1. Baecker T, Mangus K, Pfaender S, Chhabra R, Boeckers TM, Grabrucker AM. {{Loss of COMMD1 and copper overload disrupt zinc homeostasis and influence an autism-associated pathway at glutamatergic synapses}}. {Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine}. 2014 Jul 10.
Recent studies suggest that synaptic pathology in autism spectrum disorder (ASD) might be caused by the disruption of a signaling pathway at excitatory glutamatergic synapses, which can be influenced by environmental factors. Some factors, such as prenatal zinc deficiency, dysfunction of metallothioneins as well as deletion of COMMD1, all affect brain metal-ion homeostasis and have been associated with ASD. Given that COMMD1 regulates copper levels and that copper and zinc have antagonistic properties, here, we followed the idea that copper overload might induce a local zinc deficiency affecting key players of a putative ASD pathway such as ProSAP/Shank proteins as reported before. Our results show that increased copper levels indeed interfere with intracellular zinc concentrations and affect synaptic ProSAP/Shank levels, which similarly are altered by manipulation of copper and zinc levels through overexpression and knockdown of COMMD1. In line with this, acute and prenatal copper overload lead to local zinc deficiencies in mice. Pups exposed to prenatal copper overload furthermore show a reduction in ProSAP/Shank protein levels in the brain as well as a decreased NMDAR subunit 1 concentration. Thus, it might be likely that brain metal ion status influences a distinct pathway in excitatory synapses associated with genetic forms of ASD.
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2. Byiers BJ, Dimian A, Symons FJ. {{Functional communication training in rett syndrome: a preliminary study}}. {American journal on intellectual and developmental disabilities}. 2014 Jul;119(4):340-50.
Abstract Rett syndrome (RTT) is associated with a range of serious neurodevelopmental consequences including severe communicative impairments. Currently, no evidence-based communication interventions exist for the population ( Sigafoos et al., 2009 ). The purpose of the current study was to examine the effectiveness of functional assessment (FA) and functional communication training (FCT) methods for teaching 3 individuals (ages 15-47 years) with classic RTT novel communicative behaviors. Using single-case experimental designs, functional reinforcers were identified (FA) and each participant quickly learned to activate a voice-output switch to obtain a reinforcer (FCT). These results suggest that individuals with classic RTT can learn novel communicative responses, which has important implications for future intervention research.
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3. Furlano RI, Bloechliger M, Jick H, Meier CR. {{Bone fractures in children with autistic spectrum disorder}}. {Journal of developmental and behavioral pediatrics : JDBP}. 2014 Jul-Aug;35(6):353-9.
BACKGROUND: Bone fractures in children represent a source of significant disability and morbidity. Are children with autistic spectrum disorder (ASD) at an altered risk of fractures compared with typically developing children? METHODS: Using the General Practice Research Database, the authors assessed the prevalence of fractures in boys with ASD diagnosed between 2 and 8 years. A cross-sectional design was used to compare the prevalence of fractures among children with ASD and age-matched controls, conditional logistic regression to explore the relative risk of having a fracture in association with diagnosed ASD. RESULTS: The study population comprised 3,219 boys with a first-time diagnosis of ASD and 12,265 matched controls. ASD was associated with a significantly decreased risk of developing a fracture at any time in childhood (odds ratio [OR], 0.68, 95% confidence interval [CI], 0.59-0.77, p < .0001). The relative risk estimates were lower for the time period after ASD diagnosis (OR, 0.56, 95% CI, 0.48-0.66, p < .0001) but were not different for the time period before ASD diagnosis (OR, 0.96, 95% CI, 0.78-1.18, p = .6866). Adjusting for use of different drugs did not change the estimates. CONCLUSION: The relative risk of experiencing a fracture at any time in childhood is lower for boys with ASD compared with healthy boys.
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4. Gabriele S, Sacco R, Cerullo S, Neri C, Urbani A, Tripi G, Malvy J, Barthelemy C, Bonnet-Brihault F, Persico AM. {{Urinary p-cresol is elevated in young French children with autism spectrum disorder: a replication study}}. {Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals}. 2014 Jul 10:1-8.
Abstract The aromatic compound p-cresol (4-methylphenol) has been found elevated in the urines of Italian autistic children up to 8 years of age. The present study aims at replicating these initial findings in an ethnically distinct sample and at extending them by measuring also the three components of urinary p-cresol, namely p-cresylsulfate, p-cresylglucuronate and free p-cresol. Total urinary p-cresol, p-cresylsulfate and p-cresylglucuronate were significantly elevated in 33 French autism spectrum disorder (ASD) cases compared with 33 sex- and age-matched controls (p < 0.05). This increase was limited to ASD children aged </=8 years (p < 0.01), and not older (p = 0.17). Urinary levels of p-cresol and p-cresylsulfate were associated with stereotypic, compulsive/repetitive behaviors (p < 0.05), although not with overall autism severity. These results confirm the elevation of urinary p-cresol in a sizable set of small autistic children and spur interest into biomarker roles for p-cresol and p-cresylsulfate in autism.
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5. Justice MJ, Buchovecky CM, Kyle SM, Djukic A. {{A role for metabolism in Rett syndrome pathogenesis: New clinical findings and potential treatment targets}}. {Rare diseases (Austin, Tex)}. 2013;1:e27265.
Rett syndrome (RTT), an X-linked neurological disorder caused by mutations in MECP2, may have a metabolic component. We reported a genetic suppressor screen in a Mecp2-null mouse model to identify pathways for therapeutic improvement of RTT symptoms. Of note, one suppressor mutation implied that cholesterol homeostasis was perturbed in Mecp2 null mice; indeed, cholesterol synthesis was elevated in the brain and body system. Remarkably, the genetic effect of downregulating the cholesterol pathway could be mimicked chemically by statin drugs, improving motor symptoms, and increasing longevity in the mouse. Our work linked cholesterol metabolism to RTT pathology for the first time. Both neurological and systemic effects of perturbed cholesterol homeostasis overlap with many RTT symptoms. Here we show in patients that peripheral cholesterol, triglycerides, and/or LDLs may be elevated early in RTT disease onset, providing a biomarker for patients that could be aided by therapeutic interventions that modulate lipid metabolism.
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6. Poliakov E, Koonin EV, Rogozin IB. {{Impairment of translation in neurons as a putative causative factor for autism}}. {Biology direct}. 2014 Jul 10;9(1):16.
BACKGROUND: A dramatic increase in the prevalence of autism and Autistic Spectrum Disorders (ASD) has been observed over the last two decades in USA, Europe and Asia. Given the accumulating data on the possible role of translation in the etiology of ASD, we analyzed potential effects of rare synonymous substitutions associated with ASD on mRNA stability, splicing enhancers and silencers, and codon usage. PRESENTATION OF THE HYPOTHESIS: We hypothesize that subtle impairment of translation, resulting in dosage imbalance of neuron-specific proteins, contributes to the etiology of ASD synergistically with environmental neurotoxins. TESTING THE HYPOTHESIS: A statistically significant shift from optimal to suboptimal codons caused by rare synonymous substitutions associated with ASD was detected whereas no effect on other analyzed characteristics of transcripts was identified. This result suggests that the impact of rare codons on the translation of genes involved in neuron development, even if slight in magnitude, could contribute to the pathogenesis of ASD in the presence of an aggressive chemical background. This hypothesis could be tested by further analysis of ASD-associated mutations, direct biochemical characterization of their effects, and assessment of in vivo effects on animal models. IMPLICATIONS OF THE HYPOTHESIS: It seems likely that the synergistic action of environmental hazards with genetic variations that in themselves have limited or no deleterious effects but are potentiated by the environmental factors is a general principle that underlies the alarming increase in the ASD prevalence.Reviewers: This article was reviewed by Andrey Rzhetsky, Neil R. Smalheiser, and Shamil R. Sunyaev.
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7. Schroeder SR, Marquis JG, Reese RM, Richman DM, Mayo-Ortega L, Oyama-Ganiko R, LeBlanc J, Brady N, Butler MG, Johnson T, Lawrence L. {{Risk factors for self-injury, aggression, and stereotyped behavior among young children at risk for intellectual and developmental disabilities}}. {American journal on intellectual and developmental disabilities}. 2014 Jul;119(4):351-70.
Abstract Before the 1990s, research on the early identification and prevention of severe behavior disorders (SBDs), such as aggression, self-injury, and stereotyped behavior, among young children with intellectual and developmental disabilities (IDD), was mostly done with children 3 years or older. More recent work suggests that signs of SBDs may occur as early as 6 months in some infants. The present study combined a cross-sectional and longitudinal approach to examine SBDs in 180 young children aged 4-48 months recruited through mass screening, then receiving an interdisciplinary evaluation and six-month follow-ups for one year. Twelve potential risk factors related to SBDs were examined. Eight of these risk factors, including age, gender, diagnosis, intellectual and communication levels, visual impairment, parent education, family income, were differentially related to scores for Aggression, SIB, and Stereotyped Behavior subscales on the Behavior Problems Inventory (BPI-01) at initial interdisciplinary evaluation. BPI-01 scores decreased over the year for 57% of the children and increased for 43%. The amount of decrease on each BPI-01 subscale varied with age, gender, and diagnosis.
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8. Turkstra LS, Abbeduto L, Meulenbroek P. {{Social cognition in adolescent girls with fragile x syndrome}}. {American journal on intellectual and developmental disabilities}. 2014 Jul;119(4):319-39.
Abstract This study aimed to characterize social cognition, executive functions (EFs), and everyday social functioning in adolescent girls with fragile X syndrome, and identify relationships among these variables. Participants were 20 girls with FXS and 20 age-matched typically developing peers. Results showed significant between-groups differences in social cognition, accounted for by differences in IQ and language. Within the FXS group, IQ and language were related to social cognition; parent-reported social functioning was related to language and EFs; and self-reported social functioning was generally good and not related to cognitive or social cognition variables. Results suggest that intervention might focus on managing language and cognitive contributions to social functioning, rather than social cognition, and underscore the importance of considering parent and adolescent perspectives.
