1. Brendel C, Belakhov V, Werner H, Wegener E, Gartner J, Nudelman I, Baasov T, Huppke P. {{Erratum to: Readthrough of nonsense mutations in Rett syndrome: evaluation of novel aminoglycosides and generation of a new mouse model}}. {J Mol Med (Berl)};2013 (Apr 16)
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2. Dolce A, Ben-Zeev B, Naidu S, Kossoff EH. {{Rett syndrome and epilepsy: an update for child neurologists}}. {Pediatr Neurol};2013 (May);48(5):337-345.
Rett syndrome, a neurogenetic disorder predominantly affecting females, has many characteristic features including psychomotor retardation, impaired language development, hand stereotypies, gait dysfunction, and acquired microcephaly. Although each of these features undoubtedly contributes to the morbidity of this neurologic disorder, epilepsy is perhaps one of the most well-described and problematic, affecting as many as 50%-90% of patients. Seizures can often be refractory, requiring polytherapy and consideration of nonpharmacologic management (e.g., ketogenic diets and vagus nerve stimulation). In addition, many nonepileptic symptoms of Rett syndrome can occasionally be difficult to differentiate from seizures making clinical management and family counseling challenging. Our goal in this review is to better define the clinical and electrophysiological aspects of the epilepsy associated with Rett syndrome and provide practical guidance regarding management.
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3. Erickson LC, Scott-Van Zeeland AA, Hamilton G, Lincoln A, Golomb BA. {{Erratum to: Brief Report: Approaches to P-MRS in Awake, Non-Sedated Children With and Without Autism Spectrum Disorder}}. {J Autism Dev Disord};2013 (Apr 13)
We piloted a suite of approaches aimed to facilitate a successful series of up to four brain and muscle 31phosphorus-magnetic resonance spectroscopy scans performed in one session in 12 awake, non-sedated subjects (ages 6-18), 6 with autism spectrum disorders (ASD) and 6 controls. We targeted advance preparation, parental input, physical comfort, short scan protocols, allocation of extra time, and subject emotional support. One hundred percent of subjects completed at least one brain scan and one leg muscle scan: 42 of 46 attempted scans were completed (91 %), with failures dominated by exercise muscle scans (completed in 6/6 controls but 3/6 cases). One completed scan lacked usable data unrelated to subject/scan procedure (orthodonture affected a frontal brain scan). As a group, these methods provide a foundation for conduct and enhancement of future MR studies in pediatric subjects with ASD.
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4. Foldy C, Malenka RC, Sudhof TC. {{Autism-Associated Neuroligin-3 Mutations Commonly Disrupt Tonic Endocannabinoid Signaling}}. {Neuron};2013 (Apr 9)
Neuroligins are postsynaptic cell-adhesion molecules that interact with presynaptic neurexins. Rare mutations in neuroligins and neurexins predispose to autism, including a neuroligin-3 amino acid substitution (R451C) and a neuroligin-3 deletion. Previous analyses showed that neuroligin-3 R451C-knockin mice exhibit robust synaptic phenotypes but failed to uncover major changes in neuroligin-3 knockout mice, questioning the notion that a common synaptic mechanism mediates autism pathogenesis in patients with these mutations. Here, we used paired recordings in mice carrying these mutations to measure synaptic transmission at GABAergic synapses formed by hippocampal parvalbumin- and cholecystokinin-expressing basket cells onto pyramidal neurons. We demonstrate that in addition to unique gain-of-function effects produced by the neuroligin-3 R451C-knockin but not the neuroligin-3 knockout mutation, both mutations dramatically impaired tonic but not phasic endocannabinoid signaling. Our data thus suggest that neuroligin-3 is specifically required for tonic endocannabinoid signaling, raising the possibility that alterations in endocannabinoid signaling may contribute to autism pathophysiology.
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5. Jallot N, Lemonnier E, Grandgeorge M. {{Autism spectrum disorders: Head circumference and body length at birth are both relative}}. {Acta Paediatr};2013 (Apr 13)
AIM: Although the body length and weight of an infant are related to head circumference, little research on ASDs has examined these factors. Our study compared the head circumferences of neonates who were later diagnosed with ASD with a control group. Additional comparisons on morphological disproportions at birth included the head circumference-to-height and head circumference-to-weight ratios. METHODS: We recruited 422 children with ASD and 153 typically developing children. Head circumference, body length and weight at birth were collected and standardized as percentile scores according to gestational age and gender. RESULTS: Our results revealed that genuine macrocephaly was significantly higher in children with other pervasive developmental disorders compared with the control group. This difference was not observed with regard to genuine microcephaly. Relative macrocephaly and relative microcephaly were significantly more frequent in children with autism disorder compared to the control group with regard to body length. CONCLUSIONS: The differences in relative macrocephaly and microcephaly, as well as in other parameters, between diagnostic subgroups, suggest that the presence of several neurological mechanisms plays a role in the later expression of different phenotypes. An increased head circumference-to-body length ratio in newborns may be a factor to follow that could be related to ASD. This article is protected by copyright. All rights reserved.
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6. Jiang YH, Ehlers MD. {{Modeling Autism by SHANK Gene Mutations in Mice}}. {Neuron};2013 (Apr 10);78(1):8-27.
Shank family proteins (Shank1, Shank2, and Shank3) are synaptic scaffolding proteins that organize an extensive protein complex at the postsynaptic density (PSD) of excitatory glutamatergic synapses. Recent human genetic studies indicate that SHANK family genes (SHANK1, SHANK2, and SHANK3) are causative genes for idiopathic autism spectrum disorders (ASD). Neurobiological studies of Shank mutations in mice support a general hypothesis of synaptic dysfunction in the pathophysiology of ASD. However, the molecular diversity of SHANK family gene products, as well as the heterogeneity in human and mouse phenotypes, pose challenges to modeling human SHANK mutations. Here, we review the molecular genetics of SHANK mutations in human ASD and discuss recent findings where such mutations have been modeled in mice. Conserved features of synaptic dysfunction and corresponding behaviors in Shank mouse mutants may help dissect the pathophysiology of ASD, but also highlight divergent phenotypes that arise from different mutations in the same gene.
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7. Kover ST, McDuffie AS, Hagerman RJ, Abbeduto L. {{Receptive Vocabulary in Boys with Autism Spectrum Disorder: Cross-Sectional Developmental Trajectories}}. {J Autism Dev Disord};2013 (Apr 16)
In light of evidence that receptive language may be a relative weakness for individuals with autism spectrum disorder (ASD), this study characterized receptive vocabulary profiles in boys with ASD using cross-sectional developmental trajectories relative to age, nonverbal cognition, and expressive vocabulary. Participants were 49 boys with ASD (4-11 years) and 80 typically developing boys (2-11 years). Receptive vocabulary, assessed with the Peabody Picture Vocabulary Test, was a weakness for boys with ASD relative to age and nonverbal cognition. Relative to expressive vocabulary, assessed with the Expressive Vocabulary Test, receptive vocabulary increased at a lower rate for boys with ASD. Vocabulary trajectories in ASD are distinguished from typical development; however, nonverbal cognition largely accounts for the patterns observed.
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8. Larsson G, Julu PO, Witt Engerstrom I, Sandlund M, Lindstrom B. {{Normal reactions to orthostatic stress in Rett syndrome}}. {Res Dev Disabil};2013 (Apr 11);34(6):1897-1905.
The aim of this study was to investigate orthostatic reactions in females with Rett syndrome (RTT), and also whether the severity of the syndrome had an impact on autonomic reactions. Based on signs of impaired function of the central autonomic system found in RTT, it could be suspected that orthostatic reactions were affected. The orthostatic reactions in 21 females with RTT and 14 normally developed females matched by age were investigated when they rose from a sitting position, and during standing for 3min. Reactions of the heart, the blood pressure and the time for recovery of systolic blood pressure, were studied in real time, heartbeat by heartbeat, simultaneously. There was no difference between participants with RTT and the normally developed controls regarding general orthostatic reactions (heart rate, systolic and diastolic blood pressure, and mean arterial pressure) when getting up from a sitting position, and when standing erect for 3min. In the specific immediate response by the heart to standing up, the 30:15 ratio, significantly lower values were found for females with RTT. In the RTT group, the maximum fall of systolic blood pressure showed a tendency to a larger decrease, and the initial decrease in systolic blood pressure was significantly faster. The time for recovery of systolic blood pressure from standing erect did not differ between groups. At baseline the females with RTT had significantly lower systolic blood pressure and a tendency to a higher heart rate. The results do not indicate any autonomic limitations for people with RTT in getting up from a sitting position and standing. The participants with RTT had normal orthostatic reactions indicated by the heart and blood pressure responses when standing erect for 3min. A faster initial drop in systolic blood pressure in people with RTT was notable.
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9. Maenner MJ, Schieve LA, Rice CE, Cunniff C, Giarelli E, Kirby RS, Lee LC, Nicholas JS, Wingate MS, Durkin MS. {{Frequency and pattern of documented diagnostic features and the age of autism identification}}. {J Am Acad Child Adolesc Psychiatry};2013 (Apr);52(4):401-413 e408.
OBJECTIVE: The DSM-IV-TR specifies 12 behavioral features that can occur in hundreds of possible combinations to meet diagnostic criteria for autism spectrum disorder (ASD). This paper describes the frequency and variability with which the 12 behavioral features are documented in a population-based cohort of 8-year-old children under surveillance for ASD, and examines whether documentation of certain features, alone or in combination with other features, is associated with earlier age of community identification of ASD. METHOD: Statistical analysis of behavioral features documented for a population-based sample of 2,757 children, 8 years old, with ASD in 11 geographically-defined areas in the US participating in the Autism and Developmental Disabilities Monitoring Network in 2006. RESULTS: The median age at ASD identification was inversely associated with the number of documented behavioral features, decreasing from 8.2 years for children with only seven behavioral features to 3.8 years for children with all 12. Documented impairments in nonverbal communication, pretend play, inflexible routines, and repetitive motor behaviors were associated with earlier identification, whereas impairments in peer relations, conversational ability, and idiosyncratic speech were associated with later identification. CONCLUSIONS: The age dependence of some of the behavioral features leading to an autism diagnosis, as well as the inverse association between age at identification and number of behavioral features documented, have implications for efforts to improve early identification. Progress in achieving early identification and provision of services for children with autism may be limited for those with fewer ASD behavioral features, as well as features likely to be detected at later ages.
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10. Pellicano E, Rhodes G, Calder AJ. {{Reduced gaze aftereffects are related to difficulties categorizing gaze direction in autism}}. {Neuropsychologia};2013 (Apr 11)
Perceptual mechanisms are generally flexible or « adaptive », as evidenced by perceptual aftereffects: distortions that arise following exposure to a stimulus. We examined whether adaptive mechanisms for coding gaze direction are atypical in children diagnosed with an autism spectrum condition. Twenty-four typical children and 24 children with autism, of similar age and ability, were administered a developmentally sensitive eye-gaze adaptation task. In the pre-adaptation phase, children judged whether target faces showing subtle deviations in eye-gaze direction were looking leftwards, rightwards or straight-ahead. Next, children were adapted to faces gazing in one consistent direction (25 degrees leftwards/rightwards) before categorizing the direction of the target faces again. Children with autism showed difficulties in judging whether subtle deviations in gaze were directed to the left, right or straight-ahead relative to typical children. Although adaptation to leftward or rightward gaze resulted in reduced sensitivity to gaze on the adapted side for both groups, the aftereffect was significantly reduced in children with autism. Furthermore, the magnitude of children’s gaze aftereffects was positively related to their ability to categorize gaze direction. These results show that the mechanisms coding gaze are less flexible in autism and offer a potential new explanation for these children’s difficulties discriminating subtle deviations in gaze direction.
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11. Siniscalco D, Sapone A, Giordano C, Cirillo A, de Magistris L, Rossi F, Fasano A, Bradstreet JJ, Maione S, Antonucci N. {{Cannabinoid Receptor Type 2, but not Type 1, is Up-Regulated in Peripheral Blood Mononuclear Cells of Children Affected by Autistic Disorders}}. {J Autism Dev Disord};2013 (Apr 13)
Autistic disorders (ADs) are heterogeneous neurodevelopmental disorders arised by the interaction of genes and environmental factors. Dysfunctions in social interaction and communication skills, repetitive and stereotypic verbal and non-verbal behaviours are common features of ADs. There are no defined mechanisms of pathogenesis, rendering curative therapy very difficult. Indeed, the treatments for autism presently available can be divided into behavioural, nutritional and medical approaches, although no defined standard approach exists. Autistic children display immune system dysregulation and show an altered immune response of peripheral blood mononuclear cells (PBMCs). In this study, we investigated the involvement of cannabinoid system in PBMCs from autistic children compared to age-matched normal healthy developing controls (age ranging 3-9 years; mean age: 6.06 +/- 1.52 vs. 6.14 +/- 1.39 in autistic children and healthy subjects, respectively). The mRNA level for cannabinoid receptor type 2 (CB2) was significantly increased in AD-PBMCs as compared to healthy subjects (mean +/- SE of arbitrary units: 0.34 +/- 0.03 vs. 0.23 +/- 0.02 in autistic children and healthy subjects, respectively), whereas CB1 and fatty acid amide hydrolase mRNA levels were unchanged. mRNA levels of N-acylphosphatidylethanolamine-hydrolyzing phospholipase D gene were slightly decreased. Protein levels of CB-2 were also significantly increased in autistic children (mean +/- SE of arbitrary units: 33.5 +/- 1.32 vs. 6.70 +/- 1.25 in autistic children and healthy subjects, respectively). Our data indicate CB2 receptor as potential therapeutic target for the pharmacological management of the autism care.
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12. Talbott MR, Nelson CA, Tager-Flusberg H. {{Maternal Gesture Use and Language Development in Infant Siblings of Children with Autism Spectrum Disorder}}. {J Autism Dev Disord};2013 (Apr 13)
Impairments in language and communication are an early-appearing feature of autism spectrum disorders (ASD), with delays in language and gesture evident as early as the first year of life. Research with typically developing populations highlights the importance of both infant and maternal gesture use in infants’ early language development. The current study explores the gesture production of infants at risk for autism and their mothers at 12 months of age, and the association between these early maternal and infant gestures and between these early gestures and infants’ language at 18 months. Gestures were scored from both a caregiver-infant interaction (both infants and mothers) and from a semi-structured task (infants only). Mothers of non-diagnosed high risk infant siblings gestured more frequently than mothers of low risk infants. Infant and maternal gesture use at 12 months was associated with infants’ language scores at 18 months in both low risk and non-diagnosed high risk infants. These results demonstrate the impact of risk status on maternal behavior and the importance of considering the role of social and contextual factors on the language development of infants at risk for autism. Results from the subset of infants who meet preliminary criteria for ASD are also discussed.
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13. Zur O, Ronen A, Melzer I, Carmeli E. {{Vestibulo-ocular response and balance control in children and young adults with mild-to-moderate intellectual and developmental disability: A pilot study}}. {Res Dev Disabil};2013 (Apr 11);34(6):1951-1957.
The vestibulo-ocular response (VOR) may not be fully developed in children with an intellectual and developmental disability (IDD). This study aimed to identify the presence of VOR deficit in children and young adults with unspecified mild-to-moderate intellectual and developmental disability and its effect on balance control. Twenty-one children and young adults with IDD ranging in age from 8 to 22 years (mean 17.5+/-3.9 years) were included in the study. The VOR was evaluated with the Head Impulse Test and the Static and Dynamic Visual Acuity Test (S&D-VAT). Postural stability was measured in an upright standing position by the Clinical Test for Sensory Interaction in Balance (CTSIB), single leg stance (SLS) during eyes open and eyes closed, and Romberg stance under eyes open and eyes closed conditions using a force platform. Reduced vestibulo-ocular responses were found in 13 of 21 (62%) participants who were able to complete testing. In the fifth condition of the CTSIB (standing on foam with eyes closed), those without VOR deficit were able to maintain balance longer than those with VOR deficit (29s [median 30] vs. 12s [median 7.3], respectively; p=0.03). The study demonstrates potential effects of VOR deficit in children and young adults with IDD and some significant differences in balance control between those with and without a VOR deficit. VOR function in children and young adults with IDD should be routinely tested to enable early detection of deficits.
