1. {{Using Drosophila as a tool to identify pharmacological therapies for fragile X syndrome}}. {Drug discovery today Technologies}. 2013 Spring;10(1):e1-e218.
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2. {{Autism trainer manual – autism awareness training covering a level 2 qualification unit autism trainer manual – autism awareness training covering a level 2 qualification unit}}. {Nursing standard (Royal College of Nursing (Great Britain) : 1987)}. 2013 Sep 18;28(3):28.
Autism probably has more trees lost to the cause of explaining its nature than any other genetic condition. It is a fascinating and tantalising subject, and this suite of training materials captures those aspects well and without using up too much paper.
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3. Angkustsiri K, Goodlin-Jones B, Deprey L, Brahmbhatt K, Harris S, Simon TJ. {{Social Impairments in Chromosome 22q11.2 Deletion Syndrome (22q11.2DS): Autism Spectrum Disorder or a Different Endophenotype?}}. {J Autism Dev Disord}. 2013 Sep 18.
High prevalence of autism spectrum disorders (ASD) has been reported in 22q11.2DS, although this has been based solely on parent report measures. This study describes the presence of ASD using a procedure more similar to that used in clinical practice by incorporating history (Social Communication Questionnaire) AND a standardized observation measure (Autism Diagnostic Observation Schedule) and suggests that ASD is not as common as previously reported in 22q11.2DS. Differences in methodology, along with comorbid conditions such as anxiety, likely contribute to false elevations in ASD prevalence and information from multiple sources should be included in the evaluation of ASD.
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4. Avdjieva-Tzavella D, Mihailova S, Lukanov C, Naumova E, Simeonov E, Tincheva R, Toncheva D. {{Mitochondrial DNA mutations in two bulgarian children with autistic spectrum disorders}}. {Balkan journal of medical genetics : BJMG}. 2012 Dec;15(2):47-54.
Autism is a neurodevelopmental disorder of unknown origin that manifests in early childhood. Autism spectrum disorders (ASDs) refer to a broader group of neurobiological conditions, pervasive developmental disorders. Despite several arguments for a strong genetic contribution, the molecular basis in most cases remains unexplained. Several studies have reported an association between ASDs and mutations in the mitochondrial DNA (mtDNA) molecule. In order to confirm these causative relationship, we screened 21 individuals with idiopathic ASDs for a number of the most common mtDNA mutations. We identified two patients with candidate mutations: m.6852G>A that produces an amino acid change of glycine to serine in the MT-CO1 gene and m.8033A>G (Ile–>Val) in the MT-CO2 gene. Overall, these findings support the notion that mitochondrial mutations are associated with ASDs. Additional studies are needed to further define the role of mitochondrial defects in the pathogenesis of autism.
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5. Baker JP. {{Autism at 70–redrawing the boundaries}}. {The New England journal of medicine}. 2013 Sep 19;369(12):1089-91.
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6. Chanda S, Marro S, Wernig M, Sudhof TC. {{Neurons generated by direct conversion of fibroblasts reproduce synaptic phenotype caused by autism-associated neuroligin-3 mutation}}. {Proceedings of the National Academy of Sciences of the United States of America}. 2013 Sep 17.
Recent studies suggest that induced neuronal (iN) cells that are directly transdifferentiated from nonneuronal cells provide a powerful opportunity to examine neuropsychiatric diseases. However, the validity of using this approach to examine disease-specific changes has not been demonstrated. Here, we analyze the phenotypes of iN cells that were derived from murine embryonic fibroblasts cultured from littermate wild-type and mutant mice carrying the autism-associated R704C substitution in neuroligin-3. We show that neuroligin-3 R704C-mutant iN cells exhibit a large and selective decrease in AMPA-type glutamate receptor-mediated synaptic transmission without changes in NMDA-type glutamate receptor- or in GABAA receptor-mediated synaptic transmission. Thus, the synaptic phenotype observed in R704C-mutant iN cells replicates the previously observed phenotype of R704C-mutant neurons. Our data show that the effect of the R704C mutation is applicable even to neurons transdifferentiated from fibroblasts and constitute a proof-of-concept demonstration that iN cells can be used for cellular disease modeling.
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7. Erickson CA, Wink LK, Early MC, Stiegelmeyer E, Mathieu-Frasier L, Patrick V, McDougle CJ. {{Brief Report: Pilot Single-Blind Placebo Lead-In Study of Acamprosate in Youth with Autistic Disorder}}. {J Autism Dev Disord}. 2013 Sep 20.
RATIONALE: An excitatory/inhibitory (E:I) imbalance marked by enhanced glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission may contribute to the pathophysiology of autism spectrum disorders (ASD). OBJECTIVES: We report on the first single-blind placebo lead-in trial of acamprosate, a drug with putative mechanisms restoring E:I imbalance, in twelve youth with ASD. MATERIALS AND METHODS: We conducted a 12-week single-blind, placebo lead-in study of acamprosate in youth age 5-17 years with autistic disorder. RESULTS: Six of nine subjects who received active drug treatment were deemed treatment responders (defined by a score at final visit of « very much improved » or « much improved » on the Clinical Global Impressions Improvement scale) and >/=25 % improvement on the Aberrant Behavior Checklist Social Withdrawal subscale. CONCLUSION: Future larger-scale dose finding studies of acamprosate in ASD may be warranted given this preliminary indication of benefit.
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8. Friedman SH, Dani N, Rushton E, Broadie K. {{Fragile X mental retardation protein regulates trans-synaptic signaling}}. {Disease models & mechanisms}. 2013 Sep 5.
Fragile X syndrome (FXS), the most common inherited determinant of intellectual disability and autism spectrum disorders, is caused by loss of the fragile X mental retardation 1 (fmr1) gene product (FMRP), an mRNA-binding translational repressor. A number of conserved FMRP targets have been identified in the well-characterized Drosophila FXS disease model, but FMRP is highly pleiotropic in function and the full spectrum of FMRP targets has yet to be revealed. In this study, screens for upregulated neural proteins in Drosophila fmr1 (dfmr1) null mutants reveal strong elevation of two synaptic heparan sulfate proteoglycans (HSPGs): GPI-anchored glypican Dally-like Protein (Dlp) and transmembrane Syndecan (Sdc). Our recent work has shown that Dlp and Sdc act as co-receptors regulating extracellular ligands upstream of intracellular signal transduction in multiple trans-synaptic pathways driving synaptogenesis. Consistently, dfmr1 null synapses exhibit altered WNT signaling, with changes in both Wingless (Wg) ligand abundance and downstream Frizzled-2 (Fz2) receptor C-terminal nuclear import. Similarly, a parallel anterograde signaling ligand, Jelly Belly (Jeb), and downstream ERK phosphorylation (dpERK), are depressed at dfmr1 null synapses. In contrast, the retrograde BMP ligand Glass Bottom Boat (Gbb) and downstream signaling via transcription factor MAD phosphorylation (pMAD) appear not affected. To determine whether HSPG upregulation is causative for synaptogenic defects, HSPGs were genetically reduced to control levels in the dfmr1 null background. HSPG correction restored both 1) Wg and Jeb trans-synaptic signaling, and 2) synaptic architecture and transmission strength back to wildtype levels. Taken together, these data suggest that FMRP negatively regulates HSPG co-receptors controlling trans-synaptic signaling during synaptogenesis, and that loss of this regulation causes synaptic structure and function defects characterizing the FXS disease state.
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9. Gunnes N, Suren P, Bresnahan M, Hornig M, Lie KK, Lipkin WI, Magnus P, Nilsen RM, Reichborn-Kjennerud T, Schjolberg S, Susser ES, Oyen AS, Stoltenberg C. {{Interpregnancy Interval and Risk of Autistic Disorder}}. {Epidemiology (Cambridge, Mass)}. 2013 Sep 16.
BACKGROUND:: A recent California study reported increased risk of autistic disorder in children conceived within a year after the birth of a sibling. METHODS:: We assessed the association between interpregnancy interval and risk of autistic disorder using nationwide registry data on pairs of singleton full siblings born in Norway. We defined interpregnancy interval as the time from birth of the first-born child to conception of the second-born child in a sibship. The outcome of interest was autistic disorder in the second-born child. Analyses were restricted to sibships in which the second-born child was born in 1990-2004. Odds ratios (ORs) were estimated by fitting ordinary logistic models and logistic generalized additive models. RESULTS:: The study sample included 223,476 singleton full-sibling pairs. In sibships with interpregnancy intervals <9 months, 0.25% of the second-born children had autistic disorder, compared with 0.13% in the reference category (>/=36 months). For interpregnancy intervals shorter than 9 months, the adjusted OR of autistic disorder in the second-born child was 2.18 (95% confidence interval 1.42-3.26). The risk of autistic disorder in the second-born child was also increased for interpregnancy intervals of 9-11 months in the adjusted analysis (OR = 1.71 [95% CI = 1.07-2.64]). CONCLUSIONS:: Consistent with a previous report from California, interpregnancy intervals shorter than 1 year were associated with increased risk of autistic disorder in the second-born child. A possible explanation is depletion of micronutrients in mothers with closely spaced pregnancies.
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10. Ishitobi M, Kosaka H, Takahashi T, Yatuga C, Asano M, Tanaka Y, Ueno K, Okazaki R, Omori M, Hiratani M, Tomoda A, Wada Y. {{Effectiveness and tolerability of switching to aripiprazole from risperidone in subjects with autism spectrum disorders: a prospective open-label study}}. {Clinical neuropharmacology}. 2013 Sep-Oct;36(5):151-6.
BACKGROUND: Subjects with autism spectrum disorders (ASDs) often exhibit behavioral symptoms such as aggressiveness and irritability. The purpose of this study was to examine the efficacy and the tolerability of aripiprazole switched from risperidone in children and adolescents with ASD. METHODS: This prospective, 12-week, open-label study included 9 male subjects with ASD (age range, 9-22 years; mean +/- SD age, 14.8 +/- 4.0 years) followed up for 12 weeks after switching to aripiprazole from risperidone. The primary outcome measures were the Clinical Global Impression-Improvement scales and the irritability subscale of the Aberrant Behavior Checklist. RESULTS: The mean +/- SD maintenance dosages of risperidone and aripiprazole were 0.6 +/- 0.4 mg/d and 4.8 +/- 4.0 mg/d, respectively. The mean +/- SD scores of the irritability subscale of the Aberrant Behavior Checklist before switching to aripiprazole (baseline) and 12 weeks after switching to aripiprazole (end point) were 14.8 +/- 7.6 and 13.1 +/- 8.0, respectively. The mean +/- SD Clinical Global Impression-Improvement score, a comparison from baseline to end point, was 2.4 +/- 0.7. Mild somnolence was observed only in 1 subject. No significant changes in vital signs, weight, electrocardiogram, or laboratory measures occurred during switching to aripiprazole. Serum prolactin levels decreased significantly from 17.3 +/- 9.4 ng/mL (baseline) to 2.3 +/- 1.7 ng/mL (end point). CONCLUSIONS: The results show that aripiprazole might be generally well tolerated and might constitute an alternative treatment of subjects with ASD who experience poor efficacy or tolerability issues with risperidone treatment. Additional long-term controlled studies are needed to evaluate the efficacy and the safety of switching to aripiprazole from other antipsychotics in subjects with ASD.
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11. Kas MJ, Glennon JC, Buitelaar J, Ey E, Biemans B, Crawley J, Ring RH, Lajonchere C, Esclassan F, Talpos J, Noldus LP, Burbach JP, Steckler T. {{Assessing behavioural and cognitive domains of autism spectrum disorders in rodents: current status and future perspectives}}. {Psychopharmacology}. 2013 Sep 19.
The establishment of robust and replicable behavioural testing paradigms with translational value for psychiatric diseases is a major step forward in developing and testing etiology-directed treatment for these complex disorders. Based on the existing literature, we have generated an inventory of applied rodent behavioural testing paradigms relevant to autism spectrum disorders (ASD). This inventory focused on previously used paradigms that assess behavioural domains that are affected in ASD, such as social interaction, social communication, repetitive behaviours and behavioural inflexibility, cognition as well as anxiety behaviour. A wide range of behavioural testing paradigms for rodents were identified. However, the level of face and construct validity is highly variable. The predictive validity of these paradigms is unknown, as etiology-directed treatments for ASD are currently not on the market. To optimise these studies, future efforts should address aspects of reproducibility and take into account data about the neurodevelopmental underpinnings and trajectory of ASD. In addition, with the increasing knowledge of processes underlying ASD, such as sensory information processes and synaptic plasticity, phenotyping efforts should include multi-level automated analysis of, for example, representative task-related behavioural and electrophysiological read-outs.
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12. Kim SY, Hashimoto RI, Tassone F, Simon TJ, Rivera SM. {{Altered neural activity of magnitude estimation processing in adults with the fragile X premutation}}. {Journal of psychiatric research}. 2013 Sep 2.
Mutations of the fragile X mental retardation 1 (FMR1) gene are the genetic cause of fragile X syndrome (FXS). Expanded CGG trinucleotide repeat (>200 repeats) result in transcriptional silencing of the FMR1 gene and deficiency/absence of the FMR1 protein (FMRP). Carriers with a premutation allele (55-200 CGG repeats) are often associated with mildly reduced levels of FMRP and/or elevated levels of FMR1 mRNA, and are associated with the risk of developing a neurodegenerative disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). While impairments in numerical processing have been well documented in FXS, recent behavioral research suggests that premutation carriers also present with subtle but significant impairments in numerical processing. Using fMRI, the current study examined whether asymptomatic adults with the premutation would show aberrant neural correlates of magnitude estimation processing in the fronto-parietal area. Using a magnitude estimation task, we demonstrated that activity in the intraparietal sulcus and inferior frontal gyrus, associated with magnitude estimation processing, was significantly attenuated in premutation carriers compared to their neurotypical counterparts despite their comparable behavioral performance. Further, multiple regression analysis using CGG repeat size and FMR1 mRNA indicated that increased CGG repeat size is a primary factor for the decreased fronto-parietal activity, suggesting that reduced FMRP, rather than a toxic gain-of-function effect from elevated mRNA, contributes to altered neural activity of magnitude estimation processing in premutation carriers. In conclusion, we provide the first evidence on the aberrant neural correlates of magnitude estimation processing in premutation carriers accounted for by their FMR1 gene expression.
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13. Lauterborn JC, Jafari M, Babayan AH, Gall CM. {{Environmental Enrichment Reveals Effects of Genotype on Hippocampal Spine Morphologies in the Mouse Model of Fragile X Syndrome}}. {Cerebral cortex (New York, NY : 1991)}. 2013 Sep 17.
Fragile X Syndrome (FXS) and the Fmr1 knockout (KO) mouse model of this disorder exhibit abnormal dendritic spines in neocortex, but the degree of spine disturbances in hippocampus is not clear. The present studies tested if the mutation influences dendritic branching and spine measures for CA1 pyramidal cells in Fmr1 KO and wild-type (WT) mice provided standard or enriched environment (EE) housing. Automated measures from 3D reconstructions of green fluorescent protein (GFP)-labeled cells showed that spine head volumes were approximately 40% lower in KOs when compared with WTs in both housing conditions. With standard housing, average spine length was greater in KOs versus WTs but there was no genotype difference in dendritic branching, numbers of spines, or spine length distribution. However, with EE rearing, significant effects of genotype emerged including greater dendritic branching in WTs, greater spine density in KOs, and greater numbers of short thin spines in KOs when compared with WTs. Thus, EE rearing revealed greater effects of the Fmr1 mutation on hippocampal pyramidal cell morphology than was evident with standard housing, suggesting that environmental enrichment allows for fuller appreciation of the impact of the mutation and better representation of abnormalities likely to be present in human FXS.
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14. Machado C, Estevez M, Leisman G, Melillo R, Rodriguez R, Defina P, Hernandez A, Perez-Nellar J, Naranjo R, Chinchilla M, Garofalo N, Vargas J, Beltran C. {{QEEG Spectral and Coherence Assessment of Autistic Children in Three Different Experimental Conditions}}. {J Autism Dev Disord}. 2013 Sep 19.
We studied autistics by quantitative EEG spectral and coherence analysis during three experimental conditions: basal, watching a cartoon with audio (V-A), and with muted audio band (VwA). Significant reductions were found for the absolute power spectral density (PSD) in the central region for delta and theta, and in the posterior region for sigma and beta bands, lateralized to the right hemisphere. When comparing VwA versus the V-A in the midline regions, we found significant decrements of absolute PSD for delta, theta and alpha, and increments for the beta and gamma bands. In autistics, VwA versus V-A tended to show lower coherence values in the right hemisphere. An impairment of visual and auditory sensory integration in autistics might explain our results.
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15. Troili GM, Businaro R, Massoni F, Ricci L, Petrone L, Ricci P, Ricci S. {{[Indagine su un gruppo di bambini autistici: possibili fattori di rischio e considerazioni medico sociali.]}}. {La Clinica terapeutica}. 2013 Jul-Aug;164(4):e273-e8.
Obiettivo. L’obiettivo di questo studio e stato quello di studiare attraverso un’indagine medico-sociale l’associazione dell’autismo presente in un gruppo di bambini con fattori di rischio riconducibili alla familiarita per specifiche patologie ed allo sviluppo nei primi anni di vita. Materiali e Metodi. Per questo studio abbiamo somministrato un questionario anamnestico a 29 bambini autistici di una Regione del Sud Italia (la Basilicata) ed alle loro famiglie, raccogliendo i dati del bambino e dei genitori. Risultati. I risultati dimostrano che questi soggetti presentano familiarita per alcune malattie autoimmuni (psoriasi, artrite reumatoide, celiachia, arterite di Takayasu), per allergie ed intolleranze alimentari. Dai dati raccolti e emerso un potenziale coinvolgimento del sistema immunitario nello sviluppo dell’autismo. Analizzando le zone di residenza dei pazienti (Province di Potenza e Matera), con i loro fattori ambientali (depositi di scorie radioattive, inceneritori, coltivazioni intensive), abbiamo rilevato che le caratteristiche territoriali della Regione, alla nostra osservazione, non influiscono sul disturbo. Conclusioni. Essendo l’autismo uno spettro di disordini neurologici estremamente complesso sotto il profilo sia eziopatogenetico sia assistenziale, sarebbe utile approfondire gli studi gia intrapresi dal nostro gruppo, come la valutazione dell’assetto citochinico dei soggetti, e di estenderlo mediante approcci biomolecolari atti a valutare la presenza di particolari polimorfismi genetici sia per identificare i meccanismi fisiopatogenetici alla base della patologia sia per valutare il rischio predittivo allo scopo di perfezionare gli interventi assistenziali.
