1. Baj G, Patrizio A, Montalbano A, Sciancalepore M, Tongiorgi E. {{Developmental and maintenance defects in Rett syndrome neurons identified by a new mouse staging system in vitro}}. {Front Cell Neurosci};2014;8:18.
Rett Syndrome (RTT) is a neurodevelopmental disorder associated with intellectual disability, mainly caused by loss-of-function mutations in the MECP2 gene. RTT brains display decreased neuronal size and dendritic arborization possibly caused by either a developmental failure or a deficit in the maintenance of dendritic arbor structure. To distinguish between these two hypotheses, the development of Mecp2-knockout mouse hippocampal neurons was analyzed in vitro. Since a staging system for the in vitro development of mouse neurons was lacking, mouse and rat hippocampal neurons development was compared between 1-15 days in vitro (DIV) leading to a 6-stage model for both species. Mecp2-knockout hippocampal neurons displayed reduced growth of dendritic branches from stage 4 (DIV4) onwards. At stages 5-6 (DIV9-15), synapse number was lowered in Mecp2-knockout neurons, suggesting increased synapse elimination. These results point to both a developmental and a maintenance setback affecting the final shape and function of neurons in RTT.
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2. Cohen IL, Gardner JM, Karmel BZ, Kim SY. {{Rating scale measures are associated with Noldus EthoVision-XT video tracking of behaviors of children on the autism spectrum}}. {Mol Autism};2014 (Feb 18);5(1):15.
BACKGROUND: Children with Autism Spectrum Disorder (ASD) show unusual social behaviors and repetitive behaviors. Some of these behaviors, e.g., time spent in an area or turning rate/direction, can be automatically tracked. Automated tracking has several advantages over subjective ratings including reliability, amount of information provided, and consistency across laboratories, and is potentially of importance for diagnosis, animal models and objective assessment of treatment efficacy. However, its validity for ASD has not been examined. In this exploratory study, we examined associations between rating scale data with automated tracking of children’s movements using the Noldus EthoVision XT system; i.e., tracking not involving a human observer. Based on our observations and previous research, we predicted that time spent in the periphery of the room would be associated with autism severity and that rate and direction of turning would be associated with stereotypies. METHODS: Children with and without ASD were observed in a free-play situation for 3 min before and 3 min after Autism Diagnostic Observation Scale – Generic (ADOS-G) testing. The Noldus system provided measures of the rate and direction of turning, and time spent near the periphery or the parent. RESULTS: Ratings of the severity of maladaptive social behaviors, stereotypies, autism severity, and arousal problems were positively correlated with increases in percent time spent in the periphery in the total sample and in the ASD subset. Adaptive social communication skills decreased with increases in the percentage of time spent in the periphery and increases in the latency to approach the parent in the ASD group. The rate and direction of turning was linked with stereotypies only in the group without ASD (the faster the rate of a turn to the left, the worse the rating). In the ASD group, there was a shift from a neutral turning bias prior to the ADOS assessment to a strong left turn bias after the ADOS assessment. In the entire sample, this left turn bias was associated with measures of autism severity. CONCLUSION: Results suggest that automated tracking yields valid and unbiased information for assessing children with autism. Turning bias is an interesting and unexplored measure related to autism.
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3. D’Antoni S, Spatuzza M, Bonaccorso CM, Musumeci SA, Ciranna L, Nicoletti F, Huber KM, Catania MV. {{Dysregulation of group-I metabotropic glutamate (mGlu) receptor mediated signalling in disorders associated with Intellectual Disability and Autism}}. {Neurosci Biobehav Rev};2014 (Feb 15)
Activation of group-I metabotropic glutamate receptors, mGlu1 and mGlu5, triggers a variety of signalling pathways in neurons and glial cells, which are differently implicated in synaptic plasticity. The earliest and much of key studies discovered abnormal mGlu5 receptor function in Fragile X syndrome (FXS) mouse models which then motivated more recent work that finds mGlu5 receptor dysfunction in related disorders such as intellectual disability (ID), obsessive-compulsive disorder (OCD) and autism. Therefore, mGlu1/5 receptor dysfunction may represent a common aetiology of these complex diseases. Furthermore, many studies have focused on dysregulation of mGlu5 signalling to synaptic protein synthesis. However, emerging evidence finds abnormal mGlu5 receptor interactions with its scaffolding proteins in FXS which results in mGlu5 receptor dysfunction and phenotypes independent of signalling to protein synthesis. Finally, both an increased and reduced mGlu5 functioning seem to be associated with ID and autism spectrum disorders, with important consequences for potential treatment of these developmental disorders.
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4. Durdiakova J, Warrier V, Banerjee-Basu S, Baron-Cohen S, Chakrabarti B. {{STX1A and Asperger syndrome: a replication study}}. {Mol Autism};2014 (Feb 18);5(1):14.
BACKGROUND: Autism Spectrum Conditions (ASC) are a group of conditions characterized by difficulties in communication and social interaction, alongside unusually narrow interests and repetitive, stereotyped behavior. Genetic association and expression studies have suggested an important role for the GABAergic circuits in ASC. Syntaxin 1A (STX1A) encodes a protein involved in regulation of serotonergic and GABAergic systems and its expression is altered in autism. METHODS: In this study, the association between three SNPs (rs4717806, rs941298 and rs6951030) in STX1A gene and Asperger syndrome (AS) were tested in n = 650 controls and n = 479 individuals with AS, all of Caucasian ancestry. RESULTS: rs4717806 (p = 0.00334) and rs941298 (p = 0.01741) showed significant association with AS, replicating previous results. Both SNPs putatively alter transcription factor binding sites both directly and through other variants in high linkage disequilibrium. CONCLUSION: The current study confirms the role of STX1A as an important candidate gene in ASC. The exact molecular mechanisms through which STX1A contributes to the etiology remain to be elucidated.
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5. Gulsrud AC, Hellemann GS, Freeman SF, Kasari C. {{Two to Ten Years: Developmental Trajectories of Joint Attention in Children With ASD Who Received Targeted Social Communication Interventions}}. {Autism Res};2014 (Feb 18)
This study follows 40 children who were participants in a randomized controlled early intervention trial (Kasari et al.) from early childhood (2-5 years of age) to elementary school age (8-10 years). To fully utilize the available longitudinal data, the general linear mixed model was the primary analytical approach. The growth trajectories of joint attention skills (pointing, coordinated joint looking, and showing) and expressive language outcomes in these children were estimated based on five time points during the measurement period. The children were grouped by diagnosis at the last follow-up (autism, autism spectrum disorder (ASD), no diagnosis) and by their original treatment group assignment (joint attention, symbolic play, control), and differences between these groups were evaluated. Results showed that joint attention skills of coordinated joint looking and showing increased over time, and pointing to share interest increased over the first year measured and decreased thereafter. These trajectories were influenced by both original treatment assignment and diagnostic status at follow-up. In addition, a cross-lagged panel analysis revealed a causal relationship between early pointing and later language development. This study highlights the longitudinal and developmental importance of measures of early core deficits in autism, and suggests that both treatment and ASD symptomatology may influence growth in these skills over time. Autism Res 2014, : -. (c) 2014 International Society for Autism Research, Wiley Periodicals, Inc.
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6. Gupta PK, Marzook RA, Sulaibeekh L. {{Multiple intracranial abscesses: Heralding asymptomatic venosus ASD}}. {Asian J Neurosurg};2013 (Oct);8(4):202-205.
A case of multiple intracranial abscesses in an immune-competent young girl is reported. She had chicken pox. Two weeks later, she presented with multiple intracranial abscesses. No significant cardiac abnormality was detected on transthoracic echocardiogram (TTE). The condition was treated medically. However, one of the abscesses adjacent to the CSF pathways enlarged on treatment and caused obstructive hydrocephalus that required stereotactic aspiration. Gram stain showed gram positive cocci in chain. Pus was sterile on culture. She was treated with broad spectrum IV antibiotics based on Gram staining report for 6 weeks followed by another 8 weeks of oral antibiotics. She made good recovery and had been leading a normal life. The abscess capsules took 30 months to resolve completely on MRI. A repeat TTE done in the follow up showed enlarged right heart chambers with a suggestion of a venosus ASD. A trans-esophageal echocardiogram (TEE) confirmed the presence of sinus venosus ASD from the SVC side with mainly left to right shunt. There was also partial anomalous drainage of the pulmonary veins. The patient underwent correction of the defect and has been doing well.
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7. Horder J, Lavender T, Mendez MA, O’Gorman R, Daly E, Craig MC, Lythgoe DJ, Barker GJ, Murphy DG. {{Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [(1)H]MRS study}}. {Transl Psychiatry};2014;4:e364.
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8. Kimple KS, Bartelt EA, Wysocki KL, Steiner MJ. {{Performance of the Modified Checklist for Autism in Toddlers in Spanish-Speaking Patients}}. {Clin Pediatr (Phila)};2014 (Feb 17)
Objective. To compare abnormal screening rates of 2 different Spanish versions of the Modified Checklist for Autism in Toddlers (M-CHAT) in US Spanish-speaking patients. Method. Quasi-experimental design was used with historical and English language controls. Abnormal screening rates were compared between Spain and Western-hemisphere Spanish versions, as well as to English controls during the same time periods using chi square analysis. Results. M-CHAT questionnaires were scored from 589 subjects (English n = 415, Spanish n = 174). There was little difference between Spanish versions. Overall, the Spanish abnormal screening rate was double that of English (23.6% vs 11.3%, P < .001). Conclusions. Spanish M-CHAT questionnaires are abnormal more often than those in English even after changing to appropriate translation, despite lower prevalence of autism in Latinos. Issues with translation, interpretation, or cultural understanding of behaviors may contribute. Given abnormal screening rates for Latinos, the use of the M-CHAT follow-up interview in Spanish-speaking patients is beneficial but may be more time-consuming.
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9. Martin HG, Manzoni OJ. {{Late onset deficits in synaptic plasticity in the valproic acid rat model of autism}}. {Front Cell Neurosci};2014;8:23.
Valproic acid (VPA) is a frequently used drug in the treatment of epilepsy, bipolar disorders and migraines; however it is also a potent teratogen. Prenatal exposure increases the risk of childhood malformations and can result in cognitive deficits. In rodents in utero exposure to VPA also causes neurodevelopmental abnormalities and is an important model of autism. In early postnatal life VPA exposed rat pups show changes in medial prefrontal cortex (mPFC) physiology and synaptic connectivity. Specifically, principal neurons show decreased excitability but increased local connectivity, coupled with an increase in long-term potentiation (LTP) due to an up-regulation of NMDA receptor (NMDAR) expression. However recent evidence suggests compensatory homeostatic mechanisms lead to normalization of synaptic NMDARs during later postnatal development. Here we have extended study of mPFC synaptic physiology into adulthood to better understand the longitudinal consequences of early developmental abnormalities in VPA exposed rats. Surprisingly in contrast to early postnatal life and adolescence, we find that adult VPA exposed rats show reduced synaptic function. Both NMDAR mediated currents and LTP are lower in adult VPA rats, although spontaneous activity and endocannabinoid dependent long-term depression are normal. We conclude that rather than correcting, synaptic abnormalities persist into adulthood in VPA exposed rats, although a quite different synaptic phenotype is present. This switch from hyper to hypo function in mPFC may be linked to some of the neurodevelopmental defects found in prenatal VPA exposure and autism spectrum disorders in general.
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10. Nuske HJ, Vivanti G, Dissanayake C. {{Brief Report: Evidence for Normative Resting-State Physiology in Autism}}. {J Autism Dev Disord};2014 (Feb 19)
Although the conception of autism as a disorder of abnormal resting-state physiology has a long history, the evidence remains mixed. Using state-of-the-art eye-tracking pupillometry, resting-state (tonic) pupil size was measured in children with and without autism. No group differences in tonic pupil size were found, and tonic pupil size was not related to age or cognitive ability in either group, and nor was it related to autistic symptoms. We suggest that previous findings of hyper-arousal in autism at baseline may be a product of different recording methods, in particular different movement-artifact removal techniques. These results question the notion that autism is associated with a fundamental dysregulation in resting-state physiology. Further research, employing such techniques is needed to confirm these findings.
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11. Rotschafer SE, Razak KA. {{Auditory Processing in Fragile X Syndrome}}. {Front Cell Neurosci};2014;8:19.
Fragile X syndrome (FXS) is an inherited form of intellectual disability and autism. Among other symptoms, FXS patients demonstrate abnormalities in sensory processing and communication. Clinical, behavioral, and electrophysiological studies consistently show auditory hypersensitivity in humans with FXS. Consistent with observations in humans, the Fmr1 KO mouse model of FXS also shows evidence of altered auditory processing and communication deficiencies. A well-known and commonly used phenotype in pre-clinical studies of FXS is audiogenic seizures. In addition, increased acoustic startle response is seen in the Fmr1 KO mice. In vivo electrophysiological recordings indicate hyper-excitable responses, broader frequency tuning, and abnormal spectrotemporal processing in primary auditory cortex of Fmr1 KO mice. Thus, auditory hyper-excitability is a robust, reliable, and translatable biomarker in Fmr1 KO mice. Abnormal auditory evoked responses have been used as outcome measures to test therapeutics in FXS patients. Given that similarly abnormal responses are present in Fmr1 KO mice suggests that cellular mechanisms can be addressed. Sensory cortical deficits are relatively more tractable from a mechanistic perspective than more complex social behaviors that are typically studied in autism and FXS. The focus of this review is to bring together clinical, functional, and structural studies in humans with electrophysiological and behavioral studies in mice to make the case that auditory hypersensitivity provides a unique opportunity to integrate molecular, cellular, circuit level studies with behavioral outcomes in the search for therapeutics for FXS and other autism spectrum disorders.
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12. Samango-Sprouse CA, Stapleton EJ, Aliabadi F, Graw R, Vickers R, Haskell K, Sadeghin T, Jameson R, Parmele CL, Gropman AL. {{Identification of infants at risk for autism spectrum disorder and developmental language delay prior to 12 months}}. {Autism};2014 (Feb 18)
Studies have shown an increased head circumference and the absence of the head tilt reflex as possible risk factors for autism spectrum disorder, allowing for early detection at 12 months in typically developing population of infants. Our aim was to develop a screening tool to identify infants prior to 12 months at risk for autism spectrum disorder and developmental learning delay, not affected by literacy or primary parental language, and provide immediate determination of risk for autism spectrum disorder. An abrupt head circumference acceleration and the absence of head tilt reflex by 9 months were used to identify infants at risk for autism spectrum disorder. Stability of early findings was then investigated when compared to comprehensive standardized neurodevelopmental assessment results and complete neurological and genetics evaluations. A total of 1024 typically developing infants were enrolled by 9 months, with 14 identified as at risk for autism spectrum disorder and 33 for developmental learning delay. There was a good positive predictive value for the identification of autism spectrum disorder prior to 12 months. This study demonstrates an efficient means to identify infants at risk for autism spectrum disorder by 9 months of age and serves to alert primary care providers of infants who are vulnerable for autism spectrum disorder before symptoms are discernible by clinical judgment of primary care providers, parental concerns, or by screening questionnaires.
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13. Stenberg N, Bresnahan M, Gunnes N, Hirtz D, Hornig M, Lie KK, Lipkin WI, Lord C, Magnus P, Reichborn-Kjennerud T, Schjolberg S, Suren P, Susser E, Svendsen BK, von Tetzchner S, Oyen AS, Stoltenberg C. {{Identifying Children with Autism Spectrum Disorder at 18 Months in a General Population Sample}}. {Paediatr Perinat Epidemiol};2014 (Feb 18)
BACKGROUND: Previous research on clinical and high-risk samples suggests that signs of autism spectrum disorder (ASD) can be detected between 1 and 2 years of age. We investigated signs of ASD at 18 months in a population-based sample and the association with later ASD diagnosis. METHODS: The study sample includes 52 026 children born 2003 through 2008 and is a subset of children that participated in the Norwegian Mother and Child Cohort (MoBa), a population-based longitudinal study, and the Autism Birth Cohort (ABC), a sub-study on ASD. Parents completed all 23 items from the Modified Checklist for Autism in Toddlers (M-CHAT) at 18 months. RESULTS: The M-CHAT 6-critical-item criterion and the 23-item criterion had a specificity of 97.9% and 92.7% and a sensitivity of 20.8% and 34.1%, respectively. In the 173 children diagnosed with ASD to date, 60 children (34.7%) scored above the cut-off on either of the screening criteria. The items with the highest likelihood ratios were ‘interest in other children’, ‘show objects to others’ and ‘response to name’. CONCLUSION: Even though one-third of the children who later received an ASD diagnosis were identified through M-CHAT items, the majority scored below cut-off on the screening criteria at 18 months. The results imply that it might not be possible to detect all children with ASD at this age.
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14. Valenti D, de Bari L, De Filippis B, Henrion-Caude A, Vacca RA. {{Mitochondrial dysfunction as a central actor in intellectual disability-related diseases: an overview of Down syndrome, autism, Fragile X and Rett syndrome}}. {Neurosci Biobehav Rev};2014 (Feb 15)
Clinical manifestations typical of mitochondrial diseases are often present in various genetic syndromes associated with intellectual disability, a condition leading to deficit in cognitive functions and adaptive behaviors. Until now, the causative mechanism leading to intellectual disability is unknown and the progression of the condition is poorly understood. We first report latest advances on genetic and environmental regulation of mitochondrial function and its role in brain development. Starting from the structure, function and regulation of the oxidative phosphorylation apparatus, we review how mitochondrial biogenesis and dynamics play a central role in neurogenesis and neuroplasticity. We then discuss how dysfunctional mitochondria and alterations in reactive oxygen species homeostasis are potentially involved in the pathogenesis of various neurodevelopmental syndromes with a special focus on Down, Rett, Fragile X syndromes and autism spectrum disorders. Finally, we review and suggest novel therapeutic approaches aimed at improving intellectual disability by activating mitochondrial function and reducing oxidative stress to amiliorate the quality of life in the subjects affected.
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15. Zaidman-Zait A, Mirenda P, Duku E, Szatmari P, Georgiades S, Volden J, Zwaigenbaum L, Vaillancourt T, Bryson S, Smith I, Fombonne E, Roberts W, Waddell C, Thompson A. {{Examination of Bidirectional Relationships Between Parent Stress and Two Types of Problem Behavior in Children with Autism Spectrum Disorder}}. {J Autism Dev Disord};2014 (Feb 19)
Path analysis within a structural equation modeling framework was employed to examine the relationships between two types of parent stress and children’s externalizing and internalizing behaviors over a 4-year period, in a sample of 184 mothers of young children with autism spectrum disorder. Parent stress was measured with the Parenting Stress Index-Short Form and child behavior was measured with Child Behavior Checklist/1.5-5. Across all time points, parent general distress predicted both types of child behaviors, but not vice versa. In addition, there was modest evidence of a bidirectional relationship between parenting distress and both types of child behaviors from 12 months post-diagnosis to age 6. Results are compared to previous work in this area, with implications for early intervention.
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16. Zhang LW, Gu WH, Wang GX, Chen YY, Hao Y, Zhang J, Wang K, Jin M. {{[Analysis of fragile X mental retardation 1 gene premutation in multiple system atrophy patients]}}. {Zhonghua Yi Xue Za Zhi};2013 (Dec 17);93(47):3744-3747.
OBJECTIVE: To investigate whether Chinese multiple system atrophy (MSA) patients have premutation of fragile X mental retardation 1 gene(FMR1). METHODS: FMR1 CGG repeats were analyzed in 157 MSA patients by polymerase chain reaction, agarose gel electrophoresis and capillary electrophoresis. The patients were collected from Movement Disorder & Neurogenetics Research Center of China-Japan friendship hospital. There were 83 male cases and 74 female cases, including 51 MSA-C patients, 12 MSA-P patients and 94 MSA-P+C patients. RESULTS: No FMR1 CGG repeat premutation was detected in 157 MSA patients. The repeats ranged from 11-49, most common allele was 22. A MSA-C case carried 35/49 alleles did not have middle cerebellar peduncles(MCP) sign which was necessary for the diagnosis of fragile X associated tremor ataxia syndrome(FXTAS). CONCLUSION: The FMR1 premutation in Chinese MSA patients might be very rare.
