1. Alvarez-Mora MI, Calvo Escalona R, Puig Navarro O, Madrigal I, Quintela I, Amigo J, Martinez-Elurbe D, Linder-Lucht M, Aznar Lain G, Carracedo A, Mila M, Rodriguez-Revenga L. {{Comprehensive molecular testing in patients with high functioning autism spectrum disorder}}. {Mutat Res};2016 (Jan 6);784-785:46-52.
Autism spectrum disorders (ASD) include a range of complex neurodevelopmental disorders with extreme genetic heterogeneity. Exome and target sequencing studies have shown to be an effective tool for the discovery of new ASD genes. The aim of this study was to design an ASD candidate gene panel that covers 44 of the top ASD candidate genes. As a pilot study we performed comprehensive molecular diagnostic testing, including the study of the FMR1 and FMR2 repeat regions, copy number variant analysis in a collection of 50 Spanish ASD cases and mutation screening using targeted next generation sequencing-based techniques in 44 out of the total cohort. We evaluated and clinically selected our cohort, with most of the cases having high functioning ASD without facial dysmorphic features. The results of the present study allowed the detection of copy number and single nucleotide variants not yet identified. In addition, our results underscore the difficulty of the molecular diagnosis of ASD and confirm its genetic heterogeneity. The information gained from this and other genetic screenings is necessary to unravel the clinical interpretation of novel variants.
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2. Archibald AD, Hickerton CL, Wake SA, Jaques AM, Cohen J, Metcalfe SA. {{« It gives them more options »: preferences for preconception genetic carrier screening for fragile X syndrome in primary healthcare}}. {J Community Genet};2016 (Feb 3)
This study aims to explore stakeholder views about offering population-based genetic carrier screening for fragile X syndrome. A qualitative study using interviews and focus groups with stakeholders was undertaken to allow for an in-depth exploration of views and perceptions about practicalities of, and strategies for, offering carrier screening for fragile X syndrome to the general population in healthcare settings. A total of 188 stakeholders took part including healthcare providers (n = 81), relatives of people with fragile X syndrome (n = 29), and members of the general community (n = 78). The importance of raising community awareness about screening and providing appropriate support for carriers was emphasized. There was a preference for preconception carrier screening and for providing people with the opportunity to make an informed decision about screening. Primary care was highlighted as a setting which would ensure screening is accessible; however, challenges of offering screening in primary care were identified including time to discuss screening, knowledge about the test and possible outcomes, and the health professionals’ approach to offering screening. With the increasing availability of genetic carrier tests, it is essential that research now focuses on evaluating approaches for the delivery of carrier screening programs. Primary healthcare is perceived as an appropriate setting through which to access the target population, and raising awareness is essential to making genetic screening more accessible to the general community.
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3. Ben-Itzchak E, Zukerman G, Zachor DA. {{Having Older Siblings is Associated with Less Severe Social Communication Symptoms in Young Children with Autism Spectrum Disorder}}. {J Abnorm Child Psychol};2016 (Feb 3)
Among typically developing children, having sibling relationships promotes the development of social skills. This is a retrospective study of the effect of having sibling/s on the severity of the clinical presentation of autism spectrum disorder (ASD). The study included 112 children, 99 males and 15 females, mean age 29.6 +/- 9.2 months, diagnosed with ASD. The study population was composed of a group of children with ASD who had older typically developing sibling/s (n = 56) pair-matched for age and cognitive level to a group of children with ASD without sibling/s. Each participant underwent a comprehensive assessment using standardized tests. The group with older sibling/s had less severe observed social deficits (Autism Diagnostic Observation Schedule-Social Affect calibrated severity scales [ADOS-SA-CSS]) and fewer reported non-verbal communication impairments (Autism Diagnostic Interview-Revised [ADI-R]). Regression analyses revealed that, for the ADOS-SA-CSS, higher cognitive level and having older sibling/s were associated with less severe observed social affect deficits. This model explained 32.0 % of the variance. For the ADI-R communication scores, older age, higher cognitive level and having older sibling/s were associated with less severe reported non-verbal communication impairments. This model explained 33.0 % of the variance. The main finding in this study is that a familial factor, specifically having older sibling/s, was associated with better social communication abilities in children with ASD, in addition to age and cognitive ability. Having sibling/s may offer opportunities for the child with ASD to experience social interactions with children and to acquire communication skills.
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4. Berryessa CM, Milner LC, Garrison NA, Cho MK. {{Impact of Psychiatric Information on Potential Jurors in Evaluating High-Functioning Autism Spectrum Disorder (hfASD)}}. {J Ment Health Res Intellect Disabil};2015 (Jul 1);8(3-4):140-167.
During a trial involving an offender with a mental disorder, jurors are often required to evaluate information on the disorder and its characteristics. This evaluation relies on how jurors understand and synthesize psychiatric and other evidence on the disorder and this information’s impact on the case, an offender’s culpability, and the rendered verdict. The importance of this evaluation is further highlighted when jurors are faced with evaluating a disorder that may be associated with criminal actions of diagnosed offenders, such as high-functioning autism spectrum disorder (hfASD). We designed a three-part survey to assess potential jurors’ attitudes concerning an offender’s diagnosis with hfASD in terms of perceptions and decisions surrounding legal and moral responsibility, personal characteristics of the offender, the introduction of psychiatric and genetic information, and the condition’s influence on the facts of the case. A sample of 623 jury-eligible U.S. adults completed the survey. We found the majority of participants were influenced by the information provided on hfASD. Most respondents indicated that hfASD diagnosis should generally not affect the legal responsibility of an offender, but many reported the disorder as a mitigating factor when evaluating moral responsibility and legal consequences for criminal actions. Respondents reported favorable and sympathetic perceptions of individuals with autism and associated characteristics but were unsure, even after the presentation of psychiatric information on hfASD, if these disorders should be classified as « mental illness. » Further, the majority reported their views were in some way influenced by the fact that hfASD has potential genetic origins.
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5. Buckley AW, Scott R, Tyler A, Mahoney JM, Thurm A, Farmer C, Swedo S, Burroughs SA, Holmes GL. {{State-Dependent Differences in Functional Connectivity in Young Children With Autism Spectrum Disorder}}. {EBioMedicine};2015 (Dec);2(12):1905-1915.
BACKGROUND: While there is increasing evidence of altered brain connectivity in autism, the degree and direction of these alterations in connectivity and their uniqueness to autism has not been established. The aim of the present study was to compare connectivity in children with autism to that of typically developing controls and children with developmental delay without autism. METHODS: We assessed EEG spectral power, coherence, phase lag, Pearson and partial correlations, and epileptiform activity during the awake, slow wave sleep, and REM sleep states in 137 children aged 2 to 6 years with autism (n = 87), developmental delay without autism (n = 21), or typical development (n = 29). FINDINGS: We found that brain connectivity, as measured by coherence, phase lag, and Pearson and partial correlations distinguished children with autism from both neurotypical and developmentally delayed children. In general, children with autism had increased coherence which was most prominent during slow wave sleep. INTERPRETATION: Functional connectivity is distinctly different in children with autism compared to samples with typical development and developmental delay without autism. Differences in connectivity in autism are state and region related. In this study, children with autism were characterized by a dynamically evolving pattern of altered connectivity.
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6. Jefferson A, Leonard H, Siafarikas A, Woodhead H, Fyfe S, Ward LM, Munns C, Motil K, Tarquinio D, Shapiro JR, Brismar T, Ben-Zeev B, Bisgaard AM, Coppola G, Ellaway C, Freilinger M, Geerts S, Humphreys P, Jones M, Lane J, Larsson G, Lotan M, Percy A, Pineda M, Skinner S, Syhler B, Thompson S, Weiss B, Witt Engerstrom I, Downs J. {{Clinical Guidelines for Management of Bone Health in Rett Syndrome Based on Expert Consensus and Available Evidence}}. {PLoS One};2016;11(2):e0146824.
OBJECTIVES: We developed clinical guidelines for the management of bone health in Rett syndrome through evidence review and the consensus of an expert panel of clinicians. METHODS: An initial guidelines draft was created which included statements based upon literature review and 11 open-ended questions where literature was lacking. The international expert panel reviewed the draft online using a 2-stage Delphi process to reach consensus agreement. Items describe the clinical assessment of bone health, bone mineral density assessment and technique, and pharmacological and non-pharmacological interventions. RESULTS: Agreement was reached on 39 statements which were formulated from 41 statements and 11 questions. When assessing bone health in Rett syndrome a comprehensive assessment of fracture history, mutation type, prescribed medication, pubertal development, mobility level, dietary intake and biochemical bone markers is recommended. A baseline densitometry assessment should be performed with accommodations made for size, with the frequency of surveillance determined according to individual risk. Lateral spine x-rays are also suggested. Increasing physical activity and initiating calcium and vitamin D supplementation when low are the first approaches to optimizing bone health in Rett syndrome. If individuals with Rett syndrome meet the ISCD criterion for osteoporosis in children, the use of bisphosphonates is recommended. CONCLUSION: A clinically significant history of fracture in combination with low bone densitometry findings is necessary for a diagnosis of osteoporosis. These evidence and consensus-based guidelines have the potential to improve bone health in those with Rett syndrome, reduce the frequency of fractures, and stimulate further research that aims to ameliorate the impacts of this serious comorbidity.
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7. Lyu JW, Yuan B, Cheng TL, Qiu ZL, Zhou WH. {{Reciprocal regulation of autism-related genes MeCP2 and PTEN via microRNAs}}. {Sci Rep};2016;6:20392.
MeCP2 encodes a methyl-CpG-binding protein that plays a critical role in repressing gene expression, mutations of which lead to Rett syndrome and autism. PTEN is a critical tumor suppressor gene that is frequently mutated in human cancers and autism spectrum disorders. Various studies have shown that both MeCP2 and PTEN proteins play important roles in brain development. Here we find that MeCP2 and PTEN reciprocally regulate expression of each other via microRNAs. Knockdown of MeCP2 leads to upregulation of microRNA-137, which in turn represses expression of PTEN, thus PTEN would be down-regulated when MeCP2 is knockdown. Furthermore, we find that deletion of PTEN leads to phosphorylation of Serine 133 of CREB, then increases the expression of microRNA-132. miR-132 inhibits the expression of MeCP2 by targeting on the 3’UTR of MeCP2 mRNA. Our work shows that two critical disorders-related gene MeCP2 and PTEN reciprocally regulate expression of each other by distinct mechanisms, suggesting that rare mutations in various disorders may lead to dysregulation of other critical genes and yield unexpected consequences.
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8. Muskat B, Greenblatt A, Nicholas DB, Ratnapalan S, Cohen-Silver J, Newton AS, Craig WR, Kilmer C, Zwaigenbaum L. {{Parent and health care provider perspectives related to disclosure of autism spectrum disorder in pediatric emergency departments}}. {Autism};2016 (Feb 5)
Children and youth with autism spectrum disorder presenting in emergency departments face potential cognitive, sensory, and behavioral challenges, and it is crucial for providers to be aware of their unique needs. However, disclosure of a child’s autism spectrum disorder can be complex for parental caregivers and is not well understood. This qualitative study utilized a grounded theory approach and analyzed data from 28 parents and 16 health care providers related to autism spectrum disorder disclosure within two Canadian pediatric emergency departments. Study results indicated that participants identified benefits and risks of disclosure. Encouraging understanding, expediting service, and preparing health care providers for working with children with autism spectrum disorder were identified as benefits of disclosure. Risks related to disclosure included potential negative attributions toward the children and parental discomfort in disclosing a diagnosis in front of the children. Parents discussed the health care encounters they experienced following disclosure and provided recommendations for improving the disclosure process in the emergency department. It is recommended that future research explore the experiences of parents who choose not to disclose their child’s autism spectrum disorder. Greater awareness of the disclosure experience and the development of resources and tools to support communication between parents and health care providers are also recommended.
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9. Peckett H, MacCallum F, Knibbs J. {{Maternal experience of Lego Therapy in families with children with autism spectrum conditions: What is the impact on family relationships?}}. {Autism};2016 (Feb 5)
This study aimed to explore mothers’ experience of implementing Lego Therapy at home within the family. Following a Lego Therapy training session, mothers carried out hourly sessions with their child with an autism spectrum condition and the child’s sibling, once a week, for 6 weeks. Mothers were interviewed following the intervention, and the data were analysed using interpretative phenomenological analysis. Themes emerged around improved family relationships, a positive impact on the child as an individual, and changed maternal, sibling and child perspectives. Challenging and facilitative aspects also emerged, as did some ambivalence about the impact of the intervention in the wider context. The findings are supportive of previous Lego Therapy studies and have implications for strengths-based service provision.
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10. Pruitt MM, Willis K, Timmons L, Ekas NV. {{The impact of maternal, child, and family characteristics on the daily well-being and parenting experiences of mothers of children with autism spectrum disorder}}. {Autism};2016 (Feb 5)
This study utilized a daily diaries method to explore the global factors that impact daily general affect and daily parenting interactions of mothers of children with autism spectrum disorder. Eighty-three mothers of a child with autism spectrum disorder between the ages of 3 and 13 years completed global assessments of maternal depressive symptoms, child autism spectrum disorder symptom severity, and family functioning. Mothers then reported on their daily negative and positive affect as well as their daily positive and frustrating parenting interactions for 14 consecutive days. The results indicated that higher levels of maternal depressive symptoms were related to decreased daily positive affect, whereas greater child social motivation impairments were related to increased daily positive affect. Only maternal depressive symptoms were associated with increased daily negative affect. Furthermore, higher levels of family cohesion were related to increased daily positive parenting interactions. Finally, higher maternal depressive symptoms as well as family rigidity were related to increased daily frustrating parenting interactions. Implications for interventions focused on the family system are discussed.
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11. Radley KC, Hanglein J, Arak M. {{School-based social skills training for preschool-age children with autism spectrum disorder}}. {Autism};2016 (Feb 5)
Individuals with autism spectrum disorder display impairments in social interactions and communication that appear at early ages and result in short- and long-term negative outcomes. As such, there is a need for effective social skills training programs for young children with autism spectrum disorder-particularly interventions capable of being delivered in educational settings. The study evaluated the effects of the Superheroes Social Skills program on accurate demonstration of social skills in young children with autism spectrum disorder. Two preschool-age children with autism spectrum disorder participated in a weekly social skills intervention. A multiple probe design across skills was used to determine the effects of the intervention. Both participants demonstrated substantial improvements in skill accuracy. Social skills checklists also indicated improvements in social functioning over baseline levels.
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12. Rodenas-Cuadrado P, Pietrafusa N, Francavilla T, La Neve A, Striano P, Vernes SC. {{Characterisation of CASPR2 deficiency disorder – a syndrome involving autism, epilepsy and language impairment}}. {BMC Med Genet};2016;17(1):8.
BACKGROUND: Heterozygous mutations in CNTNAP2 have been identified in patients with a range of complex phenotypes including intellectual disability, autism and schizophrenia. However heterozygous CNTNAP2 mutations are also found in the normal population. Conversely, homozygous mutations are rare in patient populations and have not been found in any unaffected individuals. CASE PRESENTATION: We describe a consanguineous family carrying a deletion in CNTNAP2 predicted to abolish function of its protein product, CASPR2. Homozygous family members display epilepsy, facial dysmorphisms, severe intellectual disability and impaired language. We compared these patients with previously reported individuals carrying homozygous mutations in CNTNAP2 and identified a highly recognisable phenotype. CONCLUSIONS: We propose that CASPR2 loss produces a syndrome involving early-onset refractory epilepsy, intellectual disability, language impairment and autistic features that can be recognized as CASPR2 deficiency disorder. Further screening for homozygous patients meeting these criteria, together with detailed phenotypic and molecular investigations will be crucial for understanding the contribution of CNTNAP2 to normal and disrupted development.
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13. Rosa M, Puig O, Lazaro L, Calvo R. {{Socioeconomic status and intelligence quotient as predictors of psychiatric disorders in children and adolescents with high-functioning autism spectrum disorder and in their siblings}}. {Autism};2016 (Feb 5)
Previous studies have shown high rates of comorbid disorders in children and adolescents with autism spectrum disorder, but failed to compare them with general population and few of them have identified predictors of comorbidity. This study compared the rates of psychiatric disorders in 50 children and adolescents with autism spectrum disorder, 24 of their siblings, 32 controls from general population and 22 of their siblings. Children and adolescent with autism spectrum disorder and their siblings had higher rates of attention deficit and hyperactivity disorder compared to controls. Lower socioeconomic status and intelligence quotient were the main risk factors. The contribution of socioeconomic status and intelligence quotient to increase the risk of developing comorbidity in autism spectrum disorder and psychopathology in their siblings deserves further study.
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14. Tai DJ, Liu YC, Hsu WL, Ma YL, Cheng SJ, Liu SY, Lee EH. {{MeCP2 SUMOylation rescues Mecp2-mutant-induced behavioural deficits in a mouse model of Rett syndrome}}. {Nat Commun};2016;7:10552.
The methyl-CpG-binding protein 2 (MeCP2) gene, MECP2, is an X-linked gene encoding the MeCP2 protein, and mutations of MECP2 cause Rett syndrome (RTT). However, the molecular mechanism of MECP2-mutation-caused RTT is less known. Here we find that MeCP2 could be SUMO-modified by the E3 ligase PIAS1 at Lys-412. MeCP2 phosphorylation (at Ser-421 and Thr-308) facilitates MeCP2 SUMOylation, and MeCP2 SUMOylation is induced by NMDA, IGF-1 and CRF in the rat brain. MeCP2 SUMOylation releases CREB from the repressor complex and enhances Bdnf mRNA expression. Several MECP2 mutations identified in RTT patients show decreased MeCP2 SUMOylation. Re-expression of wild-type MeCP2 or SUMO-modified MeCP2 in Mecp2-null neurons rescues the deficits of social interaction, fear memory and LTP observed in Mecp2 conditional knockout (cKO) mice. These results together reveal an important role of MeCP2 SUMOylation in social interaction, memory and synaptic plasticity, and that abnormal MeCP2 SUMOylation is implicated in RTT.
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15. Uddin LQ. {{The Influence of Brain State on Functional Connectivity in Autism}}. {EBioMedicine};2015 (Dec);2(12):1840-1841.
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16. Vaillancourt T, Haltigan JD, Smith I, Zwaigenbaum L, Szatmari P, Fombonne E, Waddell C, Duku E, Mirenda P, Georgiades S, Bennett T, Volden J, Elsabbagh M, Roberts W, Bryson S. {{Joint trajectories of internalizing and externalizing problems in preschool children with autism spectrum disorder}}. {Dev Psychopathol};2016 (Feb 5):1-12.
The co-occurring development of internalizing and externalizing problems were examined in an inception cohort of 392 children diagnosed with autism spectrum disorder at age 3 who were assessed on four occasions. Results indicated that internalizing and externalizing problems were stable over time and highly comorbid. Joint trajectory analysis suggested that 13% of the sample followed a dual high-risk trajectory. High risk was not found to be associated with intellectual ability or autism spectrum disorder symptom severity but was linked to lower income and gender: more girls than boys were found in the high/stable internalizing problems trajectory. The results suggest that 1 in 4 preschoolers followed a trajectory of internalizing or externalizing problems (or a combination of the two) that could be characterized as clinically elevated.
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17. Vanvuchelen M, Van Schuerbeeck L, Braeken MA. {{Screening accuracy of the parent-completed Ages and Stages Questionnaires – second edition as a broadband screener for motor problems in preschoolers with autism spectrum disorders}}. {Autism};2016 (Feb 5)
Children with autism spectrum disorders are at risk for motor problems. However, this area is often overlooked in the developmental evaluation in autism diagnostic clinics. An alternative can be to identify children who should receive intensive motor assessment by using a parent-based screener. The aim of this study was to examine whether the Ages and Stages Questionnaires – second edition may be used to identify gross and fine motor problems in children. High-functioning children with autism spectrum disorder (n = 43, 22-54 m) participated in this study. Sensitivity, specificity, predictive values and areas under the receiver operating characteristic curve were calculated by comparing the Ages and Stages Questionnaires – second edition scores to the developmental evaluation of the Peabody Developmental Motor Scale – second edition. The results revealed that both the Ages and Stages Questionnaires – second edition gross and fine motor domain may be used to identify children without motor problems. In contrast, sensitivity analyses revealed the likelihood of under screening motor problems in this population. The Ages and Stages Questionnaires – second edition met only the criteria of a fair to good accuracy to identify poor gross motor (sensitivity = 100%) and below-average fine motor development (sensitivity = 71%) in this sample. Hence, the capacity of the Ages and Stages Questionnaires – second edition to identify motor problems in preschoolers with autism spectrum disorder appears to be limited. It is recommended to include a formal standardized motor test in the diagnostic procedure for all children with autism spectrum disorder.
