1. Avdjieva-Tzavella DM, Todorov TP, Todorova AP, Kirov AV, Hadjidekova SP, Rukova BB, Litvinenko IO, Hristova-Naydenova DN, Tincheva RS, Toncheva DI. {{Analysis of the genes encoding neuroligins NLGN3 and NLGN4 in Bulgarian patients with autism}}. {Genet Couns};2012;23(4):505-511.
Many studies have supported a genetic aetiology for autism. Neuroligins are postsynaptically located cell-adhesion molecules. Mutations in two X-linked neuroligin genes, NLGN3 and NLGN4, have been implicated in pathogenesis of autism. In order to confirm these causative mutations in our autistic population and to determine their frequency we screened 20 individuals affected with autism. We identified one patient with a point mutation in NLGN4 gene that substituted a Met for Thr 787 – c.2360C > T, p.(Thr787Met) and three patients with identical polymorphisms in the same gene: c.933C > T, p.(Thr311Thr) in combination with c.[1777C > T+1779C > G, p.(Leu593Leu)]. All patients tested for NLGN3 mutations were negative. These results indicate that mutations in these genes are responsible for at most a small fraction of autism cases.
2. Baruth JM, Wall CA, Patterson MC, Port JD. {{Proton Magnetic Resonance Spectroscopy as a Probe into the Pathophysiology of Autism Spectrum Disorders (ASD): A Review}}. {Autism Res};2013 (Feb 21)
Proton magnetic resonance spectroscopy ((1) H-MRS) is a safe, noninvasive way of quantifying in vivo biochemical and metabolite concentration levels in individuals with Autism Spectrum Disorders (ASD). Findings to date suggest ASD is associated with widespread reduction in N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr), choline-containing compounds (Cho), myo-inositol (mI), and glutamate plus glutamine plus gamma-Aminobutyric Acid (Glx); however, variable findings, and even substantial increases, are not uncommon depending on the study and/or region-of-interest. Widespread reduction of NAA, Cr, Cho, mI, and Glx in ASD likely reflects impaired neuronal function and/or metabolism related to abnormal neurodevelopmental processes. Future studies should attempt to relate (1) H-MRS findings to histological findings and control for variability in subject age and functioning level; this would assist in evaluating the relationship between (1) H-MRS metabolic levels and neuronal and glial cell densities, as well as neurodevelopmental process associated with ASD. Furthermore, more longitudinal (1) H-MRS studies are needed in both control and ASD subjects to attempt to standardize metabolite levels across different developmental periods in well-defined endophenotypes. This will provide for a standard rubric for which metabolic aberrations (as well as treatment responses) can be measured. With higher magnetic field strengths and spectral-editing techniques capable of quantifying less-concentrated metabolites, (1) H-MRS will continue to be an important tool in ASD research. Autism Res 2013, : -. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc.
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3. Erickson CA, Wink LK, Ray B, Early MC, Stiegelmeyer E, Mathieu-Frasier L, Patrick V, Lahiri DK, McDougle CJ. {{Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome}}. {Psychopharmacology (Berl)};2013 (Feb 24)
RATIONALE: Fragile X syndrome (FXS) is an inherited form of developmental disability and a single gene cause of autism. As a disorder with increasingly understood pathophysiology, FXS is a model form of developmental disability for targeted drug development efforts. Preclinical animal model findings have focused targeted drug treatment development in FXS on an imbalance between excessive glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission. METHODS: We conducted a prospective open-label 10-week trial of acamprosate in 12 youth aged 6-17 years (mean age: 11.9 years) with FXS. RESULTS: Acamprosate use (mean dose: 1,054 +/- 422 mg/day) was associated with treatment response (defined by a Clinical Global Impressions Improvement (CGI-I) scale score of « very much improved » or « much improved ») in nine of 12 (75 %) subjects. Improvement was noted in social behavior and inattention/hyperactivity using multiple standard behavioral outcome measures. No significant adverse effects or changes in vital signs, including weight or laboratory measures, occurred during treatment with acamprosate. Additionally, pre- and post-treatment blood biomarker analyses looking at brain-derived neurotrophic factor (BDNF) levels found a significant increase in BDNF with treatment. In our pilot sample, treatment response did not correlate with change in BDNF with treatment. CONCLUSIONS: Acamprosate was generally safe and well tolerated and was associated with a significant improvement in social behavior and a reduction in inattention/hyperactivity. The increase in BDNF that occurred with treatment may be a useful pharmacodynamic marker in future acamprosate studies. Given these findings, a double-blind, placebo-controlled study of acamprosate in youth with FXS is warranted.
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4. Kourkoulou A, Kuhn G, Findlay JM, Leekam SR. {{Eye Movement Difficulties in Autism Spectrum Disorder: Implications for Implicit Contextual Learning}}. {Autism Res};2013 (Feb 21)
It is widely accepted that we use contextual information to guide our gaze when searching for an object. People with autism spectrum disorder (ASD) also utilise contextual information in this way; yet, their visual search in tasks of this kind is much slower compared with people without ASD. The aim of the current study was to explore the reason for this by measuring eye movements. Eye movement analyses revealed that the slowing of visual search was not caused by making a greater number of fixations. Instead, participants in the ASD group were slower to launch their first saccade, and the duration of their fixations was longer. These results indicate that slowed search in ASD in contextual learning tasks is not due to differences in the spatial allocation of attention but due to temporal delays in the initial-reflexive orienting of attention and subsequent-focused attention. These results have broader implications for understanding the unusual attention profile of individuals with ASD and how their attention may be shaped by learning. Autism Res 2013, : -. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc.
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5. Muratore CR, Hodgson NW, Trivedi MS, Abdolmaleky HM, Persico AM, Lintas C, De La Monte S, Deth RC. {{Age-dependent decrease and alternative splicing of methionine synthase mRNA in human cerebral cortex and an accelerated decrease in autism}}. {PLoS One};2013;8(2):e56927.
The folate and vitamin B12-dependent enzyme methionine synthase (MS) is highly sensitive to cellular oxidative status, and lower MS activity increases production of the antioxidant glutathione, while simultaneously decreasing more than 200 methylation reactions, broadly affecting metabolic activity. MS mRNA levels in postmortem human cortex from subjects across the lifespan were measured and a dramatic progressive biphasic decrease of more than 400-fold from 28 weeks of gestation to 84 years was observed. Further analysis revealed alternative splicing of MS mRNA, including deletion of folate-binding domain exons and age-dependent deletion of exons from the cap domain, which protects vitamin B12 (cobalamin) from oxidation. Although three species of MS were evident at the protein level, corresponding to full-length and alternatively spliced mRNA transcripts, decreasing mRNA levels across the lifespan were not associated with significant changes in MS protein or methionine levels. MS mRNA levels were significantly lower in autistic subjects, especially at younger ages, and this decrease was replicated in cultured human neuronal cells by treatment with TNF-alpha, whose CSF levels are elevated in autism. These novel findings suggest that rather than serving as a housekeeping enzyme, MS has a broad and dynamic role in coordinating metabolism in the brain during development and aging. Factors adversely affecting MS activity, such as oxidative stress, can be a source of risk for neurological disorders across the lifespan via their impact on methylation reactions, including epigenetic regulation of gene expression.
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6. Pignatelli M, Feligioni M, Piccinin S, Molinaro G, Nicoletti F, Nistico R. {{Synaptic plasticity as a therapeutic target in the treatment of autism-related single-gene disorders}}. {Curr Pharm Des};2013 (Feb 13)
The term « Autism Spectrum » is often used to describe disorders that are currently classified as Pervasive Developmental Disorders. These disorders are typically characterized by social deficits, communication difficulties, stereotyped or repetitive behaviours and/or cognitive delays or mental retardation; sometimes they present high comorbidity rates with epilepsy. Although these diagnoses share some common features, individuals with these disorders are thought to be « on the spectrum » because of differences in severity across these domains. Recent advances in the genetics of autism spectrum disorders (ASDs) are offering new valuable insights into molecular and cellular mechanisms of pathology. Of particular interest are transgenic technologies that allowed the engineering of several mouse models mimicking different kinds of monogenic heritable forms of ASDs. These transgenic models provide excellent opportunities to explore in detail cellular and molecular mechanisms underlying disease pathology and to identify novel targets for therapeutic intervention. Increasing evidence suggests that the pathophysiological core of the murine model is primarily due to changes in normal synaptic transmission and plasticity. Here, we will extensively review the synaptic alterations across different animal models of ASDs and recapitulate the pharmacological strategies aimed at rescuing hippocampal plasticity phenotypes. We describe how pharmacological modulation of mGlu5 receptor, through the use of positive or negative allosteric modulators (depending on the specific disorder), may represent a promising therapeutic strategy for ASDs treatment.
7. Potvin MC, Snider L, Prelock P, Kehayia E, Wood-Dauphinee S. {{Children’s Assessment of Participation and Enjoyment/Preference for Activities of Children: Psychometric Properties in a Population With High-Functioning Autism}}. {Am J Occup Ther};2013 (Mar);67(2):209-217.
The psychometric properties of assessments must be established for specific populations. The psychometric properties of the Children’s Assessment of Participation and Enjoyment/Preference for Activities of Children have been studied only in a sample of children with physical disability. We conducted a study to determine the appropriateness of drawing inferences from this assessment for children with high-functioning autism (HFA). The content validity and test-retest reliability (r > .7) were both found to be adequate for this population. Parents’ agreement with most of their children’s self-ratings on this assessment provided an estimate of interrater reliability. We also ascertained the feasibility of gathering recreational participation information from children with HFA and found that adaptations to facilitate the self-completion of the tool should be made available. The study findings support the use of this tool to assess recreational participation among children with HFA.
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8. Prigge MD, Bigler ED, Fletcher PT, Zielinski BA, Ravichandran C, Anderson J, Froehlich A, Abildskov T, Papadopolous E, Maasberg K, Nielsen JA, Alexander AL, Lange N, Lainhart J. {{Longitudinal Heschl’s Gyrus Growth During Childhood and Adolescence in Typical Development and Autism}}. {Autism Res};2013 (Feb 21)
Heightened auditory sensitivity and atypical auditory processing are common in autism. Functional studies suggest abnormal neural response and hemispheric activation to auditory stimuli, yet the neurodevelopment underlying atypical auditory function in autism is unknown. In this study, we model longitudinal volumetric growth of Heschl’s gyrus gray matter and white matter during childhood and adolescence in 40 individuals with autism and 17 typically developing participants. Up to three time points of magnetic resonance imaging data, collected on average every 2.5 years, were examined from individuals 3-12 years of age at the time of their first scan. Consistent with previous cross-sectional studies, no group differences were found in Heschl’s gyrus gray matter volume or asymmetry. However, reduced longitudinal gray matter volumetric growth was found in the right Heschl’s gyrus in autism. Reduced longitudinal white matter growth in the left hemisphere was found in the right-handed autism participants. Atypical Heschl’s gyrus white matter volumetric growth was found bilaterally in the autism individuals with a history of delayed onset of spoken language. Heightened auditory sensitivity, obtained from the Sensory Profile, was associated with reduced volumetric gray matter growth in the right hemisphere. Our longitudinal analyses revealed dynamic gray and white matter changes in Heschl’s gyrus throughout childhood and adolescence in both typical development and autism. Autism Res 2013, : -. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc.
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9. Rogers TD, Dickson PE, McKimm E, Heck DH, Goldowitz D, Blaha CD, Mittleman G. {{Reorganization of Circuits Underlying Cerebellar Modulation of Prefrontal Cortical Dopamine in Mouse Models of Autism Spectrum Disorder}}. {Cerebellum};2013 (Feb 26)
Imaging, clinical, and pre-clinical studies have provided ample evidence for a cerebellar involvement in cognitive brain function including cognitive brain disorders, such as autism and schizophrenia. We previously reported that cerebellar activity modulates dopamine release in the mouse medial prefrontal cortex (mPFC) via two distinct pathways: (1) cerebellum to mPFC via dopaminergic projections from the ventral tegmental area (VTA) and (2) cerebellum to mPFC via glutamatergic projections from the mediodorsal and ventrolateral thalamus (ThN md and vl). The present study compared functional adaptations of cerebello-cortical circuitry following developmental cerebellar pathology in a mouse model of developmental loss of Purkinje cells (Lurcher) and a mouse model of fragile X syndrome (Fmr1 KO mice). Fixed potential amperometry was used to measure mPFC dopamine release in response to cerebellar electrical stimulation. Mutant mice of both strains showed an attenuation in cerebellar-evoked mPFC dopamine release compared to respective wildtype mice. This was accompanied by a functional reorganization of the VTA and thalamic pathways mediating cerebellar modulation of mPFC dopamine release. Inactivation of the VTA pathway by intra-VTA lidocaine or kynurenate infusions decreased dopamine release by 50 % in wildtype and 20-30 % in mutant mice of both strains. Intra-ThN vl infusions of either drug decreased dopamine release by 15 % in wildtype and 40 % in mutant mice of both strains, while dopamine release remained relatively unchanged following intra-ThN md drug infusions. These results indicate a shift in strength towards the thalamic vl projection, away from the VTA. Thus, cerebellar neuropathologies associated with autism spectrum disorders may cause a reduction in cerebellar modulation of mPFC dopamine release that is related to a reorganization of the mediating neuronal pathways.
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10. Savarese RJ. {{Moving the field: the sensorimotor perspective on autism (Commentary on « Rethinking autism: implications of sensory and motor differences, » an article by Anne Donnellan, David Hill, and Martha Leary)}}. {Front Integr Neurosci};2013;7:6.
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11. Schwichtenberg AJ, Young GS, Hutman T, Iosif AM, Sigman M, Rogers SJ, Ozonoff S. {{Behavior and Sleep Problems in Children With a Family History of Autism}}. {Autism Res};2013 (Feb 21)
The present study explores behavioral and sleep outcomes in preschool-age siblings of children with autism spectrum disorders (ASD). This study focuses on behavior problems that are common in children with ASD, such as emotional reactivity, anxiety, inattention, aggression, and sleep problems. Infant siblings were recruited from families with at least one older child with ASD (high-risk group, n = 104) or families with no history of ASD (low-risk group, n = 76). As part of a longitudinal prospective study, children completed the Mullen Scales of Early Learning and the Autism Diagnostic Observation Schedule, and parents completed the Child Behavior Checklist (CBCL) and the Social Communication Questionnaire at 36 months of age. This study focuses on developmental concerns outside of ASD; therefore, only siblings who did not develop an ASD were included in analyses. Negative binomial regression analyses revealed that children in the high-risk group were more likely to have elevated behavior problems on the CBCL Anxious/Depressed and Aggression subscales. To explore sleep problems as a correlate of these behavior problems, a second series of models was specified. For both groups of children, sleep problems were associated with elevated behavior problems in each of the areas assessed (reactivity, anxiety, somatic complaints, withdrawal, attention, and aggression). These findings support close monitoring of children with a family history of ASD for both behavioral and sleep issues. Autism Res 2013, : -. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc.
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12. Totsika V, Hastings RP, Emerson E, Lancaster GA, Berridge DM, Vagenas D. {{Is There a Bidirectional Relationship Between Maternal Well-Being and Child Behavior Problems in Autism Spectrum Disorders? Longitudinal Analysis of a Population-Defined Sample of Young Children}}. {Autism Res};2013 (Feb 21)
The aim of this study was to examine whether the relationship between maternal psychological well-being and behavior problems in children with an autism spectrum disorder (ASD) is bidirectional. Data were available at 9 months, 3 years, and 5 years old for 132 children with ASD, identified from a population-representative sample of UK children. Three-wave cross-lagged models examined reciprocal effects between child behavior and maternal well-being (psychological distress, physical health functioning, and life satisfaction). Results indicated that the relationships between maternal well-being and child problem behaviors were not bidirectional. Specifically, findings suggested that while early behavior problems are not a risk factor for later maternal well-being, maternal psychological distress, physical health limitations, and lower life satisfaction are risk factors for later child behavior problems. Autism Res 2013, : -. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc.
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13. Yoder PJ, Oller DK, Richards JA, Gray S, Gilkerson J. {{Stability and Validity of an Automated Measure of Vocal Development From Day-Long Samples in Children With and Without Autism Spectrum Disorder}}. {Autism Res};2013 (Feb 21)
Individual difference measures of vocal development may eventually aid our understanding of the variability in spoken language acquisition in children with autism spectrum disorder (ASD). Large samples of child vocalizations may be needed to maximize the stability of vocal development estimates. Day-long vocal samples can now be automatically analyzed based on acoustic characteristics of speech likeness identified in theoretically driven and empirically cross-validated quantitative models of typical vocal development. This report indicates that a single day-long recording can produce a stable estimate for a measure of vocal development that is highly related to expressive spoken language in a group of young children with ASD and in a group that is typically developing. Autism Res 2013, : -. (c) 2013 International Society for Autism Research, Wiley Periodicals, Inc.
