1. Christofolini DM, Meloni VA, de Paula Ramos MA, Oliveira MM, de Mello CB, Pellegrino R, Takeno SS, Melaragno MI. {{Autistic disorder phenotype associated to a complex 15q intrachromosomal rearrangement}}. {Am J Med Genet B Neuropsychiatr Genet}. 2012.
The proximal regions of acrocentric chromosomes, particularly 15q11.2, are frequently involved in structural rearrangement. However, interstitial duplications involving one of the chromosome 15 homologues are less frequent, with few patients described with molecular techniques. These patients present distinctive clinical findings including developmental delay and intellectual disability, minor dysmorphic facial features, epilepsy, and autistic behavior. Here we describe an interstitial rearrangement of chromosome 15 composed of a triplication approximately 6.9 Mb from 15q11.2 to 15q13.2 followed by a duplication of approximately 2.4 Mb from 15q13.2 to 15q13.3, defined using different approaches as MLPA, qPCR, array and FISH. FISH revealed that the middle part of the triplicated segment was in inverted position. The parental origin of the rearrangement was assessed using methylation assay and SNP array that revealed the maternal origin of the additional material. The patient presents most of the clinical features associated to 15q11.2 triplication: minor dysmorphic facial features, generalized epilepsy, absence seizures, intellectual disability, and autistic behavior. In conclusion, the use of more accurate molecular tools enabled a detailed investigation, providing the identification of intrachromosome duplication/triplication and bringing new light to the study of genetic causes of autistic disorders. (c) 2012 Wiley Periodicals, Inc.
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2. Duku E, Vaillancourt T, Szatmari P, Georgiades S, Zwaigenbaum L, Smith IM, Bryson S, Fombonne E, Mirenda P, Roberts W, Volden J, Waddell C, Thompson A, Bennett T. {{Investigating the Measurement Properties of the Social Responsiveness Scale in Preschool Children with Autism Spectrum Disorders}}. {J Autism Dev Disord}. 2012.
The purpose of this study was to examine the measurement properties of the Social Responsiveness Scale in an accelerated longitudinal sample of 4-year-old preschool children with the complementary approaches of categorical confirmatory factor analysis and Rasch analysis. Measurement models based on the literature and other hypothesized measurement models which were tested using categorical confirmatory factor analysis did not fit well and were not unidimensional. Rasch analyses showed that a 30-item subset met criteria of unidimensionality and invariance across item, person, and over time; and this subset exhibited convergent validity with other child outcomes. This subset was shown to have enhanced psychometric properties and could be used in measuring social responsiveness among preschool age children with Autism Spectrum Disorders.
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3. Eussen ML, Van Gool AR, Verheij F, De Nijs PF, Verhulst FC, Greaves-Lord K. {{The association of quality of social relations, symptom severity and intelligence with anxiety in children with autism spectrum disorders}}. {Autism}. 2012.
Limited quality of social relations, milder symptom severity and higher intelligence were shown to account for higher anxiety levels in autism spectrum disorders. The current study replicated and extended earlier findings by combining these three determinants of anxiety in autism spectrum disorders in one study. The sample consisted of 134 school-aged children with autism spectrum disorders, of whom 58 (43%) had a co-morbid anxiety disorder according to the Diagnostic Interview Schedule for Children-Parent version. In this sample, we tested associations between these determinants and anxiety univariately and multivariately to clarify the unique contribution of all determinants. Since we hypothesized that the association between limited quality of social relations and anxiety would be amplified by low symptom severity and/or high intelligence, we additionally tested for moderating effects. We found that higher anxiety levels were associated with a lower quality of social relations and lower symptom severity. In this mainly high-functioning sample, intelligence was not related to anxiety levels. No moderation effects were found. Since lower quality of social relations and lower symptom severity are associated with higher anxiety levels in children with autism spectrum disorders, therapeutic interventions aimed at reducing anxiety in autism spectrum disorders should pay attention to improving social relations, and presumably children with a lower symptom severity could benefit most from such interventions.
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4. Falivelli G, De Jaco A, Favaloro FL, Kim H, Wilson J, Dubi N, Ellisman MH, Abrahams BS, Taylor P, Comoletti D. {{Inherited genetic variants in autism-related CNTNAP2 show perturbed trafficking and ATF6 activation}}. {Hum Mol Genet}. 2012.
Although genetic variations in several genes encoding for synaptic adhesion proteins have been found to be associated with autism spectrum disorders, one of the most consistently replicated genes has been CNTNAP2, encoding for contactin-associated protein-like 2 (CASPR2), a multidomain transmembrane protein of the neurexin superfamily. Using immunofluorescence confocal microscopy and complementary biochemical techniques, we compared wild-type CASPR2 to 12 point mutations identified in individuals with autism. In contrast to the wild-type protein, localized to the cell surface, some of the mutants show altered cellular disposition. In particular, CASPR2-D1129H is largely retained in the endoplasmic reticulum (ER) in HEK-293 cells and in hippocampal neurons. BiP/Grp78, Calnexin and ERp57, key ER chaperones, appear to be responsible for retention of this mutant and activation of one signaling pathway of the unfolded protein response (UPR). The presence of this mutation also lowers expression and activates proteosomal degradation. A frame-shift mutation that causes a form of syndromic epilepsy (CASPR2-1253*), results in a secreted protein with seemingly normal folding and oligomerization. Taken together, these data indicate that CASPR2-D1129H has severe trafficking abnormalities and CASPR2-1253* is a secreted soluble protein, suggesting that the structural or signaling functions of the membrane tethered form are lost. Our data support a complex genetic architecture in which multiple distinct risk factors interact with others to shape autism risk and presentation.
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5. Idring S, Rai D, Dal H, Dalman C, Sturm H, Zander E, Lee BK, Serlachius E, Magnusson C. {{Autism spectrum disorders in the stockholm youth cohort: design, prevalence and validity}}. {PLoS One}. 2012; 7(7): e41280.
OBJECTIVE: Reports of rising prevalence of autism spectrum disorders (ASD), along with their profound personal and societal burden, emphasize the need of methodologically sound studies to explore their causes and consequences. We here present the design of a large intergenerational resource for ASD research, along with population-based prevalence estimates of ASD and their diagnostic validity. METHOD: The Stockholm Youth Cohort is a record-linkage study comprising all individuals aged 0-17 years, ever resident in Stockholm County in 2001-2007 (N = 589,114). ASD cases (N = 5,100) were identified using a multisource approach, involving registers covering all pathways to ASD diagnosis and care, and categorized according to co-morbid intellectual disability. Prospectively recorded information on potential determinants and consequences of ASD were retrieved from national and regional health and administrative registers. Case ascertainment was validated through case-note review, and cross validation with co-existing cases in a national twin study. RESULTS: The 2007 year prevalence of ASD in all children and young people was 11.5 per 1,000 (95% confidence interval 11.2-11.8), with a co-morbid intellectual disability recorded in 42.6% (41.0-44.2) of cases. We found 96.0% (92.0-98.4) of reviewed case-notes being consistent with a diagnosis of ASD, and confirmed ASD in 85.2% (66.2-95.8) of affected twins. CONCLUSIONS: Findings from this contemporary study accords with recently reported prevalence estimates from Western countries at around 1%, based on valid case ascertainment. The Stockholm Youth Cohort, in light of the availability of extensive information from Sweden’s registers, constitutes an important resource for ASD research. On-going work, including collection of biological samples, will enrich the study further.
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6. May T, Cornish K, Rinehart NJ. {{Gender Profiles of Behavioral Attention in Children With Autism Spectrum Disorder}}. {J Atten Disord}. 2012.
Objective: The attention profile of girls with autism spectrum disorder (ASD) is unclear compared with boys with ASD and typical children. This study aimed to investigate parent-reported ASD and ADHD symptoms in a large sample of boys and girls with and without ASD. Method: A total of 124 normally intelligent children, half of them girls, 64 with autistic disorder or Asperger’s disorder, and 60 age- and gender-matched typically developing, aged 7 to 12 years, were recruited. Parents completed questionnaires regarding autistic and ADHD symptoms. Results: No gender differences in social difficulties but more repetitive motor movements, communication difficulties, and inattention were reported in males, regardless of group. Younger boys with ASD had more elevated levels of hyperactivity-impulsivity than younger girls with ASD. Conclusion: Gender differences in autistic symptoms and inattention in ASD reflected gender differences in typical children. More pronounced hyperactivity in younger boys with ASD could contribute to higher rates of clinical referral than girls. (J. of Att. Dis. 2012; XX(X) 1-XX).
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7. Neal D, Matson JL, Hattier MA. {{A comparison of diagnostic criteria on the Autism Spectrum Disorder Observation for Children (ASD-OC)}}. {Dev Neurorehabil}. 2012.
Background: The Autism Spectrum Disorder Observation for Children (ASD-OC) is a new observation scale used to assess autistic symptomatology. As the publication of the fifth edition Diagnostic and Statistical Manual (DSM) is approaching, exploring the effect of the changing DSM criteria has begun to occur. Objective: The aim of this study was to compare severity of autistic impairment in children diagnosed with either the DSM-IV-TR or the DSM-5. Methods: ASD-OC total scores were compared between 63 children (3-15 years) in one of three groups: DSM-IV-TR group, DSM-5 group or control group. Results: The DSM-5 and DSM-IV-TR groups evinced significantly higher ASD-OC scores as compared to the control group; however, there were no significant differences between the DSM-5 and DSM-IV-TR groups in symptom severity. Conclusion: Many children who are currently diagnosed with ASD may no longer be diagnosed, despite having significant impairments roughly equal to those who meet DSM-5 criteria.
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8. Roselli F. {{Down syndrome DSCR1 causes spine pathology via the Fragile X-related protein FMRP}}. {EMBO J}. 2012.
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9. Simonoff E, Jones CR, Pickles A, Happe F, Baird G, Charman T. {{Severe mood problems in adolescents with autism spectrum disorder}}. {J Child Psychol Psychiatry}. 2012.
Introduction: Severe mood dysregulation and problems (SMP) in otherwise typically developing youth are recognized as an important mental health problem with a distinct set of clinical features, family history and neurocognitive characteristics. SMP in people with autism spectrum disorders (ASDs) have not previously been explored. Method: We studied a longitudinal, population-based cohort of adolescents with ASD in which we collected parent-reported symptoms of SMP that included rage, low and labile mood and depressive thoughts. Ninety-one adolescents with ASD provided data at age 16 years, of whom 79 had additional data from age 12. We studied whether SMP have similar correlates to those seen in typically developing youth. Results: Severe mood problems were associated with current (parent-rated) and earlier (parent- and teacher-rated) emotional problems. The number of prior psychiatric diagnoses increased the risk of subsequent SMP. Intellectual ability and adaptive functioning did not predict to SMP. Maternal mental health problems rated at 12 and 16 years were associated with SMP. Autism severity as rated by parents was associated with SMP, but the relationship did not hold for clinician ratings of autistic symptoms or diagnosis. SMP were associated with difficulty in identifying the facial expression of surprise, but not with performance recognizing other emotions. Relationships between SMP and tests of executive function (card sort and trail making) were not significant after controlling for IQ. Conclusions: This is the first study of the behavioural and cognitive correlates of severe mood problems in ASD. As in typically developing youth, SMP in adolescents with ASD are related to other affective symptoms and maternal mental health problems. Previously reported links to deficits in emotion recognition and cognitive flexibility were not found in the current sample. Further research is warranted using categorical and validated measures of SMP.
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10. So P, Greaves-Lord K, Van der Ende J, Verhulst FC, Rescorla L, de Nijs PF. {{Using the Child Behavior Checklist and the Teacher’s Report Form for identification of children with autism spectrum disorders}}. {Autism}. 2012.
This study evaluated the ability of the Child Behavior Checklist and the Teacher’s Report Form to identify children with autism spectrum disorders (ASD), using a sample of children with ASD (n = 458), referred children without ASD (n = 1109) and children from the general population (n = 999). A ten items ASD scale was constructed using half of the sample and the ability of this scale to discriminate between children with ASD and the other children was tested for the CBCL and the TRF separately and together in the other half of the sample. Using a cut-off score of 8 the combined CBCL/TRF ASD scale demonstrated high predictive values (NPV 95%, PPV 73%) in identifying children with ASD and children in the general population sample. This might be an acceptable percentage of false positives in general screening, considering the chance that these children might have other behavioural, emotional, and developmental problems which also need psychiatric evaluation. In the referred population, using a cut-off of 13, PPV was 49% and NPV was 85%. The high NPV indicates that in a referred population the scale is especially good at identifying children who do not need evaluation with a more ASD-specific instrument.
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11. Xu X, Xu Q, Zhang Y, Zhang X, Cheng T, Wu B, Ding Y, Lu P, Zheng J, Zhang M, Qiu Z, Yu X. {{A case report of Chinese brothers with inherited MECP2-containing duplication: autism and intellectual disability, but not seizures or respiratory infections}}. {BMC Med Genet}. 2012; 13(1): 75.
ABSTRACT: BACKGROUND: Autistic spectrum disorders (ASDs) are a family of neurodevelopmental disorders with strong genetic components. Recent studies have shown that copy number variations in dosage sensitive genes can contribute significantly to these disorders. One such gene is the transcription factor MECP2, whose loss of function in females results in Rett syndrome, while its duplication in males results in developmental delay and autism. CASE PRESENTATION: Here, we identified a Chinese family with two brothers both inheriting a 2.2 Mb MECP2-containing duplication (151,369,305 — 153,589,577) from their mother. In addition, both brothers also had a 213.7 kb duplication on Chromosome 2, inherited from their father. The older brother also carried a 48.4 kb duplication on Chromosome 2 inherited from the mother, and a 8.2 kb deletion at 11q13.5 inherited from the father. Based on the published literature, MECP2 is the most autism-associated gene among the identified CNVs. Consistently, the boys displayed clinical features in common with other patients carrying MECP2 duplications, including intellectual disability, autism, lack of speech, slight hypotonia and unsteadiness of movement. They also had slight dysmorphic features including a depressed nose bridge, large ears and midface hypoplasia. Interestingly, they did not exhibit other clinical features commonly observed in American-European patients with MECP2 duplication, including recurrent respiratory infections and epilepsy. CONCLUSIONS: To our knowledge, this is the first identification and characterization of Chinese Han patients with MECP2-containing duplications. Further cases are required to determine if the above described clinical differences are due to individual variations or related to the genetic background of the patients.
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12. Yamada T, Ohta H, Watanabe H, Kanai C, Tani M, Ohno T, Takayama Y, Iwanami A, Kato N, Hashimoto R. {{Functional alterations in neural substrates of geometric reasoning in adults with high-functioning autism}}. {PLoS One}. 2012; 7(8): e43220.
Individuals with autism spectrum condition (ASC) are known to excel in some perceptual cognitive tasks, but such developed functions have been often regarded as « islets of abilities » that do not significantly contribute to broader intellectual capacities. However, recent behavioral studies have reported that individuals with ASC have advantages for performing Raven’s (Standard) Progressive Matrices (RPM/RSPM), a standard neuropsychological test for general fluid intelligence, raising the possibility that ASC’s cognitive strength can be utilized for more general purposes like novel problem solving. Here, the brain activity of 25 adults with high-functioning ASC and 26 matched normal controls (NC) was measured using functional magnetic resonance imaging (fMRI) to examine neural substrates of geometric reasoning during the engagement of a modified version of the RSPM test. Among the frontal and parietal brain regions involved in fluid intelligence, ASC showed larger activation in the left lateral occipitotemporal cortex (LOTC) during an analytic condition with moderate difficulty than NC. Activation in the left LOTC and ventrolateral prefrontal cortex (VLPFC) increased with task difficulty in NC, whereas such modulation of activity was absent in ASC. Furthermore, functional connectivity analysis revealed a significant reduction of activation coupling between the left inferior parietal cortex and the right anterior prefrontal cortex during both figural and analytic conditions in ASC. These results indicate altered pattern of functional specialization and integration in the neural system for geometric reasoning in ASC, which may explain its atypical cognitive pattern, including performance on the Raven’s Matrices test.
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13. Yang JC, Chan SH, Khan S, Schneider A, Nanakul R, Teichholtz S, Niu YQ, Seritan A, Tassone F, Grigsby J, Hagerman PJ, Hagerman RJ, Olichney JM. {{Neural Substrates of Executive Dysfunction in Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS): a Brain Potential Study}}. {Cereb Cortex}. 2012.
Executive dysfunction in fragile X-associated tremor/ataxia syndrome (FXTAS) has been suggested to mediate other cognitive impairments. In the present study, event-related potentials and neuropsychological testing were combined to investigate the brain mechanisms underlying the executive dysfunction in FXTAS. Thirty-two-channel electroencephalography was recorded during an auditory « oddball » task requiring dual responses. FXTAS patients (N= 41, mean age= 62) displayed prolonged latencies of N1 and P3 and reduced amplitudes of P2 and P3, whereas their N2 measures remained within the normal range, indicating relatively preserved early-stage auditory attention but markedly impaired late-stage attention and working memory updating processes (as indexed by P3). Topographical mapping revealed a typical parietal P3 peak preceded by a prominent fronto-central P3 in normal control subjects (N= 32), whereas FXTAS patients had decreased parietal P3 amplitude and diminished fronto-central positivities with a delayed onset ( approximately 50 ms later than controls, P < 0.002). The P3 abnormalities were associated with lower executive function test (e.g., BDS-2) scores. Smaller P3 amplitudes also correlated with increased CGG repeat length of fragile X mental retardation 1 (FMR1) gene and higher FMR1 mRNA levels. These results indicate that abnormal fronto-parietal attentional network dynamics underlie executive dysfunction, the cardinal feature of cognitive impairment in FXTAS.
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14. Yudell M, Tabor HK, Dawson G, Rossi J, Newschaffer C. {{Priorities for autism spectrum disorders risk communication and ethics}}. {Autism}. 2012.
Autism spectrum disorders are an issue of increasing public health significance. The incidence of autism spectrum disorders has been increasing in recent years, and they are associated with significant personal and financial impacts for affected persons and their families. In recent years, a large number of scientific studies have been undertaken, which investigate genetic and environmental risk factors for autism, with more studies underway. At present, much remains unknown regarding autism spectrum disorder risk factors, but the emerging picture of causation is in many cases complex, with multiple genes and gene-environment interactions being at play. The complexity and uncertainty surrounding autism spectrum disorder risk factors raise a number of questions regarding the ethical considerations that should be taken into account when undertaking autism spectrum disorder risk communication. At present, however, little has been written regarding autism spectrum disorder risk communication and ethics. This article summarizes the findings of a recent conference investigating ethical considerations and policy recommendations in autism spectrum disorder risk communication, which to the authors’ knowledge is the first of its kind. Here, the authors discuss a number of issues, including uncertainty; comprehension; inadvertent harm; justice; and the appropriate roles of clinicians, scientists, and the media in autism spectrum disorder risk communication.
