1. Anwar A, Marini M, Abruzzo PM, Bolotta A, Ghezzo A, Visconti P, Thornalley PJ, Rabbani N. {{Quantitation of plasma thiamine, related metabolites and plasma protein oxidative damage markers in children with Autism Spectrum Disorder and healthy controls}}. {Free Radic Res};2016 (Sep 25):1-22.
AIMS/HYPOTHESIS: To assess thiamine and related metabolite status by analysis of plasma and urine in autistic children and healthy controls, correlations to clinical characteristics and link to plasma protein markers of oxidative damage. METHODS: 27 children with autism (21 males and 6 females) and 21 (15 males and 6 females) age-matched healthy control children were recruited. The concentration of thiamine and related phosphorylated metabolites in plasma and urine and plasma protein content of dityrosine, N-formylkynurenine and 3-nitrotyrosine was determined. RESULTS: Plasma thiamine and thiamine monophosphate concentrations were similar in both study groups (median [lower – upper quartile]): autistic children – 6.60 (4.48- 8.91) nM and 7.00 (5.51 – 8.55) nM, and healthy controls – 6.82 (4.47 – 7.02) nM and 6.82 (5.84 – 8.91) nM respectively. Thiamine pyrophosphate was decreased 24% in autistic children compared to healthy controls: 6.82 (5.81 – 8.52) versus 9.00 (8.41 – 10.71) nM, p < 0.01. Urinary excretion of thiamine and fractional renal clearance of thiamine did not change between the groups. No correlation was observed between clinical markers and the plasma and urine thiamine concentration. Plasma protein dityrosine content was increased 88% in ASD. Other oxidative markers were unchanged. CONCLUSIONS/INTERPRETATION: Autistic children had normal plasma and urinary thiamine levels whereas plasma thiamine pyrophosphate concentration was decreased. The latter may be linked to abnormal tissue handling and/or absorption from gut microbiota of thiamine pyrophosphate which warrants further investigation. Increased plasma protein dityrosine may reflect increased dual oxidase activity in response to change in mucosal immunity and host-microbe homeostasis. Lien vers le texte intégral (Open Access ou abonnement)
2. Caubit X, Gubellini P, Andrieux J, Roubertoux PL, Metwaly M, Jacq B, Fatmi A, Had-Aissouni L, Kwan KY, Salin P, Carlier M, Lieden A, Rudd E, Shinawi M, Vincent-Delorme C, Cuisset JM, Lemaitre MP, Abderrehamane F, Duban B, Lemaitre JF, Woolf AS, Bockenhauer D, Severac D, Dubois E, Zhu Y, Sestan N, Garratt AN, Le Goff LK, Fasano L. {{TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons}}. {Nat Genet};2016 (Sep 26)
TSHZ3, which encodes a zinc-finger transcription factor, was recently positioned as a hub gene in a module of the genes with the highest expression in the developing human neocortex, but its functions remained unknown. Here we identify TSHZ3 as the critical region for a syndrome associated with heterozygous deletions at 19q12-q13.11, which includes autism spectrum disorder (ASD). In Tshz3-null mice, differentially expressed genes include layer-specific markers of cerebral cortical projection neurons (CPNs), and the human orthologs of these genes are strongly associated with ASD. Furthermore, mice heterozygous for Tshz3 show functional changes at synapses established by CPNs and exhibit core ASD-like behavioral abnormalities. These findings highlight essential roles for Tshz3 in CPN development and function, whose alterations can account for ASD in the newly defined TSHZ3 deletion syndrome.
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3. Gigonzac MA, Teodoro LS, Minasi LB, Vieira TC, da Cruz AD. {{Standardization of capillary electrophoresis for diagnosis of fragile x syndrome in the brazilian public health system}}. {Electrophoresis};2016 (Sep 26)
Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability. The most common etiology of the syndrome is expansion and methylation of a CGG trinucleotide at chromosome region Xq27.3 involving FMR1. This disorder is commonly underdiagnosed in children and adolescents, given the high clinical variability. In Brazil, molecular diagnosis of FXS by capillary electrophoresis does not exist in the public health system. The current standard for separation and identification of DNA fragment sizes is 50 cm capillary electrophoresis, which is uncommon in public genotyping laboratories. This study describes the standardization of 36 cm capillary electrophoresis for fragment analysis of samples from patients with intellectual disability suggestive of FXS. Genomic dsDNA was isolated from patients and amplified by PCR using the FMR1 AmplideX(R) Kit. It was then possible to detect changes in repeat length of FMR1, such as full mutation and pre-mutation. Thus, the proposed standardization proved to be effective for the diagnosis of FXS, permitting suitable genetic counseling for families. Inclusion of molecular testing such as this in the Brazilian public health service bridges the gap between available technologies and effective diagnosis, universalizing access to genetic testing in central Brazil. This article is protected by copyright. All rights reserved.
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4. Hamza M, Halayem S, Mrad R, Bourgou S, Charfi F, Belhadj A. {{[Epigenetics’ implication in autism spectrum disorders: A review]}}. {Encephale};2016 (Sep 27)
BACKGROUND: The etiology of autism spectrum disorders (ASD) is complex and multifactorial, and the roles of genetic and environmental factors in its emergence have been well documented. Current research tends to indicate that these two factors act in a synergistic manner. The processes underlying this interaction are still poorly known, but epigenetic modifications could be the mediator in the gene/environment interface. The epigenetic mechanisms have been implicated in susceptibility to stress and also in the pathogenesis of psychiatric disorders including depression and schizophrenia. Currently, several studies focus on the consideration of the etiological role of epigenetic regulation in ASD. OBJECT: The object of this review is to present a summary of current knowledge of an epigenetic hypothesis in ASD, outlining the recent findings in this field. METHODS: Using Pubmed, we did a systematic review of the literature researching words such as: autism spectrum disorders, epigenetics, DNA methylation and histone modification. RESULTS: Epigenetic refers to the molecular process modulating gene expression without changes in the DNA sequence. The most studied epigenetic mechanisms are those that alter the chromatin structure including DNA methylation of cytosine residues in CpG dinucleotides and post-translational histone modifications. In ASD several arguments support the epigenetic hypothesis. In fact, there is a frequent association between ASD and genetic diseases whose epigenetic etiologies are recognized. A disturbance in the expression of genes involved in the epigenetic regulation has also been described in this disorder. Some studies have demonstrated changes in the DNA methylation of several autism candidate genes including the gene encoding the oxytocin receptor (OXTR), the RELN and the SHANK3 genes. Beyond the analysis of candidate genes, recent epigenome-wide association studies have investigated the methylation level of several other genes and showed hypomethylation of the whole DNA in brain and blood samples of autistic patients. The changes in epigenetic marks following exposure to environmental factors known as autism risk factors are also discussed in many reports. They include nutritional (vitamin D and folate) and toxic (sodium valproate, bisphenol A) factors. Despite a considerable contribution to understanding the complexity of ASD etiology, the epigenetic studies suffer from numerous methodological biases that limit the scope of their results and make their interpretation difficult. The cell samples used in the psychiatric studies are mostly from the post-mortem tissue of the central nervous system, and factors that might change the epigenome (age, gender, treatments received…) are not taken into account. The use of blood and buccal epithelium samples raises in turn the question as to whether the epigenome of these cells reflects that of the nerve cells. DNA methylation can also be influenced by cell subcomposition variability, transcriptional variability and by DNA sequence variants. CONCLUSION: These recent discoveries in epigenetics are the beginnings of an etiopathogenic research revolution in neurodevelopmental disorders. The conceptualization of epigenetic processes is in its early stages and despite its limited means will help integrate disparate data factors previously involved in autism. It could also be the target for the development of new therapeutic modalities.
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5. Hategan A, Bourgeois JA, Goldberg J. {{Aging with autism spectrum disorder: an emerging public health problem}}. {Int Psychogeriatr};2016 (Sep 27):1-3.
From 1943, when Leo Kanner originally described autism, and to the first objective criteria for « infantile autism » in DSM-III and the inclusion of Asperger’s disorder in DSM-IV, the subsequent classification scheme for autistic disorders has led to a substantial change with the 2013 issuance of the DSM-5 by including subcategories into one umbrella diagnosis of autism spectrum disorder (ASD) (Baker, 2013). ASD is a lifelong neurodevelopmental disorder, characterized by social and communication impairments and restricted, stereotypical patterns of behavior (Baker, 2013). It is currently expected that most, or all of the actual cases of ASD, are identified in a timely way (i.e. in early childhood). However, there are many undiagnosed older adults who may have met the current diagnostic criteria for ASD as children, but never received such a diagnosis due to the fact it had yet to be established. In addition, some patients with relatively less impairing phenotypes may escape formal diagnosis in childhood, only to later be diagnosed in adulthood. Nevertheless, the first generation of diagnosed patients with ASD is now in old age. Many such ASD patients have needed family and institutional support for their lives subsequent to childhood diagnosis. Due to aging and death of their parents and other supportive figures leading to a loss of social structures, there is no better time than now for the medical community to act.
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6. Kaplan YC, Keskin-Arslan E, Acar S, Sozmen K. {{Prenatal selective serotonin reuptake inhibitor use and the risk of autism spectrum disorder in children: A systematic review and meta-analysis}}. {Reprod Toxicol};2016 (Sep 22);66:31-43.
OBJECTIVE: To determine whether an up-to-date systematic review and meta-analysis of observational studies would support the previously suggested associations regarding prenatal selective serotonin reuptake inhibitor (SSRI) use and the risk for autism spectrum disorders (ASD) in children. METHODS: PubMed/MEDLINE, Cochrane Central Register of Controlled Trials and Reprotox databases were searched; observational studies with an exposed and unexposed group were included. RESULTS: The meta-analysis of case-control studies demonstrated a significantly increased risk of ASD in the children whose mothers were prenatally exposed to SSRIs during different exposure time windows (except third trimester). The qualitative review of the cohort studies suggested inconsistent findings. CONCLUSIONS: The significant association between preconception-only SSRI exposure and ASD in the children and negative/inconsistent findings among cohort studies weaken the significant associations detected in this meta-analysis. We suggest that confounding by indication still cannot be ruled out regarding prenatal SSRI exposure and ASD in children.
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7. Oginsky MF, Cui N, Zhong W, Johnson CM, Jiang C. {{Hyperexcitability of Mesencephalic Trigeminal Neurons and Reorganization of Ion Channel Expression in a Rett Syndrome Model}}. {J Cell Physiol};2016 (Sep 27)
People with Rett syndrome (RTT) have defects in motor function also seen in Mecp2-null mice. Motor function depends on not only central motor commands but also sensory feedback that is vulnerable to changes in excitability of propriosensory neurons. Here we report evidence for hyperexcitability of mesencephalic trigeminal (Me5) neurons in Mecp2-null mice and a novel cellular mechanism for lowering its impact. In in vitro brain slices, the Me5 neurons in both Mecp2-/Y male and symptomatic Mecp2+/- female mice were overly excitable showing increased firing activity in comparison to their wild-type (WT) male and asymptomatic counterparts. In Mecp2-/Y males, Me5 neurons showed a reduced firing threshold. Consistently, the steady-state activation of voltage-gated Na+ currents (INa ) displayed a hyperpolarizing shift in the Mecp2-null neurons with no change in the INa density. This seems to be due to NaV1.1, SCN1B and SCN4B overexpression and NaV1.2 and SCN3B under-expression. In contrast to the hyperexcitability, the sag potential and postinhibitory rebound (PIR) were reduced in Mecp2-null mice. In voltage-clamp, the IH density was deficient by approximately 33%, and the steady-state half-activation had a depolarizing shift of approximately 10 mV in the Mecp2-null mice. Quantitative PCR analysis indicated that HCN2 was decreased, HCN1 was upregulated with no change in HCN4 in Mecp2-/Y mice compared to WT. Lastly, blocking IH reduced the firing rate much more in WT than in Mecp2-null neurons. These data suggest that the Mecp2 defect causes an increase in Me5 neuronal excitability likely attributable to alterations in INa , meanwhile IH is reduced likely altering neuronal excitability as well. J. Cell. Physiol. 9999: 1-14, 2016. (c) 2016 Wiley Periodicals, Inc.
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8. Servadio M, Melancia F, Manduca A, di Masi A, Schiavi S, Cartocci V, Pallottini V, Campolongo P, Ascenzi P, Trezza V. {{Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid}}. {Transl Psychiatry};2016;6(9):e902.
Autism spectrum disorders (ASD) are characterized by altered sociability, compromised communication and stereotyped/repetitive behaviors, for which no specific treatments are currently available. Prenatal exposure to valproic acid (VPA) is a known, although still underestimated, environmental risk factor for ASD. Altered endocannabinoid activity has been observed in autistic patients, and endocannabinoids are known to modulate behavioral traits that are typically affected in ASD. On this basis, we tested the hypothesis that changes in the endocannabinoid tone contribute to the altered phenotype induced by prenatal VPA exposure in rats, with focus on behavioral features that resemble the core and associated symptoms of ASD. In the course of development, VPA-exposed rats showed early deficits in social communication and discrimination, compromised sociability and social play behavior, stereotypies and increased anxiety, thus providing preclinical proof of the long-lasting deleterious effects induced by prenatal VPA exposure. At the neurochemical level, VPA-exposed rats displayed altered phosphorylation of CB1 cannabinoid receptors in different brain areas, associated with changes in anandamide metabolism from infancy to adulthood. Interestingly, enhancing anandamide signaling through inhibition of its degradation rescued the behavioral deficits displayed by VPA-exposed rats at infancy, adolescence and adulthood. This study therefore shows that abnormalities in anandamide activity may underlie the deleterious impact of environmental risk factors on ASD-relevant behaviors and that the endocannabinoid system may represent a therapeutic target for the core and associated symptoms displayed by autistic patients.
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9. Srinivasan SM, Eigsti IM, Gifford T, Bhat AN. {{The effects of embodied rhythm and robotic interventions on the spontaneous and responsive verbal communication skills of children with Autism Spectrum Disorder (ASD): A further outcome of a pilot randomized controlled trial}}. {Res Autism Spectr Disord};2016 (Jul);27:73-87.
The current manuscript is the second in a mini-series of manuscripts reporting the effects of alternative, movement-based, rhythm and robotic interventions on the social communication skills of 36 school-age children with ASD. This pilot randomized controlled trial compared the effects of 8-weeks of rhythm and robotic interventions to those of a standard-of-care, comparison intervention. The first manuscript reported intervention effects on the spontaneous and responsive social attention skills of children. In this manuscript, we report intervention effects on the spontaneous and responsive verbal communication skills of children. Communication skills were assessed within a standardized test of responsive communication during the pretest and posttest as well as using training-specific measures of social verbalization during early, mid, and late training sessions. The rhythm and comparison groups improved on the standardized test in the posttest compared to the pretest. The rhythm and robot groups increased levels of social verbalization across training sessions. Movement-based and stationary contexts afforded different types and amounts of communication in children with ASD. Overall, movement-based interventions are a promising tool to enhance verbal and non-verbal communication skills in children with ASD.
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10. Thiemann-Bourque K, Brady N, McGuff S, Stump K, Naylor A. {{Picture Exchange Communication System and Pals: A Peer-Mediated Augmentative and Alternative Communication Intervention for Minimally Verbal Preschoolers With Autism}}. {J Speech Lang Hear Res};2016 (Sep 27):1-13.
Purpose: This study was conducted to investigate the effectiveness of a social intervention that integrates peer-mediated approaches and the Picture Exchange Communication System (PECS). Method: Effects were evaluated using a series of A-B designs replicated across 4 children with severe autism and limited verbal skills. Seven peers without disabilities were trained to use PECS and facilitative social skills. Measures of changes included rates of communication behaviors, modes, functions, and engagement. Results: Outcomes revealed an intervention effect for 1 child with autism, and this effect was replicated across 3 other children. All children improved in peer-directed communication, with greater increases for 2 children during snack time. For each child with autism, the primary communication behavior was to initiate with picture symbols to request; the peer’s primary communication was to respond. Two children increased communicative functions to comment and to share, and all 4 children showed improved social engagement. All peers increased their communication with the children with autism. Conclusions: These findings add to the limited research on the benefits of teaching typically developing peers to be responsive listeners to preschoolers with autism by learning to use PECS. These results invite further investigation of teaching peers other augmentative and alternative communication approaches and how to increase children’s communication with peers for different purposes.
