1. Abdala AP, Lioy DT, Garg SK, Knopp SJ, Paton JF, Bissonnette JM. {{Effect of Sarizotan, a 5-HT and D2-Like Receptor Agonist, on Respiration in Three Mouse Models of Rett Syndrome}}. {American journal of respiratory cell and molecular biology}. 2013 Dec 18.
Rationale: Disturbances in respiration are common and debilitating features of Rett syndrome (RTT). A previous study showed that the 5-HT1a receptor agonist 8-OH-DPAT significantly reduced the incidence of apnea and the irregular breathing pattern in a mouse model of the disorder. 8-OH-DPAT, however, is not available for clinical practice. Sarizotan, a full 5-HT1a agonist, dopamine D2-like agonist/partial agonist has been used in clinical trials for the treatment of L-dopa induced dyskinesia. Objectives: To evaluate the effects of sarizotan on respiration and locomotion in mouse models of RTT. Methods: Studies were carried out in Bird and Jaenisch strains of methyl-CpG-binding protein 2 deficient heterozygous female and Jaenisch strain Mecp2 null male mice and in knock-in heterozygous females of a common nonsense mutation (R168X). Respiratory pattern was determined with body plethysmography and locomotion with open-field recording. Sarizotan or vehicle was administered 20 min prior to a 30 min recording of respiratory pattern or motor behavior. In separate studies, a crossover design was used to administer the drug for 7 and for 14 days. Measurements and Main Results: Sarizotan reduced the incidence of apnea in all three RTT mouse models to ~15% of their pre-treatment levels. In addition, the irregular breathing pattern was corrected to that of wild type (WT) littermates. When administered for 7 or 14 days apnea decreased to 25-33% of the incidence seen with vehicle. Conclusions: This study indicates that the clinically approved drug sarizotan is an effective treatment for respiratory disorders in mouse models of RTT. Word count: 248.
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2. Berger JM, Rohn TT, Oxford JT. {{Autism as the Early Closure of a Neuroplastic Critical Period Normally Seen in Adolescence}}. {Biological systems, open access}. 2013 Aug 20;1.
The most severe cases of autism are diagnosed by extreme social dysfunction and other behavioral abnormalities. A number of genetic studies have been conducted to correlate behavioral phenotypes to genetic dysfunctions, but no « autism gene » has yet been discovered. In addition, environmental factors have been found to influence the development of autistic traits with high probability. This review will examine the role of a shortened period of neuroplasticity as a unifying feature of the autistic phenotype. The neuroplastic period of interest normally extends into adolescence, allowing for neural integration and the development of language and social skills. Early closure of this period may result in a shortened period of development, forcing the brain to rely on underdeveloped structures.
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3. Happe F. {{International society for autism research news}}. {Autism research : official journal of the International Society for Autism Research}. 2013 Dec;6(6):659.
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4. Hinkka-Yli-Salomaki S, Banerjee PN, Gissler M, Lampi KM, Vanhala R, Brown AS, Sourander A. {{The incidence of diagnosed autism spectrum disorders in Finland}}. {Nordic journal of psychiatry}. 2013 Dec 20.
Background: Previous reports indicate an increase in incidence of autism spectrum disorders (ASD). Aims: First, to assess the incidence of diagnosed ASD in children born between 1996 and 1998, based on nationwide inpatient and outpatient register information. Second, to investigate the incidence rate over time of diagnosed ASD and specifically childhood autism, Asperger’s syndrome and pervasive developmental disorder (PDD-NOS) in children born between 1987 and 1998. Methods: This is population-based cohort study with children born in Finland between 1 January 1987 and 31 December 2005; a total of more than 1.2 million children. Children were identified in the Finnish Hospital Discharge Register, and the reported diagnoses were based on the International Statistical Classification of Diseases (ICD-10, ICD-9). Results: The annual incidence rate of diagnosed ASD based on inpatient and outpatient register data was 53.7 per 10,000 (95% CI 50.4-57.2). Incidence was 82.6 per 10,000 in boys and 23.6 per 10,000 in girls, yielding a sex ratio (boys:girls) of 3.5:1. We report an eightfold increase in the incidence rates in children of diagnosed ASD and specifically in childhood autism, Asperger’s syndrome and PDD-NOS and born between 1987 and 1992 based on inpatient register information. Conclusions: Increased awareness of ASD, more precise diagnostic criteria and changes in practice for diagnosing autism may have had a substantial effect on the increased incidence of inpatient treated ASD cases from 1987 to 1992. Between 1992 and 1998, the incidence rate based on inpatient and outpatient service use remained rather stable.
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5. Hviid A, Melbye M, Pasternak B. {{Use of selective serotonin reuptake inhibitors during pregnancy and risk of autism}}. {The New England journal of medicine}. 2013 Dec 19;369(25):2406-15.
BACKGROUND: Studies have raised concern about an association between the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy and an increased risk of autism spectrum disorders in the offspring. METHODS: We conducted a cohort study of all singleton live births in Denmark from 1996 through 2005 (626,875 births), with follow-up through 2009. Using Danish population registries, we linked information on maternal use of SSRIs before and during pregnancy, autism spectrum disorders diagnosed in the offspring, and a range of potential confounders. We used a survival analysis of the time to diagnosis in the offspring with Poisson regression to estimate rate ratios of autism spectrum disorders according to maternal use of SSRIs. RESULTS: During 5,057,282 person-years of follow-up, we identified 3892 cases of autism spectrum disorder (incidence rate, 77.0 per 100,000 person-years). A total of 52 cases during 42,400 person-years of follow-up involved offspring of women who were exposed to SSRIs during their pregnancy (incidence rate, 122.6 per 100,000 person-years). As compared with no use of SSRIs both before and during pregnancy, use during pregnancy was not associated with a significantly increased risk of autism spectrum disorders (fully adjusted rate ratio, 1.20; 95% confidence interval [CI], 0.90 to 1.61). Among women who received SSRIs before pregnancy but not during pregnancy, the corresponding fully adjusted rate ratio was 1.46 (95% CI, 1.17 to 1.81). CONCLUSIONS: We did not detect a significant association between maternal use of SSRIs during pregnancy and autism spectrum disorder in the offspring. On the basis of the upper boundary of the confidence interval, our study could not rule out a relative risk up to 1.61, and therefore the association warrants further study. (Funded by the Danish Health and Medicines Authority.).
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6. Kasari C, Brady N, Lord C, Tager-Flusberg H. {{Assessing the minimally verbal school-aged child with autism spectrum disorder}}. {Autism research : official journal of the International Society for Autism Research}. 2013 Dec;6(6):479-93.
This paper addresses the issue of assessing communication, language, and associated cognitive and behavioral abilities of minimally verbal children with autism spectrum disorder (ASD), presenting a summary of a year-long series of meetings held by a group of experts in the field of ASD and National Institutes of Health staff. In this paper, our goals were to first define the population and then present general guidelines for optimizing assessment sessions for this challenging population. We then summarize the available measures that can be used across a variety of behavioral domains that are most directly relevant to developing language skills, including oral motor skills, vocal repertoire, receptive and expressive language, imitation, intentional communication, play, social behavior, repetitive and sensory behaviors, and nonverbal cognition. We conclude with a discussion of some of the limitations in the available measures and highlight recommendations for future research in this area. Autism Res 2013, 6: 479-493. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc.
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7. Kent JM, Hough D, Singh J, Karcher K, Pandina G. {{An open-label extension study of the safety and efficacy of risperidone in children and adolescents with autistic disorder}}. {Journal of child and adolescent psychopharmacology}. 2013 Dec;23(10):676-86.
Abstract Objective: The purpose of this study was to evaluate the long-term safety and efficacy of risperidone in treating irritability and related behaviors in children and adolescents with autistic disorders. Methods: In this 6 month (26 week) open-label extension (OLE) study, patients (5-17 years of age, who completed the previous fixed-dose, 6 week, double-blind [DB] phase) were flexibly dosed with risperidone based on body weight. The maximum allowed dose was 1.25 mg/day for those weighing 20 to <45 kg, and 1.75 mg/day for those weighing >/=45 kg. The study primarily assessed risperidone’s safety; efficacy was assessed as a secondary end-point. Results: Fifty-six (71%) out of 79 enrolled patients completed the OLE; the most common discontinuations were for insufficient response (7 [9%]) or adverse events (AE) (5 [6%]). The most common (>/=5% frequency in the total group) AEs were increased appetite (11% [n=9]); increased weight and vomiting (9% [n=7] each); sedation, pyrexia, and upper respiratory tract infection (8% [n=6] each); nasopharyngitis (6% [n=5]); and somnolence and fatigue (5% [n=4] each). Extrapyramidal AEs were reported in 6 (8%) patients. Increase in mean weight (11-15%) and body mass index (5-10%) occurred; one patient discontinued because of weight increase. One potentially prolactin-related AE (irregular menstruation) was reported. The risperidone high-dose group had the greatest mean improvement in sleep visual analog scale (24.6). All groups showed additional improvement in efficacy scale scores during the OLE. Conclusions: During this OLE, safety findings with risperidone treatment (maximum weight-based dose of 1.25 mg/day or 1.75 mg/day) were consistent with those observed in the DB phase, and with the current safety information for risperidone in autistic, psychiatric, and behavioral disorders. Patients experienced some additional improvement in irritability and related behaviors. Clinical Trials Registry: This phase-4 study is registered at ClinicalTrials.gov (NCT00576732).
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8. Ronconi L, Facoetti A, Bulf H, Franchin L, Bettoni R, Valenza E. {{Paternal Autistic Traits are Predictive of Infants Visual Attention}}. {J Autism Dev Disord}. 2013 Dec 20.
Since subthreshold autistic social impairments aggregate in family members, and since attentional dysfunctions appear to be one of the earliest cognitive markers of children with autism, we investigated in the general population the relationship between infants’ attentional functioning and the autistic traits measured in their parents. Orienting and alerting attention systems were measured in 8-month-old infants using a spatial cueing paradigm. Results showed that only paternal autistic traits were linked to their children’s: (1) attentional disengagement; (2) rapid attentional orienting and (3) alerting. Our findings suggest that an early dysfunction of orienting and alerting systems might alter the developmental trajectory of future ability in social cognition and communication.
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9. Stefansson H, Meyer-Lindenberg A, Steinberg S, Magnusdottir B, Morgen K, Arnarsdottir S, Bjornsdottir G, Walters GB, Jonsdottir G, Doyle OM, Tost H, Grimm O, Kristjansdottir S, Snorrason H, Davidsdottir SR, Gudmundsson LJ, Jonsson GF, Stefansdottir B, Helgadottir I, Haraldsson M, Jonsdottir B, Thygesen JH, Schwarz AJ, Didriksen M, Stensbol TB, Brammer M, Kapur S, Halldorsson JG, Hreidarsson S, Saemundsen E, Sigurdsson E, Stefansson K. {{CNVs conferring risk of autism or schizophrenia affect cognition in controls}}. {Nature}. 2013 Dec 18.
In a small fraction of patients with schizophrenia or autism, alleles of copy-number variants (CNVs) in their genomes are probably the strongest factors contributing to the pathogenesis of the disease. These CNVs may provide an entry point for investigations into the mechanisms of brain function and dysfunction alike. They are not fully penetrant and offer an opportunity to study their effects separate from that of manifest disease. Here we show in an Icelandic sample that a few of the CNVs clearly alter fecundity (measured as the number of children by age 45). Furthermore, we use various tests of cognitive function to demonstrate that control subjects carrying the CNVs perform at a level that is between that of schizophrenia patients and population controls. The CNVs do not all affect the same cognitive domains, hence the cognitive deficits that drive or accompany the pathogenesis vary from one CNV to another. Controls carrying the chromosome 15q11.2 deletion between breakpoints 1 and 2 (15q11.2(BP1-BP2) deletion) have a history of dyslexia and dyscalculia, even after adjusting for IQ in the analysis, and the CNV only confers modest effects on other cognitive traits. The 15q11.2(BP1-BP2) deletion affects brain structure in a pattern consistent with both that observed during first-episode psychosis in schizophrenia and that of structural correlates in dyslexia.
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10. Vannucchi G, Masi G, Toni C, Dell’osso L, Marazziti D, Perugi G. {{Clinical features, developmental course, and psychiatric comorbidity of adult autism spectrum disorders}}. {CNS spectrums}. 2013 Dec 19:1-8.
Autism spectrum disorders (ASDs) include a heterogeneous group of neurodevelopmental disorders with early onset in childhood. ASDs should be considered lifelong clinical entities, although there is a certain variability in developmental trajectories, and therefore should be considered of great interest also for adulthood psychiatrists. A few studies have been carried out to explore the clinical picture and course development of these disorders during adulthood, or their relationship with other mental disorders. Indeed, ASDs often share overlapping features with other disorders, such as schizophrenia and obsessive-compulsive, mood, and personality disorders, and as a result misdiagnoses often occur. The aim of this review is to summarize the available literature on ASDs in adulthood with a specific focus on the clinical picture, course, and psychiatric comorbidity. It is proposed that a careful diagnostic screening for ASDs in adults would contribute to clarifying the relationship with comorbid psychiatric disorders, while improving the possibility of treatment and outcome of such conditions.
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11. Vohra R, Madhavan S, Sambamoorthi U, St Peter C. {{Access to services, quality of care, and family impact for children with autism, other developmental disabilities, and other mental health conditions}}. {Autism}. 2013 Dec 18.
This cross-sectional study examined perceived access to services, quality of care, and family impact reported by caregivers of children aged 3-17 years with autism spectrum disorders, as compared to caregivers of children with other developmental disabilities and other mental health conditions. The 2009-2010 National Survey of Children with Special Health Care Needs was utilized to examine the association between child’s special needs condition and three outcomes (N = 18,136): access to services (difficulty using services, difficulty getting referrals, lack of source of care, and inadequate insurance coverage), quality of care (lack of care coordination, lack of shared decision making, and no routine screening), and family impact (financial, employment, and time-related burden). Multivariate logistic regressions were performed to compare caregivers of children with autism spectrum disorders to caregivers of children with developmental disabilities (cerebral palsy, Down syndrome, developmental delay, or intellectual disability), mental health conditions (attention deficit hyperactivity disorder, anxiety, behavioral/conduct problems, or depression), or both developmental disabilities and mental health conditions. Caregivers of children with autism spectrum disorders were significantly more likely to report difficulty using services, lack of source of care, inadequate insurance coverage, lack of shared decision making and care coordination, and adverse family impact as compared to caregivers of children with developmental disabilities, mental health conditions, or both.
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12. Watanabe T, Abe O, Kuwabara H, Yahata N, Takano Y, Iwashiro N, Natsubori T, Aoki Y, Takao H, Kawakubo Y, Kamio Y, Kato N, Miyashita Y, Kasai K, Yamasue H. {{Mitigation of Sociocommunicational Deficits of Autism Through Oxytocin-Induced Recovery of Medial Prefrontal Activity: A Randomized Trial}}. {JAMA psychiatry}. 2013 Dec 18.
IMPORTANCE Sociocommunicational deficits make it difficult for individuals with autism spectrum disorders (ASD) to understand communication content with conflicting verbal and nonverbal information. Despite growing prospects for oxytocin as a therapeutic agent for ASD, no direct neurobiological evidence exists for oxytocin’s beneficial effects on this core symptom of ASD. This is slowing clinical application of the neuropeptide. OBJECTIVE To directly examine whether oxytocin has beneficial effects on the sociocommunicational deficits of ASD using both behavioral and neural measures. DESIGN, SETTING, AND PARTICIPANTS At the University of Tokyo Hospital, we conducted a randomized, double-blind, placebo-controlled, within-subject-crossover, single-site experimental trial in which intranasal oxytocin and placebo were administered. A total of 40 highly functioning men with ASD participated and were randomized in the trial. INTERVENTIONS Single-dose intranasal administration of oxytocin (24 IU) and placebo. MAIN OUTCOMES AND MEASURES Using functional magnetic resonance imaging, we examined effects of oxytocin on behavioral neural responses of the participants to a social psychological task. In our previous case-control study using the same psychological task, when making decisions about social information with conflicting verbal and nonverbal contents, participants with ASD made judgments based on nonverbal contents less frequently with longer time and could not induce enough activation in the medial prefrontal cortex. Therefore, our main outcomes and measures were the frequency of the nonverbal information-based judgments (NVJs), the response time for NVJs, and brain activity of the medial prefrontal cortex during NVJs. RESULTS Intranasal oxytocin enabled the participants to make NVJs more frequently (P = .03) with shorter response time (P = .02). During the mitigated behavior, oxytocin increased the originally diminished brain activity in the medial prefrontal cortex (P < .001). Moreover, oxytocin enhanced functional coordination in the area (P < .001), and the magnitude of these neural effects was predictive of the behavioral effects (P </= .01). CONCLUSIONS AND RELEVANCE These findings provide the first neurobiological evidence for oxytocin’s beneficial effects on sociocommunicational deficits of ASD and give us the initial account for neurobiological mechanisms underlying any beneficial effects of the neuropeptide. TRIAL REGISTRATION umin.ac.jp/ctr Identifier: UMIN000002241 and UMIN000004393.
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13. Wheeler A, Raspa M, Bann C, Bishop E, Hessl D, Sacco P, Bailey DB, Jr. {{Anxiety, attention problems, hyperactivity, and the Aberrant Behavior Checklist in fragile X syndrome}}. {American journal of medical genetics Part A}. 2014 Jan;164(1):141-55.
Behavior problems are a common challenge for individuals with fragile X syndrome (FXS) and constitute the primary clinical outcome domain in trials testing new FXS medications. However, little is known about the relationship between caregiver-reported behavior problems and co-occurring conditions such as anxiety and attention problems. In this study, 350 caregivers, each with at least one son or daughter with full-mutation FXS, rated one of their children with FXS using the Aberrant Behavior Checklist-Community Version (ABC-C); the Anxiety subscale of the Anxiety, Depression, and Mood Scale; and the Attention/Hyperactivity Items from the Symptom Inventories. In addition to examining family consequences of these behaviors, this study also sought to replicate psychometric findings for the ABC-C in FXS, to provide greater confidence for its use in clinical trials with this population. Psychometric properties and baseline ratings of problem behavior were consistent with other recent studies, further establishing the profile of problem behavior in FXS. Cross-sectional analyses suggest that selected dimensions of problem behavior, anxiety, and hyperactivity are age related; thus, age should serve as an important control in any studies of problem behavior in FXS. Measures of anxiety, attention, and hyperactivity were highly associated with behavior problems, suggesting that these factors at least coincide with problem behavior. However, these problems generally did not add substantially to variance in caregiver burden predicted by elevated behavior problems. The results provide further evidence of the incidence of problem behaviors and co-occurring conditions in FXS and the impact of these behaviors on the family. (c) 2013 Wiley Periodicals, Inc.
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14. Wisessathorn M, Chanuantong T, Fisher EB. {{The impact of child’s severity on quality-of-life among parents of children with autism spectrum disorder: the mediating role of optimism}}. {Journal of the Medical Association of Thailand = Chotmaihet thangphaet}. 2013 Oct;96(10):1313-8.
OBJECTIVE: Investigate the impact of child severity and optimism on quality-of-life in parents of children with Autism Spectrum Disorder (ASD). Additionally, the role of optimism as mediator between child’s severity and parental quality-of-life was also evaluated MATERIAL AND METHOD: Three hundred three parents of children with ASD were recruited from the local autistic centers and schools in Bangkok, Thailand. A set of demographic information sheet, the Childhood Autism Rating Scale (CARS), the Life Oriented Test-Revised (LOT-R), and the WHOQOL-BREF test were submitted for collecting parental information. RESULTS: Using Pearson Correlation, a significant negative association was found between child’s severity and parental quality-of-life while optimism was found to correlate positively with parental outcomes. The finding from path-analysis confirmed that impairment of language and repetitive behavior of an ASD child associated with optimism that, in turn, predicted level of parental quality-of-life in all domains. CONCLUSION: The current findings assured a role of optimism as mediator between child’s severity and parental quality-of-life. Implications for the development of intervention focused on enhancing parent’s optimism were recommended.
15. Yasui DH, Gonzales ML, Aflatooni JO, Crary FK, Hu DJ, Gavino BJ, Golub MS, Vincent JB, Schanen NC, Olson CO, Rastegar M, Lasalle JM. {{Mice with an isoform-ablating Mecp2-exon 1 mutation recapitulate the neurologic deficits of Rett syndrome}}. {Human molecular genetics}. 2013 Dec 18.
Mutations in MECP2 cause the neurodevelopmental disorder Rett syndrome (RTT OMIM 312750)_ENREF_1. Alternative inclusion of MECP2/Mecp2 exon 1 with exons 3, and 4 encode MeCP2-e1 orMeCP2-e2 protein isoforms with unique amino termini. While most MECP2 mutations are located in exons 3 and 4 thus affecting both isoforms, MECP2 exon 1 mutations but not exon 2 mutations have been identified in RTT patients, suggesting that MeCP2-e1 deficiency is sufficient to cause RTT. As expected, genetic deletion of Mecp2 exons 3 and/or 4 recapitulate RTT-like neurologic defects in mice. However, Mecp2 exon 2 knockout mice have normal neurologic function. Here a naturally occurring MECP2 exon 1 mutation is recapitulated in a mouse model by genetic engineering. A point mutation in the translational start codon of Mecp2 exon1, transmitted through the germline, ablates MeCP2-e1 translation while preserving MeCP2-e2 production in mouse brain. The resulting MeCP2-e1 deficient mice developed forelimb stereotypy, hind limb clasping, excessive grooming, and hypo-activity prior to death between 7-31 weeks. MeCP2-e1 deficient mice also exhibited abnormal anxiety, sociability, and ambulation. Despite MeCP2-e1 and MeCP2-e2 sharing 96% amino acid identity differences were identified. A fraction of phosphorylated MeCP2-e1 differed from the bulk of MeCP2 in sub-nuclear localization and co-factor interaction. Furthermore, MeCP2-e1 exhibited enhanced stability compared with MeCP2-e2 in neurons. Therefore, MeCP2-e1 deficient mice implicate MeCP2-e1 as the sole genetic contributor to RTT with non-redundant functions.
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16. Zhao XN, Usdin K. {{Gender and Cell-Type Specific Effects of the Transcription Coupled Repair Protein, ERCC6/CSB, on Repeat Expansion in a Mouse Model of the Fragile X-Related Disorders}}. {Human mutation}. 2013 Dec 18.
The Repeat Expansion Diseases (REDs) are human genetic disorders that arise from expansion of a tandem repeat tract. The Fragile X-related disorders are members of this disease group in which the repeat unit is CGG/CCG and is located in the 5′ untranslated region of the FMR1 gene. Affected individuals often show mosaicism with respect to repeat number resulting from both expansion and contraction of the repeat tract, however, the mechanism responsible for these changes in repeat number are unknown. Work from a variety of model systems suggests that Transcription Coupled Repair (TCR) may contribute to repeat instability in diseases resulting from CAG/CTG-repeat expansion. To test whether TCR could contribute to repeat instability in the Fragile X-related disorders, we tested the effect of mutations in Csb (Cockayne Syndrome group B), a gene essential for TCR, in a knock-in mouse model of these disorders. We found that the loss of CSB affects expansions in a gender and cell type-specific manner. Our data also show an unanticipated gender difference in instability even in Csb+/+ animals that may have implications for our understanding of the mechanism of repeat expansion in the FX mouse model and perhaps for humans as well. This article is protected by copyright. All rights reserved.