1. {{[Family paracentric inversion of the short arm of chromosome X (Xp21.2p11.23) and connection with autism spectrum disorders]}}. {Srp Arh Celok Lek};2012 (Nov-Dec);140(11-12):760-764.
INTRODUCTION: Autism spectrum disorders (ASDs) are a group of complex pervasive developmental disorders characterized by impairments in communication, social interaction and behavior. In most cases autism is caused by a combination of genetic factors and environmental risk factors. In 10% to 20% of cases it has been shown that the cause of ASD is genetic. CASE OUTLINE: We are describing a 2-year-old boy who was referred to genetic counseling because of speech delay and certain autism-like behavior. By cytogenetic analysis the karyotype 46, inv(X),Y was obtained. The boy was a carrier of a paracentric inversion of the short arm of the chromosome X. After cytogenetic analysis of parental blood, it was detected that mother was a carrier of identical aberration, but had no clinical signs. The method of fluorescent in situ hybridization (FISH) yielded the precise breakpoint in the region (p21.2p11.23). Mother and son were carriers of identical X chromosome. CONCLUSION: Breakpoints are located in the regions that have already been linked to autism, which indicates that the positional effect of the gene could have been a possible cause of the patient’s genotype. In addition to positional effects, in order to better understand the etiology of autism other genetic and environmental factors should be always taken into consideration.
2. Arnold LE, Anand R, Aman M. {{Varenicline in Autistic Disorder: Hypothesis and Case Report of Single-Patient Crossover}}. {J Child Adolesc Psychopharmacol};2013 (Jan 25)
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3. Bleil Walters J, Hughes TL, Sutton LR, Marshall SN, Crothers LM, Lehman C, Paserba D, Talkington V, Taormina R, Huang A. {{Maltreatment and depression in adolescent sexual offenders with an autism spectrum disorder}}. {J Child Sex Abus};2013 (Jan);22(1):72-89.
This study examined the self-reported presence and severity of abuse, neglect, and depressive symptoms for 43 adolescents adjudicated delinquent due to a sexual offense. Twenty-seven of the adolescent sexual offenders were also diagnosed with an autism spectrum disorder, and 16 did not carry an autism spectrum disorder diagnosis. Both groups reported moderate to high levels of abuse and neglect. Adolescent sexual offenders with an autism spectrum disorder reported significantly higher depressive symptoms than those without an autism spectrum disorder. Furthermore, of the group with an autism spectrum disorder, those reporting severe levels of emotional abuse and/or emotional neglect were more likely to also have depressive symptoms. Results suggest a need to tailor treatment programs to match the unique needs of sexual offenders.
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4. Carotenuto M, Esposito M, D’Aniello A, Rippa CD, Precenzano F, Pascotto A, Bravaccio C, Elia M. {{Erratum to: Polysomnographic findings in Rett syndrome: a case-control study}}. {Sleep Breath};2013 (Jan 26)
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5. Cashin A, Browne G, Bradbury J, Mulder A. {{The effectiveness of narrative therapy with young people with autism}}. {J Child Adolesc Psychiatr Nurs};2013 (Feb);26(1):32-41.
PROBLEM: The aim of this pilot study was to be the first step toward empirically determining whether narrative therapy is effective in helping young people with autism who present with emotional and behavioral problems. Autism is increasingly being recognized in young people with average and above intelligence. Because of the nature of autism, these young people have difficulty navigating the challenges of school and adolescence. Narrative therapy can help them with their current difficulties and also help them develop skills to address future challenges. Narrative therapy involves working with a person to examine and edit the stories the person tells himself or herself about the world. It is designed to promote social adaptation while working on specific problems of living. METHOD: This pilot intervention study used a convenience sample of 10 young people with autism (10-16 years) to evaluate the effectiveness of five 1 hr sessions of narrative therapy conducted over 10 weeks. The study used the parent-rated Strengths and Difficulties Questionnaire (SDQ) as the primary outcome measure. Secondary outcome measures were the Kessler-10 Scale of Psychological Distress (K-10), the Beck Hopelessness Scale, and a stress biomarker, the salivary cortisol to dehydroepiandrosterone (DHEA) ratio. FINDINGS: Significant improvement in psychological distress identified through the K-10 was demonstrated. Significant improvement was identified on the Emotional Symptoms Scale of the SDQ. The cortisol:DHEA ratio was responsive and a power analysis indicated that further study is indicated with a larger sample. CONCLUSION: Narrative therapy has merit as an intervention with young people with autism. Further research is indicated.
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6. Daroles L, Caille I. {{[Dendritic spines and local protein synthesis contribute to Down and fragile X syndromes]}}. {Med Sci (Paris)};2013 (Jan);29(1):17-19.
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7. Kikuchi M, Yoshimura Y, Shitamichi K, Ueno S, Hirosawa T, Munesue T, Ono Y, Tsubokawa T, Haruta Y, Oi M, Niida Y, Remijn GB, Takahashi T, Suzuki M, Higashida H, Minabe Y. {{A custom magnetoencephalography device reveals brain connectivity and high reading/decoding ability in children with autism}}. {Sci Rep};2013;3:1139.
A subset of individuals with autism spectrum disorder (ASD) performs more proficiently on certain visual tasks than may be predicted by their general cognitive performances. However, in younger children with ASD (aged 5 to 7), preserved ability in these tasks and the neurophysiological correlates of their ability are not well documented. In the present study, we used a custom child-sized magnetoencephalography system and demonstrated that preserved ability in the visual reasoning task was associated with rightward lateralisation of the neurophysiological connectivity between the parietal and temporal regions in children with ASD. In addition, we demonstrated that higher reading/decoding ability was also associated with the same lateralisation in children with ASD. These neurophysiological correlates of visual tasks are considerably different from those that are observed in typically developing children. These findings indicate that children with ASD have inherently different neural pathways that contribute to their relatively preserved ability in visual tasks.
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8. Kraan CM, Hocking DR, Bradshaw JL, Fielding J, Cohen J, Georgiou-Karistianis N, Cornish KM. {{Neurobehavioral evidence for the involvement of the FMR1 gene in female carriers of fragile X syndrome}}. {Neurosci Biobehav Rev};2013 (Jan 22)
For years, premutation-carriers of fragile X-syndrome (FXS) were assumed free from any deleterious phenotype. In this review, we discuss the current literature on neurocognitive, emotional and neuromotor profiles emerging in females with the fragile-X premutation, and discuss phenotypic profiles in male premutation-carriers to gain insights into possible underlying mechanisms associated with FMR1 gene expression. We contend that this emerging phenotypic profile in females with the fragile-X premutation needs further investigation using experimentally-driven tasks sensitive to neural networks especially vulnerable to FMR1 gene expression. Further investigation of developmental aspects of the female carrier profile is needed to determine the extent to which emotional, cognitive and neurobehavioral challenges indicate at-risk profiles for later degenerative decline, or rather a stable developmental phenotype. These future research avenues will provide critical new information which will enable identification of women at greatest risk for subtle age-dependent neurobehavioral changes well before the onset of more serious clinical consequences alongside the identification of biomarkers which may be useful in establishing the efficacy of future therapeutic interventions.
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9. Lim ET, Raychaudhuri S, Sanders SJ, Stevens C, Sabo A, Macarthur DG, Neale BM, Kirby A, Ruderfer DM, Fromer M, Lek M, Liu L, Flannick J, Ripke S, Nagaswamy U, Muzny D, Reid JG, Hawes A, Newsham I, Wu Y, Lewis L, Dinh H, Gross S, Wang LS, Lin CF, Valladares O, Gabriel SB, Depristo M, Altshuler DM, Purcell SM, State MW, Boerwinkle E, Buxbaum JD, Cook EH, Gibbs RA, Schellenberg GD, Sutcliffe JS, Devlin B, Roeder K, Daly MJ. {{Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders}}. {Neuron};2013 (Jan 23);77(2):235-242.
To characterize the role of rare complete human knockouts in autism spectrum disorders (ASDs), we identify genes with homozygous or compound heterozygous loss-of-function (LoF) variants (defined as nonsense and essential splice sites) from exome sequencing of 933 cases and 869 controls. We identify a 2-fold increase in complete knockouts of autosomal genes with low rates of LoF variation (</=5% frequency) in cases and estimate a 3% contribution to ASD risk by these events, confirming this observation in an independent set of 563 probands and 4,605 controls. Outside the pseudoautosomal regions on the X chromosome, we similarly observe a significant 1.5-fold increase in rare hemizygous knockouts in males, contributing to another 2% of ASDs in males. Taken together, these results provide compelling evidence that rare autosomal and X chromosome complete gene knockouts are important inherited risk factors for ASD.
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10. Lipton J, Sahin M. {{Fragile x syndrome therapeutics: translation, meet translational medicine}}. {Neuron};2013 (Jan 23);77(2):212-213.
Fragile X syndrome, a common cause of intellectual disability and autism, is thought to occur due to abnormal regulation of neuronal protein synthesis. A study by Osterweil et al. (2013), in this issue, demonstrates that the HMG-CoA reductase inhibitor lovastatin can normalize protein synthesis and also reduce audiogenic seizures in Fmr1 knockout mice.
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11. Osterweil EK, Chuang SC, Chubykin AA, Sidorov M, Bianchi R, Wong RK, Bear MF. {{Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile x syndrome}}. {Neuron};2013 (Jan 23);77(2):243-250.
Many neuropsychiatric symptoms of fragile X syndrome (FXS) are believed to be a consequence of altered regulation of protein synthesis at synapses. We discovered that lovastatin, a drug that is widely prescribed for the treatment of high cholesterol, can correct excess hippocampal protein synthesis in the mouse model of FXS and can prevent one of the robust functional consequences of increased protein synthesis in FXS, epileptogenesis. These data suggest that lovastatin is potentially disease modifying and could be a viable prophylactic treatment for epileptogenesis in FXS.
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12. Renno P, Wood JJ. {{Discriminant and Convergent Validity of the Anxiety Construct in Children with Autism Spectrum Disorders}}. {J Autism Dev Disord};2013 (Jan 26)
Despite reports of high anxiety in children with autism spectrum disorders (ASD), there is controversy regarding differential diagnosis of ASD symptoms and anxiety symptoms. This study examined 88 children, aged 7-11 years, with ASD referred for concerns about anxiety. A multitrait-(social anxiety, separation anxiety, overall anxiety severity, and overall ASD severity), multimethod-(diagnostic interviews, parent-, and child-based measures) analysis was conducted. Results from structural equation modeling suggest statistical discrimination between anxiety and ASD severity and convergence among differing reports of two of the anxiety subdomains (separation anxiety and overall anxiety). These findings suggest that anxiety symptoms experienced by children with ASD are separate from ASD symptom severity and may instead reflect anxiety syndromes (e.g., separation anxiety) similar to those that occur in typically developing children.
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13. Ross H, Guo Y, Coleman K, Ousley O, Miller A. {{Association of IL-12p70 and IL-6:IL-10 ratio with autism-related behaviors in 22q11.2 deletion syndrome: a preliminary report}}. {Brain Behav Immun};2013 (Jan 24)
22q11.2 deletion syndrome (22q11DS) is a genetic disorder that conveys a significant risk for the development of social behavior disorders, including autism and schizophrenia. Also known as DiGeorge syndrome, 22q11DS is the second most common childhood genetic disorder and is characterized by an elevated risk for immune disorders, as 77% of individuals have an identifiable immune deficiency. We hypothesize that this immune dysfunction could contribute to the elevated risk of impaired social behavior seen in 22q11DS. The current study begins to elucidate these immune deficits and link them with the behavioral alterations associated with the disorder. Serum concentrations of a series of cytokines were examined, using a multiplex immunoassay, in sixteen individuals with 22q11DS and screened for autism-related behavior using the Autism Diagnostic Interview-Revised (ADI-R). This preliminary study examined correlations between specific immune proteins and each of the ADI-R algorithm scores (social, communication, and repetitive behavior). The inflammatory cytokine IL-1beta, as well as the ratio between the inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10, were correlated with social scores (r = 0.851, p = 0.004; r = 0.580, p = 0.018). In addition, the inflammatory cytokines interferon gamma and IL-12p70 were correlated with repetitive behaviors (r = 0.795, p = 0.033; r = 0.774, p = 0.002). Interestingly, IL-12 has been reported to be increased in autistic children. These data show a positive relationship between severity of autism-related behaviors and level of serum concentrations of inflammatory cytokines in individuals with 22q11DS, providing a basis for further inquiry.
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14. Shorter E, Wachtel LE. {{Childhood catatonia, autism and psychosis past and present: is there an ‘iron triangle’?}}. {Acta Psychiatr Scand};2013 (Jan 27)
OBJECTIVE: To explore the possibility that autism, catatonia and psychoses in children are different manifestations of a single underlying form of brain pathology – a kind of ‘Iron Triangle’ of symptomatology – rather than three separate illnesses. METHOD: Systematic evaluation of historical case literature on autism to determine if catatonic and psychotic symptoms accompanied the diagnosis, as is found in some challenging present-day cases. RESULTS: It is clear from the historical literature that by the 1920s all three diagnoses in the Iron Triangle – catatonia, autism and childhood schizophrenia – were being routinely applied to children and adolescents. Furthermore, it is apparent that children diagnosed with one of these conditions often qualified for the other two as well. Although conventional thinking today regards these diagnoses as separate entities, the presence of catatonia in a variety of conditions is being increasingly recognized, and there is also growing evidence of connections between childhood-onset psychoses and autism. CONCLUSION: Recognition of a mixed form of catatonia, autism and psychosis has important implications for both diagnosis and treatment. None of the separate diagnoses provides an accurate picture in these complex cases, and when given single diagnoses such as ‘schizophrenia’, the standard treatment options may prove markedly ineffective.
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15. Stein JL, Parikshak NN, Geschwind DH. {{Rare inherited variation in autism: beginning to see the forest and a few trees}}. {Neuron};2013 (Jan 23);77(2):209-211.
In this issue of Neuron, two papers (Lim et al., 2013; Yu et al., 2013) use whole-exome sequencing (WES) to elucidate the contribution of inherited variation to the risk for autism by leveraging the increased penetrance of homozygous and compound heterozygous rare variants in autosomes and hemizygous rare variants in the X chromosome of males. Together, they expand our knowledge about the genetic architecture of ASD, verify previously identified genes, and identify novel mutations that will guide the discovery of the critical biological processes disrupted in autism.
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16. Williams K, Perkins D, Wheeler D, Hayen A, Bayl V. {{Can questions about social interaction correctly identify preschool aged children with autism?}}. {J Paediatr Child Health};2013 (Jan 25)
AIM: We developed a questionnaire to assess social development (SIQ) in preschool children. Social development is often not included in medical assessment, though it may assist in early identification of autism spectrum disorder (ASD). METHODS: Parents of 108 children with ASD, speech and language disorders, or ‘developmental concerns’, recruited from a clinical developmental assessment and community child health service, completed the SIQ, and also a Childhood Autism Rating Scale (CARS) assessment. Receiver Operator Characteristic (ROC) curves were generated to assess the performance of different questionnaire score thresholds in correctly identifying children with a CARS score of 30 or more. Logistic regression models were used to identify the questions which had the most predictive value for a CARS score of 30 or more. RESULTS: An SIQ score of 14 or more correctly identified children with a CARS >/=30 with a sensitivity of 85%, specificity 85%, positive likelihood ratio (LR) 8.3 and negative LR 0.2. Two questions were identified as most predictive of ASD. CONCLUSIONS: The SIQ may assist clinicians in assessing social development and in making decisions about referral for autism assessment. Evaluation of the SIQ at the point of entry to a clinical service is needed.
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17. Yu TW, Chahrour MH, Coulter ME, Jiralerspong S, Okamura-Ikeda K, Ataman B, Schmitz-Abe K, Harmin DA, Adli M, Malik AN, D’Gama AM, Lim ET, Sanders SJ, Mochida GH, Partlow JN, Sunu CM, Felie JM, Rodriguez J, Nasir RH, Ware J, Joseph RM, Hill RS, Kwan BY, Al-Saffar M, Mukaddes NM, Hashmi A, Balkhy S, Gascon GG, Hisama FM, Leclair E, Poduri A, Oner O, Al-Saad S, Al-Awadi SA, Bastaki L, Ben-Omran T, Teebi AS, Al-Gazali L, Eapen V, Stevens CR, Rappaport L, Gabriel SB, Markianos K, State MW, Greenberg ME, Taniguchi H, Braverman NE, Morrow EM, Walsh CA. {{Using Whole-Exome Sequencing to Identify Inherited Causes of Autism}}. {Neuron};2013 (Jan 23);77(2):259-273.
Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.
