1. Abells D, Kirkham YA, Ornstein MP. {{Review of gynecologic and reproductive care for women with developmental disabilities}}. {Curr Opin Obstet Gynecol};2016 (Jul 1)
PURPOSE OF REVIEW: Care for women with developmental disabilities requires special consideration for unique needs related to their cognitive and physical abilities. These women and their caregivers require more support and guidance during reproductive health care. We review the literature and provide expert opinion surrounding gynecological issues for women with developmental disabilities to support healthcare providers better understand and care for this population. RECENT FINDINGS: Women with developmental disabilities are more vulnerable to abuse and experience poorer gynecological healthcare outcomes. Many women with developmental disabilities are fertile and participate in sexual activity without adequate knowledge. They are at higher risk of pregnancy and birth complications. They are less likely to receive appropriate preventive screening. SUMMARY: The review highlights important issues and practice suggestions related to the reproductive health care of women with developmental disabilities. Topics include clinic visits, menstruation, sexuality, sexual abuse, sexual health education, contraception, sexually transmitted infections, pregnancy, labor and delivery, and cancer screening/prevention. We emphasize the need for an individualized, comprehensive approach for these patients and review perceived and actual barriers to care. More education is needed on the aforementioned topics for women with developmental disabilities, their caregivers, and their providers.
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2. Chin EW, Marcy G, Yoon SI, Ma D, Rosales FJ, Augustine GJ, Goh EL. {{Choline Ameliorates Disease Phenotypes in Human iPSC Models of Rett Syndrome}}. {Neuromolecular Med};2016 (Jul 5)
Rett syndrome (RTT) is a postnatal neurodevelopmental disorder that primarily affects girls. Mutations in the methyl-CpG-binding protein 2 (MECP2) gene account for approximately 95 % of all RTT cases. To model RTT in vitro, we generated induced pluripotent stem cells (iPSCs) from fibroblasts of two RTT patients with different mutations (MECP2 R306C and MECP2 1155Delta32) in their MECP2 gene. We found that these iPSCs were capable of differentiating into functional neurons. Compared to control neurons, the RTT iPSC-derived cells had reduced soma size and a decreased amount of synaptic input, evident both as fewer Synapsin 1-positive puncta and a lower frequency of spontaneous excitatory postsynaptic currents. Supplementation of the culture media with choline rescued all of these defects. Choline supplementation may act through changes in the expression of choline acetyltransferase, an important enzyme in cholinergic signaling, and also through alterations in the lipid metabolite profiles of the RTT neurons. Our study elucidates the possible mechanistic pathways for the effect of choline on human RTT cell models, thereby illustrating the potential for using choline as a nutraceutical to treat RTT.
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3. Fairthorne JC, de Klerk NH, Leonard HM, Whitehouse AJ. {{Mothers of Children with Autism have Different Rates of Cancer According to the Presence of Intellectual Disability in Their Child}}. {J Autism Dev Disord};2016 (Jul 6)
Autism spectrum disorder (ASD) and intellectual disability (ID) are neurodevelopmental disorders with strong genetic components. Increasingly, research attention has focused on whether genetic factors conveying susceptibility for these conditions, also influence the risk of other health conditions, such as cancer. We examined the occurrence of hospital admissions and treatment/services for cancer in mothers of children with ASD with or without ID compared with other mothers. After linking Western Australian administrative health databases, we used Cox regression to estimate the hazard ratios (HRs) of any hospitalisations and treatment/services for cancer in these groups of mothers. Mothers of children with ASD without ID had greater risk of admissions for cancer (HR 1.29 [95 % CI 1.1, 1.7]), and for treatment/services in particular (HR 1.41 [95 % CI 1.0, 2.0]), than mothers of children with no ASD/ID, while mothers of children with ASD with ID were no more likely to have a cancer-related hospital admission than other mothers. Mothers of children with autism without ID had increased risk of cancer, which may relate to common genetic pathways.
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4. Haker H, Schneebeli M, Stephan KE. {{Can Bayesian Theories of Autism Spectrum Disorder Help Improve Clinical Practice?}}. {Front Psychiatry};2016;7:107.
Diagnosis and individualized treatment of autism spectrum disorder (ASD) represent major problems for contemporary psychiatry. Tackling these problems requires guidance by a pathophysiological theory. In this paper, we consider recent theories that re-conceptualize ASD from a « Bayesian brain » perspective, which posit that the core abnormality of ASD resides in perceptual aberrations due to a disbalance in the precision of prediction errors (sensory noise) relative to the precision of predictions (prior beliefs). This results in percepts that are dominated by sensory inputs and less guided by top-down regularization and shifts the perceptual focus to detailed aspects of the environment with difficulties in extracting meaning. While these Bayesian theories have inspired ongoing empirical studies, their clinical implications have not yet been carved out. Here, we consider how this Bayesian perspective on disease mechanisms in ASD might contribute to improving clinical care for affected individuals. Specifically, we describe a computational strategy, based on generative (e.g., hierarchical Bayesian) models of behavioral and functional neuroimaging data, for establishing diagnostic tests. These tests could provide estimates of specific cognitive processes underlying ASD and delineate pathophysiological mechanisms with concrete treatment targets. Written with a clinical audience in mind, this article outlines how the development of computational diagnostics applicable to behavioral and functional neuroimaging data in routine clinical practice could not only fundamentally alter our concept of ASD but eventually also transform the clinical management of this disorder.
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5. Helsmoortel C, Swagemakers SM, Vandeweyer G, Stubbs AP, Palli I, Mortier G, Kooy RF, van der Spek PJ. {{Whole genome sequencing of a dizygotic twin suggests a role for the serotonin receptor HTR7 in autism spectrum disorder}}. {Am J Med Genet B Neuropsychiatr Genet};2016 (Jul 6)
Whole genome sequencing of a severely affected dizygotic twin with an autism spectrum disorder and intellectual disability revealed a compound heterozygous mutation in the HTR7 gene as the only variation not detected in control databases. Each parent carries one allele of the mutation, which is not present in an unaffected stepsister. The HTR7 gene encodes the 5-HT7 serotonin receptor that is involved in brain development, synaptic transmission, and plasticity. The paternally inherited p.W60C variant is situated at an evolutionary conserved nucleotide and predicted damaging by Polyphen2. A mutation akin to the maternally inherited pV286I mutation has been reported to significantly affect the binding characteristics of the receptor. Therefore, the observed sequence alterations provide a first suggestive link between a genetic abnormality in the HTR7 gene and a neurodevelopmental disorder. (c) 2016 Wiley Periodicals, Inc.
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6. Higashimori H, Schin CS, Chiang MS, Morel L, Shoneye TA, Nelson DL, Yang Y. {{Selective Deletion of Astroglial FMRP Dysregulates Glutamate Transporter GLT1 and Contributes to Fragile X Syndrome Phenotypes In Vivo}}. {J Neurosci};2016 (Jul 6);36(27):7079-7094.
How the loss of fragile X mental retardation protein (FMRP) in different brain cell types, especially in non-neuron glial cells, induces fragile X syndrome (FXS) phenotypes has just begun to be understood. In the current study, we generated inducible astrocyte-specific Fmr1 conditional knock-out mice (i-astro-Fmr1-cKO) and restoration mice (i-astro-Fmr1-cON) to study the in vivo modulation of FXS synaptic phenotypes by astroglial FMRP. We found that functional expression of glutamate transporter GLT1 is 40% decreased in i-astro-Fmr1-cKO somatosensory cortical astrocytes in vivo, which can be fully rescued by the selective re-expression of FMRP in astrocytes in i-astro-Fmr1-cON mice. Although the selective loss of astroglial FMRP only modestly increases spine density and length in cortical pyramidal neurons, selective re-expression of FMRP in astrocytes significantly attenuates abnormal spine morphology in these neurons of i-astro-Fmr1-cON mice. Moreover, we found that basal protein synthesis levels and immunoreactivity of phosphorylated S6 ribosomal protein (p-s6P) is significantly increased in i-astro-Fmr1-cKO mice, while the enhanced cortical protein synthesis observed in Fmr1 KO mice is mitigated in i-astro-Fmr1-cON mice. Furthermore, ceftriaxone-mediated upregulation of surface GLT1 expression restores functional glutamate uptake and attenuates enhanced neuronal excitability in Fmr1 KO mice. In particular, ceftriaxone significantly decreases the growth rate of abnormally accelerated body weight and completely corrects spine abnormality in Fmr1 KO mice. Together, these results show that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, presumably through dysregulated astroglial glutamate transporter GLT1 and impaired glutamate uptake. These results suggest the involvement of astrocyte-mediated mechanisms in the pathogenesis of FXS. SIGNIFICANCE STATEMENT: Previous studies to understand how the loss of function of fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS) have largely focused on neurons; whether the selective loss of astroglial FMRP in vivo alters astrocyte functions and contributes to the pathogenesis of FXS remain essentially unknown. This has become a long-standing unanswered question in the fragile X field, which is also relevant to autism pathogenesis. Our current study generated astrocyte-specific Fmr1 conditional knock-out and restoration mice, and provided compelling evidence that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, likely through the dysregulated astroglial glutamate transporter GLT1 expression and impaired glutamate uptake. These results demonstrate previously undescribed astrocyte-mediated mechanisms in the pathogenesis of FXS.
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7. Kharrat M, Hsairi I, Doukali H, Fendri-Kriaa N, Kammoun H, Ammar-Keskes L, Triki C, Fakhfakh F. {{Phenotypic variability in two infants sharing the same MECP2 mutation: evidence of chromosomal rearrangements and high sister-chromatid exchange levels in Rett syndrome}}. {Acta Neurol Belg};2016 (Jul 5)
Rett syndrome (RTT) whose major cause is the mutations in the X-linked MECP2 gene is a genetic disease that affects females. We screened two RTT patients using cytogenetic studies and in silico analysis as well as molecular analysis by the direct sequencing of MECP2. The cytogenetic results showed that although patient A was karyotypically normal, patient B showed chromosomal abnormalities, including chromosomal breakage in both chromosomes 2 and 5. In addition, chromosome 9 was detected on heteromorphic pattern (9ph+). A significant increase in sister-chromatid exchange (SCE) frequency was also observed in this patient. Although both patients were karyotypically different, they share the same MeCP2 mutation (p.P152R) which was predicted to be deleterious. To our knowledge, we describe the first association between MECP2 mutation, chromosomal abnormalities and high SCE frequency, which further validates the importance of the thorough chromosomal and molecular analyses that should be performed on the suspected RTT cases.
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8. Kumari D, Usdin K. {{Sustained expression of FMR1 mRNA from reactivated fragile X syndrome alleles after treatment with small molecules that prevent trimethylation of H3K27}}. {Hum Mol Genet};2016 (Jul 4)
Expansion of a CGG-repeat tract in the 5′-untranslated region of the FMR1 gene to >200 repeats results in epigenetic silencing of the gene by a mechanism that is still unknown. FMR1 gene silencing results in fragile X syndrome (FXS), the most common heritable cause of intellectual disability. We have previously shown that reactivation of FMR1 gene in FXS cells with 5-azadeoxycytidine (AZA) leads to the transient recruitment of EZH2, the polycomb repressive complex 2 (PRC2) component responsible for H3K27 trimethylation, and that this recruitment depends on the presence of the FMR1 transcript. However, whether H3K27 trimethylation was essential for FMR1 re-silencing was not known. We show here that EZH2 inhibitors increased FMR1 expression and significantly delayed re-silencing of the FMR1 gene in AZA-treated FXS cells. This delay occurred despite the fact that EZH2 inhibition did not prevent the return of DNA methylation. Treatment with compound 1a, a small molecule that targets CGG-repeats in the FMR1 mRNA, also resulted in sustained expression of the FMR1 gene in AZA-treated cells. This effect of 1a was also associated with a decrease in the levels of H3K27 trimethylation but not DNA methylation. Thus, our data show that EZH2 plays a critical role in the FMR1 gene silencing process and that its inhibition can prolong expression of the FMR1 gene even in the presence of its transcript.
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9. Liu HH, Cline HT. {{Fragile X Mental Retardation Protein Is Required to Maintain Visual Conditioning-Induced Behavioral Plasticity by Limiting Local Protein Synthesis}}. {J Neurosci};2016 (Jul 6);36(27):7325-7339.
Fragile X mental retardation protein (FMRP) is thought to regulate neuronal plasticity by limiting dendritic protein synthesis, but direct demonstration of a requirement for FMRP control of local protein synthesis during behavioral plasticity is lacking. Here we tested whether FMRP knockdown in Xenopus optic tectum affects local protein synthesis in vivo and whether FMRP knockdown affects protein synthesis-dependent visual avoidance behavioral plasticity. We tagged newly synthesized proteins by incorporation of the noncanonical amino acid azidohomoalanine and visualized them with fluorescent noncanonical amino acid tagging (FUNCAT). Visual conditioning and FMRP knockdown produce similar increases in FUNCAT in tectal neuropil. Induction of visual conditioning-dependent behavioral plasticity occurs normally in FMRP knockdown animals, but plasticity degrades over 24 h. These results indicate that FMRP affects visual conditioning-induced local protein synthesis and is required to maintain the visual conditioning-induced behavioral plasticity. SIGNIFICANCE STATEMENT: Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Exaggerated dendritic protein synthesis resulting from loss of fragile X mental retardation protein (FMRP) is thought to underlie cognitive deficits in FXS, but no direct evidence has demonstrated that FMRP-regulated dendritic protein synthesis affects behavioral plasticity in intact animals. Xenopus tadpoles exhibit a visual avoidance behavior that improves with visual conditioning in a protein synthesis-dependent manner. We showed that FMRP knockdown and visual conditioning dramatically increase protein synthesis in neuronal processes. Furthermore, induction of visual conditioning-dependent behavioral plasticity occurs normally after FMRP knockdown, but performance rapidly deteriorated in the absence of FMRP. These studies show that FMRP negatively regulates local protein synthesis and is required to maintain visual conditioning-induced behavioral plasticity in vivo.
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10. Marchetto MC, Belinson H, Tian Y, Freitas BC, Fu C, Vadodaria KC, Beltrao-Braga PC, Trujillo CA, Mendes AP, Padmanabhan K, Nunez Y, Ou J, Ghosh H, Wright R, Brennand KJ, Pierce K, Eichenfield L, Pramparo T, Eyler LT, Barnes CC, Courchesne E, Geschwind DH, Gage FH, Wynshaw-Boris A, Muotri AR. {{Altered proliferation and networks in neural cells derived from idiopathic autistic individuals}}. {Mol Psychiatry};2016 (Jul 5)
Autism spectrum disorders (ASD) are common, complex and heterogeneous neurodevelopmental disorders. Cellular and molecular mechanisms responsible for ASD pathogenesis have been proposed based on genetic studies, brain pathology and imaging, but a major impediment to testing ASD hypotheses is the lack of human cell models. Here, we reprogrammed fibroblasts to generate induced pluripotent stem cells, neural progenitor cells (NPCs) and neurons from ASD individuals with early brain overgrowth and non-ASD controls with normal brain size. ASD-derived NPCs display increased cell proliferation because of dysregulation of a beta-catenin/BRN2 transcriptional cascade. ASD-derived neurons display abnormal neurogenesis and reduced synaptogenesis leading to functional defects in neuronal networks. Interestingly, defects in neuronal networks could be rescued by insulin growth factor 1 (IGF-1), a drug that is currently in clinical trials for ASD. This work demonstrates that selection of ASD subjects based on endophenotypes unraveled biologically relevant pathway disruption and revealed a potential cellular mechanism for the therapeutic effect of IGF-1.Molecular Psychiatry advance online publication, 5 July 2016; doi:10.1038/mp.2016.95.
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11. Nakagawa Y, Chiba K. {{Involvement of neuroinflammation during brain development in social cognitive deficits in autism spectrum disorder and schizophrenia}}. {J Pharmacol Exp Ther};2016 (Jul 6)
Development of social cognition, a unique and high-order function, depends on brain maturation from childhood to adulthood in humans. Autism spectrum disorder (ASD) and schizophrenia have similar social cognitive deficits while age of onset in each disorder is different. Pathogenesis of these disorders is complex and contains several features including genetic risk factors, environmental risk factors, and sites of abnormalities in the brain. Although several hypotheses have been postulated, they seem to be insufficient to explain how brain alterations associated with symptoms in these disorders develop at distinct developmental stages. Development of ASD appears to be related to cerebellar dysfunction and subsequent thalamic hyperactivation in early childhood. By contrast, schizophrenia seems to be triggered by thalamic hyperactivation in late adolescence while hippocampal aberration has been possibly initiated in childhood. One of the possible culprits is metal homeostasis disturbances that can induce dysfunction of blood-cerebrospinal fluid barrier. Thalamic hyperactivation is thought to be induced by microglia-mediated neuroinflammation and abnormalities of intracerebral environment. Consequently, it is likely that the thalamic hyperactivation triggers dysregulation of the dorsolateral prefrontal cortex for lower brain regions related to social cognition. In this review, we summarize the brain aberration in ASD and schizophrenia and provide a possible mechanism underlying social cognitive deficits in these disorders based on their distinct ages of onset.
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12. Pastor-Cerezuela G, Fernandez-Andres MI, Feo-Alvarez M, Gonzalez-Sala F. {{Semantic Verbal Fluency in Children with and without Autism Spectrum Disorder: Relationship with Chronological Age and IQ}}. {Front Psychol};2016;7:921.
We administered a semantic verbal fluency (SVF) task to two groups of children (age range from 5 to 8): 47 diagnosed with Autism Spectrum Disorder (ASD Group) and 53 with typical development (Comparison Group), matched on gender, chronological age, and non-verbal IQ. Four specific indexes were calculated from the SVF task, reflecting the different underlying cognitive strategies used: clustering (component of generativity and lexical-semantic access), and switching (executive component, cognitive flexibility). First, we compared the performance of the two groups on the different SVF task indicators, with the ASD group scoring lower than the Comparison Group, although the difference was greater on switching than on clustering. Second, we analyzed the relationships between the different SVF measures and chronological age, verbal IQ and non-verbal IQ. While in the Comparison Group chronological age was the main predictor of performance on the SVF task, in the ASD Group verbal IQ was the best predictor. In the children with ASD, therefore, greater linguistic competence would be associated with better performance on the SVF task, which should be taken into account in speech therapies designed to achieve improvements in linguistic generativity and cognitive flexibility.
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13. Schauder KB, Bennetto L. {{Toward an Interdisciplinary Understanding of Sensory Dysfunction in Autism Spectrum Disorder: An Integration of the Neural and Symptom Literatures}}. {Front Neurosci};2016;10:268.
Sensory processing differences have long been associated with autism spectrum disorder (ASD), and they have recently been added to the diagnostic criteria for the disorder. The focus on sensory processing in ASD research has increased substantially in the last decade. This research has been approached from two different perspectives: the first focuses on characterizing the symptoms that manifest in response to real world sensory stimulation, and the second focuses on the neural pathways and mechanisms underlying sensory processing. The purpose of this paper is to integrate the empirical literature on sensory processing in ASD from the last decade, including both studies characterizing sensory symptoms and those that investigate neural response to sensory stimuli. We begin with a discussion of definitions to clarify some of the inconsistencies in terminology that currently exist in the field. Next, the sensory symptoms literature is reviewed with a particular focus on developmental considerations and the relationship of sensory symptoms to other core features of the disorder. Then, the neuroscience literature is reviewed with a focus on methodological approaches and specific sensory modalities. Currently, these sensory symptoms and neuroscience perspectives are largely developing independently from each other leading to multiple, but separate, theories and methods, thus creating a multidisciplinary approach to sensory processing in ASD. In order to progress our understanding of sensory processing in ASD, it is now critical to integrate these two research perspectives and move toward an interdisciplinary approach. This will inevitably aid in a better understanding of the underlying biological basis of these symptoms and help realize the translational value through its application to early identification and treatment. The review ends with specific recommendations for future research to help bridge these two research perspectives in order to advance our understanding of sensory processing in ASD.
