1. Baker E, Jeste SS. {{Diagnosis and Management of Autism Spectrum Disorder in the Era of Genomics: Rare Disorders Can Pave the Way for Targeted Treatments}}. {Pediatr Clin North Am};2015 (Jun);62(3):607-618.
Although the diagnosis of autism spectrum disorder (ASD) is based on behavioral signs and symptoms, the evaluation of a child with ASD has become increasingly focused on the identification of the genetic etiology of the disorder. In this review, we begin with a clinical overview of ASD, highlighting the heterogeneity of the disorder. We then discuss the genetics of ASD and present updated guidelines on genetic testing. We then consider the insights gained from the identification of both single gene disorders and rare variants, with regard to clinical phenomenology and potential treatment targets.
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2. Gdalyahu A, Lazaro M, Penagarikano O, Golshani P, Trachtenberg JT, Geschwind DH. {{Correction: The Autism Related Protein Contactin-Associated Protein-Like 2 (CNTNAP2) Stabilizes New Spines: An In Vivo Mouse Study}}. {PLoS One};2015;10(5):e0129638.
[This corrects the article DOI: 10.1371/journal.pone.0125633.].
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3. Itahashi T, Yamada T, Watanabe H, Nakamura M, Ohta H, Kanai C, Iwanami A, Kato N, Hashimoto R. {{Alterations of local spontaneous brain activity and connectivity in adults with high-functioning autism spectrum disorder}}. {Mol Autism};2015;6:30.
BACKGROUND: Previous autism research has hypothesized that abnormalities of functional connectivity in autism spectrum disorder (ASD) may vary with the spatial distance between two brain regions. Although several resting-state functional magnetic resonance imaging (rsfMRI) studies have extensively examined long-range (or distant) connectivity in the adult ASD brain, short-range (or local) connectivity has been investigated in less depth. Furthermore, the possible relationship between functional connectivity and brain activity level during the resting state remains unclear. METHODS: We acquired rsfMRI data from 50 adults with high-functioning ASD and 50 matched controls to examine the properties of spontaneous brain activity using measures of local and distant connectivity together with a measure of the amplitude of brain activity, known as fractional amplitude of low-frequency fluctuation (fALFF). The two connectivity measures were calculated using a common graph-theoretic framework. We also examined the spatial overlaps between these measures and possible relationships of these disrupted functional measures with autistic traits assessed by the Autism-Spectrum Quotient (AQ). RESULTS: Compared to the controls, participants with ASD exhibited local over-connectivity in the right superior frontal gyrus and middle frontal gyrus, accompanied by local under-connectivity in the bilateral fusiform gyri (FG) and right middle temporal gyrus (MTG). On the other hand, we did not find any significant alterations in distant connectivity. Participants with ASD also exhibited reduced fALFF in the right middle occipital gyrus, lingual gyrus, and FG. Further conjunction and spatial overlap analyses confirmed that the spatial pattern of reduced fALFF substantially overlapped with that of local under-connectivity, demonstrating the co-occurrence of disrupted connectivity and spontaneous activity level in the right inferior occipital gyrus, posterior MTG (pMTG), and FG. Finally, within the ASD group, disrupted local connectivity in the right pMTG significantly correlated with the « social interaction » subscale score of the AQ. CONCLUSIONS: These findings revealed local functional disruptions in the occipital and temporal regions, especially the right FG and pMTG, in the form of co-occurrence of spontaneous brain activity level and local connectivity, which may underline social and communicative dysfunctions in adult ASD.
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4. Jaiswal P, Mohanakumar KP, Rajamma U. {{Serotonin mediated immunoregulation and neural functions: Complicity in the aetiology of autism spectrum disorders}}. {Neurosci Biobehav Rev};2015 (May 27)
Serotonergic system has long been implicated in the aetiology of autism spectrum disorders (ASD), since platelet hyperserotonemia is consistently observed in a subset of autistic patients, who respond well to selective serotonin reuptake inhibitors. Apart from being a neurotransmitter, serotonin functions as a neurotrophic factor directing brain development and as an immunoregulator modulating immune responses. Serotonin transporter (SERT) regulates serotonin level in lymphoid tissues to ensure its proper functioning in innate and adaptive responses. Immunological molecules such as cytokines in turn regulate the transcription and activity of SERT. Dysregulation of serotonergic system could trigger signalling cascades that affect normal neural-immune interactions culminating in neurodevelopmental and neural connectivity defects precipitating behavioural abnormalities, or the disease phenotypes. Therefore, we suggest that a better understanding of the cross talk between serotonergic genes, immune systems and serotonergic neurotransmission will open wider avenues to develop pharmacological leads for addressing the core ASD behavioural deficits.
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5. Keskin M, Erdeve SS, Aycan Z. {{Rett syndrome and precocious puberty association}}. {J Pediatr Endocrinol Metab};2015 (May 30)
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6. Luongo FJ, Horn ME, Sohal VS. {{Putative Microcircuit-Level Substrates for Attention Are Disrupted in Mouse Models of Autism}}. {Biol Psychiatry};2015 (Apr 28)
BACKGROUND: Deep layer excitatory circuits in the prefrontal cortex represent the strongest locus for genetic convergence in autism, but specific abnormalities within these circuits that mediate key features of autism, such as cognitive or attentional deficits, remain unknown. Attention normally increases the sensitivity of neural populations to incoming signals by decorrelating ongoing cortical circuit activity. Here, we investigated whether mechanisms underlying this phenomenon might be disrupted within deep layer prefrontal circuits in mouse models of autism. METHODS: We isolated deep layer prefrontal circuits in brain slices then used single-photon GCaMP imaging to record activity from many (50 to 100) neurons simultaneously to study patterns of spontaneous activity generated by these circuits under normal conditions and in two etiologically distinct models of autism: mice exposed to valproic acid in utero and Fmr1 knockout mice. RESULTS: We found that modest doses of the cholinergic agonist carbachol normally decorrelate spontaneous activity generated by deep layer prefrontal networks. This effect was disrupted in both valproic acid-exposed and Fmr1 knockout mice but intact following other manipulations that did not model autism. CONCLUSIONS: Our results suggest that cholinergic modulation may contribute to attention by acting on local cortical microcircuits to decorrelate spontaneous activity. Furthermore, defects in this mechanism represent a microcircuit-level endophenotype that could link diverse genetic and developmental disruptions to attentional deficits in autism. Future studies could elucidate pathways leading from various etiologies to this circuit-level abnormality or use this abnormality itself as a target and identify novel therapeutic strategies that restore normal circuit function.
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7. Ornoy A, Weinstein-Fudim L, Ergaz Z. {{Prenatal factors associated with Autism Spectrum Disorder (ASD)}}. {Reprod Toxicol};2015 (May 25)
Autism spectrum disorder (ASD) affecting about 1% of all children is associated, in addition to complex genetic factors, with a variety of prenatal, perinatal and postnatal etiologies. We discuss the known associated prenatal factors affecting the fetus throughout pregnancy; whenever relevant, also summarize some animal data. Among the maternal diseases in pregnancy associated with ASD are pregestational and/or gestational diabetes mellitus (PGDM, GDM), maternal infections (i.e. rubella, cytomegalovirus (CMV)), prolonged fever and maternal inflammation, which cause changes in a variety of inflammatory cytokines. Among the drugs are valproic acid, thalidomide, and possibly misoprostol and serotonin reuptake inhibitors (SSRIs). Associations were described with ethanol, and possibly cocaine heavy metals heavy smoking, and Folic acid deficiency. Heavy exposure to pesticides and air pollution during pregnancy was recently associated with ASD. We need more epidemiologic data to establish many of these associations; if proven, they might be promising avenues for prevention.
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8. Pinto R, Rijsdijk F, Ronald A, Asherson P, Kuntsi J. {{The Genetic Overlap of Attention-Deficit/Hyperactivity Disorder and Autistic-like Traits: an Investigation of Individual Symptom Scales and Cognitive markers}}. {J Abnorm Child Psychol};2015 (May 30)
Attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASDs) frequently co-occur. However, due to previous exclusionary diagnostic criteria, little is known about the underlying causes of this covariation. Twin studies assessing ADHD symptoms and autistic-like traits (ALTs) suggest substantial genetic overlap, but have largely failed to take into account the genetic heterogeneity of symptom subscales. This study aimed to clarify the phenotypic and genetic relations between ADHD and ASD by distinguishing between symptom subscales that characterise the two disorders. Moreover, we aimed to investigate whether ADHD-related cognitive impairments show a relationship with ALT symptom subscales; and whether potential shared cognitive impairments underlie the genetic risk shared between the ADHD and ALT symptoms. Multivariate structural equation modelling was conducted on a population-based sample of 1312 twins aged 7-10. Social-communication ALTs correlated moderately with both ADHD symptom domains (phenotypic correlations around 0.30) and showed substantial genetic overlap with both inattention and hyperactivity-impulsivity (genetic correlation = 0.52 and 0.44, respectively). In addition to previously reported associations with ADHD traits, reaction time variability (RTV) showed significant phenotypic (0.18) and genetic (0.32) association with social-communication ALTs. RTV captured a significant proportion (24 %) of the genetic influences shared between inattention and social-communication ALTs. Our findings suggest that social-communication ALTs underlie the previously observed phenotypic and genetic covariation between ALTs and ADHD symptoms. RTV is not specific to ADHD symptoms, but is also associated with social-communication ALTs and can, in part, contribute to an explanation of the co-occurrence of ASD and ADHD.
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9. Stendal K, Balandin S. {{Virtual worlds for people with autism spectrum disorder: a case study in Second Life}}. {Disabil Rehabil};2015 (May 29):1-8.
PURPOSE: The purpose of this study is to explore the use of virtual worlds by people with autism spectrum disorder (ASD), with a particular focus on the virtual world Second Life. METHOD: Case study methodology was selected to explore the experiences of Wolf, a participant with ASD, in Second Life. Wolf participated in three in-depth interviews. The interviews were analyzed using a content analysis to identify themes and sub-themes. RESULTS: Analysis identified four main themes: social factors and communication, empowerment, virtual world versus physical world, and social cues and body language. CONCLUSION: Anecdotally Wolf’s experiences suggest that people with ASD enjoy using a virtual world and may feel more comfortable communicating in the virtual world context than the physical world. Virtual worlds offer a venue for people with ASD to be a part of a virtual society, lowers communication barriers experienced in the physical world, and gives the participant a unique opportunity to create and maintain friendships. Virtual worlds offer an arena for people with ASD to meet their peers on equal terms, not being dependent on social cues, which in the physical world can be a barrier for communication for this group. Further research in this area is required. Implications for Rehabiliation People with autism spectrum disorder enjoy using a virtual world and may feel more comfortable communicating in the virtual world context than the physical world. Virtual worlds offer a venue for people with autism spectrum disorder to be a part of a virtual society. Virtual worlds offer an arena for people with autism spectrum disorder to meet their peers on equal terms, not being dependent on social cues, which in the physical world can be a barrier for this group.
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10. Tonhajzerova I, Ondrejka I, Mestanik M, Mikolka P, Hrtanek I, Mestanikova A, Bujnakova I, Mokra D. {{Inflammatory Activity in Autism Spectrum Disorder}}. {Adv Exp Med Biol};2015 (May 29)
Autism spectrum disorder (ASD) is a severe neurodevelopmental disorder in early childhood characterized by impairment in communication and behavior. Recent research is focused on the immune dysregulation as a potential pathomechanism leading to ASD. Thus, we addressed the hypothesis that inflammatory activity might be enhanced in children suffering from ASD. We examined 15 children with ASD (13 boys/2 girls, mean age of 9.3 +/- 0.7 years) and 20 age/gender-matched healthy subjects as a control group. All children were medication free and in good health. Hematological parameters in venous blood and plasma levels of pro-inflammatory cytokines – tumor necrosis factor alpha (TNF-alpha), interleukin 1ss (IL-1ss), and interleukin 8 (IL-8) – were assessed in each subject using human ultra-sensitive ELISA kits. In addition, TBARS as a marker of oxidative stress was evaluated. We found that the level of IL-8 was significantly increased in the ASD children, whereas the other markers remained unappreciably changed compared to controls (p = 0.003). In conclusion, the study demonstrates a discrete immune dysfunction in ASD of pro-inflammatory character.
