1. {{Research delves into role of key proteins in fragile X syndrome: Study explores relationship between enzymes, FXS symptoms; identifies candidate drug for targeted treatment}}. {Am J Med Genet A}. 2015; 167(3): ix.
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2. Ariza J, Steward C, Rueckert F, Widdison M, Coffman R, Afjei A, Noctor SC, Hagerman R, Hagerman P, Martinez-Cerdeno V. {{Dysregulated iron metabolism in the choroid plexus in fragile X-associated tremor/ataxia syndrome}}. {Brain Res}. 2015; 1598: 88-96.
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder associated with premutation alleles of the FMR1 gene that is characterized by progressive action tremor, gait ataxia, and cognitive decline. Recent studies of mitochondrial dysfunction in FXTAS have suggested that iron dysregulation may be one component of disease pathogenesis. We tested the hypothesis that iron dysregulation is part of the pathogenic process in FXTAS. We analyzed postmortem choroid plexus from FXTAS and control subjects, and found that in FXTAS iron accumulated in the stroma, transferrin levels were decreased in the epithelial cells, and transferrin receptor 1 distribution was shifted from the basolateral membrane (control) to a predominantly intracellular location (FXTAS). In addition, ferroportin and ceruloplasmin were markedly decreased within the epithelial cells. These alterations have implications not only for understanding the pathophysiology of FXTAS, but also for the development of new clinical treatments that may incorporate selective iron chelation.
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3. Bowler DM, Gaigg SB, Gardiner JM. {{Brief Report: The Role of Task Support in the Spatial and Temporal Source Memory of Adults with Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2015.
Adults with autism spectrum disorder (ASD) show intact recognition (supported procedure) but impaired recall (unsupported procedure) of incidentally-encoded context. Because this has not been demonstrated for temporal source, we compared the temporal and spatial source memory of adults with ASD and verbally matched typical adults. Because of difficulties with temporal processing in ASD, we predicted ASD adults would benefit from test support for location but not temporal occurrence of studied words. We found similar levels of recognition and source memory for both groups but there was a greater effect of support on memory for location source in the ASD group. The lack of an effect of support for temporal source may simply reflect a difficulty in operationalising temporal cues.
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4. Brian JA, Bryson SE, Zwaigenbaum L. {{Autism spectrum disorder in infancy: developmental considerations in treatment targets}}. {Curr Opin Neurol}. 2015.
PURPOSE OF REVIEW: This review explores recent literature to prioritize aspects of development to be targeted by intervention for infants and toddlers with autism spectrum disorder (ASD). RECENT FINDINGS: Recent investigation of early development in ASD, including prospective studies of infants at increased risk (i.e., those with an affected older sibling) identifies impairments in four key developmental domains that are predictive of ASD. These domains are early attentional control, emotion regulation, social orienting/approach, and communication development. Reciprocal relationships exist among these domains, both in ASD and in typical development. Thus, these domains represent key intervention targets, informing treatment models under investigation in recent clinical trials. SUMMARY: By targeting the earliest and foundational manifestations of atypical development, we can capitalize on neural plasticity and build skills that are most likely to have scaffolding effects on development. The optimal timing and procedures of intervention remain empirical questions, but as the field moves toward earlier identification of risk, we are now poised to evaluate the impact of tailored approaches before the developmental cascade that leads to ASD is fully manifested. Consideration regarding community translation of ASD-specific interventions for infants and toddlers is also needed, with a focus on feasibility, cost-effectiveness, and sustainability.
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5. Brook E, Usman M. {{SSRIs in Rett syndrome}}. {Aust N Z J Psychiatry}. 2015.
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6. Duerden EG, Taylor MJ, Lee M, McGrath PA, Davis KD, Roberts W. {{Decreased sensitivity to thermal stimuli in adolescents with autism spectrum disorder: Relation to symptomatology and cognitive ability}}. {J Pain}. 2015.
Social communication deficits and repetitive behaviours are established characteristics of autism spectrum disorder (ASD) and the focus of considerable study. Alterations in pain sensitivity have been widely noted clinically, but remain understudied and poorly understood. The ASD population may be at greater risk for having their pain undermanaged, especially in children with impaired cognitive ability and limited language skills, which may affect their ability to express pain. Given that sensitivity to noxious stimuli in adolescents with ASD has not been systematically assessed, here we measured warm and cool detection thresholds (WDT and CDT) and heat and cold pain threshold (HPT and CPT) levels in 20 high-functioning adolescents with ASD and 55 typically-developing individuals using a method-of-limits quantitative sensory testing protocol. Adolescents with ASD had a loss of sensory function for thermal detection (p<0.001, both WDT and CDT), but not pain threshold (p>0.05, both HPT and CPT) in comparison to controls, with no evidence for significant age or sex effects (p>0.05). Intelligence quotients (IQ) and symptomatology were significantly correlated with a loss of some types of thermal perception in the ASD population (p<0.05, WDT, CDT, HPT). Decreased thermal sensitivity in adolescents with ASD may be associated with cognitive impairments relating to attentional deficits. In conclusion, our findings are consistent with previous literature indicating an association between thermal perception and cortical thickness in brain regions involved in somatosensation, cognition and salience detection. Further brain-imaging research is needed to determine the neural mechanisms underlying thermal perceptual deficits in adolescents with ASD. PERSPECTIVE: We report quantitative evidence for altered thermal thresholds in adolescents with autism spectrum disorder. Reduced sensitivity to warm, cool and heat pain were related to impaired cognitive ability. Caregivers and clinicians should consider cognitive ability when assessing and managing pain in adolescents with autism spectrum disorder.
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7. Ebrahimi-Fakhari D, Sahin M. {{Autism and the synapse: emerging mechanisms and mechanism-based therapies}}. {Curr Opin Neurol}. 2015.
PURPOSE OF REVIEW: Recent studies have implicated hundreds of genetic variants in the cause of autism spectrum disorder (ASD). Genes involved in ‘monogenic’ forms of syndromic ASD converge on common pathways that are involved in synaptic development, plasticity and signaling. In this review, we discuss how these ‘developmental synaptopathies’ inform our understanding of the molecular disease in ASD and highlight promising approaches that have bridged the gap between the bench and the clinic. RECENT FINDINGS: Accumulating evidence suggests that synaptic deficits in syndromic and nonsyndromic ASD can be mapped to gene mutations in pathways that control synaptic protein synthesis and degradation with postsynaptic scaffold architecture and neurotransmitter receptors. This is recapitulated in models of Fragile X syndrome (FXS), Tuberous Sclerosis Complex (TSC), Angelman syndrome and Phelan-McDermid syndrome (PMS), all of which cause syndromic ASD. Important recent advances include the development of mouse models and patient-derived induced pluripotent stem cell (iPSC) lines that enable a detailed investigation of synaptic deficits and the identification of potential targets for therapy. Examples of the latter include mGluR5 antagonists in FXS, mTOR inhibitors in TSC and insulin-like growth factor 1 (IGF-1) in PMS. SUMMARY: Identifying converging pathways in syndromic forms of ASD will uncover novel therapeutic targets for non-syndromic ASD. Insights into developmental synaptopathies will lead to rational development of mechanism-based therapies and clinical trials that may provide a blueprint for other common pathways implicated in the molecular neuropathology of ASD.
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8. Fuentes-Albero M, Puig-Alcaraz C, Cauli O. {{Lead excretion in spanish children with autism spectrum disorder}}. {Brain Sci}. 2015; 5(1): 58-68.
Among epigenetic factors leading to increased prevalence of juvenile neuropsychiatric disorders, including autism spectrum disorder, exposure to metals, such as lead (Pb) have led to conflicting results. The aim of the present study was to determine the levels of Pb in the urine of children with autism spectrum disorder (ASD) compared with typically developing children (TD) age- and sex-matched, and to analyze any association between core symptoms of ASD, special diets, supplements intake or prescription drugs and the concentration of Pb. The study was performed in a group of children with ASD (n = 35, average age 7.4 +/- 0.5 years) and TD (n = 34, average age 7.7 +/- 0.9 years). Measurement of lead in urine was performed by atomic absorption spectrometry; symptoms of ASD were analyzed by diagnostic and statistical manual of mental disorders (DMS-IV) using the questionnary ADI-R. Careful clinical evaluation was also undertaken and statistical analysis was done taking into account any possible confounding factor.
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9. Fukai R, Hiraki Y, Yofune H, Tsurusaki Y, Nakashima M, Saitsu H, Tanaka F, Miyake N, Matsumoto N. {{A case of autism spectrum disorder arising from a de novo missense mutation in POGZ}}. {J Hum Genet}. 2015.
Autism spectrum disorder (ASD) is a clinically heterogeneous psychiatric disorder with various genetic backgrounds. Here, we report a novel mutation in the pogo transposable element-derived protein with zinc finger domain gene (POGZ) identified by trio-based whole exome sequencing. To date, a total of seven de novo POGZ mutations in ASD have been reported. POGZ contains a total of five functional domains, and this study reports the first de novo missense mutation in the centromere protein B-like DNA-binding domain. POGZ is highly expressed in the human fetal brain and is involved in mitosis and the regulation of neuronal proliferation. Therefore its loss-of-function or pathogenic missense mutations are likely to be causative of ASD.Journal of Human Genetics advance online publication, 19 February 2015; doi:10.1038/jhg.2015.13.
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10. Kasari C. {{Update on behavioral interventions for autism and developmental disabilities}}. {Curr Opin Neurol}. 2015.
PURPOSE OF REVIEW: Given the explosion in published behavioral interventions over the past several years, this review highlights the latest trends over the past year (2014) for children with complex learning and developmental needs. RECENT FINDINGS: There were virtually no rigorous intervention studies published on developmental disorders in which the cause of the disorder is well known. Nearly all studies focus on autism spectrum disorder. Trends over the past year emphasize modular interventions with design improvements including comparisons of two active treatments and larger and more diverse samples. Far more community-implemented treatments on understudied populations were conducted, including minimally verbal children, girls, very young infants, and low-resourced families. Finally, new pilot data on prevention and neural mechanisms were published. SUMMARY: An uptick in the number of rigorous tests of different interventions conducted in real-world settings with outcomes focused on core deficits bodes well for wide dissemination and implementation by nonspecialists in the community. Pilot and uncontrolled data on prevention and mechanism await further rigorous testing before conclusions can be drawn.
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11. Nadel J. {{Perception-action coupling and imitation in autism spectrum disorder}}. {Dev Med Child Neurol}. 2015; 57 Suppl 2: 55-8.
This paper focuses on the key function of imitation in motor and social development of typically developing infants and low-functioning children with autism spectrum disorder (ASD). We suggest that it might also be a developmental cornerstone for other neurodevelopmental disorders. Why this suggestion? First, imitation just requires relating one’s motor patterns to perceived motor patterns. This is always possible if the actions seen are not beyond the individual’s motor scope; for instance, newborn infants can already imitate tongue protrusion, eye blinking, or mouth opening, because these movements are part of their foetal repertoire. Second, imitation is a ‘use it or lose it’ capacity: the more it is used, the more the repertoire grows (plasticity). Finally, imitation is an efficient tool for two main adaptive functions: learning and communication. Imitation-based communication is available through the use of the two facets of imitation: imitating and being imitated. The two facets afford two roles that the partners can exchange as a turn-taking while they synchronize matched activities. Neuroimaging studies of interactive imitation have shown that such communicative systems involve a coordination of bottom-up and top-down processes. In this line, imitation is a booster of development that can also be of benefit for children with neurodevelopmental disorders.
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12. Pantelis PC, Byrge L, Tyszka JM, Adolphs R, Kennedy DP. {{A specific hypoactivation of right temporo-parietal junction/posterior superior temporal sulcus in response to socially awkward situations in autism}}. {Soc Cogn Affect Neurosci}. 2015.
People with autism spectrum disorders (ASD) often have difficulty comprehending social situations in the complex, dynamic contexts encountered in the real world. To study the social brain under conditions which approximate naturalistic situations, we measured brain activity with fMRI while participants watched a full-length episode of the sitcom The Office. Having quantified the degree of social awkwardness at each moment of the episode, as judged by an independent sample of controls, we found that both individuals with ASD and control participants showed reliable activation of several brain regions commonly associated with social perception and cognition (e.g., those comprising the « mentalizing network ») during the more awkward moments. However, individuals with ASD showed less activity than controls in a region near right temporo-parietal junction (RTPJ) extending into the posterior end of the right superior temporal sulcus (RSTS). Further analyses suggested that, despite the free-form nature of the experimental design, this group difference was specific to this RTPJ/RSTS area of the mentalizing network; other regions of interest showed similar activity across groups with respect to both location and magnitude. These findings add support to a body of evidence suggesting that RTPJ/RSTS plays a special role in social processes across modalities and may function atypically in individuals with ASD navigating the social world.
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13. Parlade MV, Iverson JM. {{The Development of Coordinated Communication in Infants at Heightened Risk for Autism Spectrum Disorder}}. {J Autism Dev Disord}. 2015.
This study evaluated the extent to which developmental change in coordination of social communication in early infancy differentiates children eventually diagnosed with ASD from those not likely to develop the disorder. A prospective longitudinal design was used to compare nine infants at heightened risk for ASD (HR) later diagnosed with ASD, to 13 HR infants with language delay, 28 HR infants with no diagnosis, and 30 low risk infants. Hierarchical linear modeling analyses revealed that ASD infants exhibited significantly slower growth in coordinations overall and in gestures coordinated with vocalizations, even relative to HR infants with language delay. Disruption in the development of gesture-vocalization coordinations may result in negative cascading effects that adversely impact later social and linguistic development.
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14. Rice LM, Wall CA, Fogel A, Shic F. {{Computer-Assisted Face Processing Instruction Improves Emotion Recognition, Mentalizing, and Social Skills in Students with ASD}}. {J Autism Dev Disord}. 2015.
This study examined the extent to which a computer-based social skills intervention called FaceSay was associated with improvements in affect recognition, mentalizing, and social skills of school-aged children with Autism Spectrum Disorder (ASD). FaceSay offers students simulated practice with eye gaze, joint attention, and facial recognition skills. This randomized control trial included school-aged children meeting educational criteria for autism (N = 31). Results demonstrated that participants who received the intervention improved their affect recognition and mentalizing skills, as well as their social skills. These findings suggest that, by targeting face-processing skills, computer-based interventions may produce changes in broader cognitive and social-skills domains in a cost- and time-efficient manner.
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15. Scharoun SM, Bryden PJ. {{Is strength of handedness reliable over repeated testing? An examination of typical development and autism spectrum disorder}}. {Front Psychol}. 2015; 6: 17.
Despite a lack of agreement concerning the age at which adult-like patterns of handedness emerge, it is generally understood that hand preference presents early in life and development is variable. Young children (ages 3-5 years) are described as having weak hand preference; however, older children (ages 7-10 years) display stronger patterns. Here, strength of hand preference refers to reliable use of the preferred hand. In comparison to their typically developing (TD) peers, individuals with autism spectrum disorder (ASD) are described as having a weak hand preference. This study aimed to extend the literature to assess three measures of handedness (Waterloo Handedness Questionnaire – WHQ, Annett pegboard – AP, and WatHand Cabinet Test – WHCT) in two repeated sessions. The first research question aimed to delineate if the strength of hand use changes across testing sessions as a function of age in typical development. Right-handed children reported a reliable preference for the right hand on the WHQ, similar to adults. A marginally significant difference was revealed between 3- to 4- and 5- to 6-year-olds on the AP. This was attributed to weak lateralization in 3- to 4-year-olds, where the establishment of hand preference by age 6 leads to superior performance with the preferred hand in 5- to 6-year-olds. Finally, for the WHCT, 3- to 4-year-olds had the highest bimanual score, indicating use of the same hand to lift the cabinet door and retrieve an object. It is likely that the task was not motorically complex enough to drive preferred hand selection for older participants. The second research question sought to determine if there is difference between (TD) children and children with ASD. No differences were revealed; however, children with ASD did display variable AP performance, providing partial support for previous literature. Findings will be discussed in light of relevant literature.
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16. Welham A, Lau J, Moss J, Cullen J, Higgs S, Warren G, Wilde L, Marr A, Cook F, Oliver C. {{Are Angelman and Prader-Willi syndromes more similar than we thought? Food-related behavior problems in Angelman, Cornelia de Lange, Fragile X, Prader-Willi and 1p36 deletion syndromes}}. {Am J Med Genet A}. 2015; 167(3): 572-8.
Food-related behavior problems are well documented in Prader-Willi syndrome (PWS), with impaired satiety, preoccupation with food and negative food-related behaviors (such as taking and storing food) frequently reported as part of the behavioral phenotype of older children and adults. Food-related behavior problems in other genetic neurodevelopmental syndromes remain less well studied, including those seen in Angelman Syndrome (AS), the ‘sister imprinted disorder’ of PWS. Food-related behavior problems were assessed in 152 participants each with one of five genetic neurodevelopmental syndromes – PWS, AS, 1p36 deletion, Cornelia de Lange, and fragile X. Predictably, levels of food-related behavior problems reported in participants with PWS significantly exceeded those of at least one other groups in most areas (impaired satiety; preoccupation with food; taking and storing food; composite negative behavior). However, in some areas people with AS were reported to display food-related problems at least as severe as those with PWS, with the AS group reported to display significantly more food-related behavior problems than at least one comparison group on measures of taking and storing food, composite negative behaviors, impaired satiety and preoccupation with food. Over 50% of participants in the AS group scored above the median point of the distribution of PWS scores on a measure of taking and storing food. These findings indicate further investigation of eating problems in AS are warranted and have implications for current theoretical interpretations of the behavioral differences between AS and PWS. (c) 2015 Wiley Periodicals, Inc.
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17. Whipple CM, Gfeller K, Driscoll V, Oleson J, McGregor K. {{Do Communication Disorders Extend to Musical Messages? An Answer from Children with Hearing Loss or Autism Spectrum Disorders}}. {J Music Ther}. 2015.
BACKGROUND: Effective musical communication requires conveyance of the intended message in a manner perceptible to the receiver. Communication disorders that impair transmitting or decoding of structural features of music (e.g., pitch, timbre) and/or symbolic representation may result in atypical musical communication, which can have a negative impact on music therapy interventions. OBJECTIVE: This study compared recognition of symbolic representation of emotions or movements in music by two groups of children with different communicative characteristics: severe to profound hearing loss (using cochlear implants [CI]) and autism spectrum disorder (ASD). Their responses were compared to those of children with typical-development and normal hearing (TD-NH). Accuracy was examined as a function of communicative status, emotional or movement category, and individual characteristics. METHODS: Participants listened to recorded musical excerpts conveying emotions or movements and matched them with labels. Measures relevant to auditory and/or language function were also gathered. RESULTS: There was no significant difference between the ASD and TD-NH groups in identification of musical emotions or movements. However, the CI group was significantly less accurate than the other two groups in identification of both emotions and movements. Mixed effects logistic regression revealed different patterns of accuracy for specific emotions as a function of group. CONCLUSION: Conveyance of emotions or movements through music may be decoded differently by persons with different types of communication disorders. Because music is the primary therapeutic tool in music therapy sessions, clinicians should consider these differential abilities when selecting music for clinical interventions focusing on emotions or movement.
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18. Zantomio D, Chana G, Laskaris L, Testa R, Everall I, Pantelis C, Skafidas E. {{Convergent evidence for mGluR5 in synaptic and neuroinflammatory pathways implicated in ASD}}. {Neurosci Biobehav Rev}. 2015.
The pathogenesis of Autism spectrum disorder (ASD), a serious neurodevelopmental disorder, is poorly understood. We review evidence for alterations in glutamatergic signalling in the aetiology of ASD, with a focus on the metabotropic glutamate receptor-5 (mGluR5). mGluR5 signalling is important for synapse formation, neuroplasticity and long term potentiation as well as neuroprotection and has been shown to have a regulatory role in neuroinflammation. Evidence for neuroinflammation in ASD is supported by increase in pro-inflammatory cytokines in the blood and cerebrospinal fluid (CSF) and increased number and activation of microglia in postmortem dorsolateral prefrontal cortex (DLPFC). mGlur5 signalling has also been shown to downregulate microglial activation. Therefore, we focus on the mGluR5 as a potential unifying explanation for synapse alteration and neuroinflammation seen in ASD. Data from mGluR5 knockout mouse models, syndromic and non syndromic forms of ASD are discussed in relation to how alterations in mGluR5 are associated with ASD symptoms. This review supports altered mGluR5 functioning as a convergent point in ASD pathogenesis and indicates more research is warranted into mGluR5 as a potential therapeutic target.
