1. Anketell PM, Saunders KJ, Gallagher SM, Bailey C, Little JA. {{Brief Report: Vision in Children with Autism Spectrum Disorder: What Should Clinicians Expect?}}. {J Autism Dev Disord};2015 (Apr 7)
Anomalous visual processing has been described in individuals with autism spectrum disorder (ASD) but relatively few studies have profiled visual acuity (VA) in this population. The present study describes presenting VA in children with ASD (n = 113) compared to typically developing controls (n = 206) and best corrected visual acuity (BCVA) in a sub-group of children with ASD (n = 29). There was no statistically significant difference in presenting VA between groups (z = -1.75, p = 0.08); ASD group median VA (interquartile range, IQR) -0.05 logMAR (IQR: -0.125 to 0.025 logMAR) and typically developing control group -0.075 logMAR (IQR: -0.150 to -0.025 logMAR). Median BCVA was -0.175 logMAR (IQR: -0.200 to -0.125 logMAR) for the ASD sub-group. Clinicians should not anticipate reduced VA when assessing children with ASD.
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2. DeRamus TP, Kana RK. {{Anatomical likelihood estimation meta-analysis of grey and white matter anomalies in autism spectrum disorders}}. {Neuroimage Clin};2015;7:525-536.
Autism spectrum disorders (ASD) are characterized by impairments in social communication and restrictive, repetitive behaviors. While behavioral symptoms are well-documented, investigations into the neurobiological underpinnings of ASD have not resulted in firm biomarkers. Variability in findings across structural neuroimaging studies has contributed to difficulty in reliably characterizing the brain morphology of individuals with ASD. These inconsistencies may also arise from the heterogeneity of ASD, and wider age-range of participants included in MRI studies and in previous meta-analyses. To address this, the current study used coordinate-based anatomical likelihood estimation (ALE) analysis of 21 voxel-based morphometry (VBM) studies examining high-functioning individuals with ASD, resulting in a meta-analysis of 1055 participants (506 ASD, and 549 typically developing individuals). Results consisted of grey, white, and global differences in cortical matter between the groups. Modeled anatomical maps consisting of concentration, thickness, and volume metrics of grey and white matter revealed clusters suggesting age-related decreases in grey and white matter in parietal and inferior temporal regions of the brain in ASD, and age-related increases in grey matter in frontal and anterior-temporal regions. White matter alterations included fiber tracts thought to play key roles in information processing and sensory integration. Many current theories of pathobiology ASD suggest that the brains of individuals with ASD may have less-functional long-range (anterior-to-posterior) connections. Our findings of decreased cortical matter in parietal-temporal and occipital regions, and thickening in frontal cortices in older adults with ASD may entail altered cortical anatomy, and neurodevelopmental adaptations.
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3. D’Mello AM, Crocetti D, Mostofsky SH, Stoodley CJ. {{Cerebellar gray matter and lobular volumes correlate with core autism symptoms}}. {Neuroimage Clin};2015;7:631-639.
Neuroanatomical differences in the cerebellum are among the most consistent findings in autism spectrum disorder (ASD), but little is known about the relationship between cerebellar dysfunction and core ASD symptoms. The newly-emerging existence of cerebellar sensorimotor and cognitive subregions provides a new framework for interpreting the functional significance of cerebellar findings in ASD. Here we use two complementary analyses – whole-brain voxel-based morphometry (VBM) and the SUIT cerebellar atlas – to investigate cerebellar regional gray matter (GM) and volumetric lobular measurements in 35 children with ASD and 35 typically-developing (TD) children (mean age 10.4 +/- 1.6 years; range 8-13 years). To examine the relationships between cerebellar structure and core ASD symptoms, correlations were calculated between scores on the Autism Diagnostic Observation Schedule (ADOS) and Autism Diagnostic Interview (ADI) and the VBM and volumetric data. Both VBM and the SUIT analyses revealed reduced GM in ASD children in cerebellar lobule VII (Crus I/II). The degree of regional and lobular gray matter reductions in different cerebellar subregions correlated with the severity of symptoms in social interaction, communication, and repetitive behaviors. Structural differences and behavioral correlations converged on right cerebellar Crus I/II, a region which shows structural and functional connectivity with fronto-parietal and default mode networks. These results emphasize the importance of the location within the cerebellum to the potential functional impact of structural differences in ASD, and suggest that GM differences in cerebellar right Crus I/II are associated with the core ASD profile.
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4. Duyzend MH, Eichler EE. {{Genotype-first analysis of the 16p11.2 deletion defines a new type of « autism »}}. {Biol Psychiatry};2015 (May 1);77(9):769-771.
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5. Fieremans N, Van Esch H, de Ravel T, Van Driessche J, Belet S, Bauters M, Froyen G. {{Microdeletion of the escape genes KDM5C and IQSEC2 in a girl with severe intellectual disability and autistic features}}. {Eur J Med Genet};2015 (Apr 7)
Intellectual disability (ID) is a very heterogeneous disorder with over 100 ID genes located on the X chromosome alone. Of these, KDM5C and IQSEC2 are located adjacent to each other at the Xp11.22 locus. While mutations in either of these genes are associated with severe ID in males, female carriers are mostly unaffected. Here, we report on a female patient with severe ID and autistic features carrying a de novo 0.4 Mb deletion containing six coding genes including KDM5C and IQSEC2. X-inactivation analysis revealed skewing in a lymphocyte-derived cell line from this patient with preferential inactivation of the mutant X chromosome. As the brain-expressed KDM5C and IQSEC2 genes escape X-inactivation, deletion of these alleles could still be detrimental despite skewing of X-inactivation. Indeed, mutations in either of both genes have been reported in a few female ID patients. Expression analysis in the patients’ cell line revealed decreased KDM5C mRNA levels compared to female controls. IQSEC2 levels could not be compared due to very low expression in blood. Overall, our data suggest that heterozygous loss-of-function of the escape genes KDM5C and/or IQSEC2 can contribute to severe ID in female patients and should be taken into account in diagnostics.
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6. Kalinowska M, Castillo C, Francesconi A. {{Quantitative profiling of brain lipid raft proteome in a mouse model of fragile x syndrome}}. {PLoS One};2015;10(4):e0121464.
Fragile X Syndrome, a leading cause of inherited intellectual disability and autism, arises from transcriptional silencing of the FMR1 gene encoding an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). FMRP can regulate the expression of approximately 4% of brain transcripts through its role in regulation of mRNA transport, stability and translation, thus providing a molecular rationale for its potential pleiotropic effects on neuronal and brain circuitry function. Several intracellular signaling pathways are dysregulated in the absence of FMRP suggesting that cellular deficits may be broad and could result in homeostatic changes. Lipid rafts are specialized regions of the plasma membrane, enriched in cholesterol and glycosphingolipids, involved in regulation of intracellular signaling. Among transcripts targeted by FMRP, a subset encodes proteins involved in lipid biosynthesis and homeostasis, dysregulation of which could affect the integrity and function of lipid rafts. Using a quantitative mass spectrometry-based approach we analyzed the lipid raft proteome of Fmr1 knockout mice, an animal model of Fragile X syndrome, and identified candidate proteins that are differentially represented in Fmr1 knockout mice lipid rafts. Furthermore, network analysis of these candidate proteins reveals connectivity between them and predicts functional connectivity with genes encoding components of myelin sheath, axonal processes and growth cones. Our findings provide insight to aid identification of molecular and cellular dysfunctions arising from Fmr1 silencing and for uncovering shared pathologies between Fragile X syndrome and other autism spectrum disorders.
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7. Kenmuir C, Richardson M, Ghearing G. {{Surgical treatment for medically refractory focal epilepsy in a patient with fragile X syndrome}}. {Brain Dev};2015 (Apr 7)
RATIONALE: Medication resistant temporal lobe epilepsy occurs in a small population of patients with fragile X syndrome. We present the case of a 24-year-old man with medically refractory temporal lobe epilepsy and fragile X syndrome who underwent left anterior temporal lobectomy resulting in cessation of seizures. METHODS: Our patient was diagnosed with fragile X syndrome with a fully mutated, fully methylated FMR1 gene resulting in 572 CGG repeats. He developed seizures initially controlled with Depakote monotherapy, but progressed to become medically refractive to combination treatment with Depakote, lamotrigine and zonisamide. Prolonged video EEG monitoring revealed interictal left temporal sharp waves and slowing as well as subclinical and clinical seizures, each with left temporal onset. 3T MRI was consistent with left mesial temporal sclerosis. After discussing the case in our multidisciplinary surgical epilepsy conference, he was referred for presurgical evaluation including neuropsychological testing and Wada testing. RESULTS: He underwent an asleep left anterior temporal lobectomy, sparing the superior temporal gyrus. Pathology showed neuronal loss and gliosis in the hippocampus and amygdala. Twelve months after surgery, the patient has not experienced a seizure. He is described by his parents as less perseverative and less restless. CONCLUSIONS: We have presented the case of a 24year-old-man with fragile X syndrome who underwent successful left anterior temporal lobectomy for the treatment of medically refractory epilepsy who is now seizure free without further functional impairment. This case report demonstrates the feasibility of surgical treatment for a patient with comorbid fragile X syndrome and mesial temporal sclerosis.
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8. Koolschijn PC, Geurts HM, van der Leij AR, Scholte HS. {{Are Autistic Traits in the General Population Related to Global and Regional Brain Differences?}}. {J Autism Dev Disord};2015 (Apr 7)
There is accumulating evidence that autistic-related traits in the general population lie on a continuum, with autism spectrum disorders representing the extreme end of this distribution. Here, we tested the hypothesis of a possible relationship between autistic traits and brain morphometry in the general population. Participants completed the short autism-spectrum quotient-questionnaire (AQ); T1-anatomical and DWI-scans were acquired. Associations between autistic traits and gray matter, and white matter microstructural-integrity were performed on the exploration-group (N = 204; 105 males, M-age = 22.85), and validated in the validation-group (N = 304; 155 males, M-age = 22.82). No significant associations were found between AQ-scores and brain morphometry in the exploration-group, or after pooling the data. This questions the assumption that autistic traits and their morphological associations do lie on a continuum in the general population.
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9. McPartland JC, Jeste SS. {{Connectivity in context: emphasizing neurodevelopment in autism spectrum disorder}}. {Biol Psychiatry};2015 (May 1);77(9):772-774.
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10. Mullegama SV, Alaimo JT, Chen L, Elsea SH. {{Phenotypic and molecular convergence of 2q23.1 deletion syndrome with other neurodevelopmental syndromes associated with autism spectrum disorder}}. {Int J Mol Sci};2015;16(4):7627-7643.
Roughly 20% of autism spectrum disorders (ASD) are syndromic with a well-established genetic cause. Studying the genes involved can provide insight into the molecular and cellular mechanisms of ASD. 2q23.1 deletion syndrome (causative gene, MBD5) is a recently identified genetic neurodevelopmental disorder associated with ASD. Mutations in MBD5 have been found in ASD cohorts. In this study, we provide a phenotypic update on the prevalent features of 2q23.1 deletion syndrome, which include severe intellectual disability, seizures, significant speech impairment, sleep disturbance, and autistic-like behavioral problems. Next, we examined the phenotypic, molecular, and network/pathway relationships between nine neurodevelopmental disorders associated with ASD: 2q23.1 deletion Rett, Angelman, Pitt-Hopkins, 2q23.1 duplication, 5q14.3 deletion, Kleefstra, Kabuki make-up, and Smith-Magenis syndromes. We show phenotypic overlaps consisting of intellectual disability, speech delay, seizures, sleep disturbance, hypotonia, and autistic-like behaviors. Molecularly, MBD5 possibly regulates the expression of UBE3A, TCF4, MEF2C, EHMT1 and RAI1. Network analysis reveals that there could be indirect protein interactions, further implicating function for these genes in common pathways. Further, we show that when MBD5 and RAI1 are haploinsufficient, they perturb several common pathways that are linked to neuronal and behavioral development. These findings support further investigations into the molecular and pathway relationships among genes linked to neurodevelopmental disorders and ASD, which will hopefully lead to common points of regulation that may be targeted toward therapeutic intervention.
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11. Nomi JS, Uddin LQ. {{Developmental changes in large-scale network connectivity in autism}}. {Neuroimage Clin};2015;7:732-741.
BACKGROUND: Disrupted cortical connectivity is thought to underlie the complex cognitive and behavior profile observed in individuals with autism spectrum disorder (ASD). Previous neuroimaging research has identified patterns of both functional hypo- and hyper-connectivity in individuals with ASD. A recent theory attempting to reconcile conflicting results in the literature proposes that hyper-connectivity of brain networks may be more characteristic of young children with ASD, while hypo-connectivity may be more prevalent in adolescents and adults with the disorder when compared to typical development (TD) (Uddin etal., 2013). Previous work has examined only young children, mixed groups of children and adolescents, or adult cohorts in separate studies, leaving open the question of developmental influences on functional brain connectivity in ASD. METHODS: The current study tests this developmental hypothesis by examining within- and between-network resting state functional connectivity in a large sample of 26 children, 28 adolescents, and 18 adults with ASD and age- and IQ-matchedTD individuals for the first time using an entirely data-driven approach. Independent component analyses (ICA) and dual regression was applied to data from three age cohorts to examine the effects of participant age on patterns of within-networkwhole-brain functional connectivity in individuals with ASD compared with TD individuals. Between-network connectivity differences were examined for each age cohort by comparing correlations between ICA components across groups. RESULTS: We find that in the youngest cohort (age 11 and under), children with ASD exhibit hyper-connectivity within large-scale brain networks as well as decreased between-network connectivity compared with age-matchedTD children. In contrast, adolescents with ASD (age 11-18) do not differ from TD adolescents in within-network connectivity, yet show decreased between-network connectivity compared with TD adolescents. Adults with ASD show no within- or between-network differences in functional network connectivity compared with neurotypical age-matched individuals. CONCLUSIONS: Characterizing within- and between-network functional connectivity in age-stratified cohorts of individuals with ASD and TD individuals demonstrates that functional connectivity atypicalities in the disorder are not uniform across the lifespan. These results demonstrate how explicitly characterizing participant age and adopting a developmental perspective can lead to a more nuanced understanding of atypicalities of functional brain connectivity in autism.
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12. Radley KC, Ford WB, McHugh MB, Dadakhodjaeva K, O’Handley RD, Battaglia AA, Lum JD. {{Brief Report: Use of Superheroes Social Skills to Promote Accurate Social Skill Use in Children with Autism Spectrum Disorder}}. {J Autism Dev Disord};2015 (Apr 5)
The current study evaluated the use of Superheroes Social Skills to promote accurate use of discrete social skills in training and generalization conditions in two children with autism spectrum disorder. Participants attended a twice weekly social skills training group over 5 weeks, with lessons targeting nonverbal, requesting, responding, and conversation skills. A multiple probe across social skills design, replicated across participants, was utilized to assess the effects of participation of the intervention on skill accuracy. Following introduction of the intervention, participants demonstrated abrupt improvements in skill accuracy in both training and generalization conditions. Additionally, parental reports of participant social functioning indicated improvements following participation in the intervention. Limitations and future directions are discussed.
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13. Rios C, Costa Andrada B. {{The changing face of autism in Brazil}}. {Cult Med Psychiatry};2015 (Apr 5)
At the end of 2012, after intensive lobbying by parent activist associations, a federal law recognized autism as a « disability for all legal purposes » in Brazil. Defining autism as a disability was more than a change of legal status to guarantee social benefits. It was also a political maneuver, orchestrated by parent associations, aimed to take the responsibility for treatment away from the public mental health network of services. This article examines the controversies that have set parent associations in direct antagonism with mental health professionals in the public health system. We draw from ethnographic data and theoretical discussions in the field of disability studies to situate these controversies within the context of a larger debate on the relationship between health, rights, and citizenship. We found similarities between the ethical and political goals of parent activists and mental health professionals in Brazil, but we argue that the main cause of dissent is the role that each of these social actors assigns to identity politics in their clinical and political projects.
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14. Rosenfeld CS. {{Microbiome Disturbances and Autism Spectrum Disorders}}. {Drug Metab Dispos};2015 (Apr 7)
Autism spectrum disorders (ASD) are considered a heterogenous set of neurobehavioral diseases with the rates of diagnosis dramatically increasing in the past few decades. As genetics alone does not explain the underlying cause in many cases, attention has turned to other environmental factors as potential etiological agents. Gastrointestinal disorders are a common comorbidity in ASD patients. It was thus hypothesized that a gut-brain link may account for some autistic cases. With the characterization of the human microbiome, this concept has been expanded to include the microbiota-gut-brain axis. There are mounting reports in animal models and human epidemiological studies linking disruptive alterations in the gut microbiota or dysbiosis and ASD symptomology. In this review, we will explore the current evidence that gut dysbiosis in animal models and ASD patients correlates with disease risk and severity. The studies to date have surveyed how gut microbiome changes may affect these neurobehavioral disorders. However, we harbor other microbiomes reside in the body that might impact brain function. We will consider these other microbiomes in the oral cavity, vagina, and the most recently discovered one in the placenta. Based on the premise that gut microbiota alterations may be causative agents in ASD, several therapeutic options have been tested, such as diet modulations, prebiotics, probiotics, synbiotics, postbiotics, antibiotics, fecal transplantation, and activated charcoal. The potential benefits of these therapies will be considered. Lastly, the possible mechanisms by which changes in the gut bacterial communities may result in ASD and related neurobehavioral disorders will be examined.
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15. Seung H, Ji J, Kim SJ, Sung I, Youn YA, Hong G, Lee H, Lee YH, Youm HK. {{Examination of the Korean Modified Checklist of Autism in Toddlers: Item Response Theory}}. {J Autism Dev Disord};2015 (Apr 7)
The study examined the clinical utility and psychometric properties of the Korean Modified Checklist of Autism in Toddlers (K-M-CHAT)-2. A sample of 2300 parents of 16- to 36-month-old children was recruited across South Korea. A phone interview was utilized to follow up with participants who initially screened positive for autism spectrum disorder (ASD). Item response theory was applied to assess the psychometric properties of the K-M-CHAT-2. Parents’ responses were substantially changed after the follow-up, and the final screen-positive rate was 2.3 %. Results indicated that the psychometric properties of items 1, 3, 11, 18 and 22 were not as strong as the other items. The K-M-CHAT-2 is a useful ASD screening test when implemented with a follow-up.
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16. Tabet AC, Verloes A, Pilorge M, Delaby E, Delorme R, Nygren G, Devillard F, Gerard M, Passemard S, Heron D, Siffroi JP, Jacquette A, Delahaye A, Perrin L, Dupont C, Aboura A, Bitoun P, Coleman M, Leboyer M, Gillberg C, Benzacken B, Betancur C. {{Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorder}}. {Mol Autism};2015;6:19.
BACKGROUND: Apparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD). Genome-wide microarrays reveal cryptic genomic imbalances, related or not to the breakpoints, in 25% to 50% of patients with an abnormal phenotype carrying a microscopically balanced chromosomal rearrangement. Here we performed microarray analysis of 18 patients with ASD carrying balanced chromosomal abnormalities to identify submicroscopic imbalances implicated in abnormal neurodevelopment. METHODS: Eighteen patients with ASD carrying apparently balanced chromosomal abnormalities were screened using single nucleotide polymorphism (SNP) arrays. Nine rearrangements were de novo, seven inherited, and two of unknown inheritance. Genomic imbalances were confirmed by fluorescence in situ hybridization and quantitative PCR. RESULTS: We detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality. The sizes ranged from 3.3 to 4.9 Mb; three were related to the breakpoint regions and one occurred elsewhere. We report a patient with a duplication of the Wolf-Hirschhorn syndrome critical region, contributing to the delineation of this rare genomic disorder. The patient has a chromosome 4p inverted duplication deletion, with a 0.5 Mb deletion of terminal 4p and a 4.2 Mb duplication of 4p16.2p16.3. The other cases included an apparently balanced de novo translocation t(5;18)(q12;p11.2) with a 4.2 Mb deletion at the 18p breakpoint, a subject with de novo pericentric inversion inv(11)(p14q23.2) in whom the array revealed a de novo 4.9 Mb deletion in 7q21.3q22.1, and a patient with a maternal inv(2)(q14.2q37.3) with a de novo 3.3 Mb terminal 2q deletion and a 4.2 Mb duplication at the proximal breakpoint. In addition, we identified a rare de novo deletion of unknown significance on a chromosome unrelated to the initial rearrangement, disrupting a single gene, RFX3. CONCLUSIONS: These findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings.
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17. Uddin LQ. {{Idiosyncratic connectivity in autism: developmental and anatomical considerations}}. {Trends Neurosci};2015 (Apr 1)
Hahamy and colleagues demonstrate individualized alterations of functional connectivity in the brains of adults with autism, suggesting that previous characterizations of general under- or over-connectivity may be overly simplistic. Adopting a developmental perspective spanning both cortical and subcortical landscapes will further clarify the nature and extent of these atypicalities.
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18. Walton KM, Ingersoll BR. {{Psychosocial Adjustment and Sibling Relationships in Siblings of Children with Autism Spectrum Disorder: Risk and Protective Factors}}. {J Autism Dev Disord};2015 (Apr 7)
This study compared sibling adjustment and relationships in siblings of children with Autism Spectrum Disorder (ASD-Sibs; n = 69) and siblings of children with typical development (TD-Sibs; n = 93). ASD-Sibs and TD-Sibs demonstrated similar emotional/behavioral adjustment. Older male ASD-Sibs were at increased risk for difficulties. Sibling relationships of ASD-Sibs involved less aggression, less involvement, and more avoidance than those of TD-Sibs. Partial support for a diathesis-stress conceptualization of sibling difficulties was found for ASD-Sibs. For TD-Sibs, broader autism phenotype (BAP) was related to psychosocial difficulties regardless of family stressors. For ASD-Sibs, BAP was related to difficulties only when family stressors were present. This suggests that having a sibling with ASD may be a protective factor that attenuates the negative impact of sibling BAP.
