1. Brown AC, Mehl-Madrona L. {{Autoimmune and gastrointestinal dysfunctions: does a subset of children with autism reveal a broader connection?}}. {Expert Rev Gastroenterol Hepatol};2011 (Aug);5(4):465-477.
A large number of autoimmune disorders have a gastrointestinal (GI) dysfunction component that may interplay with genetic, hormonal, environmental and/or stress factors. This narrarive review investigates possible links between autism, immune system abnormalities and GI symptoms in a subgroup of children with autism. A literature search on Medline (1950 to September 2010) was conducted to identify relevant articles by using the keywords ‘autism and gastrointestinal’ (71 publications) and ‘autism and immune’ (237 publications), cross-referencing and general searching to evaluate the available literature on the immunological and GI aspects of autism. Sufficient evidence exists to support that a subgroup of children with autism may suffer from concomitant immune-related GI symptoms.
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2. Darnell JC, Van Driesche SJ, Zhang C, Hung KY, Mele A, Fraser CE, Stone EF, Chen C, Fak JJ, Chi SW, Licatalosi DD, Richter JD, Darnell RB. {{FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism}}. {Cell};2011 (Jul 22);146(2):247-261.
FMRP loss of function causes Fragile X syndrome (FXS) and autistic features. FMRP is a polyribosome-associated neuronal RNA-binding protein, suggesting that it plays a key role in regulating neuronal translation, but there has been little consensus regarding either its RNA targets or mechanism of action. Here, we use high-throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) to identify FMRP interactions with mouse brain polyribosomal mRNAs. FMRP interacts with the coding region of transcripts encoding pre- and postsynaptic proteins and transcripts implicated in autism spectrum disorders (ASD). We developed a brain polyribosome-programmed translation system, revealing that FMRP reversibly stalls ribosomes specifically on its target mRNAs. Our results suggest that loss of a translational brake on the synthesis of a subset of synaptic proteins contributes to FXS. In addition, they provide insight into the molecular basis of the cognitive and allied defects in FXS and ASD and suggest multiple targets for clinical intervention. PAPERCLIP:
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3. Dawson G. {{Coming closer to describing the variable onset patterns in autism}}. {J Am Acad Child Adolesc Psychiatry};2011 (Aug);50(8):744-746.
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4. Hara M, Nishi Y, Yamashita Y, Yoh J, Takahashi S, Nagamitsu SI, Kakuma T, Hosoda H, Kangawa K, Kojima M, Matsuishi T. {{Ghrelin levels are reduced in Rett syndrome patients with eating difficulties}}. {Int J Dev Neurosci};2011 (Jul 18)
Most patients with Rett syndrome (RTT) have both gastrointestinal problems and somatic growth failure, including microcephaly. Ghrelin is a peptide hormone involved in growth hormone secretion, interdigestive motility, and feeding behavior. Plasma ghrelin assays have previously been described for other neurodevelopmental disorders. To examine the pathophysiology of RTT, we measured plasma levels of ghrelin in patients with RTT. A case-control study examining plasma levels of ghrelin, serum growth hormone, and insulin-like growth factor-1 (IGF-1) was performed on 27 patients with RTT and 53 controls. Plasma levels of total (T)- and octanoyl (O)-ghrelin were significantly lower in patients with RTT than in controls. Plasma levels of T-ghrelin correlated significantly with serum IGF-1 levels and head circumference. Significantly lower levels of plasma T-ghrelin and O-ghrelin were observed in RTT patients with eating difficulties, while lower levels of plasma T-ghrelin were observed in RTT patients with constipation, in comparison to patients without either of these symptoms. Alterations in plasma ghrelin levels may reflect various clinical symptoms and signs in RTT patients, including growth failure, acquired microcephalus, autonomic nerve dysfunction, and feeding difficulties. We describe the role of ghrelin in RTT and suggest this peptide as a novel biological marker in patients with RTT.
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5. Hessl D, Wang JM, Schneider A, Koldewyn K, Le L, Iwahashi C, Cheung K, Tassone F, Hagerman PJ, Rivera SM. {{Decreased Fragile X Mental Retardation Protein Expression Underlies Amygdala Dysfunction in Carriers of the Fragile X Premutation}}. {Biol Psychiatry};2011 (Jul 21)
BACKGROUND: The fragile X premutation provides a unique opportunity for the study of genetic and brain mechanisms of behavior and cognition in the context of neurodevelopment and neurodegeneration. Although the neurodegenerative phenotype, fragile X-associated tremor/ataxia syndrome, is well described, evidence of a causal link between the premutation and psychiatric disorder earlier in life, clear delineation of a behavioral/cognitive phenotype, and characterization of the physiological basis of observed symptoms have been elusive. METHODS: We completed functional magnetic resonance imaging targeting the amygdala with an emotion-matching task and concurrent infrared eye tracking, FMR1 molecular genetic testing, and neuropsychological assessment in 23 men with the premutation (mean age = 32.9 years) and 25 male control subjects (mean age = 30.1 years). RESULTS: Premutation carriers had significantly smaller left and right amygdala volume and reduced right amygdala activation during the task relative to control subjects. Although both elevated FMR1 messenger RNA and reduced fragile X mental retardation protein (FMRP) were associated with the reduced activation, multiple regression analysis suggested that reduced FMRP is the primary factor. Premutation carriers also had higher ratings of autism spectrum symptoms than control subjects, which were associated with the reduced amygdala response. CONCLUSIONS: Although prior studies have emphasized a toxic gain-of-function effect of elevated messenger RNA associated with the premutation, the current results point to the role of reduced FMRP in alterations of brain activity and behavior.
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6. Hunsaker MR, Greco CM, Spath MA, Smits AP, Navarro CS, Tassone F, Kros JM, Severijnen LA, Berry-Kravis EM, Berman RF, Hagerman PJ, Willemsen R, Hagerman RJ, Hukema RK. {{Widespread non-central nervous system organ pathology in fragile X premutation carriers with fragile X-associated tremor/ataxia syndrome and CGG knock-in mice}}. {Acta Neuropathol};2011 (Jul 23)
Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder generally presenting with intention tremor and gait ataxia, but with a growing list of co-morbid medical conditions including hypothyroidism, hypertension, peripheral neuropathy, and cognitive decline. The pathological hallmark of FXTAS is the presence of intranuclear inclusions in both neurons and astroglia. However, it is unknown to what extent such inclusions are present outside the central nervous system (CNS). To address this issue, we surveyed non-CNS organs in ten human cases with FXTAS and in a CGG repeat knock-in (CGG KI) mouse model known to possess neuronal and astroglial inclusions. We find inclusions in multiple tissues from FXTAS cases and CGG KI mice, including pancreas, thyroid, adrenal gland, gastrointestinal, pituitary gland, pineal gland, heart, and mitral valve, as well as throughout the associated autonomic ganglia. Inclusions were observed in the testes, epididymis, and kidney of FXTAS cases, but were not observed in mice. These observations demonstrate extensive involvement of the peripheral nervous system and systemic organs. The finding of intranuclear inclusions in non-CNS somatic organ systems, throughout the PNS, and in the enteric nervous system of both FXTAS cases as well as CGG KI mice suggests that these tissues may serve as potential sites to evaluate early intervention strategies or be used as diagnostic factors.
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7. Jiao Y, Chen R, Ke X, Cheng L, Chu K, Lu Z, Herskovits EH. {{Single Nucleotide Polymorphisms Predict Symptom Severity of Autism Spectrum Disorder}}. {J Autism Dev Disord};2011 (Jul 24)
Autism is widely believed to be a heterogeneous disorder; diagnosis is currently based solely on clinical criteria, although genetic, as well as environmental, influences are thought to be prominent factors in the etiology of most forms of autism. Our goal is to determine whether a predictive model based on single-nucleotide polymorphisms (SNPs) can predict symptom severity of autism spectrum disorder (ASD). We divided 118 ASD children into a mild/moderate autism group (n = 65) and a severe autism group (n = 53), based on the Childhood Autism Rating Scale (CARS). For each child, we obtained 29 SNPs of 9 ASD-related genes. To generate predictive models, we employed three machine-learning techniques: decision stumps (DSs), alternating decision trees (ADTrees), and FlexTrees. DS and FlexTree generated modestly better classifiers, with accuracy = 67%, sensitivity = 0.88 and specificity = 0.42. The SNP rs878960 in GABRB3 was selected by all models, and was related associated with CARS assessment. Our results suggest that SNPs have the potential to offer accurate classification of ASD symptom severity.
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8. Kushki A, Chau T, Anagnostou E. {{Erratum to: Handwriting Difficulties in Children with Autism Spectrum Disorders: A Scoping Review}}. {J Autism Dev Disord};2011 (Jul 24)
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9. Ozonoff S, Iosif AM, Young GS, Hepburn S, Thompson M, Colombi C, Cook IC, Werner E, Goldring S, Baguio F, Rogers SJ. {{Onset patterns in autism: correspondence between home video and parent report}}. {J Am Acad Child Adolesc Psychiatry};2011 (Aug);50(8):796-806 e791.
OBJECTIVE: The onset of autism is usually conceptualized as occurring in one of two patterns, early onset or regressive. This study examined the number and shape of trajectories of symptom onset evident in coded home movies of children with autism and examined their correspondence with parent report of onset. METHOD: Four social-communicative behaviors were coded from the home video of children with autism (n = 52) or typical development (n = 23). All home videos from 6 through 24 months of age were coded (3199 segments). Latent class modeling was used to characterize trajectories and determine the optimal number needed to describe the coded home video. These trajectories were then compared with parent reports of onset patterns, as defined by the Autism Diagnostic Interview-Revised. RESULTS: A three-trajectory model best fit the data from the participants with autism. One trajectory displayed low levels of social-communication across time. A second trajectory displayed high levels of social-communication early in life, followed by a significant decrease over time. A third trajectory displayed initial levels of behavior that were similar to the typically developing group but little progress in social-communication with age. There was poor correspondence between home video-based trajectories and parent report of onset. CONCLUSIONS: More than two onset categories may be needed to describe the ways in which symptoms emerge in children with autism. There is low agreement between parent report and home video, suggesting that methods for improving parent report of early development must be developed.
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10. Rudie JD, Shehzad Z, Hernandez LM, Colich NL, Bookheimer SY, Iacoboni M, Dapretto M. {{Reduced Functional Integration and Segregation of Distributed Neural Systems Underlying Social and Emotional Information Processing in Autism Spectrum Disorders}}. {Cereb Cortex};2011 (Jul 22)
A growing body of evidence suggests that autism spectrum disorders (ASDs) are related to altered communication between brain regions. Here, we present findings showing that ASD is characterized by a pattern of reduced functional integration as well as reduced segregation of large-scale brain networks. Twenty-three children with ASD and 25 typically developing matched controls underwent functional magnetic resonance imaging while passively viewing emotional face expressions. We examined whole-brain functional connectivity of two brain structures previously implicated in emotional face processing in autism: the amygdala bilaterally and the right pars opercularis of the inferior frontal gyrus (rIFGpo). In the ASD group, we observed reduced functional integration (i.e., less long-range connectivity) between amygdala and secondary visual areas, as well as reduced segregation between amygdala and dorsolateral prefrontal cortex. For the rIFGpo seed, we observed reduced functional integration with parietal cortex and increased integration with right frontal cortex as well as right nucleus accumbens. Finally, we observed reduced segregation between rIFGpo and the ventromedial prefrontal cortex. We propose that a systems-level approach-whereby the integration and segregation of large-scale brain networks in ASD is examined in relation to typical development-may provide a more detailed characterization of the neural basis of ASD.
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11. Selmeczy D, Koldewyn K, Wang JM, Lee A, Harvey D, Hessl DR, Tassone F, Adams P, Hagerman RJ, Hagerman PJ, Rivera SM. {{Investigation of amygdala volume in men with the fragile X premutation}}. {Brain Imaging Behav};2011 (Jul 26)
Premutation fragile X carriers have a CGG repeat expansion (55 to 200 repeats) in the promoter region of the fragile X mental retardation 1 (FMR1) gene. Amygdala dysfunction has been observed in premutation symptomatology, and recent research has suggested the amygdala as an area susceptible to the molecular effects of the premutation. The current study utilizes structural magnetic resonance imaging (MRI) to examine the relationship between amygdala volume, CGG expansion size, FMR1 mRNA, and psychological symptoms in male premutation carriers without FXTAS compared with age and IQ matched controls. No significant between group differences in amygdala volume were found. However, a significant negative correlation between amygdala volume and CGG was found in the lower range of CGG repeat expansions, but not in the higher range of CGG repeat expansions.
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12. Wang L, Christophersen CT, Sorich MJ, Gerber JP, Angley MT, Conlon MA. {{The relative abundance of the mucolytic bacterium Akkermansia muciniphila and Bifidobacterium spp. is lower in feces of children with autism}}. {Appl Environ Microbiol};2011 (Jul 22)
Gastrointestinal disturbance is frequently reported in autism. We used quantitative real-time PCR to quantify fecal bacteria that could influence gastrointestinal health in children with and without autism. Lower relative abundances of Bifidobacteria and the mucolytic bacterium Akkermansia muciniphila were found in children with autism, the latter suggesting mucus barrier changes.
