1. Barneveld PS, Swaab H, van Engeland H, de Sonneville L. {{Cross-Sectional Evidence for a Decrease in Cognitive Function With Age in Children With Autism Spectrum Disorders?}}. {Autism Res}. 2014.
Autism spectrum disorders (ASD) are associated with early disturbances in brain maturation processes and these interferences presumably have their consequences for the progressive emergence of cognitive deficits later in life, as expressed in intelligence profiles. In this study, we addressed the impact of age on cognitive functioning of 6- to 15-year-old children and adolescents with ASD. Intelligence profiles were measured by the Wechsler Intelligence Scale for Children and compared among four consecutive age cohorts (children aged 6.17-8.03 years, 8.04-9.61 years, and 9.68-11.50 years and adolescents aged 11.54-15.85 years) of 237 high-functioning boys with ASD. The results clearly demonstrated that the global intelligence level was lower in children aged 8 years and older, when compared with 6- and 7-year-old children with ASD. This is mostly due to the Freedom From Distractibility factor, suggesting that older children were less able to sustain their attention, they were more distractible, or had more graph motor difficulties. Moreover, an effect of age was also found with respect to the relatively poor performance on the subtest Comprehension when compared with other verbal comprehension subtests, indicating that specifically the impairments in verbal comprehension and social reasoning abilities were more profound in older children when compared with 6- and 7-year-old children with ASD. Findings of this cross-sectional study showed that it is relevant to take age into account when evaluating the impact of cognitive impairments on intelligence in children with ASD, because the impact of these developmental disorders might be different at different ages. Autism Res 2014, : -. (c) 2014 International Society for Autism Research, Wiley Periodicals, Inc.
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2. Chaudhry A, Noor A, Degagne B, Baker K, Bok LA, Brady AF, Chitayat D, Hon-Yin BC, Cytrynbaum C, Dyment D, Filges I, Helm B, Hutchison HT, Jeng LJ, Laumonnier F, Marshall CR, Menzel M, Parkash S, Parker MJ, Raymond FL, Rideout AL, Roberts W, Rupps R, Schanze I, Speevak MD, Stavropoulos DJ, Stevens SJ, Thomas ER, Toutain A, Vergano S, Weksberg R, Scherer SW, Vincent JB, Carter MT. {{Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder}}. {Clin Genet}. 2014.
Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioural issues. Over 40 percent of subjects have ASD or ASD-like behaviours. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviours. Detailed neuropsychological studies are needed to better define the cognitive and behavioural phenotype.
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3. Cuccaro ML, Czape K, Alessandri M, Lee J, Deppen AR, Bendik E, Dueker N, Nations L, Pericak-Vance M, Hahn S. {{Genetic testing and corresponding services among individuals with autism spectrum disorder (ASD)}}. {Am J Med Genet A}. 2014.
The purpose of this study was to assess use of genetic testing and corresponding genetic services for children with Autism Spectrum Disorder (ASD). Survey data from 397 parents of individuals with ASD was collected using the Center for Autism and Related Disabilities client registry. Participants reported that 41.2% of the individuals with ASD had undergone any type of genetic testing. However, only 21.3% of individuals with ASD had been referred to a genetics specialist. Diagnosis and level of functioning were significantly associated with both referral to a genetics specialist and having undergone any genetic testing. In addition, Hispanic ancestry was associated with increased referral to genetic testing. Concerns about the limited benefits of genetic testing and prohibitive costs were potential barriers to pursuing genetic testing. Overall, low numbers of individuals with ASD have a history of undergoing genetic testing or receiving genetic services. Possible reasons include low referral rates as well as concerns by parents about cost and relevance, and lack of availability. These findings confirm the historical trend for providing genetic testing and genetic services to those with the greatest impairments. (c) 2014 Wiley Periodicals, Inc.
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4. Curran J. {{‘I move therefore I am’: The anoetic ideomotor theory of autism}}. {Aust N Z J Psychiatry}. 2014.
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5. Falck-Ytter T, Carlstrom C, Johansson M. {{Eye Contact Modulates Cognitive Processing Differently in Children With Autism}}. {Child Dev}. 2014.
In humans, effortful cognitive processing frequently takes place during social interaction, with eye contact being an important component. This study shows that the effect of eye contact on memory for nonsocial information is different in children with typical development than in children with autism, a disorder of social communication. Direct gaze facilitated memory performance in children with typical development (n = 25, 6 years old), but no such facilitation was seen in the clinical group (n = 10, 6 years old). Eye tracking conducted during the cognitive test revealed strikingly similar patterns of eye movements, indicating that the results cannot be explained by differences in overt attention. Collectively, these findings have theoretical significance and practical implications for testing practices in children.
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6. Gordon K, Murin M, Baykaner O, Roughan L, Livermore-Hardy V, Skuse D, Mandy W. {{A randomised controlled trial of PEGASUS, a psychoeducational programme for young people with high-functioning autism spectrum disorder}}. {J Child Psychol Psychiatry}. 2014.
BACKGROUND: Psychoeducation is an essential component of postdiagnostic care for people with ASD (autism spectrum disorder), but there is currently no evidence base for clinical practice. We designed, manualised and evaluated PEGASUS (psychoeducation group for autism spectrum understanding and support), a group psychoeducational programme aiming to enhance the self-awareness of young people with ASD by teaching them about their diagnosis. METHODS: This single-blind RCT (randomised control trial) involved 48 young people (9-14 years) with high-functioning ASD. Half were randomly assigned to PEGASUS, administered in six weekly group sessions, with the others receiving no additional intervention. ASD-related self-awareness, the primary outcome, was evaluated using the bespoke Autism Knowledge Quiz (AKQ). Secondary outcome measures included the Rosenberg Self-Esteem Scale. All measures were collected during home visits and scored by researchers blind to group assignment. The trial is registered on ClinicalTrials (NCT01187940, http://www.clinicaltrials.gov) and was funded by the Baily Thomas Charitable Trust. RESULTS: Bootstrap multiple regression showed ASD knowledge (beta = .29, p < .001, 95% CIs [0.13, 0.44]) and ASD self-awareness (beta = .42, p = .001, 95% CIs [0.17, 0.67]), measured by number of ASD-related personal strengths and difficulties listed by participants, increased for those who attended PEGASUS (n = 24) compared with controls (n = 24). There was no effect of PEGASUS on self-esteem by self-report (beta = .10, p = .404, 95% CIs [-0.14, 0.35]) or parent report (beta = .12, p = .324, 95% CIs [-0.12, 0.36]). CONCLUSIONS: After PEGASUS, participants had more general knowledge about ASD, and showed a greater awareness of their collection of unique strengths and difficulties associated with ASD. Psychoeducation did not lower self-esteem. This RCT provides initial evidence for PEGASUS’s efficacy as a psychoeducation programme for people with ASD.
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7. Hustyi KM, Hall SS, Jo B, Lightbody AA, Reiss AL. {{Longitudinal trajectories of aberrant behavior in fragile X syndrome}}. {Res Dev Disabil}. 2014; 35(11): 2691-701.
The Aberrant Behavior Checklist-Community (ABC-C; Aman et al., 1995) has been increasingly adopted as a primary tool for measuring behavioral change in clinical trials for individuals with fragile X syndrome (FXS). To our knowledge, however, no study has documented the longitudinal trajectory of aberrant behaviors in individuals with FXS using the ABC-C. As part of a larger longitudinal study, we examined scores obtained on the ABC-C subscales for 124 children and adolescents (64 males, 60 females) with FXS who had two or more assessments (average interval between assessments was approximately 4 years). Concomitant changes in age-equivalent scores on the Vineland Adaptive Behavior Scales (VABS) were also examined. As expected for an X-linked genetic disorder, males with FXS obtained significantly higher scores on all subscales of the ABC-C and significantly lower age-equivalent scores on the VABS than females with FXS. In both males and females with FXS, scores on the Irritability/Agitation and Hyperactivity/Noncompliance subscales of the ABC-C decreased significantly with age, with little to no change occurring over time on the Lethargy/Social Withdrawal, Stereotypic Behavior, and Inappropriate Speech subscales. The decrease in scores on the Hyperactivity/Noncompliance domain was significantly greater for males than for females. In both males and females, age-equivalent scores on the VABS increased significantly over this developmental period. These results establish a basis upon which to evaluate long-term outcomes from intervention-based research. However, longitudinal direct observational studies are needed to establish whether the severity of problem behavior actually decreases over time in this population.
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8. Kim JW, Seung H, Kwon KJ, Ko MJ, Lee EJ, Oh HA, Choi CS, Kim KC, Gonzales EL, You JS, Choi DH, Lee J, Han SH, Yang SM, Cheong JH, Shin CY, Bahn GH. {{Subchronic treatment of donepezil rescues impaired social, hyperactive, and stereotypic behavior in valproic Acid-induced animal model of autism}}. {PLoS One}. 2014; 9(8): e104927.
Autism spectrum disorder (ASD) is a group of pervasive developmental disorders with core symptoms such as sociability deficit, language impairment, and repetitive/restricted behaviors. Although worldwide prevalence of ASD has been increased continuously, therapeutic agents to ameliorate the core symptoms especially social deficits, are very limited. In this study, we investigated therapeutic potential of donepezil for ASD using valproic acid-induced autistic animal model (VPA animal model). We found that prenatal exposure of valproic acid (VPA) induced dysregulation of cholinergic neuronal development, most notably the up-regulation of acetylcholinesterase (AChE) in the prefrontal cortex of affected rat and mouse offspring. Similarly, differentiating cortical neural progenitor cell in culture treated with VPA showed increased expression of AChE in vitro. Chromatin precipitation experiments revealed that acetylation of histone H3 bound to AChE promoter region was increased by VPA. In addition, other histone deacetyalse inhibitors (HDACIs) such as trichostatin A and sodium butyrate also increased the expression of AChE in differentiating neural progenitor cells suggesting the essential role of HDACIs in the regulation of AChE expression. For behavioral analysis, we injected PBS or donepezil (0.3 mg/kg) intraperitoneally to control and VPA mice once daily from postnatal day 14 all throughout the experiment. Subchronic treatment of donepezil improved sociability and prevented repetitive behavior and hyperactivity of VPA-treated mice offspring. Taken together, these results provide evidence that dysregulation of ACh system represented by the up-regulation of AChE may serve as an effective pharmacological therapeutic target against autistic behaviors in VPA animal model of ASD, which should be subjected for further investigation to verify the clinical relevance.
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9. Parker KJ, Garner JP, Libove RA, Hyde SA, Hornbeak KB, Carson DS, Liao CP, Phillips JM, Hallmayer JF, Hardan AY. {{Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder}}. {Proc Natl Acad Sci U S A}. 2014; 111(33): 12258-63.
The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3-12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h(2) = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the « G » allele of rs53576 showed impaired affect recognition performance and carriers of the « A » allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD.
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10. Peprah E. {{Understanding decreased fertility in women carriers of the FMR1 premutation: a possible mechanism for Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)}}. {Reprod Health}. 2014; 11(1): 67.
Fragile X syndrome (FXS) and its associated disorders are caused by the expansion of the CGG repeat in the 5′ untranslated region of the fragile X mental retardation 1 gene (FMR1). The full mutation, defined as >200 cytosine-guanine-guanine (CGG) triplet repeats, causes FXS. Individuals with 55-199 CGG repeats, classified as premutation carriers, are affected by two distinct disorders depending on their premutation status. Disorders associated with premutation carriers include: Fragile X-associated Tremor Ataxia Syndrome (FXTAS) and Fragile X-associated Primary Ovarian Insufficiency (FXPOI). The molecular similarities of FXTAS and FXPOI (e.g. overabundance of FMR1 transcript and intranuclear inclusions) suggest that similar molecular mechanisms underlie both FXTAS and FXPOI. The current hypothesis describes the underlying mechanism for FXTAS as an mRNA gain-of-function mutation, however the underlying mechanism for FXPOI remains unresolved. New data suggests that repeat associated non-AUG (RAN) translation could underlie FXPOI.
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11. Pileggi LA, Malcolm-Smith S, Solms M. {{Investigating the role of social-affective attachment processes in cradling bias: The absence of cradling bias in children with Autism Spectrum Disorders}}. {Laterality}. 2014: 1-17.
Previous studies suggest that leftward cradling bias may facilitate mother-infant relationships, as it preferentially locates the infant in the mother’s left hemi-space, which is specialized for several social-affective processes. If leftward cradling bias is mediated by social-affective attachment processes, it should be reduced in humans who are deficient in such processes. Individuals diagnosed with Autism Spectrum Disorders (ASDs) constitute a population with known deficits in social and emotional relating. A pilot study confirmed reduced bias in this group, and in the present study, we elaborated methods to assess also the impact of higher cognitive processes on cradling bias. Direct systematic observation was used to investigate the occurrence of cradling bias in ASD, non-ASD intellectually disabled children and typically developing children. Ninety-three participants aged 5-15 years cradled a life-like doll on four separate occasions. Intelligence and executive functions were assessed. Regression analyses revealed that ASD diagnosis was the only significant predictor of atypical cradling preference. While intellectually disabled and typically developing children clearly preferred to cradle to the left, no preference was evident in the ASD group. Results support the hypothesis that leftward cradling bias is associated with basic social-affective capacities.
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12. Romero-Martinez A, Moya-Albiol L. {{Prenatal testosterone of progenitors could be involved in the etiology of both anorexia nervosa and autism spectrum disorders of their offspring}}. {Am J Hum Biol}. 2014.
OBJECTIVES: High intrauterine testosterone (T) levels seem to play a role in the development of autism spectrum disorders (ASDs), but their role in anorexia nervosa (AN) is controversial. Parents with masculinized 2D:4D ratios, a marker of the organizational effects of T, may have other relevant biological characteristics, in particular exposing their offspring to high T levels in the prenatal environment. This would increase the likelihood of their offspring developing these disorders. METHODS: The present study examined whether parents of offspring with AN (n=34; mean age= 51) and ASD (n=36; mean age=45) differ from control parents (n=40; mean age=43) in 2D:4D ratio, as well as by salivary T levels and its relationships. RESULTS: Our results revealed that AN and ASD parents (fathers and mothers) have masculinized 2D:4D ratios of the right hand compared to control parents. However, the difference compared to controls was larger in the ASD than the AN group. Furthermore, current salivary T levels were negatively related to the 2D:4D ratio in ASD and AN parents only. CONCLUSIONS: Our data partially support the view of high prenatal masculinization as a potential intermediate phenotype to the development of these disorders in their offspring. Am. J. Hum. Biol., 2014. (c) 2014 Wiley Periodicals, Inc.
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13. Sundquist J, Sundquist K, Ji J. {{Autism and attention-deficit/hyperactivity disorder among individuals with a family history of alcohol use disorders}}. {Elife}. 2014; 3: e02917.
Recent studies suggest de novo mutations may involve the pathogenesis of autism and attention-deficit/hyperactivity disorder (ADHD). Based on the evidence that excessive alcohol consumption may be associated with an increased rate of de novo mutations in germ cells (sperms or eggs), we examine here whether the risks of autism and ADHD are increased among individuals with a family history of alcohol use disorders (AUDs). The standardized incidence ratios (SIRs) of autism and ADHD among individuals with a biological parental history of AUDs were 1.39 (95% CI 1.34-1.44) and 2.19 (95% CI 2.15-2.23), respectively, compared to individuals without an affected parent. Among offspring whose parents were diagnosed with AUDs before their birth, the corresponding risks were 1.46 (95% CI 1.36-1.58) and 2.70 (95% CI 2.59-2.81), respectively. Our study calls for extra surveillance for children with a family history of AUDs, and further studies examining the underlying mechanisms are needed.DOI: http://dx.doi.org/10.7554/eLife.02917.001.
14. Trasande L. {{Environmental Contributors to Autism: The Pediatricians Role}}. {Curr Probl Pediatr Adolesc Health Care}. 2014.
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15. Zhang J, Wang A, Li Y, Lu X, Wang F, Fang F. {{Association of NCAM1 Polymorphisms with Autism and Parental Age at Conception in Chinese Han Population}}. {Genet Test Mol Biomarkers}. 2014.
Aims: The neural cell adhesion molecule (NCAM) has been reported to be involved in the development of the central nervous system and its mRNA level might decrease in the serum of autistic patients. However, there was no evidence of the association of the NCAM1 gene polymorphisms with autism. In the present study, we enrolled 237 children with autism and 451 healthy control subjects. Then, we used the direct DNA sequencing for genotyping five tag single-nucleotide polymorphisms (SNPs) in the NCAM1 gene. Results: By using case-control association analyses, we found that three SNPs at the NCAM1 gene were associated with autism (rs4937786, p=0.015; rs12418058, p=0.0076; rs1436109, p=0.0023). Two of them remained significant after the Bonferroni multiple testing correction (rs12418058, pcorrcted=0.038; rs1436109, pcorrcted=0.012). Moreover, two of the SNPs were associated with the parental age at conception in autism (rs12418058, p=0.037; rs1436109, p=0.01). Conclusion: These results showed that NCAM1 might play an important role in the pathogenesis of autism.
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16. Zhubi A, Cook EH, Guidotti A, Grayson DR. {{Epigenetic mechanisms in autism spectrum disorder}}. {Int Rev Neurobiol}. 2014; 115: 203-44.
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social interactions, language deficits, as well as restrictive or repetitive behaviors. ASD is clinically heterogeneous with a complex etiopathogenesis which may be conceptualized as a dynamic interplay between heterogeneous environmental cues and predisposing genetic factors involving complex epigenetic mechanisms. Inherited and de novo copy number variants provide novel information regarding genes contributing to ASD. Epigenetic marks are stable, yet potentially reversible, chromatin modifications that alter gene expression profiles by locally changing the degree of nucleosomal compaction, thereby opening or closing promoter access to the transcriptional machinery. Here, we review progress on studies designed to provide a better understanding of how epigenetic mechanisms impact transcriptional programs operative in the brain that contribute to ASD.
