1. {{Gene silencing in fragile X syndrome explained: Researchers pinpoint how excessive nucleotide repeats shut down protein production}}. {Am J Med Genet A};2014 (Jun);164(6):vii-viii.
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2. Crowe BH, Salt AT. {{Autism: the management and support of children and young people on the autism spectrum (NICE Clinical Guideline 170)}}. {Arch Dis Child Educ Pract Ed};2014 (May 8)
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3. De Filippis B, Nativio P, Fabbri A, Ricceri L, Adriani W, Lacivita E, Leopoldo M, Passarelli F, Fuso A, Laviola G. {{Pharmacological Stimulation of the Brain Serotonin Receptor 7 as a Novel Therapeutic Approach for Rett Syndrome}}. {Neuropsychopharmacology};2014 (May 9)
Rett syndrome (RTT) is a rare neurodevelopmental disorder, characterized by severe behavioral and physiological symptoms. Mutations in the methyl CpG binding protein 2 gene (MECP2) cause more than 95% of classic cases, and currently there is no cure for this devastating disorder. The serotonin receptor 7 (5-HT7R) is linked to neuro-physiological regulation of circadian rhythm, mood, cognition and synaptic plasticity. We presently report that 5-HT7R density is consistently reduced in cortical and hippocampal brain areas of symptomatic MeCP2-308 male mice, a RTT model. Systemic repeated treatment with LP-211 (0.25 mg/kg once/day for 7 days), a brain-penetrant selective 5-HT7R agonist, was able to rescue RTT-related defective performance: anxiety-related profiles in a Light/Dark test, motor abilities in a Dowel test, the exploratory behavior in the Marble Burying test, as well as memory in the Novelty Preference task. In the brain of RTT mice, LP-211 also reversed the abnormal activation of PAK and cofilin (key regulators of actin cytoskeleton dynamics) and of the ribosomal protein (rp) S6, whose reduced activation in MECP2 mutant neurons by mTOR is responsible for the altered protein translational control. Present findings indicate that pharmacological targeting of 5-HT7R improves specific behavioral and molecular manifestations of RTT, thus representing a first step towards the validation of an innovative systemic treatment. Beyond RTT, the latter might be extended to other disorders associated with intellectual disability.Neuropsychopharmacology accepted article preview online, 09 May 2014; doi:10.1038/npp.2014.105.
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4. Hourston S, Schafer M, Gard M, Barrett R, Zwickey H. {{Micronutrient levels in adults with autism spectrum disorders}}. {J Altern Complement Med};2014 (May);20(5):A74.
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5. Leitner Y. {{The Co-Occurrence of Autism and Attention Deficit Hyperactivity Disorder in Children – What Do We Know?}}. {Front Hum Neurosci};2014;8:268.
Symptoms of attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD) often co-occur. The DSM-IV had specified that an ASD diagnosis is an exclusion criterion for ADHD, thereby limiting research of this common clinical co-occurrence. As neurodevelopmental disorders, both ASD and ADHD share some phenotypic similarities, but are characterized by distinct diagnostic criteria. The present review will examine the frequency and implications of this clinical co-occurrence in children, with an emphasis on the available data regarding pre-school age. The review will highlight possible etiologies explaining it, and suggest future research directions necessary to enhance our understanding of both etiology and therapeutic interventions, in light of the new DSM-V criteria, allowing for a dual diagnosis.
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6. Miller S, Reed C, Tang F, Manek N, Tiller WA. {{Impact of broadcast intention on autism spectrum behaviors}}. {J Altern Complement Med};2014 (May);20(5):A146.
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7. Muskat B, Burnham Riosa P, Nicholas DB, Roberts W, Stoddart KP, Zwaigenbaum L. {{Autism comes to the hospital: The experiences of patients with autism spectrum disorder, their parents and health-care providers at two Canadian paediatric hospitals}}. {Autism};2014 (May 8)
Youth with autism spectrum disorder are a vulnerable, often poorly understood patient group, who may experience periodic and chronic health challenges, in addition to their primary developmental social and communication problems. Developmental and behavioural challenges can complicate management of acute health-care needs. To date, there is an absence of empirical research exploring the hospital experiences of children and youth with autism spectrum disorder, their families and their health-care providers. Therefore, the purpose of this study was to understand these experiences in order to inform hospital-based care. A total of 42 participants were interviewed (youth with autism spectrum disorder, their parents and health-care providers) at one of two Canadian paediatric hospitals, representing 20 distinct cases of patients with autism spectrum disorder. Results from the qualitative analyses indicated that patients with autism spectrum disorder faced several challenges in the context of health-care delivery in the hospital setting, as did their families and health-care provider team. Problems identified included communication and sensory challenges, and the degree of flexibility of health-care providers and the hospital organization. Supportive health-care providers were those who acknowledged parents as experts, inquired about the requirements of patients with autism spectrum disorder and implemented strategies that accommodated the unique clinical presentation of the individual patient. These recommendations have wide-reaching utility for hospital and health-care practices involving this patient group.
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8. Puscian A, Leski S, Gorkiewicz T, Meyza K, Lipp HP, Knapska E. {{A novel automated behavioral test battery assessing cognitive rigidity in two genetic mouse models of autism}}. {Front Behav Neurosci};2014;8:140.
Repetitive behaviors are a key feature of many pervasive developmental disorders, such as autism. As a heterogeneous group of symptoms, repetitive behaviors are conceptualized into two main subgroups: sensory/motor (lower-order) and cognitive rigidity (higher-order). Although lower-order repetitive behaviors are measured in mouse models in several paradigms, so far there have been no high-throughput tests directly measuring cognitive rigidity. We describe a novel approach for monitoring repetitive behaviors during reversal learning in mice in the automated IntelliCage system. During the reward-motivated place preference reversal learning, designed to assess cognitive abilities of mice, visits to the previously rewarded places were recorded to measure cognitive flexibility. Thereafter, emotional flexibility was assessed by measuring conditioned fear extinction. Additionally, to look for neuronal correlates of cognitive impairments, we measured CA3-CA1 hippocampal long term potentiation (LTP). To standardize the designed tests we used C57BL/6 and BALB/c mice, representing two genetic backgrounds, for induction of autism by prenatal exposure to the sodium valproate. We found impairments of place learning related to perseveration and no LTP impairments in C57BL/6 valproate-treated mice. In contrast, BALB/c valproate-treated mice displayed severe deficits of place learning not associated with perseverative behaviors and accompanied by hippocampal LTP impairments. Alterations of cognitive flexibility observed in C57BL/6 valproate-treated mice were related to neither restricted exploration pattern nor to emotional flexibility. Altogether, we showed that the designed tests of cognitive performance and perseverative behaviors are efficient and highly replicable. Moreover, the results suggest that genetic background is crucial for the behavioral effects of prenatal valproate treatment.
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9. Reynolds LC, Inder TE, Neil JJ, Pineda RG, Rogers CE. {{Maternal obesity and increased risk for autism and developmental delay among very preterm infants}}. {J Perinatol};2014 (May 8)
Objective:Thirty-five percent of women of child-bearing age are obese, and there is evidence that maternal obesity may increase the risk for adverse neurodevelopmental outcome. However, research regarding obesity and neurodevelopment among children born preterm is limited. This study aimed to determine associations between maternal obesity and neurodevelopment in very preterm children at age 2 years.Study Design:Maternal/infant dyads (n=62) born 30 weeks gestation were enrolled in a prospective cohort study at a level-III neonatal intensive care unit. Mothers were classified as obese or non-obese based on pre-pregnancy body mass index. Infants underwent magnetic resonance imaging at term equivalent and developmental testing at age 2. Maternal obesity was investigated for associations with neurodevelopment.Result:Maternal obesity was associated with positive screen for autism (odds ratio=9.88, P=0.002) and lower composite language scores (beta=-9.36, (confidence interval=-15.11, -3.61), P=0.002).Conclusion:Maternal obesity was associated with adverse neurodevelopmental outcome at age 2 in this cohort of very preterm children. This study requires replication, but may support targeted surveillance of infants born to women with maternal obesity.Journal of Perinatology advance online publication, 8 May 2014; doi:10.1038/jp.2014.80.
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10. Smith LN, Jedynak JP, Fontenot MR, Hale CF, Dietz KC, Taniguchi M, Thomas FS, Zirlin BC, Birnbaum SG, Huber KM, Thomas MJ, Cowan CW. {{Fragile x mental retardation protein regulates synaptic and behavioral plasticity to repeated cocaine administration}}. {Neuron};2014 (May 7);82(3):645-658.
Repeated cocaine exposure causes persistent, maladaptive alterations in brain and behavior, and hope for effective therapeutics lies in understanding these processes. We describe here an essential role for fragile X mental retardation protein (FMRP), an RNA-binding protein and regulator of dendritic protein synthesis, in cocaine conditioned place preference, behavioral sensitization, and motor stereotypy. Cocaine reward deficits in FMRP-deficient mice stem from elevated mGluR5 (or GRM5) function, similar to a subset of fragile X symptoms, and do not extend to natural reward. We find that FMRP functions in the adult nucleus accumbens (NAc), a critical addiction-related brain region, to mediate behavioral sensitization but not cocaine reward. FMRP-deficient mice also exhibit several abnormalities in NAc medium spiny neurons, including reduced presynaptic function and premature changes in dendritic morphology and glutamatergic neurotransmission following repeated cocaine treatment. Together, our findings reveal FMRP as a critical mediator of cocaine-induced behavioral and synaptic plasticity. VIDEO ABSTRACT:
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11. Voorhuis M, Onland-Moret NC, Janse F, Ploos van Amstel HK, Goverde AJ, Lambalk CB, Laven JS, van der Schouw YT, Broekmans FJ, Fauser BC. {{The significance of fragile X mental retardation gene 1 CGG repeat sizes in the normal and intermediate range in women with primary ovarian insufficiency}}. {Hum Reprod};2014 (May 7)
STUDY QUESTION: Are fragile X mental retardation gene 1 (FMR1) CGG repeats in the normal and intermediate range (up to 55 repeats) associated with primary ovarian insufficiency (POI) in a large case-control study? SUMMARY ANSWER: No association was found between CGG repeats of intermediate size and POI compared with controls. WHAT IS KNOWN ALREADY: CGG repeats in the FMR1 gene in the premutation range (55-200 repeats) have consistenly associated with POI. Intermediate range CGG repeats have been considered for a potential association with POI. STUDY DESIGN, SIZE: A case-control study in 375 well-phenotyped Dutch women diagnosed with POI and 3368 controls with natural menopause >/=40 years of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: The FMR1 CGG repeat number was determined by PCR amplification in women diagnosed with POI and women with a known age at natural menopause >/=40 years. The prevalence of intermediate sized CGG repeats (45-54 repeats) was compared between POI cases and controls using Fisher’s exact test. Differences in mean CGG repeat lengths on allele 1 and allele 2 between POI cases and controls were tested using analysis of variance. MAIN RESULTS AND THE ROLE OF CHANCE: The frequency of intermediate sized CGG repeats on the allele with the longest triple repeat number was not statistically significantly different between POI cases and controls (2.7 and 3.8%, respectively, odds ratio 0.72, 95% confidence interval: 0.38-1.39, P = 0.38). In women with POI, linear regression analysis for age at POI diagnosis and CGG repeat size also failed to show any association (beta = -0.018, P = 0.74). LIMITATIONS, REASONS FOR CAUTION: FMR1 CGG repeat lengths in POI cases and controls were genotyped in two different laboratories. The distributions of CGG repeats may vary among the different ethnic populations in our study. Also, in our study women with primary amenorrhea (N = 17) were included in the POI group. WIDER IMPLICATIONS OF THE FINDINGS: We found no association between intermediate sized CGG repeats and POI compared with controls. Therefore, a role for FMR1 CGG repeat sizes up to 55 repeats in the ovarian ageing process may be questioned. Moreover, there seems limited value in the evaluation of normal- and intermediate FMR1 repeat size in the diagnostic work-up of women affected by POI, or for prognostic purposes in women at risk of developing POI. STUDY FUNDING/COMPETING INTEREST(S): The Prospect-EPIC study was funded by ‘Europe Against Cancer’ Program of the European Commission (SANCO); the Dutch Ministry of Health; the Dutch Cancer Society; ZonMW the Netherlands Organization for Health Research and Development; World Cancer Research Fund (WCRF) and the Dutch Heart Association.
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12. Wade JL, Cox NB, Reeve RE, Hull M. {{Brief Report: Impact of Child Problem Behaviors and Parental Broad Autism Phenotype Traits on Substance Use Among Parents of Children with ASD}}. {J Autism Dev Disord};2014 (May 8)
Using data from the Simons Simplex Collection, the present study examined the impact of child externalizing behavior and parental broad autism phenotype traits on substance use among parents of children with autism spectrum disorder (n = 2,388). For both fathers and mothers, child externalizing behaviors predicted tobacco use (OR = 1.01 and OR = 1.02, respectively), whereas rigidity increased risk of tobacco use for fathers (OR = 1.29) but not mothers. Additionally, among mothers, child externalizing behaviors increased risk of illegal substance use (OR = 1.04), whereas maternal rigidity decreased risk of alcohol use (OR = .83). Collectively, results suggest that child externalizing behaviors and parental rigidity may have differing impacts on the types of substances used by parents.
