1. Bonnet-Brilhault F, Alirol S, Blanc R, Bazaud S, Marouillat S, Thepault RA, Andres CR, Lemonnier E, Barthelemy C, Raynaud M, Toutain A, Gomot M, Laumonnier F. {{GABA/Glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disability}}. {Mol Psychiatry};2015 (Jun 9)
Phenotypic and genetic heterogeneity is predominant in autism spectrum disorders (ASD), for which the molecular and pathophysiological bases are still unclear. Significant comorbidity and genetic overlap between ASD and other neurodevelopmental disorders are also well established. However, little is understood regarding the frequent observation of a wide phenotypic spectrum associated with deleterious mutations affecting a single gene even within multiplex families. We performed a clinical, neurophysiological (in vivo electroencephalography-auditory-evoked related potentials) and genetic (whole-exome sequencing) follow-up analysis of two families with known deleterious NLGN4X gene mutations (either truncating or overexpressing) present in individuals with ASD and/or with intellectual disability (ID). Complete phenotypic evaluation of the pedigrees in the ASD individuals showed common specific autistic behavioural features and neurophysiological patterns (abnormal MisMatch Negativity in response to auditory change) that were absent in healthy parents as well as in family members with isolated ID. Whole-exome sequencing in ASD patients from each family identified a second rare inherited genetic variant, affecting either the GLRB or the ANK3 genes encoding NLGN4X interacting proteins expressed in inhibitory or in excitatory synapses, respectively. The GRLB and ANK3 mutations were absent in relatives with ID as well as in control databases. In summary, our findings provide evidence of a double-hit genetic model focused on excitatory/inhibitory synapses in ASD, that is not found in isolated ID, associated with an atypical in vivo neurophysiological pattern linked to predictive coding.Molecular Psychiatry advance online publication, 9 June 2015; doi:10.1038/mp.2015.75.
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2. Brewer R, Biotti F, Catmur C, Press C, Happe F, Cook R, Bird G. {{Can Neurotypical Individuals Read Autistic Facial Expressions? Atypical Production of Emotional Facial Expressions in Autism Spectrum Disorders}}. {Autism Res};2015 (Jun 6)
The difficulties encountered by individuals with autism spectrum disorder (ASD) when interacting with neurotypical (NT, i.e. nonautistic) individuals are usually attributed to failure to recognize the emotions and mental states of their NT interaction partner. It is also possible, however, that at least some of the difficulty is due to a failure of NT individuals to read the mental and emotional states of ASD interaction partners. Previous research has frequently observed deficits of typical facial emotion recognition in individuals with ASD, suggesting atypical representations of emotional expressions. Relatively little research, however, has investigated the ability of individuals with ASD to produce recognizable emotional expressions, and thus, whether NT individuals can recognize autistic emotional expressions. The few studies which have investigated this have used only NT observers, making it impossible to determine whether atypical representations are shared among individuals with ASD, or idiosyncratic. This study investigated NT and ASD participants’ ability to recognize emotional expressions produced by NT and ASD posers. Three posing conditions were included, to determine whether potential group differences are due to atypical cognitive representations of emotion, impaired understanding of the communicative value of expressions, or poor proprioceptive feedback. Results indicated that ASD expressions were recognized less well than NT expressions, and that this is likely due to a genuine deficit in the representation of typical emotional expressions in this population. Further, ASD expressions were equally poorly recognized by NT individuals and those with ASD, implicating idiosyncratic, rather than common, atypical representations of emotional expressions in ASD. Autism Res 2015. (c) 2015 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research.
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3. Burkett K, Morris E, Manning-Courtney P, Anthony J, Shambley-Ebron D. {{African American Families on Autism Diagnosis and Treatment: The Influence of Culture}}. {J Autism Dev Disord};2015 (Jun 9)
Cultural factors such as health care access and autism spectrum disorder (ASD) symptom interpretations have been proposed as impacting delayed diagnosis and treatment for African American children with ASD. A qualitative study of urban African American families caring for their child with autism was conducted with 24 family members and 28 ASD professionals. Cultural caring meant families protected their child from harm including potential or actual distrustful encounters, and took action for their child and community to optimize their child’s health and address the knowledge deficits of ASD within their community. Families and professionals believed cultural influences delayed families’ receiving and seeking appropriate health care for the African American child with ASD affecting timely autism diagnosis and treatment.
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4. Chana G, Laskaris L, Pantelis C, Gillett P, Testa R, Zantomio D, Burrows EL, Hannan AJ, Everall IP, Skafidas E. {{Decreased expression of mGluR5 within the dorsolateral prefrontal cortex in autism and increased microglial number in mGluR5 knockout mice: Pathophysiological and neurobehavioral implications}}. {Brain Behav Immun};2015 (Jun 5)
Metabotropic glutamate receptor 5 (mGluR5) and microglial abnormalities have been implicated in autism spectrum disorder (ASD). However, controversy exists as to whether the receptor is down or upregulated in functioning in ASD. In addition, whilst activation of mGluR5 has been shown to attenuate microglial activation, its role in maintaining microglial homeostasis during development has not been investigated. We utilised published microarray data from the dorsolateral prefrontal cortex (DLPFC) of control (n=30) and ASD (n=27) individuals to carry out regression analysis to assess gene expression of mGluR5 downstream signalling elements. We then conducted a post-mortem brain stereological investigation of the DLPFC, to estimate the proportion of mGluR5-positive neurons and glia. Finally, we carried out stereological investigation into numbers of microglia in mGluR5 knockout mice, relative to wildtype littermates, together with assessment of changes in microglial somal size, as an indicator of activation status. We found that gene expression of mGluR5 was significantly decreased in ASD versus controls (p=0.018) as well as downstream elements SHANK3 (p=0.005) and PLCB1 (p=0.009) but that the pro-inflammatory marker NOS2 was increased (p=0.047). Intensity of staining of mGluR5-positive neurons was also significantly decreased in ASD versus controls (p=0.016). Microglial density was significantly increased in mGluR5 knockout animals versus wildtype controls (p=0.011). Our findings provide evidence for decreased expression of mGluR5 and its signalling components representing a key pathophysiological hallmark in ASD with implications for the regulation of microglial number and activation during development. This is important in the context of microglia being considered to play key roles in synaptic pruning during development, with preservation of appropriate connectivity relevant for normal brain functioning.
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5. Constantino JN, Zhang Y, Holzhauer K, Sant S, Long K, Vallorani A, Malik L, Gutmann DH. {{Distribution and Within-Family Specificity of Quantitative Autistic Traits in Patients with Neurofibromatosis Type I}}. {J Pediatr};2015 (Jun 4)
OBJECTIVE: To examine the distribution of quantitative autistic traits (QATs) in an independent neurofibromatosis type I (NF1) sample, the relationships between QAT, sex, and attention deficit hyperactivity disorder (ADHD) symptomatology, and to explore evidence for QAT mutational specificity within families. STUDY DESIGN: Age-appropriate versions of the Social Responsiveness Scale, second edition and the Conners Adult ADHD Rating Scales were completed for 103 patients with NF1 from the Washington University Neurofibromatosis Center. RESULTS: Patients with NF1 exhibited a pathologically shifted unimodal distribution for QAT. Forty-four percent of the subjects exhibited a QAT burden at or above 1 SD from the population mean; 13% scored at or above the extreme first percentile of the general population distribution. Elevations in ADHD symptomatology exhibited a distinct bimodal distribution; however, mean ADHD index scores were equivalent in patients who had been diagnosed in the community with ADHD compared with those who had not. We observed striking within-family associations for QAT, reflected by an Social Responsiveness Scale, second edition intraclass correlation of 0.77 in pairings of first degree relatives with NF1. CONCLUSIONS: Impairments in reciprocal social behavior and attention affect a large proportion of patients with NF1 throughout life and are often clinically unrecognized. Further exploration of genotype-phenotype correlation is strongly warranted for the purpose of gaining insights into mechanisms by which specific mutational variations in the NF1 gene may influence autistic trait severity.
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6. Currais A, Farrokhi C, Dargusch R, Goujon-Svrzic M, Maher P. {{Dietary glycemic index modulates the behavioral and biochemical abnormalities associated with autism spectrum disorder}}. {Mol Psychiatry};2015 (Jun 9)
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder of unknown etiology, but very likely resulting from both genetic and environmental factors. There is good evidence for immune system dysregulation in individuals with ASD. However, the contribution of insults such as dietary factors that can also activate the immune system have not been explored in the context of ASD. In this paper, we show that the dietary glycemic index has a significant impact on the ASD phenotype. By using BTBR mice, an inbred strain that displays behavioral traits that reflect the diagnostic symptoms of human ASD, we found that the diet modulates plasma metabolites, neuroinflammation and brain markers of neurogenesis in a manner that is highly reflective of ASD in humans. Overall, the manuscript supports the idea that ASD results from gene-environment interactions and that in the presence of a genetic predisposition to ASD, diet can make a large difference in the expression of the condition.Molecular Psychiatry advance online publication, 9 June 2015; doi:10.1038/mp.2015.64.
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7. Duffney LJ, Zhong P, Wei J, Matas E, Cheng J, Qin L, Ma K, Dietz DM, Kajiwara Y, Buxbaum JD, Yan Z. {{Autism-like Deficits in Shank3-Deficient Mice Are Rescued by Targeting Actin Regulators}}. {Cell Rep};2015 (Jun 9);11(9):1400-1413.
Haploinsufficiency of the Shank3 gene, which encodes a scaffolding protein at glutamatergic synapses, is a highly prevalent and penetrant risk factor for autism. Using combined behavioral, electrophysiological, biochemical, imaging, and molecular approaches, we find that Shank3-deficient mice exhibit autism-like social deficits and repetitive behaviors, as well as the significantly diminished NMDA receptor (NMDAR) synaptic function and synaptic distribution in prefrontal cortex. Concomitantly, Shank3-deficient mice have a marked loss of cortical actin filaments, which is associated with the reduced Rac1/PAK activity and increased activity of cofilin, the major actin depolymerizing factor. The social deficits and NMDAR hypofunction are rescued by inhibiting cofilin or activating Rac1 in Shank3-deficient mice and are induced by inhibiting PAK or Rac1 in wild-type mice. These results indicate that the aberrant regulation of synaptic actin filaments and loss of synaptic NMDARs contribute to the manifestation of autism-like phenotypes. Thus, targeting actin regulators provides a strategy for autism treatment.
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8. Gliga T, Bedford R, Charman T, Johnson MH. {{Enhanced Visual Search in Infancy Predicts Emerging Autism Symptoms}}. {Curr Biol};2015 (Jun 9)
In addition to core symptoms, i.e., social interaction and communication difficulties and restricted and repetitive behaviors, autism is also characterized by aspects of superior perception [1]. One well-replicated finding is that of superior performance in visual search tasks, in which participants have to indicate the presence of an odd-one-out element among a number of foils [2-5]. Whether these aspects of superior perception contribute to the emergence of core autism symptoms remains debated [4, 6]. Perceptual and social interaction atypicalities could reflect co-expressed but biologically independent pathologies, as suggested by a « fractionable » phenotype model of autism [7]. A developmental test of this hypothesis is now made possible by longitudinal cohorts of infants at high risk, such as of younger siblings of children with autism spectrum disorder (ASD). Around 20% of younger siblings are diagnosed with autism themselves [8], and up to another 30% manifest elevated levels of autism symptoms [9]. We used eye tracking to measure spontaneous orienting to letter targets (O, S, V, and +) presented among distractors (the letter X; Figure 1). At 9 and 15 months, emerging autism symptoms were assessed using the Autism Observation Scale for Infants (AOSI; [10]), and at 2 years of age, they were assessed using the Autism Diagnostic Observation Schedule (ADOS; [11]). Enhanced visual search performance at 9 months predicted a higher level of autism symptoms at 15 months and at 2 years. Infant perceptual atypicalities are thus intrinsically linked to the emerging autism phenotype.
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9. Guo W, Polich ED, Su J, Gao Y, Christopher DM, Allan AM, Wang M, Wang F, Wang G, Zhao X. {{Fragile X Proteins FMRP and FXR2P Control Synaptic GluA1 Expression and Neuronal Maturation via Distinct Mechanisms}}. {Cell Rep};2015 (Jun 4)
Fragile X mental retardation protein (FMRP) and its autosomal paralog FXR2P are selective neuronal RNA-binding proteins, and mice that lack either protein exhibit cognitive deficits. Although double-mutant mice display more severe learning deficits than single mutants, the molecular mechanism behind this remains unknown. In the present study, we discovered that FXR2P (also known as FXR2) is important for neuronal dendritic development. FMRP and FXR2P additively promote the maturation of new neurons by regulating a common target, the AMPA receptor GluA1, but they do so via distinct mechanisms: FXR2P binds and stabilizes GluA1 mRNA and enhances subsequent protein expression, whereas FMRP promotes GluA1 membrane delivery. Our findings unveil important roles for FXR2P and GluA1 in neuronal development, uncover a regulatory mechanism of GluA1, and reveal a functional convergence between fragile X proteins in neuronal development.
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10. Kanduri C, Kantojarvi K, Salo PM, Vanhala R, Buck G, Blancher C, Lahdesmaki H, Jarvela I. {{The landscape of copy number variations in Finnish families with autism spectrum disorders}}. {Autism Res};2015 (Jun 6)
Rare de novo and inherited copy number variations (CNVs) have been implicated in autism spectrum disorder (ASD) risk. However, the genetic underpinnings of ASD remain unknown in more than 80% of cases. Therefore, identification of novel candidate genes and corroboration of known candidate genes may broaden the horizons of determining genetic risk alleles, and subsequent development of diagnostic testing. Here, using genotyping arrays, we characterized the genetic architecture of rare CNVs (<1% frequency) in a Finnish case-control dataset. Unsurprisingly, ASD cases harbored a significant excess of rare, large (>1 Mb) CNVs and rare, exonic CNVs. The exonic rare de novo CNV rate ( approximately 22.5%) seemed higher compared to previous reports. We identified several CNVs in well-known ASD regions including GSTM1-5, DISC1, FHIT, RBFOX1, CHRNA7, 15q11.2, 15q13.2-q13.3, 17q12, and 22q11.21. Additionally, several novel candidate genes (BDKRB1, BDKRB2, AP2M1, SPTA1, PTH1R, CYP2E1, PLCD3, F2RL1, UQCRC2, LILRB3, RPS9, and COL11A2) were identified through gene prioritization. The majority of these genes belong to neuroactive ligand-receptor interaction pathways, and calcium signaling pathways, thus suggesting that a subset of these novel candidate genes may contribute to ASD risk. Furthermore, several metabolic pathways like caffeine metabolism, drug metabolism, retinol metabolism, and calcium-signaling pathway were found to be affected by the rare exonic ASD CNVs. Additionally, biological processes such as bradykinin receptor activity, endoderm formation and development, and oxidoreductase activity were enriched among the rare exonic ASD CNVs. Overall, our findings may add data about new genes and pathways that contribute to the genetic architecture of ASD. Autism Res 2015. (c) 2015 International Society for Autism Research, Wiley Periodicals, Inc.
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11. Machado C, Estevez M, Rodriguez R, Leisman G, Melillo R, Chinchilla M, Portela L. {{ANATOMIC AND FUNCTIONAL CONNECTIVITY RELATIONSHIP IN AUTISTIC CHILDREN DURING THREE DIFFERENT EXPERIMENTAL CONDITIONS}}. {Brain Connect};2015 (Jun 7)
A group of 21 autistic children was studied for determining the relationship between the anatomic (AC) vs. functional (FC) connectivity, considering short-range and long-range brain networks. AC was assessed by the DW-MRI technique and FC by EEG coherence calculation, in three experimental conditions: basal, watching a popular cartoon with audio (V-A), and with muted audio track (VwA). For short-range connections, basal records, statistical significant correlations were found for all EEG bands in the left hemisphere, but no significant correlations were found for fast EEG frequencies in the right hemisphere. For the V-A condition, significant correlations mainly diminished for the left hemisphere; for the right hemisphere, no significant correlations were found for the fast EEG frequency bands. For the VwA condition, significant correlations for the rapid EEG frequencies mainly disappeared for the right hemisphere. For long-range connections, basal records showed similar correlations both hemispheres. For the right hemisphere, significant correlations incremented to all EEG bands for the V-A condition, but these significant correlations disappeared for the fast EEG frequencies in the VwA condition. It appears that in a resting-state condition, AC is better associated with functional connectivity for short-range connections in the left hemisphere. V-A experimental condition enriches AC and FC association for long-range connections in the right hemisphere. This might be related to an effective connectivity improvement due to full video stimulation (visual and auditory). An impaired audio-visual interaction in the right hemisphere might explain why significant correlations disappeared for the fast EEG frequencies in the VwA experimental condition.
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12. Masuya Y, Okamoto Y, Inohara K, Matsumura Y, Fujioka T, Wada Y, Kosaka H. {{Sex-different abnormalities in the right second to fourth digit ratio in Japanese individuals with autism spectrum disorders}}. {Mol Autism};2015;6:34.
BACKGROUND: The prevalence of autism spectrum disorders (ASDs) is higher in men than in women. The extreme male brain theory proposes that excessive prenatal testosterone activity could be a risk factor for ASDs. However, it is unclear whether prenatal sex hormone activity is a risk factor for women. The ratio of the length of the second to fourth digits (2D:4D) is considered to be a biomarker of the prenatal ratio of testosterone to estrogen. Therefore, this study compared the 2D:4D ratios of women with and without ASDs to determine if prenatal sex hormone activity could be a risk factor for ASDs in women. METHODS: The study included 35 Japanese men with ASDs, 17 Japanese women with ASDs, 59 typically developed (TD) Japanese men, and 57 TD Japanese women. We measured digit lengths and compared the 2D:4D ratios among the four groups. We also examined the relationship between the 2D:4D ratio and the autism-spectrum quotient score of each group. RESULTS: In our cohort, men with ASDs tended to have lower right-hand 2D:4D ratios relative to TD men. In contrast, the right 2D:4D ratios in women with ASDs were higher compared to those of TD women. No significant correlations were found between the 2D:4D ratios and the autism-spectrum quotient scores in any group. The higher right 2D:4D ratios in women could not be explained by age or full-scale intelligent quotients. This group difference was not found for the left 2D:4D or right-left 2D:4D ratios. CONCLUSIONS: We found a reverse direction of abnormality in the right 2D:4D ratio for men and women with ASDs. It has been posited that high prenatal testosterone levels lead to a lower 2D:4D ratio. However, a recent animal study showed that testosterone injection to dam leads to a higher right 2D:4D ratio especially for female offspring, which might be mediated by abnormal adipose accumulation in the fingertip. Therefore, the present findings suggest that high prenatal testosterone could be a risk factor both for Japanese men and women with ASDs, elucidating one potential etiology of ASDs in women.
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13. Mottron L, Duret P, Mueller S, Moore RD, Forgeot d’Arc B, Jacquemont S, Xiong L. {{Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism}}. {Mol Autism};2015;6:33.
Several observations support the hypothesis that differences in synaptic and regional cerebral plasticity between the sexes account for the high ratio of males to females in autism. First, males are more susceptible than females to perturbations in genes involved in synaptic plasticity. Second, sex-related differences in non-autistic brain structure and function are observed in highly variable regions, namely, the heteromodal associative cortices, and overlap with structural particularities and enhanced activity of perceptual associative regions in autistic individuals. Finally, functional cortical reallocations following brain lesions in non-autistic adults (for example, traumatic brain injury, multiple sclerosis) are sex-dependent. Interactions between genetic sex and hormones may therefore result in higher synaptic and consecutively regional plasticity in perceptual brain areas in males than in females. The onset of autism may largely involve mutations altering synaptic plasticity that create a plastic reaction affecting the most variable and sexually dimorphic brain regions. The sex ratio bias in autism may arise because males have a lower threshold than females for the development of this plastic reaction following a genetic or environmental event.
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14. Murdaugh DL, Maximo JO, Kana RK. {{Changes in intrinsic connectivity of the brain’s reading network following intervention in children with autism}}. {Hum Brain Mapp};2015 (Jun 9)
While task-based neuroimaging studies have identified alterations in neural circuitry underlying language processing in children with autism spectrum disorders [ASD], resting state functional magnetic resonance imaging [rsfMRI] is a promising alternative to the constraints posed by task-based fMRI. This study used rsfMRI, in a longitudinal design, to study the impact of a reading intervention on connectivity of the brain regions involved in reading comprehension in children with ASD. Functional connectivity was examined using group independent component analysis (GICA) and seed-based correlation analysis of Broca’s and Wernicke’s areas, in three groups of participants: an experimental group of ASD children (ASD-EXP), a wait list control group of ASD children (ASD-WLC), and a group of typically developing (TD) control children. Both GICA and seed-based analyses revealed stronger functional connectivity of Broca’s and Wernicke’s areas in the ASD-EXP group postintervention. Additionally, improvement in reading comprehension in the ASD-EXP group was correlated with greater connectivity in both Broca’s and Wernicke’s area in the GICA identified reading network component. In addition, increased connectivity between the Broca’s area and right postcentral and right STG, and the Wernicke’s area and LIFG, were also correlated with greater improvement in reading comprehension. Overall, this study revealed widespread changes in functional connectivity of the brain’s reading network as a result of intervention in children with ASD. These novel findings provide valuable insights into the neuroplasticity of brain areas underlying reading and the impact of intensive intervention in modifying them in children with ASD. Hum Brain Mapp, 2015. (c) 2015 Wiley Periodicals, Inc.
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15. Ouhtit A, Al-Farsi Y, Al-Sharbati M, Waly M, Gupta I, Al-Farsi O, Al-Khaduri M, Al-Shafaee M, Al-Adawi S. {{Underlying Factors Behind the Low Prevalence of Autism Spectrum Disorders in Oman: Sociocultural perspective}}. {Sultan Qaboos Univ Med J};2015 (May);15(2):e213-217.
Epidemiological surveys from various countries indicate an increased prevalence of autism spectrum disorders (ASD), leading researchers to debate whether there are now ‘more affected’ or ‘more detected’. The epidemiology of ASD in developing countries, such as Oman, has generally indicated a lower prevalence compared to developed countries in the West. In Oman, the prevalence is low; however, this article highlights some of the factors that could contribute to the appearance of a low ASD rate: cross-cultural variations in the presentation of distress; a lack of reliable biological markers for diagnosing ASD, and a lack of health services for children with ASD, thus limiting the number of participants in epidemiological surveys. While the defining features of ASD have yet to be established, pilot studies in Oman indicate a substantial number of children with these disorders. Therefore, it is important that these discrepancies be addressed and the need for appropriate services for this patient population in Oman be highlighted.
16. Pohodich AE, Zoghbi HY. {{Rett syndrome: disruption of epigenetic control of postnatal neurological functions}}. {Hum Mol Genet};2015 (Jun 9)
Loss of function mutations in the X-linked gene Methyl-CpG-binding protein 2 (MECP2) cause a devastating pediatric neurological disorder called Rett syndrome. In males, these mutations typically result in severe neonatal encephalopathy and early lethality. On the other hand, owing to expression of the normal allele in approximately 50% of cells, females do not suffer encephalopathy but instead develop Rett syndrome. Typically females with Rett syndrome exhibit a delayed onset of neurologic dysfunction that manifests around the child’s first birthday and progresses over the next few years. Features of this disorder include loss of acquired language and motor skills, intellectual impairment, and hand stereotypies. The developmental regression observed in patients with Rett syndrome arises from altered neuronal function and is not the result of neurodegeneration. Maintenance of an appropriate level of MeCP2 appears integral to the function of healthy neurons as patients with increased levels of MeCP2, due to duplication of the Xq28 region encompassing the MECP2 locus, also present with intellectual disability and progressive neurologic symptoms. Despite major efforts over the past two decades to elucidate the molecular functions of MeCP2, the mechanisms underlying the delayed appearance of symptoms remain unclear. In this review, we will highlight recent findings that have expanded our knowledge of MeCP2’s functions, and we will discuss how epigenetic regulation, chromatin organization, and circuit dynamics may contribute to the postnatal onset of Rett syndrome.
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17. Sandin S, Schendel D, Magnusson P, Hultman C, Suren P, Susser E, Gronborg T, Gissler M, Gunnes N, Gross R, Henning M, Bresnahan M, Sourander A, Hornig M, Carter K, Francis R, Parner E, Leonard H, Rosanoff M, Stoltenberg C, Reichenberg A. {{Autism risk associated with parental age and with increasing difference in age between the parents}}. {Mol Psychiatry};2015 (Jun 9)
Advancing paternal and maternal age have both been associated with risk for autism spectrum disorders (ASD). However, the shape of the association remains unclear, and results on the joint associations is lacking. This study tests if advancing paternal and maternal ages are independently associated with ASD risk and estimates the functional form of the associations. In a population-based cohort study from five countries (Denmark, Israel, Norway, Sweden and Western Australia) comprising 5 766 794 children born 1985-2004 and followed up to the end of 2004-2009, the relative risk (RR) of ASD was estimated by using logistic regression and splines. Our analyses included 30 902 cases of ASD. Advancing paternal and maternal age were each associated with increased RR of ASD after adjusting for confounding and the other parent’s age (mothers 40-49 years vs 20-29 years, RR=1.15 (95% confidence interval (CI): 1.06-1.24), P-value<0.001; fathers50 years vs 20-29 years, RR=1.66 (95% CI: 1.49-1.85), P-value<0.001). Younger maternal age was also associated with increased risk for ASD (mothers <20 years vs 20-29 years, RR=1.18 (95% CI: 1.08-1.29), P-value<0.001). There was a joint effect of maternal and paternal age with increasing risk of ASD for couples with increasing differences in parental ages. We did not find any support for a modifying effect by the sex of the offspring. In conclusion, as shown in multiple geographic regions, increases in ASD was not only limited to advancing paternal or maternal age alone but also to differences parental age including younger or older similarly aged parents as well as disparately aged parents.Molecular Psychiatry advance online publication, 9 June 2015; doi:10.1038/mp.2015.70.
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18. Stewart PA, Hyman SL, Schmidt BL, Macklin EA, Reynolds A, Johnson CR, James SJ, Manning-Courtney P. {{Dietary Supplementation in Children with Autism Spectrum Disorders: Common, Insufficient, and Excessive}}. {J Acad Nutr Diet};2015 (Jun 2)
BACKGROUND: Little is known about the effect on dietary adequacy of supplements given to children with autism spectrum disorder (ASD). OBJECTIVE: This cross-sectional study examines dietary supplement use and micronutrient intake in children with ASD. DESIGN: Three-day diet/supplement records and use of a gluten/casein-free diet (GFCF) were documented. Estimates of usual intake of micronutrients from food and supplements were compared with the Dietary Reference Intakes. PARTICIPANTS: Children aged 2 to 11 years (N=288) with ASD from five Autism Treatment Network sites from 2009-2011. MAIN OUTCOME MEASURES: Percentage of children meeting or exceeding upper limits of micronutrient intake with or without supplements and relative to GFCF diet status. STATISTICAL ANALYSIS: Micronutrient intake from food and supplements was compared by Spearman rank correlation. Usual intake was estimated by the National Cancer Institute method adjusted for age, sex, supplement use, and GFCF diet. Adequacy of intake was compared between supplement use status and between food and total intake in supplement users relative to Dietary Reference Intakes limits. RESULTS: Dietary supplements, especially multivitamin/minerals, were used by 56% of children with ASD. The most common micronutrient deficits were not corrected (vitamin D, calcium, potassium, pantothenic acid, and choline) by supplements. Almost one-third of children remained deficient for vitamin D and up to 54% for calcium. Children receiving GFCF diets had similar micronutrient intake but were more likely to use supplements (78% vs 56%; P=0.01). Supplementation led to excess vitamin A, folate, and zinc intake across the sample, vitamin C, and copper among children aged 2 to 3 years, and manganese and copper for children aged 4 to 8 years. CONCLUSIONS: Few children with ASD need most of the micronutrients they are commonly given as supplements, which often leads to excess intake. Even when supplements are used, careful attention should be given to adequacy of vitamin D and calcium intake.
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19. von Gontard A, Pirrung M, Niemczyk J, Equit M. {{Incontinence in children with autism spectrum disorder}}. {J Pediatr Urol};2015 (May 22)
INTRODUCTION: Autism spectrum disorder (ASD) and incontinence (nocturnal enuresis (NE), daytime urinary incontinence (DUI), fecal incontinence (FI)) are relevant disorders in childhood. In general, children with special needs such as intellectual disability (ID) or ASD are more often affected by incontinence than typically developing children. OBJECTIVE: In the few studies conducted on children with ASD, gastrointestinal (GI) symptoms have received more attention than NE, DUI and lower urinary tract symptoms (LUTS). The aim of the present study was to assess the prevalence of incontinence, LUTS and psychological symptoms/disorders in children with ASD compared to controls. STUDY DESIGN: Forty children with ASD (12 children with infantile or childhood autism, 15 with atypical autism and 13 with Asperger’s syndrome) (mean age 11.3 years) and 43 age-matched control children (mean age 10.7 years) were assessed. A questionnaire referring to incontinence and the International Consultation on Incontinence Questionnaire-Pediatric LUTS (ICIQ-CLUTS) were administered. Child psychopathology was assessed with the Child Behavior Checklist (CBCL/4-18). Child psychiatric ICD-10 diagnoses were based on a structured psychiatric interview (Kinder-DIPS). RESULTS: Children with ASD showed increased rates of NE (30.0% vs 0%) and DUI (25.0% vs 4.7%) compared to controls. Among children with ASD, daytime bladder control (>/=5 years of age: 20.5% vs 0%) and bowel control (>/=4 years of age: 42.5% vs 7.5%) were delayed compared to controls. Children with ASD had a higher LUTS score. Additionally, children with ASD were more often affected by psychological symptoms and disorders. Rates of clinically relevant externalizing symptoms (32.5% vs 0%), internalizing symptoms (67.5% vs 9.3%) and total problem score (70.0% vs 2.1%) were higher in children with ASD than the controls (see table). Children with ASD had more ICD-10 diagnoses than the controls (47.5% vs 4.7%). DISCUSSION: The present study showed that children with ASD are more at risk of DUI and NE than healthy controls. In addition, children with ASD had more LUTS, especially urgency and postponement, and they needed a longer time to become dry and continent. Additionally, according to the parental CBCL questionnaire, children with ASD showed higher rates of clinically relevant psychological symptoms (externalizing and internalizing symptoms), and according to the psychiatric interview, they had higher rates of comorbid psychological disorders. CONCLUSION: Autism spectrum disorder is an incapacitating disorder with significant impairment in social functioning. In most cases, psychological symptoms and disorders co-occur. Additionally, children with ASD are at a greater risk of being affected by different forms of incontinence and LUTS. Therefore, screening for incontinence and, if indicated, treatment of these disorders is recommended.
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20. Woo CC, Donnelly JH, Steinberg-Epstein R, Leon M. {{Environmental Enrichment as a Therapy for Autism: A Clinical Trial Replication and Extension}}. {Behav Neurosci};2015 (Jun 8)
Based on work done in animal models showing that autism-like symptoms are ameliorated following exposure to an enriched sensorimotor environment, we attempted to develop a comparable therapy for children with autism. In an initial randomized controlled trial, children with autism who received sensorimotor enrichment at home for 6 months had significant improvements in both their cognitive ability and the severity of their autism symptoms (Woo & Leon, 2013). We now report the outcomes of a similar randomized controlled trial in which children with autism, 3 to 6 years old, were randomly assigned to groups that received either daily sensorimotor enrichment, administered by their parents, along with standard care, or they received standard care alone. After 6 months, enriched children showed statistically significant gains in their IQ scores, a decline in their atypical sensory responses, and an improvement in their receptive language performance, compared to controls. Furthermore, after 6 months of enrichment therapy, 21% of the children who initially had been given an autism classification, using the Autism Diagnostic Observation Schedule, improved to the point that, although they remained on the autism spectrum, they no longer met the criteria for classic autism. None of the standard care controls reached an equivalent level of improvement. Finally, the outcome measures for children who received only a subset of sensory stimuli were similar to those receiving the full complement of enrichment exercises. Sensorimotor enrichment therapy therefore appears to be a cost-effective means of treating a range of symptoms for children with autism.
