1. Cho IYK, Jelinkova K, Schuetze M, Vinette SA, Rahman S, McCrimmon A, Dewey D, Bray S. {{Circumscribed interests in adolescents with Autism Spectrum Disorder: A look beyond trains, planes, and clocks}}. {PLoS One}. 2017; 12(11): e0187414.
Adolescence is a unique developmental period, characterized by physical and emotional growth and significant maturation of cognitive and social skills. For individuals with Autism Spectrum Disorder (ASD), it is also a vulnerable period as cognitive and social skills can deteriorate. Circumscribed interests (CIs), idiosyncratic areas of intense interest and focus, are a core symptom of ASD that may be associated with social development. Yet, relatively little is known about the expression of CIs in adolescents with ASD. Many studies investigating CIs have used images depicting items of special interest; however, it is not clear how images should be customized for adolescent studies. The goal of this study was to gain insight into the types of images that may be appropriate for studies of CIs in adolescents with ASD. To this end, we used a mixed methods design that included, 1) one-on-one interviews with 10 adolescents (4 with ASD and 6 TD), to identify categories of images that were High Autism Interest (‘HAI’) or High Typically Developing Interest (‘HTD’), and 2) an online survey taken by fifty-three adolescents with ASD (42 male) and 135 typically developing (TD) adolescents (55 male) who rated how much they liked 105 ‘HAI’ and ‘HTD’ images. Although we found a significant interaction between ‘HAI’ and ‘HTD’ categories and diagnosis, neither group significantly preferred one category over the other, and only one individual category (‘Celebrities’) showed a significant group effect, favored by TD adolescents. Males significantly preferred ‘HAI’ images relative to females, and TD adolescents significantly preferred images with social content relative to adolescents with ASD. Our findings suggest that studies investigating affective or neural responses to CI-related stimuli in adolescents should consider that stereotypical ASD interests (e.g. trains, gadgets) may not accurately represent individual adolescents with ASD, many of whom show interests that overlap with TD adolescents (e.g. video games).
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2. Clements CC, Wenger TL, Zoltowski AR, Bertollo JR, Miller JS, de Marchena AB, Mitteer LM, Carey JC, Yerys BE, Zackai EH, Emanuel BS, McDonald-McGinn DM, Schultz RT. {{Critical region within 22q11.2 linked to higher rate of autism spectrum disorder}}. {Mol Autism}. 2017; 8: 58.
BACKGROUND: Previous studies have reported no clear critical region for medical comorbidities in children with deletions or duplications of 22q11.2. The purpose of this study was to evaluate whether individuals with small nested deletions or duplications of the LCR-A to B region of 22q11.2 show an elevated rate of autism spectrum disorder (ASD) compared to individuals with deletions or duplications that do not include this region. METHODS: We recruited 46 patients with nested deletions (n = 33) or duplications (n = 13) of 22q11.2, including LCR-A to B (ndel = 11), LCR-A to C (ndel = 4), LCR-B to D (ndel = 14; ndup = 8), LCR-C to D (ndel = 4; ndup = 2), and smaller nested regions (n = 3). Parent questionnaire, record review, and, for a subset, in-person evaluation were used for ASD diagnostic classification. Rates of ASD in individuals with involvement of LCR-B to LCR-D were compared with Fisher’s exact test to LCR-A to LCR-B for deletions, and to a previously published sample of LCR-A to LCR-D for duplications. The rates of medical comorbidities and psychiatric diagnoses were determined from questionnaires and chart review. We also report group mean differences on psychiatric questionnaires. RESULTS: Individuals with deletions involving LCR-A to B showed a 39-44% rate of ASD compared to 0% in individuals whose deletions did not involve LCR-A to B. We observed similar rates of medical comorbidities in individuals with involvement of LCR-A to B and LCR-B to D for both duplications and deletions, consistent with prior studies. CONCLUSIONS: Children with nested deletions of 22q11.2 may be at greater risk for autism spectrum disorder if the region includes LCR-A to LCR-B. Replication is needed.
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3. DePriest J, Glushko A, Steinhauer K, Koelsch S. {{Language and music phrase boundary processing in Autism Spectrum Disorder: An ERP study}}. {Sci Rep}. 2017; 7(1): 14465.
Autism spectrum disorder (ASD) is frequently associated with communicative impairment, regardless of intelligence level or mental age. Impairment of prosodic processing in particular is a common feature of ASD. Despite extensive overlap in neural resources involved in prosody and music processing, music perception seems to be spared in this population. The present study is the first to investigate prosodic phrasing in ASD in both language and music, combining event-related brain potential (ERP) and behavioral methods. We tested phrase boundary processing in language and music in neuro-typical adults and high-functioning individuals with ASD. We targeted an ERP response associated with phrase boundary processing in both language and music – i.e., the Closure Positive Shift (CPS). While a language-CPS was observed in the neuro-typical group, for ASD participants a smaller response failed to reach statistical significance. In music, we found a boundary-onset music-CPS for both groups during pauses between musical phrases. Our results support the view of preserved processing of musical cues in ASD individuals, with a corresponding prosodic impairment. This suggests that, despite the existence of a domain-general processing mechanism (the CPS), key differences in the integration of features of language and music may lead to the prosodic impairment in ASD.
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4. Grossberg S. {{Acetylcholine Neuromodulation in Normal and Abnormal Learning and Memory: Vigilance Control in Waking, Sleep, Autism, Amnesia and Alzheimer’s Disease}}. {Front Neural Circuits}. 2017; 11: 82.
Adaptive Resonance Theory, or ART, is a neural model that explains how normal and abnormal brains may learn to categorize and recognize objects and events in a changing world, and how these learned categories may be remembered for a long time. This article uses ART to propose and unify the explanation of diverse data about normal and abnormal modulation of learning and memory by acetylcholine (ACh). In ART, vigilance control determines whether learned categories will be general and abstract, or specific and concrete. ART models how vigilance may be regulated by ACh release in layer 5 neocortical cells by influencing after-hyperpolarization (AHP) currents. This phasic ACh release is mediated by cells in the nucleus basalis (NB) of Meynert that are activated by unexpected events. The article additionally discusses data about ACh-mediated tonic control of vigilance. ART proposes that there are often dynamic breakdowns of tonic control in mental disorders such as autism, where vigilance remains high, and medial temporal amnesia, where vigilance remains low. Tonic control also occurs during sleep-wake cycles. Properties of Up and Down states during slow wave sleep arise in ACh-modulated laminar cortical ART circuits that carry out processes in awake individuals of contrast normalization, attentional modulation, decision-making, activity-dependent habituation, and mismatch-mediated reset. These slow wave sleep circuits interact with circuits that control circadian rhythms and memory consolidation. Tonic control properties also clarify how Alzheimer’s disease symptoms follow from a massive structural degeneration that includes undermining vigilance control by ACh in cortical layers 3 and 5. Sleep disruptions before and during Alzheimer’s disease, and how they contribute to a vicious cycle of plaque formation in layers 3 and 5, are also clarified from this perspective.
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5. Hameed SS, Hassan R, Muhammad FF. {{Selection and classification of gene expression in autism disorder: Use of a combination of statistical filters and a GBPSO-SVM algorithm}}. {PLoS One}. 2017; 12(11): e0187371.
In this work, gene expression in autism spectrum disorder (ASD) is analyzed with the goal of selecting the most attributed genes and performing classification. The objective was achieved by utilizing a combination of various statistical filters and a wrapper-based geometric binary particle swarm optimization-support vector machine (GBPSO-SVM) algorithm. The utilization of different filters was accentuated by incorporating a mean and median ratio criterion to remove very similar genes. The results showed that the most discriminative genes that were identified in the first and last selection steps included the presence of a repetitive gene (CAPS2), which was assigned as the gene most highly related to ASD risk. The merged gene subset that was selected by the GBPSO-SVM algorithm was able to enhance the classification accuracy.
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6. Hanson KL, Lew CH, Hrvoj-Mihic B, Groeniger KM, Halgren E, Bellugi U, Semendeferi K. {{Increased glia density in the caudate nucleus in williams syndrome: Implications for frontostriatal dysfunction in autism}}. {Dev Neurobiol}. 2017.
Williams syndrome (WS) is a rare neurodevelopmental disorder with a well-described, known genetic etiology. In contrast to Autism Spectrum Disorders (ASD), WS has a unique phenotype characterized by global reductions in IQ and visuospatial ability, with relatively preserved language function, enhanced reactivity to social stimuli and music, and an unusual eagerness to interact socially with strangers. A duplication of the deleted region in WS has been implicated in a subset of ASD cases, defining a spectrum of genetic and behavioral variation at this locus defined by these opposite extremes in social behavior. The hypersociability characteristic of WS may be linked to abnormalities of frontostriatal circuitry that manifest as deficits in inhibitory control of behavior. Here, we examined the density of neurons and glia in associative and limbic territories of the striatum including the caudate, putamen, and nucleus accumbens regions in Nissl stained sections in five pairs of age, sex, and hemisphere-matched WS and typically-developing control (TD) subjects. In contrast to what is reported in ASD, no significant increase in overall neuron density was observed in this study. However, we found a significant increase in the density of glia in the dorsal caudate nucleus, and in the ratio of glia to neurons in the dorsal and medial caudate nucleus in WS, accompanied by a significant increase in density of oligodendrocytes in the medial caudate nucleus. These cellular abnormalities may underlie reduced frontostriatal activity observed in WS, with implications for understanding altered connectivity and function in ASD. (c) 2017 Wiley Periodicals, Inc. Develop Neurobiol, 2017.
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7. Lee GT, Feng H, Xu S, Jin SJ. {{Increasing « Object-Substitution » Symbolic Play in Young Children With Autism Spectrum Disorders}}. {Behav Modif}. 2017: 145445517739276.
Children with autism spectrum disorders (ASD) may not develop symbolic play skills, so such skills need to be taught specifically. We report an experiment regarding a procedure targeting « object-substitution » symbolic play skills. The « object-substitution » symbolic play behavior occurred when the child labeled a common object with the name of a substitute and used the object to perform a play action (e.g., As she put a bowl on her head, she called it a hat). A multiple probe across behaviors design was employed with five children (four boys and one girl, aged 3 to 6 years) with ASD. All children had verbal communication and demonstrated functional play and generalized imitation, but no symbolic play skills prior to the study. The instruction consisted of intraverbal training, picture prompts, and modeling of play actions. All children demonstrated object-substitution symbolic play skills after the instruction. The occurrences of response generalization were also discussed.
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8. Lessel D, Schob C, Kury S, Reinders MRF, Harel T, Eldomery MK, Coban-Akdemir Z, Denecke J, Edvardson S, Colin E, Stegmann APA, Gerkes EH, Tessarech M, Bonneau D, Barth M, Besnard T, Cogne B, Revah-Politi A, Strom TM, Rosenfeld JA, Yang Y, Posey JE, Immken L, Oundjian N, Helbig KL, Meeks N, Zegar K, Morton J, Schieving JH, Claasen A, Huentelman M, Narayanan V, Ramsey K, Brunner HG, Elpeleg O, Mercier S, Bezieau S, Kubisch C, Kleefstra T, Kindler S, Lupski JR, Kreienkamp HJ. {{De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder}}. {Am J Hum Genet}. 2017; 101(5): 716-24.
DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.
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9. Nguyen TTM, Murakami Y, Sheridan E, Ehresmann S, Rousseau J, St-Denis A, Chai G, Ajeawung NF, Fairbrother L, Reimschisel T, Bateman A, Berry-Kravis E, Xia F, Tardif J, Parry DA, Logan CV, Diggle C, Bennett CP, Hattingh L, Rosenfeld JA, Perry MS, Parker MJ, Le Deist F, Zaki MS, Ignatius E, Isohanni P, Lonnqvist T, Carroll CJ, Johnson CA, Gleeson JG, Kinoshita T, Campeau PM. {{Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia}}. {Am J Hum Genet}. 2017; 101(5): 856-65.
Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs *102] and c.920delG [p.Gly307Alafs *11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.
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10. Russell G, Starr S, Elphick C, Rodogno R, Singh I. {{Selective patient and public involvement: The promise and perils of pharmaceutical intervention for autism}}. {Health Expect}. 2017.
BACKGROUND: Guidelines suggest the patient community should be consulted from the outset when designing and implementing basic biomedical research, but such patient communities may include conflicting views. We examined how engagement occurred in one such instance. OBJECTIVE: Our objective was to scrutinize patient and public involvement (PPI) by a pan-European biomedical consortium working to develop drugs to treat autism. We aimed to use this as an example to illustrate how PPI has been utilized in biomedical research. SETTING, PARTICIPANTS AND ANALYSIS: Two public events, one in the UK and one in Denmark were conducted as part of the consortium’s on-going PPI activities in 2014 and 2015. Sixty-six individuals submitted written comments on the consortium’s research after these events. The textual data produced were analysed using a thematic approach. Approximately 71% of respondents reported themselves to be adults on the autism spectrum or parents of children with autism. RESULTS: The themes identified illustrated major differences between some community concerns and the biomedical research agenda. While treating autism per se. was seen as problematic by some, treating specific co-occurring problems was seen as helpful in some circumstances. The biomedical consortium selected PPI with a limited user viewpoint at its outset and more widely once basic research was on-going. DISCUSSION: This case illustrates what we term « selective PPI » where only a sympathetic and/or limited patient viewpoint is included. Findings highlight the perils of using selective PPI to legitimise scientific endeavours, and the possibilities for constructive dialogue.
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11. Vasquez A. {{Biological plausibility of the gut-brain axis in autism}}. {Ann N Y Acad Sci}. 2017.
Organic abnormalities with neuroinflammatory and psychiatric consequences involving abnormal kynurenine and purine metabolism, neurotransmitter and cytokine imbalances, and altered levels of nutrients and metabolites are noted in autism, and many of these abnormalities-specifically including increased intestinal permeability, microbial metabolites, and heightened serum levels of endotoxin-originate from the gut.
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12. Yang XL, Liang S, Zou MY, Sun CH, Han PP, Jiang XT, Xia W, Wu LJ. {{Are gastrointestinal and sleep problems associated with behavioral symptoms of autism spectrum disorder?}}. {Psychiatry Res}. 2017; 259: 229-35.
Many children with autism spectrum disorder (ASD) suffer from concurrent medical symptoms, including gastrointestinal (GI) and sleeping problems. However, there is limited information on the correlation between co-morbidities and autistic behavioral symptoms. In this study, we estimated the prevalence of GI and sleep problems in Chinese ASD children, examined the impacts of GI and sleep problems on autistic behavioral symptoms, and investigated the factors associated with GI and sleep problems. The survey included 169 ASD and 172 healthy children. Data regarding demographic characteristics, GI symptoms, sleep disturbances and behavioral symptoms were collected through questionnaires. GI and sleep problems were prevalent in Chinese ASD children. Moreover, ASD children with GI symptoms reported more severe ASD core symptoms than others. Autistic children’s GI symptoms were associated with maternal sleep problems during pregnancy, child’s 0-6 month food sources and picky eating. ASD children with sleep disturbances had lower performance in daily living skills, social cognition, social communication and intellectual development than ASD children without sleep disturbances. Sleep disturbances were associated with extra nutrient supply during lactation and feeding, and child’s picky eating. Autistic children with GI or/and sleep problems may represent clinically relevant subtypes of ASD, for which targeted treatments may be needed.
