1. Filosa S, Pecorelli A, D’Esposito M, Valacchi G, Hajek J. {{Exploring the possible link between MeCP2 and oxidative stress in Rett syndrome}}. {Free Radic Biol Med};2015 (May 7)
Rett syndrome (RTT, MIM 312750), is a rare and orphan progressive neurodevelopmental disorder affecting almost exclusively the female gender with a frequency of 1:15,000 live births. The disease is characterized by a period of 6 to 18 months of apparently normal neurodevelopment, followed by an early neurological regression, with a progressive loss of acquired cognitive, social, and motor skills. RTT is known to be caused in the 95% of the cases by sporadic de novo loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene encoding methyl-CpG binding protein 2 (MeCP2), a nuclear protein able to regulates gene expression. Despite almost two decades of research into the functions and role of MeCP2, little is known about the mechanisms leading from MECP2 mutation to the disease. Oxidative stress (OS) is involved in the pathogenic mechanisms of several neurodevelopmental and neurodegenerative disorders although in many cases it is not clear whether OS is a cause of a consequence of the pathology. Fairly recently it has been demonstrated the presence of a systemic OS also in RTT patients with the strong correlation with the patients clinical status. At today it is not clear the link between MECP2 mutation and the redox imbalance found in RTT. Animal studies have anyway suggested a possible direct correlation between Mecp2 mutation and increased OS levels. In addition, the restoration of Mecp2 function in astrocytes significantly improves the developmental outcome of Mecp2-null mice and re-expression of Mecp2 gene in the brain of null mice rescued oxidative damage, suggesting that Mecp2 loss-of-function can be involved in oxidative brain damage. Starting from the evidences that oxidative damage in the brain of Mecp2-null mice precedes the onset of symptoms, we evaluated whether, based on the current literature, the dysfunctions described in RTT could be a consequence or, in contrast, are caused by OS. We also analyzed if the therapies, that at least partially rescued some RTT symptoms, can have a role in the defense against OS. At this stage we can propose that OS could be one of the main causes of the dysfunctions observed in RTT. In addition, it should be mentioned that the major part of the therapies recommended to alleviate RTT symptoms have been shown to interfere with oxidative homeostasis, suggesting that MeCP2 could be somehow involved in the protection of the brain from OS.
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2. Gizzonio V, Avanzini P, Campi C, Orivoli S, Piccolo B, Cantalupo G, Tassinari CA, Rizzolatti G, Fabbri-Destro M. {{Failure in Pantomime Action Execution Correlates with the Severity of Social Behavior Deficits in Children with Autism: A Praxis Study}}. {J Autism Dev Disord};2015 (May 12)
Here we describe the performance of children with autism, their siblings, and typically developing children using the Florida Apraxia Battery. Children with autism showed the lowest performance in all sections of the test. They were mostly impaired in pantomime actions execution on imitation and on verbal command, and in imitation of meaningless gestures. Interestingly, a correlation was found between performance in pantomime actions and the severity of social behavior deficits. We conclude that the presence of a rigid internal model prevents the execution of an exact copy of the observed pantomime actions and that the deficit in imitation of meaningless gestures is most likely due to a deficit in the mechanisms responsible for visuomotor transformations.
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3. Kadak MT, Demirel OF, Gokalp B, Erdogdu Z, Demirel A. {{Relationship between temperament-character and autistic trait in parents of children with autistic spectrum disorder}}. {Int J Psychiatry Clin Pract};2015 (May 12):1-20.
OBJECTIVE: Previous studies revealed distinct features for autism with higher harm avoidance and lower reward dependence, novelty seeking. It is assumed that high harm aviodance, low novelty seeking, reward dependance, cooperativeness and self-directedness are related with broad autism phenotype as in autistic individual. METHOD: This study examined association between Temperament and Character Inventory (TCI) and The Autism Spectrum Quotient (AQ) and in parents of children with ASD. RESULT: There was significant correlation between total AQ and total harm avoidance, cooperativeness, self-directedness (p < 0.05). In the stepwise analysis, self-directedness and education emerged significantly (F(2,67)= 19.71, p < .005). This model modestly explained 35 % of variance (Adjusted R2= .350). CONCLUSION: Our findings suggest that self-directedness may be autistic trait.
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4. Kamio Y, Haraguchi H, Miyake A, Hiraiwa M. {{Brief report: large individual variation in outcomes of autistic children receiving low-intensity behavioral interventions in community settings}}. {Child Adolesc Psychiatry Ment Health};2015;9:6.
BACKGROUND: Despite widespread awareness of the necessity of early intervention for children with autism spectrum disorders (ASDs), evidence is still limited, in part, due to the complex nature of ASDs. This exploratory study aimed to examine the change across time in young children with autism and their mothers, who received less intensive early interventions with and without applied behavior analysis (ABA) methods in community settings in Japan. METHODS: Eighteen children with autism (mean age: 45.7 months; range: 28-64 months) received ABA-based treatment (a median of 3.5 hours per week; an interquartile range of 2-5.6 hours per week) and/or eclectic treatment-as-usual (TAU) (a median of 3.1 hours per week; an interquartile range of 2-5.6 hours per week). Children’s outcomes were the severity of autistic symptoms, cognitive functioning, internalizing and externalizing behavior after 6 months (a median of 192 days; an interquartile range of 178-206 days). In addition, maternal parenting stress at 6-month follow-up, and maternal depression at 1.5-year follow-up (a median of 512 days; an interquartile range of 358-545 days) were also examined. RESULTS: Large individual variations were observed for a broad range of children’s and mothers’ outcomes. Neither ABA nor TAU hours per week were significantly associated with an improvement in core autistic symptoms. A significant improvement was observed only for internalizing problems, irrespective of the type, intensity or monthly cost of treatment received. Higher ABA cost per month (a median of 1,188 USD; an interquartile range of 538-1,888 USD) was associated with less improvement in language-social DQ (a median of 9; an interquartile range of -6.75-23.75). CONCLUSIONS: To determine an optimal program for each child with ASD in areas with poor ASD resources, further controlled studies are needed that assess a broad range of predictive and outcome variables focusing on both individual characteristics and treatment components.
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5. Khan AJ, Nair A, Keown CL, Datko MC, Lincoln AJ, Muller RA. {{Cerebro-cerebellar Resting-State Functional Connectivity in Children and Adolescents with Autism Spectrum Disorder}}. {Biol Psychiatry};2015 (Apr 1)
BACKGROUND: The cerebellum plays important roles in sensori-motor and supramodal cognitive functions. Cellular, volumetric, and functional abnormalities of the cerebellum have been found in autism spectrum disorders (ASD), but no comprehensive investigation of cerebro-cerebellar connectivity in ASD is available. METHODS: We used resting-state functional connectivity magnetic resonance imaging in 56 children and adolescents (28 subjects with ASD, 28 typically developing subjects) 8-17 years old. Partial and total correlation analyses were performed for unilateral regions of interest (ROIs), distinguished in two broad domains as sensori-motor (premotor/primary motor, somatosensory, superior temporal, and occipital) and supramodal (prefrontal, posterior parietal, and inferior and middle temporal). RESULTS: There were three main findings: 1) Total correlation analyses showed predominant cerebro-cerebellar functional overconnectivity in the ASD group; 2) partial correlation analyses that emphasized domain specificity (sensori-motor vs. supramodal) indicated a pattern of robustly increased connectivity in the ASD group (compared with the typically developing group) for sensori-motor ROIs but predominantly reduced connectivity for supramodal ROIs; and 3) this atypical pattern of connectivity was supported by significantly increased noncanonical connections (between sensori-motor cerebral and supramodal cerebellar ROIs and vice versa) in the ASD group. CONCLUSIONS: Our findings indicate that sensori-motor intrinsic functional connectivity is atypically increased in ASD, at the expense of connectivity supporting cerebellar participation in supramodal cognition.
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6. Krumm N, Turner TN, Baker C, Vives L, Mohajeri K, Witherspoon K, Raja A, Coe BP, Stessman HA, He ZX, Leal SM, Bernier R, Eichler EE. {{Excess of rare, inherited truncating mutations in autism}}. {Nat Genet};2015 (May 11)
To assess the relative impact of inherited and de novo variants on autism risk, we generated a comprehensive set of exonic single-nucleotide variants (SNVs) and copy number variants (CNVs) from 2,377 families with autism. We find that private, inherited truncating SNVs in conserved genes are enriched in probands (odds ratio = 1.14, P = 0.0002) in comparison to unaffected siblings, an effect involving significant maternal transmission bias to sons. We also observe a bias for inherited CNVs, specifically for small (<100 kb), maternally inherited events (P = 0.01) that are enriched in CHD8 target genes (P = 7.4 x 10-3). Using a logistic regression model, we show that private truncating SNVs and rare, inherited CNVs are statistically independent risk factors for autism, with odds ratios of 1.11 (P = 0.0002) and 1.23 (P = 0.01), respectively. This analysis identifies a second class of candidate genes (for example, RIMS1, CUL7 and LZTR1) where transmitted mutations may create a sensitized background but are unlikely to be completely penetrant.
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7. Lord C, Bishop S, Anderson D. {{Developmental trajectories as autism phenotypes}}. {Am J Med Genet C Semin Med Genet};2015 (May 10)
Numerous studies of Autism Spectrum Disorder have attempted to link behavioral phenotypes to genetic findings. Reliance on cross-sectional behavioral data in samples that span wide age ranges may have limited this endeavor because ASD behaviors are not static within individuals across development. This study uses quantitative methods to describe specific aspects of changes in autism-related and more general behaviors in order to yield trajectories that could be used in place of single time-point data as behavioral phenotypes in neurobiological studies of both Autism Spectrum Disorders and overlapping conditions. Building on previous analyses, we examined trajectories of parent-reported social-communication deficits, social adaptive functioning, and two types of repetitive behaviors, repetitive sensory motor (RSM) behaviors and insistence on sameness (IS) behaviors, in a relatively large sample of participants referred for possible autism at age 2 years and followed into young adulthood (n = 85). A strength of this sample was the diverse range of outcomes, including young adults with intellectual disability and persistent autism related difficulties, those with IQs in the borderline or average range who continued to experience functional impairment related to Autism Spectrum Disorders, and a small group of young adults (n = 8) with IQs in the average range who were judged to be functioning socially and adaptively at age-appropriate levels at age 19 years, despite a previous childhood diagnosis of autism.
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8. Mandleco B, Webb AE. {{Sibling perceptions of living with a young person with Down syndrome or autism spectrum disorder: An integrated review}}. {J Spec Pediatr Nurs};2015 (May 12)
PURPOSE: This integrative review synthesized current information from 28 research articles meeting inclusion criteria that examined sibling experiences when living with a young person with Down syndrome or autism spectrum disorder. CONCLUSIONS: Five themes emerged related to sibling experiences: their knowledge of the condition, relationships with others, perceptions of the condition, emotional reactions to the situation, and behavioral/personality outcomes. PRACTICE IMPLICATIONS: Nurses caring for families raising youth with Down syndrome or autism spectrum disorder can enhance sibling development by providing individual interventions reflecting siblings’ perceptions of the experience.
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9. Parr JR, De Jonge MV, Wallace S, Pickles A, Rutter ML, Le Couteur AS, van Engeland H, Wittemeyer K, McConachie H, Roge B, Mantoulan C, Pedersen L, Isager T, Poustka F, Bolte S, Bolton P, Weisblatt E, Green J, Papanikolaou K, Baird G, Bailey AJ. {{New Interview and Observation Measures of the Broader Autism Phenotype: Description of Strategy and Reliability Findings for the Interview Measures}}. {Autism Res};2015 (May 10)
Clinical genetic studies confirm the broader autism phenotype (BAP) in some relatives of individuals with autism, but there are few standardized assessment measures. We developed three BAP measures (informant interview, self-report interview, and impression of interviewee observational scale) and describe the development strategy and findings from the interviews. International Molecular Genetic Study of Autism Consortium data were collected from families containing at least two individuals with autism. Comparison of the informant and self-report interviews was restricted to samples in which the interviews were undertaken by different researchers from that site (251 UK informants, 119 from the Netherlands). Researchers produced vignettes that were rated blind by others. Retest reliability was assessed in 45 participants. Agreement between live scoring and vignette ratings was very high. Retest stability for the interviews was high. Factor analysis indicated a first factor comprising social-communication items and rigidity (but not other repetitive domain items), and a second factor comprised mainly of reading and spelling impairments. Whole scale Cronbach’s alphas were high for both interviews. The correlation between interviews for factor 1 was moderate (adult items 0.50; childhood items 0.43); Kappa values for between-interview agreement on individual items were mainly low. The correlations between individual items and total score were moderate. The inclusion of several factor 2 items lowered the overall Cronbach’s alpha for the total set. Both interview measures showed good reliability and substantial stability over time, but the findings were better for factor 1 than factor 2. We recommend factor 1 scores be used for characterising the BAP. Autism Res 2015. (c) 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.
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10. Shigemori T, Sakai A, Takumi T, Itoh Y, Suzuki H. {{Altered Microglia in the Amygdala Are Involved in Anxiety-related Behaviors of a Copy Number Variation Mouse Model of Autism}}. {J Nippon Med Sch};2015;82(2):92-99.
BACKGROUND AND PURPOSE: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic basis. Although anxiety is a common major psychiatric condition in ASD, the underlying mechanisms of the anxiety are poorly understood. In individuals with ASD, evidence indicates a structural abnormality in the amygdala, a key component involved in anxiety and social behavior. Microglia, which are central nervous system-resident immune cells implicated in neurodevelopmental processes, are also reportedly altered in ASD. In the present study, we examined the involvement of microglia in the anxiety-related behaviors of ASD model mouse. METHODS: Mice that have a 6.3-Mb paternal duplication (patDp/+) corresponding to human chromosome 15q11-q13 were used as an ASD model. Iba1, a microglial activation marker, was examined in the amygdala using immunofluorescence. Effects of perinatal treatment with minocycline, a microglial modulator, on anxiety-related behaviors were examined in neonatal and adolescent patDp/+ mice. RESULTS: In patDp/+ mice, Iba1 was decreased in the basolateral amygdala at postnatal day 7, but not at postnatal days 37-40. Perinatal treatment with minocycline restored the Iba1 expression and reduced anxiety-related behaviors in patDp/+ adolescent mice. CONCLUSIONS: Perinatal microglia in the basolateral amygdala may play a pathogenic role in the anxiety observed in a mouse model of ASD with duplication of human chromosome 15q11-q13.
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11. Tessier S, Lambert A, Chicoine M, Scherzer P, Soulieres I, Godbout R. {{Intelligence measures and stage 2 sleep in typically-developing and autistic children}}. {Int J Psychophysiol};2015 (May 8)
The relationship between intelligence measures and 2 EEG measures of non-rapid eye movement sleep, sleep spindles and Sigma activity, was examined in 13 typically-developing and 13 autistic children with normal IQ and no complaints of poor sleep. Sleep spindles and Sigma EEG activity were computed for frontal (Fp1, Fp2) and central (C3, C4) recording sites. Time in stage 2 sleep and IQ was similar in both groups. Autistic children presented less spindles at Fp2 compared to the TD children. TD children showed negative correlation between verbal IQ and sleep spindle density at Fp2. In the autistic group, verbal and full-scale IQ scores correlated negatively with C3 sleep spindle density. The duration of sleep spindles at Fp1 was shorter in the autistic group than in the TD children. The duration of sleep spindles at C4 was positively correlated with verbal IQ only in the TD group. Fast Sigma EEG activity (13.25-15.75Hz) was lower at C3 and C4 in autistic children compared to the TD children, particularly in the latter part of the night. Only the TD group showed positive correlation between performance IQ and latter part of the night fast Sigma activity at C4. These results are consistent with a relationship between EEG activity during sleep and cognitive processing in children. The difference between TD and autistic children could derive from dissimilar cortical organization and information processing in these 2 groups.
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12. Vogt D, Cho KK, Lee AT, Sohal VS, Rubenstein JL. {{The Parvalbumin/Somatostatin Ratio Is Increased in Pten Mutant Mice and by Human PTEN ASD Alleles}}. {Cell Rep};2015 (May 12);11(6):944-956.
Mutations in the phosphatase PTEN are strongly implicated in autism spectrum disorder (ASD). Here, we investigate the function of Pten in cortical GABAergic neurons using conditional mutagenesis in mice. Loss of Pten results in a preferential loss of SST(+) interneurons, which increases the ratio of parvalbumin/somatostatin (PV/SST) interneurons, ectopic PV(+) projections in layer I, and inhibition onto glutamatergic cortical neurons. Pten mutant mice exhibit deficits in social behavior and changes in electroencephalogram (EEG) power. Using medial ganglionic eminence (MGE) transplantation, we test for cell-autonomous functional differences between human PTEN wild-type (WT) and ASD alleles. The PTEN ASD alleles are hypomorphic in regulating cell size and the PV/SST ratio in comparison to WT PTEN. This MGE transplantation/complementation assay is efficient and is generally applicable for functional testing of ASD alleles in vivo.
