASD relative to TD females. Analyses of Witelson subdivisions revealed a decrease in midsagittal area of the corpus callosum in both males and females with ASD but no regional differences in specific subdivisions. Longitudinal analyses revealed no diagnostic or sex differences in the growth rate or change in diffusion measures of the corpus callosum from 3 to 5 years of age. CONCLUSIONS: There are sex differences in the pattern of altered corpus callosum neuroanatomy in preschool-aged children with ASD.
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17. Real Fernandez F, Di Pisa M, Rossi G, Auberger N, Lequin O, Larregola M, Benchohra A, Mansuy C, Chassaing G, Lolli F, Hayek J, Lavielle S, Rovero P, Mallet JM, Papini AM. {{Antibody Recognition In Multiple Sclerosis And Rett Syndrome Using A Collection Of Linear And Cyclic N-glucosylated antigenic probes}}. {Biopolymers};2015 (May 13)
Antibody detection in autoimmune disorders such as Multiple Sclerosis (MS) and Rett syndrome (RTT) can be achieved more efficiently using synthetic peptides. The previously developed synthetic antigenic probe CSF114(Glc), a type I’ beta-turn N-glucosylated peptide structure, is able to recognize antibodies in MS and RTT patients’ sera as a sign of immune system derangement. We report herein the design, synthesis, conformational analysis, and immunological evaluation of a collection of glycopeptide analogs of CSF114(Glc) to characterize the specific role of secondary structures in MS and RTT antibody recognition. Therefore, we synthesized a series of linear and cyclic short glucosylated sequences, mimicking different beta-turn conformations, which were evaluated in inhibition enzyme-linked immunosorbent assays (ELISA). Calculated IC50 ranking analysis allowed the selection of the candidate octapeptide containing two (S)-2-amino-4-pentynoic acid (L-Pra) residues Ac-Pra-RRN(Glc)GHT-Pra-NH2 , with an IC50 in the nanomolar range. This peptide was adequately modified for solid-phase ELISA (SP-ELISA) and surface plasmon resonance (SPR) experiments. Pra-RRN(Glc)GHT-Pra-NH2 peptide was modified with an alkyl chain linked to the N-terminus, favoring immobilization on solid phase in SP-ELISA and differentiating IgG antibody recognition between patients and healthy blood donors with a high specificity. However, this peptide displayed a loss in IgM specificity and sensitivity. Moreover, an analog was obtained after modification of the octapeptide candidate Ac-Pra-RRN(Glc)GHT-Pra-NH2 to favor immobilization on SPR sensor chips. SPR technology allowed us to determine its affinity (KD = 16.4 nM), 2.3-times lower than the affinity of the original glucopeptide CSF114(Glc) (KD = 7.1 nM). This article is protected by copyright. All rights reserved.
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18. Tanabe Y, Fujita-Jimbo E, Momoi MY, Momoi T. {{CASPR2 forms a complex with GPR37 via MUPP1 but not with GPR37(R558Q), an autism spectrum disorder-related mutation}}. {J Neurochem};2015 (May 13)
Autism spectrum disorder (ASD) is a developmental brain disorder. Mutations in synaptic components including synaptic adhesion molecules have been found in ASD patients. Contactin-associated protein-like 2 (CASPR2) is one of the synaptic adhesion molecules associated with ASD. CASPR2 forms a complex with receptors via interaction with multiple PDZ domain protein 1 (MUPP1). Little is known about the relationship between impaired CASPR2-MUPP1-receptor complex and the pathogenesis of ASD. GPR37 is a receptor for survival factors. We recently identified mutations including R558Q in the G-protein-coupled receptor 37 (GPR37) gene in ASD patients. The mutated GPR37s accumulate in the ER. In the present study, we show that GPR37 is a component of the CASPR2-MUPP1 receptor complex in the mouse brain. CASPR2 and GPR37 mainly interacted with the PDZ3 and PDZ11 domains of MUPP1, respectively. Compared to GPR37, GPR37(R558Q) slightly interacted with MUPP1 and caused dendritic alteration. GPR37, but not GPR37(R558Q) nor GPR37-deltaC which lacks its PDZ binding domain, was transported to the cell surface by MUPP1. In primary hippocampal neurons, GPR37 co-localized with MUPP1 and CASPR2 at the synapse, but not GPR37(R558Q). Thus, ASD-related mutation of GPR37 may cause the impaired CASPR2-MUPP1-GPR37 complex on the dendrites associated with one of the pathogenesis of ASD. This article is protected by copyright. All rights reserved.
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19. Werling DM, Geschwind DH. {{Recurrence rates provide evidence for sex-differential, familial genetic liability for autism spectrum disorders in multiplex families and twins}}. {Mol Autism};2015;6:27.
BACKGROUND: Autism spectrum disorders (ASDs) are more prevalent in males, suggesting a multiple threshold liability model in which females are, on average, protected by sex-differential mechanisms. Under this model, autistic females are predicted to carry a more penetrant risk variant load than males and to share this greater genetic liability with their siblings. However, reported ASD recurrence rates have not demonstrated significantly increased risk to siblings of affected girls. Here, we characterize recurrence patterns in multiplex families from the Autism Genetics Resource Exchange (AGRE) to determine if risk in these families follows a female protective model. METHODS: We assess recurrence rates and quantitative traits in full siblings from 1,120 multiplex nuclear families and concordance rates in 305 twin pairs from AGRE. We consider the first two affected children per family, and one randomly selected autistic twin per pair, as probands. We then compare recurrence rates and phenotypes between males and females and between twin pairs or families with at least one female proband (female-containing (FC)) versus those with only male probands (male-only (MO)). RESULTS: Among children born after two probands, we observe significantly higher recurrence in males (47.5%) than in females (21.1%; relative risk, RR = 2.25; adjusted P = 6.22e-08) and in siblings of female (44.3%) versus siblings of male probands (30.4%; RR = 1.46; adj. P = 0.036). This sex-differential recurrence is also robust in dizygotic twin pairs (males = 61.5%, females = 19.1%; RR = 3.23; adj. P = 7.66e-09). Additionally, we find a significant negative relationship between interbirth interval and ASD recurrence that is driven by children in MO families. CONCLUSIONS: By classifying families as MO or FC using two probands instead of one, we observe significant recurrence rate differences between families harboring sex-differential familial liability. However, a significant sex difference in risk to children within FC families suggests that female protective mechanisms are still operative in families carrying high genetic risk loads. Furthermore, the male-specific relationship between shorter interbirth intervals and increased ASD risk is consistent with a potentially greater contribution from environmental factors in males versus higher genetic risk in affected females and their families. Understanding the mechanisms driving these sex-differential risk profiles will be useful for treatment development and prevention.
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20. Wood AG, Nadebaum C, Anderson V, Reutens D, Barton S, O’Brien TJ, Vajda F. {{Prospective assessment of autism traits in children exposed to antiepileptic drugs during pregnancy}}. {Epilepsia};2015 (May 11)
PURPOSE: The association between autism spectrum disorders (ASDs) and prenatal anticonvulsant exposure is increasingly investigated, but comprehensive, blinded assessment using a validated instrument for autism within a well-characterized prospective cohort has not been conducted. Thus, existing studies may represent an underestimate of the true risk. Herein we present a prospective cohort study in children exposed to anticonvulsants during pregnancy, with all assessments conducted by examiners who were blinded to drug-exposure status. METHODS: Participants were 105 Australian children aged 6-8 years who were recruited via the Australian Pregnancy Register for Women on Antiepileptic Medication. Maternal epilepsy, pregnancy, and medical history data were obtained prospectively. Autism traits were assessed using the Childhood Autism Rating Scale (CARS). RESULTS: Eleven children (10.5%) had elevated CARS scores. Two were exposed to valproate monotherapy (2/26; 7.7%), two to carbamazepine monotherapy (2/34; 5.9%), and seven to valproate in polytherapy (7/15; 46.7%). Linear regression analysis showed that the mean valproate dose during pregnancy was a significant predictor of CARS scores after controlling for polytherapy, mean carbamazepine dose, folic acid use, seizures during pregnancy, tobacco and marijuana use, maternal intelligence quotient (IQ), and socioeconomic status. First trimester folic acid supplementation and marijuana use were also significant predictors of CARS scores. SIGNIFICANCE: Using direct assessment of children in our prospective study, we found an elevated rate of autism traits across the sample. The most important determinant of association with autistic traits was higher doses of sodium valproate exposure. The use of valproate in women who may become pregnant is now generally avoided; however, there are insufficient data regarding the risk of ASD with low-dose valproate. If this risk is no greater than with other antiepileptic drugs (AED)s, it may enable women with genetic generalized epilepsy to retain optimal seizure control as well as minimize harm to their unborn child.
